Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs

Pharmaceutical Anti-Counterfeiting

Pharmaceutical Anti-Counterfeiting Combating the Real Danger from Fake Drugs

Mark Davison Blue Sphere Health Ltd. Cambridge, U.K.

A JOHN WILEY & SONS, INC., PUBLICATION

Copyright © 2011 by John Wiley & Sons, Inc. All rights reserved. Published by John Wiley & Sons, Inc., Hoboken, New Jersey. Published simultaneously in Canada. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, or online at http://www.wiley.com/go/permission. Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com. Library of Congress Cataloging-in-Publication Data: Davison, Mark, 1968 Mar. 1– Pharmaceutical anti-counterfeiting : combating the real danger from fake drugs / Mark Davison. p. ; cm. Includes index. ISBN 978-0-470-61617-8 (cloth) 1. Product counterfeiting. 2. Drug adulteration. I. Title. [DNLM: 1. Drug Contamination. 2. Consumer Product Safety. 3. Fraud–prevention & control. 4. Pharmaceutical Preparations–standards. QV 773] HD9665.5.D38 2011 615.1068 4–dc22 2010044590 Printed in the United States of America oBook ISBN: 9781118023679 ePDF ISBN: 9781118023655 ePub ISBN: 9781118023662 10 9 8 7 6 5 4 3 2 1

For Gillian, Daniel, and Matthew

Contents

PREFACE

xxi

ACKNOWLEDGMENTS PART 1

xxiii

GENERAL THEMES

1 Introduction

3

Why Write This Book? / 3 Doesn’t This Book Just Help the Criminals? / 4 Who Is the Book Aimed At? / 5 2 Origins and Context of Counterfeiting in Healthcare

7

Background and Nature of the Threat / 7 R&D Costs, Patent Life, and the Profit Imperative / 9 A Low Cost, High Profit Business / 10 Research and Development / 10 Regulatory Approval / 10 Manufacturing / 11 Packaging / 11

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CONTENTS

Marketing / 11 Logistics / 12 Permissive Legal Environment / 12 Role of the Internet / 13 Global Growth of Counterfeiting / 14 3 A Snapshot of the Problem

15

Case Study: Malaria / 18 4 Risks and Costs of Counterfeit Pharmaceuticals

21

Risks and Costs for Consumers / 21 The Drugs Do Not Work / 21 Toxic Products / 23 Fear and Mistrust of the Medical Profession / 24 Risks and Costs for Businesses / 24 Revenue Loss / 24 Brand Erosion / 28 Litigation / 30 Loss of Public Trust / 30 Risks and Costs for Governments / 31 Public Concern / 31 Increased Social and Healthcare Costs / 32 Tension between Affordability and Quality / 34 Increased Regulatory Costs / 34 5 Anti-Counterfeiting Definitions

35

Terminology and General Principles / 36 Counterfeiting / 38 Diversion / 45 Parallel Trade and Re-Importation / 46 6 Protecting and Educating Consumers Consumer Behavior / 49 Engagement with the Consumer / 50 Engaging Through Social Media / 51

49

CONTENTS

ix

Social Networking and Blogging as Anti-Counterfeiting Tools / 52 Consumer-Focused Authentication Technology / 54 Cultural Sensitivity / 55 7 Business Risks and Strategy

57

Establishing a Baseline and Prioritizing At-Risk Products / 59 Doing the Simple Things / 60 Used Manufacturing Equipment / 61 Layering of Countermeasures / 62 Information Management and “Need-To-Know” / 62 Integration with Corporate Strategy / 63 8 Government Issues

65

Legal Framework / 66 Link with Reimbursement and Social Healthcare / 68 Law Enforcement Issues / 69 Data Mining / 69 Money Transfer and Credit Cards / 70 Internet Service Providers and Search Engines / 71 9 Intellectual Property and Anti-Counterfeiting

73

Establishing Ownership of Intellectual Property Rights (IPR) / 74 Patents / 74 Patenting of Security Technologies / 75 Trademarks / 75 Online Intellectual Property / 78 Criminal Prosecution Versus Civil Suit / 79 10 Traceability or Authentication?

81

x

CONTENTS

PART 2

AUTHENTICATION

11 What Is Authentication?

87

Digital Versus Sensory Authentication / 88 Types of Authentication Technologies / 89 International Standards and Norms / 91 12 Authentication of the Person

93

13 Authentication of Bulk Products

97

14 On-Dose and In-Dose Authentication

103

On-Dose Features / 104 In-Dose Features / 106 Regulatory Reporting / 109 Labeling and Disclosure of On-Dose and In-Dose Approaches / 110 Concealment of Identity / 110 On-Product and In-Product Approaches Aimed at Consumers / 111 Formulation Additives in Products other than SODFs / 112 15 Analytical Detection of Counterfeit Dosage Forms Simple Chemical and Physical Analysis Methods / 114 Colorimetry / 115 Hardness and Dissolution Tests / 115 Thin Layer Chromatography (TLC) / 116 Ultraviolet and Visible Spectroscopy / 117 Laboratory-Based Methods / 118 Atomic Absorption Spectrophotometry (AAS) / 118 X-ray Techniques / 119 Nuclear Magnetic Resonance (NMR) Spectroscopy / 119 Mass Spectrometry (MS) / 120 Gas Chromatography (GC) / 120

113

CONTENTS

xi

Liquid Chromatography (LC) / 121 Capillary Electrophoresis (CE) / 121 Forensic Palynology / 121 Non-Destructive Methods / 123 X-ray Diffraction / 123 Infrared Spectroscopy / 123 Fourier Transform Infrared (FTIR) Spectroscopy / 124 Near-Infrared (NIR) / 125 Raman Spectroscopy / 125 Terahertz Imaging / 126 Conclusions on the Analysis of Dosage Forms / 126 16 The Role of Packaging

127

Packaging Design / 128 Being Just Slightly Better than the Opposition / 130 Security Features on Packaging / 131 Integration into Packaging: Bulk Packaging Material at Source / 131 Integration into Packaging: By Design Complexity / 132 Addition to Packaging: Labels, Printed Packaging, etc. / 132 17 Printing Technologies Offset Lithography / 135 Flexography / 136 Gravure / 136 Screen Printing / 137 Laser Printing / 137 Clich´e or Pad Printing / 138 Embossing and Debossing / 138 Laser Engraving / 138 Inkjet Printing / 138 Some Technical Considerations / 140

135

xii

CONTENTS

How Much Surface Area Is Available for the Feature? / 140 What Is the Budget? / 141 Is the Product Surface Flat or Curved? / 141 Is the Product Orientation Predictable and Constant? / 142 How Much Time Is Available? / 142 Direct Application onto Packaging Versus Use of Labeling / 143 18 Security Labels

145

Adhesive / 146 Frangibility / 147 Security Cuts and Perforation / 148 Voiding / 148 Alignment / 149 General Considerations / 149 Label Reconciliation and Storage Conditions / 151 19 Holograms and DOVIDs

153

Types of Holograms / 154 Other Optically Variable Devices / 156 20 Specialty Inks Colorshift Inks / 160 Other Security Inks / 161 Iridescent / 161 Metallic / 162 Fluorescent / 162 Bi-fluorescent / 162 Thermochromic / 163 Photochromic / 163 Coin Reactive / 163 Microstructured Taggants / 163

159

CONTENTS

21 Covert Taggants and Forensic Markers

xiii

165

Infrared-Absorbing Inks / 165 Forensic Markers / 166 Isotopic Tags / 167 DNA Markers / 167 Antibody Systems / 168 X-Ray Detection of Specific Added Elements / 168 Other Markers / 168 22 General Conclusions on Printed Packaging and Security Labels

169

Layering / 169 Guidelines / 170 Flexibility and Vigilance / 170 23 Security of Primary Packaging Contact with Dosage Form / 173 Types of Primary Packaging / 175 Blister Packs / 175 Wallets, Carded Blisters, Compliance-Prompting Packaging, etc. / 179 Strip Packs, Sachets, and Pouches / 180 Bottles or Jars / 181 Tubes / 183 Vials and Ampoules / 184 Other Dosage Forms / 187 Syringes / 187 Inhalers and Related Devices / 187 Implantable Drug-Containing Devices / 189 Equipment and Consumables for Diagnostic Products / 189 Medical Devices / 190 Analytical Considerations for Primary Packaging / 191

173

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CONTENTS

24 Security of Secondary Packaging

193

Role of Secondary Cartons / 193 Outsourced or In-House Application / 196 Outsourced Security Features / 198 In-House Security Application / 198 Planning Ahead / 199 Tamper-Evidence: Seals, Shrink Wraps, Pack Closures, and Adhesive / 200 Definitions / 200 Snap-Off Caps / 200 Glued End-Flaps / 201 Seals / 201 Induction Seals / 203 Shrink Wrap and Tear Tape / 203 25 Analytical Methods for Packaging

205

Visual Inspection (Visible Light) / 206 Other Optical Methods (UV, IR, Polarized Light) / 207 Other Methods / 207 26 Security of Other Packaging Types

209

Drug–Device Combinations / 209 Patient Information Leaflets and Labels / 211 Other Documentation / 212 Certificates of Analysis, Import Licenses, etc. / 212 Prescriptions / 213 Reimbursement / 213 27 Bulk Packaging and Transport Security Theft of Cargo from Trucks and Warehouses / 216 Vigilance / 218 Information Management / 218 Training / 218 Other Factors / 219

215

CONTENTS

xv

Technology Approaches: RFID and GPS / 219 Radio Frequency Identification (RFID) Technology / 219 Global Positioning System (GPS) Technology / 220

PART 3

PRODUCT TRACKING

28 Rationale for Pharmaceutical Tracking

225

29 Tracking Technologies

231

Serial Numbers / 232 Linear Bar Codes / 234 Matrix Codes / 234 2D Codes and Mobile Phones / 236 Technical Issues with 2D Codes / 237 Radio Frequency Identification (RFID) / 238 Mobile Phones / 242 Other Tracking Technologies / 244 Applicability of Tracking Systems Worldwide / 245 30 Data Format, Generation, and Storage

247

Serialization / 247 Randomization / 250 Pedigree/ePedigree / 251 Track and Trace / 253 Fingerprinting / 254 Physical Authentication + Digital Tracking = Enhanced Security / 256 31 Management of Packaging Hierarchy Inference Approaches / 257 “Bookend” Approaches / 262 Batch Level Traceability Versus Full Serialization / 266

257

xvi

CONTENTS

Digital Signatures / 266 Supply Chain Benefits / 266 32 Geographical Perspectives U.S. State Laws / 269 California / 270 Federal Initiatives in the United States / 271 Europe / 273 The Concept of “Medicrime” / 275 European Committee on Crime Problems (CDPC) / 275 Purpose / 276 Scope / 276 Definitions / 276 Manufacturing of Counterfeits / 278 Supplying, Offering to Supply, and Trafficking in Counterfeits / 278 Falsification of Documents / 279 Similar Crimes Involving Threats to Public Health / 279 Aiding or Abetting and Attempt / 279 Jurisdiction / 280 Corporate Liability / 281 Sanctions and Measures / 281 Aggravating Circumstances / 282 Criminal Investigations / 282 Cooperation and Information Exchange / 283 Measures for Prevention / 283 Measures for Protection / 284 International Cooperation / 284 Monitoring Mechanism / 284 EFPIA Pilot Coding Project / 285 India / 287 Malaysia Meditag System / 288 Turkey / 289 Brazil / 290

269

CONTENTS

33 Product Tracking in Other Industries

xvii

291

Excise Products: Tobacco and Alcohol / 291 Food and Beverage / 292 Toys / 293 Conclusions / 294 34 Supply Chain Security Processes

295

General Security / 295 Forward Logistics / 296 Reverse Logistics: Returns and Customer Complaints / 297 Insider Fraud / 298 Security of Security Materials / 301 Security of Evidence / 302 35 Implementing Anti-Counterfeiting Initiatives—Practical Issues

303

How to Work Together: Getting the Best from Security Partnerships / 303 What Do Pharmaceutical Companies Need? / 304 What Do Security Suppliers Need? / 305 What Do Print and Packaging Suppliers Need? / 306 General Observations on Business Models for Product Security / 307 Unit Fee Pricing / 308 Commodity Pricing / 308 Insurance Premium / 309 Other Pharmaceutical Service Industries / 309

PART 4

CONCLUSIONS AND THE FUTURE

36 Where Do We Go from Here? Future Scenario: Risk of Inaction / 313

313

xviii

CONTENTS

Future Scenario: Risk of Incomplete Action / 314 Future Scenario: Risk of Inappropriate Action / 314 Future Policy Approaches / 315 Future Authentication Approaches / 317 Future Traceability Approaches / 318 Global Standards, Worldwide Tracking / 318 RFID / 319 GPS / 319 37 New Models, New Approaches

321

Non-Technological Approaches / 322 Lack of Availability of Genuine Drugs / 323 Huge Profit Potential / 323 Low Entry Costs / 324 Law Enforcement Issues / 324 Legal Approaches / 324 Conclusions / 325 38 Selected Examples from Around the World Argentina / 329 Brazil / 330 Canada / 330 China / 330 European Union / 331 India / 331 Laos and Southeast Asia / 331 Nigeria / 331 Russia / 332 Uganda/East Africa / 332 United Kingdom / 333 United States / 333

329

CONTENTS

PART 5

xix

FURTHER RESOURCES

A PATIENT’S GUIDE TO AVOIDING COUNTERFEIT DRUGS

337

Do I Need This Particular Medication? / 337 Is My Desired Drug Approved and Available in My Country? / 338 Are My Drug Sources and Methods of Purchase Safe? / 338 What Does the Packaging Look Like? / 339 What Does the Product Itself Look Like? / 340 When Taking the Drug / 341 After Taking the Drug / 341 NOTES AND REFERENCES

343

GLOSSARY

363

INFORMATION SOURCES

379

General Readership / 379 Specialist Readership / 380 News / 381 Education / 381 Organizations / 381 DRUG REGULATORS

385

INDEX

391

Preface

Counterfeit drugs are fundamentally a security issue. Writing a book like this is, therefore, both stimulating and frustrating. The urgency and seriousness of the threat to our healthcare systems has spurred me on, but I have also been mindful of who might be reading the book. There are many areas where I would have liked to have added more detail, but the constraints of commercial confidentiality and a strong desire not to provide help to criminal counterfeiters has meant that some subjects are deliberately omitted or covered thinly. In my work, I have seen many excellent real-life case studies of counterfeiting incidents, accompanied by great visuals and photographs. Sometimes these are presented at security conferences to the cognoscenti, but are not usually released to the public. Therefore, to avoid legal issues and difficulties in obtaining permissions (to use real pack shots, for example) all of the figures and diagrams used in the book are either public domain materials or original diagrams that I have devised and developed myself. They are based on general principles and real product designs, but not on any specific brands or counterfeiting incidents. To heighten the realism slightly, I have used an imaginary drug company (Starma Corp.) and imaginary brand names in some of the diagrams (Ingesta, Injexa, etc.). These are, of course, for illustrative purposes only and any resemblance to real companies, logos, or products is entirely coincidental and unintentional. Similarly, where there is discussion of real-world brands and events in the text, it is on a neutral basis—any perceived praise or criticism of individuals or corporations is unintentional. xxi

xxii

PREFACE

The global nature of the counterfeit drugs problem means that all societies, countries, and regulatory jurisdictions are affected. Addressing the specific situation in every individual country would make for an unwieldy volume, so I have used examples to illustrate the general themes. Many of these examples are based on American or European laws or initiatives, simply because the United States and Europe have well-developed regulatory systems and are the major powerhouses of the innovative pharmaceutical industry. I remain very mindful of the impact of fake drugs in developing countries. The anti-counterfeiting area is starting to move very rapidly and it is inevitable that some of the information in this book will be superseded by events. Readers are particularly advised to check for updates to any of the regulations and legal requirements discussed in the book before taking any action on the basis of the information provided. I welcome correspondence—including corrections, additions, and suggestions for improvement— via the publisher or www.bluespherehealth.com. Mark Davison Cambridge, U.K. December 2010

Acknowledgments

This book simply would not have been possible without the prior work of others, many of whom have been striving for years to protect their customers or to raise awareness of the serious and growing problem of counterfeit pharmaceuticals and medical devices. There are too many people and organizations to thank by name here, but I have tried to acknowledge these inputs through the references and further reading sections. If I have missed anyone out or misattributed any material, I apologize. Although the book rests entirely on the bedrock of other people’s labor, all the errors are mine. I would particularly like to thank Maurice A. Amon and Philippe Amon, Executive Co-Chairmen of SICPA Holding, S.A., for their personal commitment to the fight against counterfeiting around the world and in many industries, and for giving me the opportunity to work at SICPA for four fascinating and rewarding years. Although I have not (for obvious reasons) discussed any confidential aspects of my work in this book, I thank the many colleagues and friends who have contributed ideas and inspiration. Thanks also to my editor at John Wiley & Sons, Jonathan Rose, who had the original idea for this volume and helped me to turn the project from proposal to reality. I am grateful to David Teale and David S. Howard, both well-known anti-counterfeiting experts, for their comments and advice. Their wide and deep knowledge of the field has been very helpful. My family is the center of my life, and I thank my wife and children for their love and for their forbearance while I have been traveling the world on business or hammering away at a keyboard behind a closed door. Thanks also to my parents for their lifelong support and encouragement. xxiii

Part

1

General Themes

Chapter

1

Introduction

The problem of counterfeit drugs is not a new one, but it is a growing issue and one that cannot be ignored. Of course, this book does not review all of the possible situations or contain all the answers necessary to solve the problem. Nevertheless, I hope that it provides some guidance on the principles of anti-counterfeiting and gives some food for thought on strategy and technology choices. Counterfeit medicines cannot be tolerated–we all have an urgent obligation to do something about it. It is not just a few technical specialists or even the whole pharmaceutical industry that needs to take action: counterfeit medicines are everybody’s problem. We may not be able to stop fake drugs entirely, but we have to keep that as our aim. One life lost because of a counterfeit medicine is a death too many.

WHY WRITE THIS BOOK?

Counterfeiting is a growing, worldwide criminal trend that affects us all.1 It is now present in almost all industry sectors, not just consumer goods, and fake products are getting ever harder to avoid. We can choose not to buy obviously counterfeit “designer” items sold at bargain prices by street traders. By buying only from authorized outlets, we consider ourselves safe from being ripped off. But in many cases, fakes are not so easy to Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

3

4

INTRODUCTION

spot, however vigilant we are. The same profit motive that has led to rip-offs in the consumer goods industry has caused an alarming rise in counterfeit medicines. These are very difficult for the average consumer to spot and they are starting to turn up in local pharmacies around the world. They are already endemic in developing countries and evidence suggests that they kill hundreds of thousands of people every year.2 Almost everyone on the planet will take pharmaceutical drugs at some point during their lifetime. Some people must take dozens of pills every day just to stay alive. Every time we take a painkiller for a headache or get our children immunized, we are placing our safety or that of our loved ones in the hands of the drug supply chain. We rightly anticipate that our sore head will benefit from analgesic drugs and our children’s future health will benefit from vaccinations. We do not expect our immediate or future well-being to be harmed by toxic effects or by ineffective medicines that expose us to preventable danger. Twenty years ago that may have been a relatively safe assumption, but today, the activities of organized criminals have turned counterfeit medicines and medical products into a global parallel industry, with the potential to undermine progress in healthcare if its growth is not checked. The reasons why drug counterfeiting occurs are many, varied and complex. These subjects are well covered elsewhere and I have included references for those interested in these issues. I have spent the last few years working as part of a small industry that is trying to use technology first to control and eventually to prevent the spread of counterfeit products. My work has taken me around the world and into several different industries. Although I will give an overview of the counterfeiting problem, this book is deliberately and specifically about anti-counterfeiting. Whether we like it or not, counterfeit drugs have gained a foothold. This book is a primer for those who want to know more about the problem and how to deal with it.

DOESN’T THIS BOOK JUST HELP THE CRIMINALS?

The paradox of writing about anti-counterfeiting is that it runs the risk of educating the very people we are trying to thwart. I therefore took several key decisions when planning this book. Firstly, this book is not a technical manual or a directory of security suppliers and their capabilities. None of the technical information or realworld examples given is based on privileged information and this book does not discuss specific details of the proprietary technologies used by any brand owner or vendor. All of the technical information given is

WHO IS THE BOOK AIMED AT?

5

available elsewhere in the public domain and I neither endorse nor criticize any of the technologies discussed. I explain the general principles of various techniques, but in general, the book focuses on policy and strategy issues—which in any case are often far more critical to success than the technology employed. There are also some technical subject areas which I have deliberately covered in less detail to avoid giving help to counterfeiters. In particular, these areas relate to specific covert and forensic technologies, which are confidential and not publicly disclosed. Pharmaceutical product protection, like all security functions, should follow the need-to-know principle. In the interests of transparency, I should again point out that I was previously employed by a leading security vendor, but of course none of the confidential aspects of my work there are mentioned in this book. There are many excellent technology providers and sources of independent advice, and I encourage the reader to contact me privately or to seek other expert guidance when assessing technology choices. The “Further Resources” section contains contact details for various trade associations. Secondly, with only one or two well-studied exceptions, I have chosen not to use illustrations and case studies which involve specific brands. The pragmatic reason is that drug companies are often reluctant to give permission for photographs of their products to be used, but the main argument is that it is unfair to single out individual corporations. All manufacturers and all price levels of products are now vulnerable to counterfeiting. Vigilant and transparent companies often have a higher apparent incidence of counterfeits only because they look harder and report fully. Therefore, in most cases, I have used illustrations of generic types of counterfeiting to show the methods used, with links to public domain information about real examples where appropriate. WHO IS THE BOOK AIMED AT?

Pharmaceutical company executives, in all disciplines, need to be conversant with the issue of counterfeit drugs and with the technical and policy approaches required to combat them. Other pharmaceutical employees, from R&D scientists to sales representatives to manufacturing supervisors, should also have a working knowledge of the issues discussed in this book. Only by involving all levels and functions in constant vigilance can we begin to get on top of the counterfeiting and diversion problem. More specifically, most drug companies and other organizations involved in the production, distribution, or monitoring of drug supplies now have individuals with responsibility for anti-counterfeiting and supply chain security. I hope this book will provide them with some fresh insights.

6

INTRODUCTION

Pharmacists and doctors are key arbiters of drug quality and provide the final professional link in the chain of custody from drug manufacturer to patient. Many of the drug tracking and anti-counterfeiting systems currently being piloted are heavily reliant on pharmacists’ participation. This volume is an ideal primer on these issues for trainee and qualified pharmacists and doctors. Many governments and non-government institutions have created agencies and appointed individuals to monitor and combat fake drugs. Resources are usually limited and these organizations are lobbied hard by technology vendors, pharmaceutical companies, and trade associations representing often conflicting views from various supply chain stakeholders. This book provides a neutral view of the issues to help civil servants to take informed judgements. Although technical issues are discussed, I have also tried to ensure that the book remains accessible to the interested layman. We are all customers of the medical system and the more the general public is informed about counterfeit drugs, then the more vigilant society will become.

Chapter

2

Origins and Context of Counterfeiting in Healthcare BACKGROUND AND NATURE OF THE THREAT

The use of unproven medical claims to make a living is probably as old as mankind, from shamanism1 to snake oil sellers.2 Just read the advertisement section of any newspaper and you can find companies selling herbal remedies, magnetic healing devices, and a myriad of other panaceas. Beneath a big headline, the supporting text is carefully and ambiguously worded (“May help . . . ,” “Thought to improve . . . ”). The claims are not supported by any clinical evidence, let alone a randomized, double-blind, placebo-controlled trial.3 There is usually a disclaimer, printed in a tiny font, but what the consumer responds to is the deliberately emotive headline, which promises to solve their real or perceived medical problem. The gullible will continue to be duped in this way, but generally these items are discretionary purchases and the products cause mild financial loss but not medical harm. Most people do not buy their day-to-day medication from small advertisements in the newspaper. Within the last 10 years or so, there has been a dramatic increase in another form of medical deception—counterfeiting of drugs and medical devices. This is a much more menacing threat than the peddling of Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

7

8

ORIGINS AND CONTEXT OF COUNTERFEITING IN HEALTHCARE

quack remedies described above. The consumer thinks they are getting a genuine, tested, safe, and efficacious product from a well-known manufacturer. They expect that product to have a positive impact on their life. But medicine is a complex area. Doctors and patients know that most diseases have more than one contributing factor and that most medications are not miracle cures. Therefore, if the patient does not get the desired benefit, they often simply stop treatment or their doctor switches them to an alternative product, without considering the possibility of counterfeiting. In the worst case, the patient may not live to find out that their drugs are fake. People die of pre-existing medical conditions every day. We do not routinely analyze the contents of their bathroom medicine cabinets to check for counterfeit medication. It is now clear that fake drugs and medical devices place an increasing disease burden on society. Counterfeit drugs have come to dominate some markets so that they represent the majority of available medicines, with disastrous results. For example, the spread of fake antimalarial drugs is a tragedy4 that has already cost thousands of lives. The volume and variety of fake pharmaceutical products is astonishing. All types of drugs and medical products are affected. When labor and raw material costs are low, even cheap branded items can provide a profit opportunity for criminals. Disposable products such as sutures, dressings, and hypodermic needles are copied using poor quality materials. Even worse, used and contaminated items are salvaged from disposal sites and repackaged as new products, complete with fake “sterile” status. However, counterfeiting is not just an issue for tropical areas or developing countries. The rise of the Internet and the advent of so-called “lifestyle drugs” have driven the expansion of the counterfeit drug industry worldwide. Lifestyle drugs are aimed at indications where treatment is largely a matter of patient choice and not a medical requirement. They are often expensive and in many cases, they treat conditions (e.g., erectile dysfunction, obesity) that patients consider embarrassing. The high profile, high price, high demand nature of these products provides an obvious economic incentive to criminals. Within the pharmaceutical industry as a whole, the major pharmaceutical companies especially have come under heavy criticism from some quarters for their perceived high prices. Many discussions of the counterfeit pharmaceutical problem, particularly those concentrating on intellectual property (IP) rights, tend to focus on the price of legitimate drugs in order to highlight the apparent financial incentive to counterfeiters. The reality is that price is not a strong predictor of counterfeiting. Even cheap generic antibiotics are copied, and in many developing countries it is the widespread presence of counterfeit versions of these critical drugs

R&D COSTS, PATENT LIFE, AND THE PROFIT IMPERATIVE

9

which is the main problem. To understand why pharmaceutical and medical device companies charge the prices that they do, we need to examine the economics of the pharmaceutical industry. R&D COSTS, PATENT LIFE, AND THE PROFIT IMPERATIVE

Discovering and developing an innovative drug or medical device is difficult. It requires a multidisciplinary team of highly qualified people, expensive research facilities, complex animal studies, and challenging clinical trials. It takes lots of time and money and often some luck. The preclinical development time “from suggestion to ingestion” can be several years. There follows a hugely expensive clinical development process that takes even longer. One widely quoted estimate puts the total cost of developing a new chemical entity, including the cost of all the failed drug candidates and the cost of capital, at over 800 million dollars.5 That does not include the huge marketing and sales budgets necessary to ensure the commercial success of a product that makes it to the market. Almost all innovative pharmaceutical products are discovered and developed by for-profit organizations, whether privately or publicly held, and the shareholders of these corporations naturally expect returns on their investments. But the patent life of a new product is finite—typically 20 years—and the long development process eats heavily into this time. Many newly launched drugs have only 5–10 years of market exclusivity remaining, before their patent protection expires and legitimate generic competition moves in. In this short time, the sales of the new drug are expected to recoup the development costs and eventually to make a net profit. All these factors mean that drug prices are often relatively high. In the developed world, consumers and third-party payors (e.g., governments or health insurers) are generally prepared to pay these high prices. Why? In part, it is because “innovator” drug companies employ advertising campaigns and sales representatives to detail the benefits of their products directly to physicians and consumers and thereby build brand awareness. Moreover, in developed countries, the strict regulatory process ensures that manufacturers’ claims have to be substantiated. The simple fact is that patented, branded drugs generally work. They are manufactured to a high standard, they are mostly effective in treating or alleviating disease, and they often save lives. However, the same rigorous process that means that approved drugs have to be safe and effective also means that most experimental drugs fail to make it through the development phase. The survival of a pharmaceutical company is therefore dependent on its approved drugs carrying

10

ORIGINS AND CONTEXT OF COUNTERFEITING IN HEALTHCARE

the full cost burden of the corporation (including the failures) and on new drugs coming onto the market regularly. To add to the pressure, the overall productivity of the industry is falling. This is happening for various reasons, such as inefficient R&D structures, increasing regulatory hurdles, and sometimes just bad luck (such as rare but serious adverse events that only show up late on the development process or even after product launch). The prices charged by major drug companies for their patented products can therefore be explained (although I neither justify nor criticize them here). What is the opportunity for counterfeiters?

A LOW COST, HIGH PROFIT BUSINESS

A combination of factors creates a huge opportunity for criminals to exploit. These include high market prices, high customer demand, global brand awareness, consumer trust painstakingly created and supported by drug company R&D. Criminals producing fake drugs and medical devices have none of the commercial burdens discussed above in relation to drug companies. They have an advantage at all stages of the product life cycle. Research and Development

Counterfeiters have almost zero R&D costs. Even if they wish to include an active ingredient or functional component in their product, they can simply copy the genuine article using reverse engineering or readily available information. Counterfeiters do not need research campuses. They do not sponsor blue-sky research into complex disease areas. They have no patent applications to submit and defend. They do not spend money complying with good manufacturing practice (GMP).6 Regulatory Approval

The regulatory review process, designed to protect the public by ensuring that only safe and effective drugs reach the market, can take a year or more. Even after dozens of clinical trials have been completed and a dossier of thousands of pages of data has been generated and submitted, regulators may request more data or turn down the application outright. In many countries, the drug company pays a large fee7 for this process. The counterfeiter has no such impediment. Fake versions of potential new blockbuster drugs can appear even before the original is authorized for sale.8

A LOW COST, HIGH PROFIT BUSINESS

11

Manufacturing

For branded pharmaceuticals and higher margin medical devices, the raw material costs are usually relatively low compared to the selling price. Even for generic drugs, the active pharmaceutical ingredient (API) price is usually not the key driver of product cost. With the growth of pharmaceutical manufacturing worldwide, it is now possible to source most APIs either legitimately or on the black market. This ability to source active ingredients cheaply provides a low barrier to entry for counterfeits—assuming that the products actually contain some of the correct ingredients. Many of the cheap APIs in counterfeits are of poor quality and contain impurities, but there is a way to decrease costs yet further. Some fake drugs are made from entirely “unorthodox” and often toxic ingredients such as building materials, chalk, paint, antifreeze, and printer ink. The results are sometimes fatal.9

Packaging

Modern digital scanning and printing techniques mean that packaging can often be easily and cheaply duplicated. Some pharmaceutical companies have identified fake products on the basis that the packaging was of a better standard than their own. Since packaging is often the only basis by which anyone other than an industry expert can differentiate genuine from counterfeit products, most of the technical effort of counterfeiters has gone into producing visually accurate packaging— boxes, blisters, vials, etc. The anti-counterfeiting strategies that are discussed in this book are therefore often focused around increasing the technological complexity of pharmaceutical and medical device packaging, with codes, taggants, markings, etc. This helps to reduce its vulnerability to copying, or at least provides a means to identify when it has happened.

Marketing

Counterfeiters have no need for expensive marketing campaigns. The innovator drug companies have to run magazine advertisements or attend conferences or send representatives to detail physicians about the benefits of the drug. The counterfeiters’ fake products are just brand parasites and feed off the reputation and hard-won name recognition of the genuine brand. The Internet provides a very low cost marketing channel. Combined with spam e-mail, it allows counterfeiters to reach a worldwide market at negligible cost.

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ORIGINS AND CONTEXT OF COUNTERFEITING IN HEALTHCARE

Logistics

The unauthorized supply and distribution of fake pharmaceutical products is relatively easy and cheap. Counterfeiters increasingly combine the tools of legitimate business and international organized crime to make their businesses both highly efficient and hard to detect. Production is outsourced, perhaps to countries with production expertise and low costs but weak governance and a poor record of IP enforcement, such as India or China. Third-party freight forwarders are used to legitimize the movement of products. Convoluted international routes, often using free trade zones, hide the origin of product and enable it to be laundered. Those providing the money often never see or touch the finished goods. PERMISSIVE LEGAL ENVIRONMENT

Given the profits available, it is not surprising that the growth of counterfeiting in pharmaceuticals has been inexorable. This has happened despite the obvious dangers to society and the many attempts to curb the problem. Although almost all governments have a stated aim of eradicating counterfeiting, one of the main problems has been the weak and patchy legal tools available to them. In most countries, the laws used to combat drug counterfeiting are based on infringement of IP, and are often the same laws used to prosecute those who sell knock-off running shoes or fake fragrance. Even in the unlikely event that the pharmaceutical counterfeiter is caught and convicted, the penalties are often relatively light. In most jurisdictions, the penal risks of pharmaceutical counterfeiting are still much lower than those of the narcotics trade, for example, despite similar or better profit margins and arguably greater risk to society if the rise of fake medicines is allowed to go unchecked. The situation is slowly improving as legislators wake up to the threat. The introduction into Congress of the Food and Drug Administration Globalization Act of 2009, H.R. 759,10 has the potential to increase the jail terms for drug counterfeiters in the United States to a maximum of 20 years, or a maximum of life imprisonment if the fake drug is a “proximate cause of death.” Stronger legal powers are now being discussed worldwide, with the creation of the concept of “pharmaceutical crime.”11 The creation of the International Medicinal Product Anti-Counterfeiting Taskforce (IMPACT12 ) by the World Health Organization (WHO) in 2006 was also a big step toward coordination of legal and technological approaches. One of the IMPACT sub-committees was tasked with the creation of common legal frameworks

ROLE OF THE INTERNET

13

that can be used by developing countries to strengthen their judicial processes to deal with this type of crime. Despite the occasional criticism of the WHO and IMPACT, the global coordination and focus provided by such an independent secretariat is valuable because pharmaceutical counterfeiting is a global criminal activity that must be fought on an internationally coordinated and apolitical basis.

ROLE OF THE INTERNET

The Internet now pervades all areas of modern life. In the last decade, online commerce has taken off and the sale of drugs on the Internet has grown very rapidly. For the consumer, there are many apparent benefits of buying medications online. The main draw is often the opportunity to obtain drugs at lower cost than in a retail pharmacy. However, the convenience of direct delivery is also attractive to those in remote areas or with mobility problems. For busy professionals, gaining access to medication without a time-consuming trip to a medical practitioner may be the main reason for purchasing online. Avoidance of the standard medical channels may also be a motive—for those with embarrassing conditions or who do not wish to disclose their condition for whatever reason. Many online pharmacy sites dispense prescription medication without a prescription and with no questions asked (or medical care given). The Internet is the perfect hiding place for counterfeiters. It provides an international, low cost sales channel, as well as anonymity and ease of concealment. Combined with the demand from the consumer, the ease of setting up an online pharmacy has led to a sharp rise in their numbers. The increasing number of consumer complaints and incidents of counterfeit drugs has caused regulatory authorities to issue warnings and take countermeasures.13 Evidence shows that most internet pharmacies supply counterfeit drugs. For example, the European Alliance for Access to Safe Medicines14 conducted a “mystery shopper” internet pharmacy survey in 2008. They examined over 100 online pharmacies and purchased over 30 common prescription-only medicines. They found that over 90% of the sampled sites supplied prescription-only medicines without a prescription. Furthermore, 62% of the medicines they purchased online were fake or substandard. There are now several accredited validation schemes for internet pharmacies, such as the Verified Internet Pharmacy Practice Sites (VIPPS) scheme run by the National Association of Boards of Pharmacy in the United States,15 but the unwary or the desperate will continue to be fooled

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ORIGINS AND CONTEXT OF COUNTERFEITING IN HEALTHCARE

by the promise of low cost medicine delivered to their door. As well as clamping down on illegal, bogus pharmacy websites, we also need to address the reasons why people buy drugs over the Internet.

GLOBAL GROWTH OF COUNTERFEITING

The worldwide growth of counterfeiting has been inexorable, in almost all areas of trade.16 Some of this is driven by consumer demand, or at least acquiescence.17 People want the glamour of branded consumer goods without the high price. There are large numbers of consumers who clearly perceive (wrongly) that some forms of counterfeiting constitute a victimless crime.18 The same is rarely true when they are asked about counterfeit medicines. The rampant expansion of criminal drug counterfeiting concerns almost everyone, but most people have no direct experience of fake medicines (that they know of) and tend to assume that this is a backstreet operation supplying illicit sales channels. Many early counterfeit medicines were indeed comparatively basic. They were often made in dirty environments, with low cost ingredients, potentially toxic contaminants, usually little or no active component, and poor quality imitation packaging. This is not usually the case today. Counterfeiting of medical devices and pharmaceuticals is no longer a localized, opportunistic, small-scale crime. These crude early attempts were quickly replaced with more sophisticated versions when organized crime became involved, and international networks with industrial manufacturing capabilities now control most of the counterfeit drug trade. Their reach and sophistication often rivals that of the legitimate pharmaceutical industry. In some cases, especially in the developing world, the fake product may be the only locally available and affordable option. Many of these criminal pharmaceutical networks are also involved in other organized crime and some have links to terrorist groups.19 The advances made in medicine over the last century have given us many effective treatments for disease and have dramatically increased the life expectancy in most societies. Counterfeiting of pharmaceutical products is a global problem that, unless checked, threatens to undermine this progress. This book addresses these important themes and looks at the ways society is trying to fight back.

Chapter

3

A Snapshot of the Problem

The global annual revenues of the pharmaceutical industry1 were $827 billion in 2009, according to market intelligence consultancy IMS Health.2 That equates to about $150 for every person on the planet but this average figure hides very wide variations. The US market, for example, has unique characteristics and historically the major drug companies have made up to half of their profits in the United States (although in recent years this has fallen to around 40%). So what is the scale of the counterfeiting problem? Until a few years ago, the widely quoted WHO figure of a 10% prevalence of counterfeit medicines was used. The WHO revised and finessed this figure in 2006.3 The 10% estimation still circulates very widely (especially in the sales literature of security vendors) but it is based on no factual evidence, has not been validated or tested in any meaningful way, and should be entirely ignored. The reality is that accurate figures are almost impossible to establish on a meaningful geographical scale. The prevalence may range from almost ubiquitous in one village market on one day to very rare in more controlled environments. The average worldwide prevalence, even if we could determine it, would be a misleading number, which would merely act as a red herring to journalists and policy makers. Any incidence of fake drugs has the potential to injure or kill, and there should be no “tolerable level” of counterfeiting. Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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A SNAPSHOT OF THE PROBLEM

If we take the United Kingdom as a fairly typical example of a nonUS, developed economy, we find that, according to the UK regulator Medicines and Healthcare products Regulatory Agency (MHRA),4 around 700 million medical prescriptions are written annually, or an average of 11 per year for every inhabitant. The MHRA states that there were nine cases of counterfeits actually reaching the market (and leading to product recalls) between 2005 and 2009. These cases, although relatively significant incidents involving multiple packs, were clearly infrequent. Nevertheless, it is startling that on nine separate occasions, the UK pharmaceutical supply chain—one of the most controlled environments— was penetrated by counterfeits. The Pharmaceutical Security Institute (PSI) is a global, not-for-profit, industry-funded body, which collects data about counterfeiting and helps to coordinate the efforts of drug makers to combat the problem. In 2009 (the last year for which consolidated figures were publicly available at the time of writing), the number of incidents reported to the PSI was a shocking 2003. This continues an unbroken rising trend for the previous seven years during which figures were collected.5 However, in comparison to the size of the global drug industry, this number looks relatively small, if only in statistical terms. If there are 2003 reported incidents in a trillion dollar industry, then pharmaceutical counterfeiting looks, at first glance, like a tiny issue. Playing the devil’s advocate role for a moment, why should society invest time and money on a worrying but seemingly rare problem, when there are bigger, more immediate threats to social cohesion such as poverty, famine, natural disasters, and terrorism? We should take fake drugs extremely seriously, for several reasons. Firstly, the problem seems to be growing very rapidly and has the potential to grow out of control, driven by nothing more than market forces. Owing to the high R&D costs and stringent quality requirements of the pharmaceutical industry, drugs are relatively expensive commodities. Fakes, however, can be made very cheaply. Marketing theory teaches that high-priced products that can be readily imitated at low cost will always attract new competitors.6 Secondly, fake drugs do not exist in isolation. Counterfeiting is now mostly controlled by organized crime,7 and profits from the sale of fake drugs are used to finance other criminal activity. Organized crime is a worldwide phenomenon and does not refer simply to the mafia or any specific grouping. There are local, national, and regional crime groupings and there are international links between groups—the supply chains for narcotics and counterfeit medicines probably overlap. Corrupt government

A SNAPSHOT OF THE PROBLEM

17

officials may also be involved in some cases.8 Counterfeit medicines disproportionately affect those who cannot afford to buy their drugs from secure and reliable sources, and they exacerbate the detrimental effects of poverty on health. There is also mounting evidence that counterfeit drugs are used as a key source of profit by terrorist groups.9 Furthermore, these groups could develop the capability to use these distribution channels to attempt a mass poisoning attack. Therefore, the control of counterfeiting is both directly and indirectly an issue of national security for all governments. Finally, the apparent rarity of fake drugs is almost certainly an artifact of poor data. The number of counterfeit pharmaceuticals in circulation is probably far higher than the numbers quoted above would suggest, for a number of reasons. • Incidents reported to the PSI tend to involve brands owned by the

•

•

•

•

•

PSI members. This group, although important, is only a subset of the medicine brands used worldwide. Most counterfeit drugs are found in the developing world where anticounterfeiting surveillance may be less intensive and supply chains less secure. Surveillance and enforcement resources are always limited, particularly in poorer countries. For an incident to be reported, it must first be discovered. Drug company investigation teams are small and require the cooperation of local law enforcement officials if they are to identify problems. Police and customs officials have many competing obligations and may not give the seizure of fake drugs top priority. Counterfeiting is a disease of society and, as with many diseases, the apparent prevalence is rising as the efficiency of diagnosis increases. Many of the highest apparent incidences of counterfeit drugs in the developed economies are in states with highly developed surveillance mechanisms. The harder you look, the more you see. Many of the most prevalent counterfeits in the developing world are copies of low cost, locally branded products such as painkillers and anti-malarials. Since even the original brand may not have premium quality packaging or security features, it is often difficult to differentiate genuine from fake product without recourse to laboratory analysis of the ingredients, which is time consuming and expensive. In some places, law enforcement and government agencies may be part of the problem. Corruption is endemic in many countries and junior public servants are often not well paid. Even if the authorities

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A SNAPSHOT OF THE PROBLEM

have a strict official line on counterfeit drugs, individual officials may be bribed to look the other way. • In the informal economies of the developing world, it is often hard to prove a causative link between counterfeit medicines and illness or death. Even if the patient or victim still has some evidence of counterfeit medicines (packaging, remaining pills, etc.), they may have bought it from a market or other transient, hard-to-trace source. Illness and death are more common in poorer societies, and autopsies and toxicology reports are rare, so proving the true impact of counterfeit drugs is difficult. • Using “drop shipment” logistics allows counterfeiters to remain almost invisible and very difficult to trace. The counterfeiter is usually an elusive middle man between the contract manufacturer and the customer. He often has almost no fixed assets and the fake product need never touch his hands. International money transfer and multiple layers of shell companies make the identification and prosecution of the criminal bosses very difficult and the true extent of the problem is difficult to determine. The World Customs Organization10 believes that there may be more fake drugs in circulation worldwide than genuine ones.11 By their estimation, in 2007–2008 alone the figure for known counterfeits rose by almost 600%. The impact of fake drugs is real, significant, and growing. The damage to public health has already been felt in Africa and Asia, where thousands of children have died needlessly from malaria.

CASE STUDY: MALARIA

In my experience, most members of the public in rich, developed countries are either not aware that counterfeit drugs exist or they assume that only those buying erectile dysfunction drugs on the Internet are at risk. “Malaria” is my one-word answer when asked why drug counterfeiting is a problem we must fight with all our strength. Probably, more than a million people (many of them children under five) have died because of fake or substandard malaria medications. Various international programs, such as Roll Back Malaria,12 have made a significant impact on the prevalence of malaria. Simple tactics, such as the distribution of insecticide-treated nets, have proved very effective but despite all of the advances, infection with malaria is still common in many countries. Luckily, there are effective drug treatments for malaria,

CASE STUDY: MALARIA

19

notably the natural product artemisinin and its semi-synthetic, watersoluble derivative artesunate. These must be used carefully in artemisininbased combination therapies (ACTs) with other antimalarial drugs in order to avoid the emergence of resistant strains. Sub-dose, counterfeit products labeled as ACTs are an easy option for criminals looking to make money. The counterfeiters add just enough active ingredient to fool the standard color-change assays used to test for artesunate in the field, but not enough to cure the disease. This crime has direct and often tragic consequences for the recipients of the fake medicine. The indirect effect is also becoming clear. Low-dose artesunate does not kill malaria parasites but encourages the emergence of artesunate-resistant strains.13 Since artesunate is one of the few remaining effective treatments for malaria, the proliferation of fake versions poses a serious threat to global malaria control. The situation is not helped by market dynamics, which provide huge incentives for counterfeiters. The WHO World Malaria Report 2009 contains the following excerpt14 : [T]he expansion in agricultural production of Artemisia annua and extraction of artemisinin in 2006–2007 were not matched by a similar increase in demand for artemisinin by ACT manufactures and suppliers of artemisininbased active pharmaceutical ingredients [which] led to a reduction in the prices of artemisinin raw material, even to below production costs . . . . The subsequent withdrawal of many artemisinin producers and extractors from the market in 2008 is likely to create a shortage of artemisinin-based active pharmaceutical ingredients in 2010, when demand for ACTs will increase . . . . . . Production of artemisinin-based antimalarial medicines will remain dependent on agricultural production, as production of artemisinin with biotechnology from yeast culture will not become available until at least 2012.

Prevention of counterfeiting would be well served by non-governmental organizations (NGOs) intervening to match the supply of raw materials to market demand or to support the price of artemisinin. We also need to find robust and cost-effective ways to help doctors, pharmacists, and consumers to differentiate genuine, effective ACT products from counterfeit, dangerous ones. The continuing mortality due to fake or substandard malaria drugs has been estimated at 250,000 per annum.15 That is equivalent to two Boeing 747s crashing every day. Even if the estimate is over by a factor of two, it is still a hugely shocking figure. Malaria alone should be reason enough to take action against counterfeit drugs, but there are other costs and risks of counterfeit drugs, which apply everywhere.

Chapter

4

Risks and Costs of Counterfeit Pharmaceuticals RISKS AND COSTS FOR CONSUMERS

The primary driver of all anti-counterfeiting strategies must be the safety of the consumer. The person ingesting, injecting, or inhaling a pharmaceutical product has very little opportunity to verify the quality of that medicine for themselves. They face a number of risks from counterfeit and substandard medicines. The Drugs Do Not Work

The reason that many ineffective drugs and devices are not noticed may be due to the fact that the public is already used to medicines not working every time. When I worked in clinical research, it used to be said (only half jokingly) that most drugs on the market were effective for one-third of the population, ineffective for another third, and might have side effects in the final third. Disease is a complex thing and many important classes of medicines work by controlling symptoms rather than curing the underlying Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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RISKS AND COSTS OF COUNTERFEIT PHARMACEUTICALS

illness. These symptoms may naturally vary on a daily basis and patients generally do not ascribe this variation to changes in the medication. Against this background, if a 65-year-old obese man dies of a heart attack, it is unlikely that an analysis will be performed on his medication and counterfeit drugs will probably not be suspected as a cause of death. Therefore, the true extent of the counterfeit drug problem may be heavily under-reported, although the lack of evidence is one factor that makes this a very difficult field to analyze. For scientists and managers trying to provide a financial “return on investment” argument, the lack of hard data is problematic. Many drug companies have therefore chosen initially to invest only in anti-counterfeiting features for their highest profile drugs. As the risks of fake products become more apparent, and the number of counterfeits of lower priority brands rises, many brand owners are revising this view and are now considering all products to be “at risk.” Very few countries have specific regulatory environments which mandate anti-counterfeiting features on pharmaceutical packaging. Therefore, drug manufacturers have taken the financially cautious view that they should delay investments until the regulatory environment becomes clear. This combination of factors has led to an opportunity for counterfeiters to exploit the lack of protection from many products. Even when legitimate drugs are protected, the lack of a clear regulatory framework can easily lead to confusion in the marketplace. Consumers are unclear about which features to look for and counterfeiters can hide behind legal arguments and judicial gray areas. Ineffective drugs may only cause minor inconvenience to the patient in some cases. A headache may not go away so quickly but if the painkiller is not poisonous it may cause no other negative effects. But in many disease areas, counterfeits do not have to be toxic to kill. Perfectly safe but ineffective drugs can kill if they are substituted for life-saving products. As discussed above, the problem of fake anti-malarial drugs in Africa and Southeast Asia is probably causing the deaths of hundreds of thousands of people per year—a tragedy that has been under-reported in the general media. Is it also possible that thousands of people in both developed and developing countries could die early from heart disease, diabetes, myocardial infarction, and so on, because of the undetected infiltration of substrength or ineffective counterfeit medicines into their healthcare systems? Unless the physician is vigilant, the connection between symptoms and fake drugs can easily be missed.1 Finally, and perhaps most frightening of all, the widespread use of substandard antibiotic drugs could lead to a potentially explosive increase in the prevalence of drug-resistant bacteria. The drug industry has largely deinvested from antibiotic research, which is traditionally a difficult and

RISKS AND COSTS FOR CONSUMERS

23

not very profitable area of R&D. If we allow the effectiveness of existing drugs to become compromised by counterfeits, then we risk a “doublewhammy” with rising levels of drug resistance and not enough time to restart the innovation engine. Despite the medical successes of the past century in reducing the burden of infectious disease, bacterial infections have not gone away. If we allow our main weapons against them to be blunted, the consequences could be disastrous.2 There is a growing trend for fake drugs to contain small amounts of the active ingredient, presumably to evade simple tests and to enable the perpetrator to argue that the fake should be classified as sub-potent rather than counterfeit, if and when it is discovered. Sub-potent fakes are a major threat to global health and we must put control measures in place so that criminals are not allowed any leeway to escape justice on a technicality. Toxic Products

Most of the well-publicized cases of counterfeit medicines, fake medical devices, and adulterated food have involved toxic products. These products caused immediate and harmful effects in those exposed to them. In cases such as diethylene glycol in cough syrup and toothpaste,3 or melamine4 in baby milk, these products were lethal. In the early days of counterfeit drugs, some of the ingredients used were primitive, cheap, and not intended for human consumption. Building materials were used as bulking agents, paint was substituted for coloring. Many of the small-scale counterfeiting operations used highly inappropriate and unhygienic industrial machinery such as cement mixers. As a consequence, these products were often dangerous and in some cases undoubtedly lethal. The increasing organization of the counterfeit drug trade of the last 10 years has led to a new industrial approach in the production of fake medicines. The backyard operations are still found, particularly in Africa and Latin America, but organized crime is now using industrial scale production. They copy the methods of the drug companies. Their products, while not usually produced to any meaningful quality standards, generally use less toxic starting materials than those found a decade ago. However, safe pharmaceutical manufacturing involves much more than just having pure starting materials. Machinery must be cleaned, contamination avoided. Analysis of counterfeit products routinely reveals the presence of adulterants, which could kill, such as penicillin. Batch-to-batch variation and lack of statutory decontamination processes make counterfeits dangerous even when they contain some of the purported active ingredient.

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Fear and Mistrust of the Medical Profession

Doctors and the medical profession are typically placed very highly in surveys of public trust,5 as are pharmacists. The great majority of people do not have the knowledge or the skills to make medical judgments for themselves, therefore they rely on professionals. Counterfeit drugs, if they become widespread, have the potential to undermine this public trust—with harmful consequences for society and for the healthcare industry. The pharmaceutical industry is unusual in that it relies to a large extent on brand awareness to generate sales but it cannot usually sell directly to its end consumers. There is a complex chain of custody from factory to patient that must be secured at all stages. In order to protect the public, anti-counterfeiting strategy needs to be coordinated across the whole medical profession. All downstream stakeholders—importers, distributors, repackagers, physicians, pharmacists, and finally patients themselves—have a role to play in ensuring that only good quality, genuine medicines reach those who need them. Pharmacists, in particular, have arguably been under-used in the fight against counterfeits. They are often consulted by consumers on medical issues (for self-medication products, for example) and they are in a good position to spot counterfeits. Some pharmacy point-of-sale verification systems are already in place (in Belgium and Greece, for example) and are proving effective.6 The effectiveness of evidence-based, scientific medicine is due in large part to the trust between doctor and patient or pharmacist and patient. This applies especially in preventative medicine, where the patient may be taking expensive drugs to address symptoms, which he or she does not feel (raised blood pressure, high cholesterol) because the doctor has assured them that the medicine will be beneficial for the patient’s longterm health. If this trust breaks down, it will be very hard to repair, risking both patient welfare and the medical profession itself. RISKS AND COSTS FOR BUSINESSES

Although patient safety is the key driver for anti-counterfeiting, the financial and business risks to brand owners and legitimate drug producers are also significant. These fall into several categories, with both direct and indirect consequences to the health of the business. Revenue Loss

The economic effect of counterfeiting in general has been well described elsewhere. See, for example, the recent report by the Organization for

RISKS AND COSTS FOR BUSINESSES

25

Economic Cooperation and Development.7 Many of the general factors analyzed there also apply in the drug industry. Counterfeit products cause loss of revenue to drug companies in a number of ways. • Consumers buy accurate copies of branded products without realizing

that they are not genuine (primary market). This is a very high-margin business opportunity for criminals. The consumer or other payor (health insurer, national public health system) pays the market price as agreed or regulated for the genuine product. This price is often relatively high for the reasons discussed in Chapter 2—it has to include the costs of R&D, corporate infrastructure, returns for shareholders, etc. However, what the patient unknowingly receives is a fake product for the same price. Since the criminals have much lower costs (no research, simple development, usually no permanent infrastructure), most of the purchase price is pure profit. This is profit stolen directly from the brand owner, since the customer believes that they are purchasing the brand owner’s product but the money is diverted to criminals. The fact that this scenario occurs for some products in some markets is not disputed by most brand owners, but quantifying the extent and the financial impact is extremely difficult. Measuring the true amount of counterfeit product in the marketplace is notoriously difficult. Usually these products are not openly displayed or advertised in pharmacies, stores, or market stalls. In some cases, the pharmacist may not even be aware that the product is fake, but in other cases, they may be complicit and may receive tip-offs before a raid, allowing them to hide counterfeit products. The counterfeit discovery process therefore often involves the brand owner or their agents in “mystery shopper” activities where the manufacturer either buys their own products for laboratory testing or conducts open or concealed testing at the point of sale. This activity can be dangerous if it arouses the suspicion and hostility of the criminals behind the counterfeit trade. It also provides only a patchy view of the situation. Therefore, most pharmaceutical companies have no fully accurate picture of the extent to which their revenues are being eroded by unauthorized copies of their products. They know that it happens, but financially they are peering through fog. This has implications for how a drug company management team perceives the problem of counterfeiting. It can be hard to make a case for adding cost to the product by implementing an anti-counterfeiting feature when the benefit cannot be accurately quantified. The fact

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RISKS AND COSTS OF COUNTERFEIT PHARMACEUTICALS

that manufacturing and sales often have conflicting incentives does not help. The manufacturing organization is incentivized (often at an individual level through staff bonuses) to reduce the cost of goods sold (COGS). This means that all elements of the product and its packaging are continually examined to see if costs can be trimmed. Suppliers are continuously under pressure to reduce their prices. It is also the manufacturing function that is most commonly in charge of the procurement and implementation of anti-counterfeiting technology. Many anti-counterfeiting features employ cutting edge, proprietary materials, and know-how, which is not available from multiple suppliers. These materials may be inherently expensive and often carry significant intellectual property value and high development costs, which carry through into pricing. On a per pound basis, security products can appear relatively expensive, compared to bulk commodities used in manufacturing. If the procurement of anti-counterfeiting features proceeds only on a lowest cost basis, then some of the solutions, which are selected may not always be fit for purpose. While the manufacturing function bears the cost, the main beneficiaries of anti-counterfeiting features are usually found in the sales function. They may be thousands of miles distant from the manufacturing plant and may have specific counterfeiting pressures in their own markets that are eroding their market share. Unless these two functions are well connected and there is good communication between them, there is potential for poor business decisions to be made regarding anti-counterfeiting technologies and their use. Many companies have therefore established centralized product security teams whose role is to coordinate selection and procurement of technologies to secure the supply chain. These functions often have an independent budget, which helps to remove the internal tension between manufacturing and sales described above. In general, the more strategic and pre-planned the decisions that are taken when procuring or selecting anti-counterfeiting features, the cheaper the eventual unit costs will be and the more effective the brand security program. Another unresolved issue in product protection is that the costs of anti-counterfeiting features tend to fall mostly or wholly on the producer, whereas the benefits do not. Serialization may be an exception, since all stakeholders need to invest in infrastructure to read codes, but even here, the manufacturer has the highest fixed costs. For nondigital authentication features such as holograms and specialty inks, the manufacturer is usually on their own. A drug pack will pass

RISKS AND COSTS FOR BUSINESSES

27

through many hands on its journey from factory gate to patient and the manufacturer is clearly not the only one making a profit. The appropriate distribution of costs and benefits will need to be addressed if large-scale projects are to be successful. This should first be done internally, with brand owners considering product security as an integral part of the development process and allocating costs well upstream of where they are today, but cost sharing might also need to occur across the supply chain. • Some people buy cheaper lookalike brands knowing them to be copies but believing them to be “generic versions” of similar efficacy (secondary market). Popular brands attract brand parasites—lookalikes that do not exactly copy the original but trade-off its expensively generated brand recognition and kudos. Pfizer Inc’s heavily targeted Viagra® is a classic example of this. Although there are very close copies of Viagra® available, with packaging designed to look like the original in every way, many of the products, which erode Pfizer’s revenues are not labeled Viagra® but carry a similar sounding name. They may claim to be “generic” versions, “authorized copies,” or use other pseudomedical terms. The packaging may not be identical but will usually be closely related to the feel and brand style of the original. Many other well-known brands are targeted in this way. The aim of the producers of such lookalikes is to make the consumer believe that the product they are buying, for a fraction of the price of the branded original, is just as good and just as effective. It can be argued that for high-priced products, the presence of unauthorized brand approximations, which are not accurate copies does not erode brand revenue, since they are bought knowingly by consumers who could never afford the original product. Whether or not this argument is true, unauthorized copies do not have the safety profile or the manufacturing controls or the regulatory oversight of the originals and are therefore inherently more dangerous. They also diffuse brand identity and make it harder for the manufacturers to differentiate their products. • Some people are dissuaded from buying at all due to the potential for receiving fake product.8 It has been shown in other industries that well-publicized, repeated incidences of substandard or counterfeit products lead people to overestimate the prevalence of these products and the risks associated with them. They therefore choose not to buy something, which they may need, for fear of receiving a substandard product and causing

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themselves harm. This scenario, although almost impossible to quantify, could further magnify revenue erosion in markets where fake products are highly prevalent. Brand Erosion

Branded pharmaceutical products are designed to promote name recognition and customer loyalty. They are also usually able to command a price premium over similar unbranded or generic products. Assuming that the product’s biochemical function is the same (and for authorized generic products this must be proved with clinical data), the premium reflects the extra money that the customer is willing to pay for the intangible aspects of the product. In the drug industry, the main intangibles are brand awareness and trust. Consumers purchasing higher priced products presumably take a view that they would rather buy their medication from a drug company that they know, and whose products and branding they see and hear about daily in the media, than from a corporation they have never heard of. This does not just apply to drug manufacturers: own-label drug products sold by chain drug stores and supermarkets also have brand recognition. Brand building takes a heavy investment of time and money but with luck, good products, and good marketing, pharmaceutical brands can come to dominate their sector and generate billions of dollars of revenue for their parent corporation. Customer perception of the brand changes over time and can go down as well as up. Negative events can cause damage to the brand’s image and value: so-called “brand erosion.” The phenomenon of brand erosion can be subtle and gradual or it can be catastrophic and sudden (Figure 4.1). Repeated news stories about fake products, which also mention the genuine brand and the corporate rights holder will gradually cause a negative association in the minds of consumers—which may harm future sales of the affected genuine product. If alternative drugs exist, patients may request those different brands from their physician. Recovery of such lost market share requires additional marketing expenditure, which erodes profitability. Worse still, brand erosion can decrease public trust in the parent corporation itself and can therefore damage brands unaffected by the original counterfeiting incidents. In some cases, the impact of an adulterated medicine incident is instant and the brand damage is major. Although caused by criminal adulteration rather than counterfeiting, the Tylenol® episode of 1982, which cost the lives of seven people, is an excellent example of sudden brand erosion in the drug industry. The event highlights the potential for immediate financial damage due to safety issues in pharmaceutical products. In the week following the incident, the Johnson & Johnson stock price was

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Star m a C or p

Figure 4.1. The potential impact of fake drugs on corporate reputation.

highly volatile and at one point had decreased by 18% from its previous high. The market share of Tylenol® collapsed from 37% to 7%. This was despite a highly praised and prompt reaction from Johnson & Johnson itself, which recalled an estimated 31 million bottles with a retail value of over $100,000,000. After packaging redesigns and heavy price promotion, Tylenol® eventually recovered its market leading position.9 It is entirely probable that major counterfeiting tragedies will have the same damaging effect on drug companies.10 Corporate fall-out will be

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severe. In the aftermath of a major incident, executives may be forced to find cost-cutting measures such as headcount reductions and cuts in R&D spending at the same time as funding increased marketing to regain customer trust. On balance, the risk of doing too little to protect consumers from counterfeit products is much greater than the risk of premature action on product security. Litigation

Intuitively, the perpetration of a criminal act by one person or organization should not lead to legal retribution against another innocent party and, in general, brand owners have not been penalized for the damage caused by counterfeit versions of their products. If someone dies after taking a fake medicine, the liability rests solely with the criminal manufacturer. The legitimate rights holders have hitherto taken the view that they need not take general steps to reduce their own liability. Corporate investment decisions in anti-counterfeiting have therefore been on the basis of protection of patient safety, valuable revenues, and corporate brand assets rather than reduction of corporate liability. This legal situation seems likely to evolve toward a more allencompassing legal view of the role of the original brand in influencing consumer buying decisions. Courts may take the view that the rights holder must be able to prove unambiguously that a given product is genuine or fake, and must take steps to inform their customers of the differences between the two and to protect them from harm.11 Only if these steps and precautions have been taken will the rights holder be deemed to have discharged their obligations fully. If this legal evolution continues, it will change the perception of anticounterfeiting from a manufacturing cost to a necessary insurance investment. Corporate liability insurers may start to insist on a greater degree of product protection before they will underwrite the risks. If this change of emphasis becomes widespread, it may lead to innovation and new business models in the anti-counterfeiting industry. Partnerships between technology providers and insurers may provide a useful mechanism to offer economies of scale and comprehensive reach to their drug company customers. Loss of Public Trust

Branded prescription medicines manufactured by multinational drug companies have to pass tough tests. Regulatory regimes are in place in most countries to ensure that only products with clear evidence of safety and

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efficacy and quality are approved for marketing. In the eyes of the public, doctors and pharmacists have traditionally been the custodians of medical knowledge and they are trusted to prescribe the best product for the patient’s needs. With the advent of the Internet, many patients now have access to more medical information than ever before and can often participate in the choices that are made about their treatment. But the whole system relies on the trust of the consumer, who can only check medical information online, not who made the drugs they are about to consume. The patient has no realistic way to check the authenticity of their medicine. The relatively high price of prescription products is tolerated by the consumer and by society because there is still this framework of trust. If the perception of quality and safety of medicines is eroded, then the public trust of the entire medical profession is put at risk and the pharmaceutical industry will feel the backlash.

RISKS AND COSTS FOR GOVERNMENTS

Counterfeit drugs pose an increasing threat to society as well as to individuals. Many of these threats are obvious but some are more subtle and reach deep into the social fabric of a nation. Public servants and elected officials need to be mindful of the impact of fake medicines, both for their potential direct harm to the public and for their effects on healthcare, policing, and social welfare budgets. A spate of incidents of drug counterfeiting can also lead to damage to the international image of a country, leading to a general impact on trade. Public Concern

The impact of a safety incident linked to counterfeit drugs can be significant. The public’s trust in the medical system is shaken and in severe cases, the public may blame politicians and regulators for perceived lack of oversight. The early stages of a counterfeiting incident are often uncertain and chaotic and clear, timely communication is important. Unfortunately, all the facts may not yet be available and there may be little that the public can do to protect themselves. A typical press release on the subject of counterfeit drugs looks like this: Regulator Warns Consumers about Counterfeit XXXXX The Drug Regulator is today warning consumers about a counterfeit and potentially harmful version of XXXXX capsules.

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Preliminary laboratory tests conducted by the manufacturer revealed that the counterfeit version did not contain the active ingredient. Instead, the counterfeit product contained YYYYY. The manufacturer has determined that the counterfeit product has been sold over the internet. However, it is unknown at this time whether the counterfeit product has been sold through other channels, such as retail stores. The counterfeit product looks similar to the authentic product, with a few notable differences. The counterfeit has: • Outer cardboard packaging missing a “Lot” code; • Expiration date that includes the month, day, and year; authentic expiration date includes only the month and year (e.g.:–/XX); • Packaging in a plastic bottle that has a slightly taller and wider cap with coarser ribbing than the genuine product; • Plain foil inner safety seal under the plastic cap without any printed words; the authentic product seal is printed with “SEALED for YOUR PROTECTION”; • Contains larger capsules with a white powder, instead of small white pellets.

Note that in this typical example, edited from a real case, many of the differences described are relatively minor and may not be readily spotted by the consumer. The only differentiating factor noted about the external packaging is the missing lot code and inconsistently formatted date stamp. This is quite typical of counterfeit incidents. Consumer confusion due to repeated outbreaks of counterfeiting in health systems which have hitherto been considered secure will lead to fear and could provoke a backlash against public authorities. Increased Social and Healthcare Costs

The impact of counterfeit medicines and medical products on societies and governments is multifaceted. There are direct costs due to illness, injury, or death caused by known cases of fake or adulterated products. As noted above, these are the most commonly highlighted effects, as they are relatively easy to detect. However, the full impact on national productivity and on the health of the nation may be harder to quantify but even more profound. The European Union (EU) has estimated the likely annual cost impact, due to the direct and indirect effects of counterfeit drugs, to be many billions of Euros.12 The overall effect of fake drugs is therefore to increase the price of healthcare. Patients may take longer to be cured, spend longer in hospital, and require more expensive medical treatment to correct the effect (or lack of effect) of the counterfeit medicine. The

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emotional and financial cost of such extra healthcare is borne by the patient, their family, and friends. Indirectly, we all pay the cost financially, whether through increased insurance premiums or increased taxes. In some countries with social healthcare systems, the repeated circulation of the same drugs occurs in so-called “carousel frauds.” These frauds work because payment becomes disconnected from the product. The patient presents a real or fake prescription and receives medication at little or no net cost to themselves: the drugs are either provided free or the cost is subsequently reimbursed by the state. The patient then sells this medication, via criminal intermediaries or in some cases, directly back to the pharmacists. The drug thus re-enters the supply chain, where it is reused. In a simpler scheme, corrupt pharmacists may simply submit false paperwork or invent fictitious patients (Figure 4.2). Although not usually examples of counterfeiting (except perhaps of prescription paperwork), these crimes lead to a massive burden on the state healthcare system. One of the prime motivations for the introduction of a government drug tracking system is often to reduce this cost. Organized crime is a growing threat in many areas of life and almost all governments are now dealing with an increase in its reach, scope, and complexity. Counterfeit drugs are very profitable and therefore are frequently linked with other areas of international crime. For a government to fight prostitution, people trafficking, narcotics, and illegal gambling without addressing counterfeit drugs is now a flawed strategy. Rising Healthcare Costs

Re-selling of state-financed medicines

Prescription fraud

Figure 4.2. The Rising Spiral of Healthcare Costs. The fraudulent acquisition and resale of prescription medicines in a subsidized healthcare system fuels a rising spiral of healthcare costs and increases the financial burden for all stakeholders.

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Tension between Affordability and Quality

The high price of prescription medicine means that modern drugs are out of the financial reach of the poor in developing countries. Unless they have access to donated drugs, the poor have no choice but to purchase cheaper lookalike brands, either manufactured locally or imported from countries with few controls on intellectual property. In my experience and that of other investigators, drugstores in developing countries sometimes have two separate stocks: Westerners and rich locals are offered expensive “European” or “American” medicines and there are cheaper drugs behind the counter for those who cannot afford the genuine brands. Incidentally, both types may be counterfeits and in many places, a recognized brand name is not a guarantee of authenticity. This trade-off of quality versus cost may be done knowingly or unknowingly by the purchaser, but it is always based on necessity and not on choice. In general, people buy the best drugs they can afford. The purchase of cheap medicines by someone in the developing world, who knows the product may be counterfeit, involves a totally different buying decision to that of a rich tourist buying a counterfeit handbag or watch in London or New York. Increased Regulatory Costs

In order to address the growing safety threat from counterfeit and substandard food and drugs coming into the United States from worldwide markets, the US FDA (Food and Drug Administration) now has offices in China (Beijing, Shanghai, and Guangzhou), India (New Delhi and Mumbai), Costa Rica (San Jose), Mexico (Mexico City), Chile (Santiago), and Jordan (Amman).13 This places a direct financial burden on the US government and the taxpayer. Other governments such as Brazil and Nigeria are also starting to adopt the approach of validating suppliers at source rather than during or after import. Many government regulatory agencies are now exchanging liaison staff to ensure that they work together more effectively to combat substandard and counterfeit drugs. By imposing clear standards for authentication and tracking of APIs, excipients and finished products, government regulators can make it easier to control and identify imported products. Vigilance abroad is necessary, but needs to be combined with tighter regulations at home. Bringing the necessary legal and regulatory resources to bear in order to control counterfeits will become an increasing and recurring cost for all governments if the problem of counterfeit drugs is allowed to escalate further.

Chapter

5

Anti-Counterfeiting Definitions The growth of pharmaceutical counterfeiting has been met with a variety of corporate responses. Some have done little, perhaps hoping that the issue would not land on their doorstep or relying on the legal framework not to penalize them for the crimes of others hiding under their brand name. Some have been (either deliberately or not) reactive in their approach. They have dealt with incidents as they have occurred, but have done little forward planning. This may be to minimize adverse publicity, to reduce the costs of anti-counterfeiting measures, or simply because the issue has not received senior management attention as a priority issue. This “observe-and-react” approach often appears to be the appropriate tactic in an unpredictable situation, but once the threat is established in its intensity and predictable in its likelihood of occurrence (and I would argue that counterfeit drugs fulfil both criteria), something more proactive is needed. Best practice, and the most successful and cost-effective approach, has been to examine the full spectrum of threats and vulnerabilities across all products and all commercial territories and then to design integrated strategies to address them. The rest of this book will address specific anti-counterfeiting tactics that can be used individually or as part of a more effective and financially efficient strategic approach. The previous chapters have set the scene and outlined the impact of counterfeiting in the medical industry. Having described some of the Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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effects of counterfeit drugs and the rationale for aggressive action against them, what can be done specifically to control them? I use the word “control” rather than “eliminate” because the total elimination of fake drugs is like the total elimination of burglary. It is a useful aim for the society but unrealistic to expect it to happen. With drug security, as with home security, it is possible to reduce the risks by increasing deterrents, but it may be financially impractical to stop the tiny minority of determined or desperate criminals. That does not mean that locking the windows is futile. It is easy to be too technology-led when dealing with counterfeit drugs. The self-penned description of some security vendors as “solution providers” probably does not help. Today, there is no single technology which is a “solution” in the sense that it will completely eradicate pharmaceutical counterfeiting (and I know of one head of product security who refuses to take calls from anyone styling themselves a solution provider). Nevertheless, it is natural that vendors with products to sell (mea culpa here) tend to reinforce the idea that every vulnerability requires technology to fix it: either a technical addition to the product or its packaging or some form of high-tech device to measure innate properties. There is great merit in technology and it has a valuable place in the anti-counterfeiting arsenal, but it can never be the complete answer on its own. The context of how and why counterfeiting occurs is very important. Situational crime prevention principles1 suggest that, as well as evaluating technology, we also need to take a much deeper collective look at how we deter pharmaceutical crime by analyzing all elements of the potential “crime scene” in closer detail and taking all appropriate steps to reduce the criminal opportunity. Some of these changes may be simple, quick, and cost-neutral but some will require sustained investment over some years. This chapter will discuss these complementary elements of anticounterfeiting strategy from both the technical and process viewpoints.

TERMINOLOGY AND GENERAL PRINCIPLES

Before we get into detail, we need to look at some basic principles and terminology. Although few dispute the potential harm caused by substandard medicines, whether counterfeit or genuine but poorly made, there is a long-running controversy involving the definitions. Substandard drugs are a relatively straightforward concept—they are physically, chemically, or biologically unsuitable for the purpose for which they are sold. The definition of counterfeit medicines, on the other hand, has become entangled in

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the unrelated areas of quality and intellectual property, creating confusion and controversy. It is possible to produce superb quality counterfeit drugs, which are as effective as the real product but which are entirely illegal due to infringement of the patents and trademarks of the original rights holder. It is also possible for production defects to cause well-known branded drugs from major manufacturers to fall dangerously below the acceptable quality standards. The desire and ability of developing nations to produce low-cost drugs for their own people and for export has led to conflict with multinational drug companies who see the activity as an infringement of their patents and the resulting products as counterfeits. The issue of intellectual property is considered contentious by many others, including some major non-governmental organizations and donors, who would rather the focus was on ensuring adequate drug quality regardless of source. Drug companies, among others, respond that loose intellectual property laws and lax enforcement are being used not only to provide low-cost, effective drugs to the poor but also as to cover for criminal counterfeiting activities. The international definition of counterfeit drugs is therefore controversial. According to the World Health Organization.2 A counterfeit medicine is one which is deliberately and fraudulently mislabeled with respect to identity and/or source. Counterfeiting can apply to both branded and generic products and counterfeit products may include products with the correct ingredients or with the wrong ingredients, without active ingredients, with insufficient active ingredients or with fake packaging.

By comparison, the US Federal Food Drug and Cosmetic Act3 defines “counterfeit drug” as: a drug which, or the container or labeling of which, without authorization, bears the trademark, trade name, or other identifying mark, imprint, or device, or any likeness thereof, of a drug manufacturer, processor, packer, or distributor other than the person or persons who in fact manufactured, processed, packed, or distributed such drug and which thereby falsely purports or is represented to be the product of, or to have been packed or distributed by, such other drug manufacturer, processor, packer, or distributor.

The arguments over the exact definition of counterfeits or the interpretation of intellectual property legislation, although important, do not need to concern us for the purposes of this book. The core issue is that patients are put at risk by substandard drugs which are not what they appear to be. There is no such thing as a good counterfeit.

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Beyond these definitions, there are many specific terms used to describe the various counterfeiting issues and countermeasures (see Glossary for details). In general, there are two broad categories of criminal activity which need to be addressed: counterfeiting and diversion. Although frequently linked, these are separate activities and are discussed in detail below. Counterfeiting

As discussed above, counterfeiting does not have a universally recognized definition, but deliberate deception is the common theme. Counterfeiting typically involves one or more manufacturing steps in producing, repackaging, or modifying a pharmaceutical product for the purposes of deceiving either the immediate buyer or the end-user. Those steps could be carried out by hand in a squalid backstreet den, or could be undertaken on an industrial scale in a pharmaceutical plant. Counterfeiting is, therefore, not a uniform activity. The output (“product”) is also very variable and can take many forms. Counterfeit Product in Counterfeit Packaging. This is the most intuitively obvious form of counterfeiting and the one that the general public most readily associates with fake drugs. In this scenario, both the packaging and its contents are entirely false and designed to deceive. Pharmaceutical packaging has traditionally been fairly simple in form and content, with most of the science being in the pill rather than the pack. In recent years, packaging has become more complex due to concerns over tampering, need for child-proofing, introduction of unit dose packs, and so on. However, the globalization of pharmaceutical manufacturing means that the ability to produce good quality packaging is now widespread. Coupled with the availability, low cost, and high quality of digital printing, this means that accurate reproduction of even quite complex packaging has now become common place. Almost anything which is produced by standard processes and is visible to the naked eye can be reproduced to a level of accuracy, which makes it difficult to differentiate fakes from the original even for brand owners. In several cases, counterfeits have been uncovered primarily because the fake products were packaged in better quality materials than the originals. The quality of counterfeit packaging also gives clues as to the intended commercial strategy of the criminals. Generally, “perfect” packaging indicates that the producer of the fake product is trying to sell it via the legitimate supply chain. If they are selling through markets or other informal channels, then packaging may often be cheap and shoddy.

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39

The increased globalization of drug production and the drive for cost reduction has spread advanced manufacturing technologies into countries with poor controls over intellectual property and weak regulatory environments. These countries are often the source of both low-cost legitimate production and counterfeit products, sometimes even from the same factories. The wide choice of illicit pharmaceutical producers, and their low prices, combined with global money transfer and international freight shipment means that it is now easier than ever to organize production and delivery of counterfeit medicines. Criminals can supply their markets without ever touching the product. If so much counterfeit product, with counterfeit packaging, is circulating, then why is it not intercepted by customs officials more frequently? Some of the answers lies in the gray areas caused by unclear definitions of counterfeits, which allow exporters to claim that goods detained in transit are destined for a third country—perhaps one where intellectual properties are also light or poorly enforced. One of the practical reasons why drugs are hard to stop in transit is that they are relatively lightweight, high-value products. Large amounts, albeit in small individual consignments, are shipped by air freight direct to the consumer. Alternatively, counterfeit drugs may be concealed, during transit, in other products such as toys. To reduce the risk of discovery still further for larger consignments, it is common for the pills, packaging, and leaflets to be sourced and transported separately and then assembled in backstreet workshops just prior to sale. Note that this type of counterfeit product in fake packaging can be of widely varying product quality, from formulations that are almost identical to the real brand down to medicines with little or no API or with missing excipients or additional contaminants. Repackaging of Genuine Product in Counterfeit Packaging. Compared to the scenario above, where all the components of the product are counterfeit, the use of fake packaging with genuine product may seem counterintuitive, but this practice can provide benefits for the criminal. The detection of counterfeits relies on diverse and incomplete surveillance mechanisms and thinly stretched law enforcement agencies. The use of fake packaging is an opportunity for the criminal to “dilute” a consignment of authentic medicines, which may have been obtained illegally or by theft. For example, blister-packed drugs are separated from their secondary box and the intact blisters are repacked into fake boxes. The real boxes are then repacked with fake blisters. This provides a doubling of unit volume, and all items have at least some genuine components.

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Upon inspection at customs, should the consignment happen to be checked, the presence of genuine features may cause enough confusion and uncertainty that the absence of other expected features (on the fake elements) may be overlooked or not noticed. A variation of this tactic is the packaging of drugs with a deliberately incorrect country of origin. In Nigeria, drugs found to have been manufactured in China carried “Made in India” labels, perhaps because the Indian drug industry is well-established in Africa and stating this apparent country of origin conveys an element of consumer recognition.4 In this case, the branding that was copied was not that of the drug producer (these were generic drugs) but the “brand” of the producing country. Repackaging also allows the replacement of use-by dates to enable expired, stolen, or withdrawn stock to be fraudulently resold. Once “reborn” in this way, it is difficult to identify these potentially degraded and dangerous medicines. It is very important to note that the act of repackaging itself is not necessarily a criminal activity and is in fact an everyday legitimate business practice in some markets, most notably the EU. See the section on “Diversion” below for an explanation. Refilling or Reusing Genuine Packaging with Counterfeit Ingredients. In the developed world at least, most discarded packaging has little value except perhaps as a bulk material for recycling (glass, metals, paper, etc.). However, the retrieval and reuse of individual units of medical packaging can be a very lucrative criminal activity. This form of illegal recycling affects most dosage forms, from pills to vaccines. Since security features on the original product (if present) are often found on the packaging rather than the medicine itself, reusing legitimate packs with fake contents has proved an effective way to conceal counterfeits. The apparently authentic packaging, even if slightly scuffed or damaged, often provides enough of a smoke screen to allow counterfeit products to evade detection by first-line checks. Discarded pill bottles are refilled with fake pills. Genuine secondary carton boxes receive fake blister packs. Vaccine vials are refilled with tap water. Used needles are wiped and repackaged. The used packaging may be obtained by “dumpster diving”—the practice where medical waste from clinics and hospitals is scavenged from the waste stream and reused. In Colombia, for example, it is estimated that 40% of counterfeits use recycled packaging.5 Alternatively, the packaging itself may never reach the patient. In some countries, it is common practice for the dispensing pharmacist to remove some or all of the packaging before giving the drugs to the patient. This may then be reused,

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41

with or without the knowledge of the pharmacist. Evidence from Brazil6 suggests that home delivery schemes for prescription medications present another opportunity for substitution of real for fake medicines. Even if the real product leaves the pharmacy, the contents of the pack may be switched for fake ones en route. Again, this may occur with or without the involvement of the pharmacist. Although the vast majority of doctors and pharmacists are honest, the reuse of packaging can happen both with and without the complicity of those in the authorized supply chain and countermeasures must reflect this fact. Relabeling of Expired or Withdrawn Stock. One of the key safety advances in food and drug safety in the last 100 years is the system of useby dates or expiry dates. This simple data point gives professionals and consumers critical information on the safety of the product. The use-by date for pharmaceuticals must be supported by scientific evidence of shelf life, usually gained through time-consuming and costly stability studies. An item, which is past its use-by date is of unknown safety profile. Even if the product remains safe, the use-by date gives the consumer and the dispenser due warning when the product has exceeded the limits of what can be safely be assumed about its behavior over time. Most countries therefore ban the sale of expired stock. For the unscrupulous criminal, expired medicines represent a golden opportunity. The product is original, in original packaging and from legitimate sources. The only problem is the four to eight digits, MM–YY to DD–MM–YYYY, that give away its age. By changing these numbers, the product can be instantly increased in value. The layperson may wonder why expired stock is available and why valuable medicine is not either used within its shelf life or disposed of promptly and thoroughly as soon as it expires. Even in well-managed dispensaries, infrequently used items may sit on the shelf until their use-by date and then need to be destroyed. The disposal process may be poorly controlled or contracted to specialists and a breach in security can allow expired product back onto the market. Theft from the waste stream is one source of expired medicines, but some cases may also involve insider complicity. In many countries, the management of drug inventory is haphazard and rudimentary, even in government facilities and hospitals. Often basic warehousing stock rotation principles such as first-in-first-out (FIFO) are not followed. Therefore, there may be a lot of potential wastage. If the expired products are highvalue items, such as cancer drugs, then this may represent a potential bureaucratic embarrassment and a large financial loss, providing ample incentive for a cover-up. Even for lower cost drugs, there is a temptation

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either to sell expired stock, to recoup some of the original purchase cost, or simply to relabel or change the use-by dates. Relabeling of Low-Dose Products to Indicate (More Expensive) Higher Doses. In order to tailor the dose of the drug to the needs of individual medical practitioners and patients, many pharmaceuticals are produced in several different strengths or dosages. Until quite recently, it was common for different dosage strengths of the same drug to be sold in almost identical packaging, with the only obvious packaging or labeling change being a substitution of “10 mg,” “20 mg,” or “80 mg” (for example) according to the different dosages. The other major difference, of course, was the selling price. Counterfeiters discovered that simply by changing or altering the label on a genuine low-dose product to that for its high-dose equivalent, they could produce fantastic profits with minimal effort.7 The product produced in this way is entirely genuine in its constituents and of high quality, with all the right seals and packaging features, but of much lower potency than that shown on the label. This devastatingly simple crime has had catastrophic results for patients. Thankfully, the drug industry is now more aware of the need for well-differentiated packaging between different dosage strengths. Dilution. The relabeling or “uplabeling” scenario discussed above is actually just a more sophisticated form of dilution, in that the actual dosage strength is lower than the labeled dosage, although in the case of uplabeling, the injected material itself is usually not tampered with. Dilution of medicines is a highly profitable criminal activity and the simplest and crudest way to achieve this end is to physically dilute the relatively expensive medicine product with a cheaper alternative. For liquid products, such as vaccines, this is commonly part of an unauthorized reuse scenario. The dilution may often be done with non-sterile water—hard to detect with the naked eye but with potentially devastating consequences for the victim. Solid dosage forms may be diluted at the point of manufacture with inert solids (at best) or toxic materials such as building waste. The advantage of dilution to the criminal is that the counterfeiter is paid for more medicine than he actually delivers. A diluted product is also more likely to pass the first-line field tests used to establish the presence of the active product in suspect samples (and counterfeiters are sophisticated enough to test this in advance). Quantitative analysis in the laboratory is the surest way to detect dilution, although some portable techniques exist. The addition of known concentrations of tracers during manufacturing can help to prove that dilution has occurred and to differentiate it from other possible causes of an apparent low level of API (such as degradation).

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Selling Products Not Authorized for Sale. As discussed in earlier chapters, the research and development process for pharmaceuticals is very long. However, a new drug is not first announced to the world on the day of its commercial launch. The drug industry is increasingly measured on its R&D productivity and therefore produces regular updates to investors and the financial press on potential new drugs as they pass through development and long before they reach the market. When picked up by the general media, the buzz around a potential new blockbuster can generate significant consumer interest and demand well before the product is ready. Criminals can take advantage of this demand and of the time needed to complete development and gain marketing approval for the genuine drug. The lack of such controls and delays for fake drugs means that counterfeiters need only copy the chemical formula, or even substitute another drug with a similar effect, and produce some plausible packaging. Sometimes, such fake products are offered for sale by counterfeiters before the original has even been granted marketing authorization. Alternatively, products authorized in one market may be illegally diverted to another market where they are not authorized. Often, they may be sold in forms, which are also not authorized (e.g., loose tablets sold over the Internet). Another common form of unauthorized selling is the sale of medical samples. In many countries, it is common practice for sales representatives from drug companies to provide free samples of new or established drugs to doctors, to encourage the future prescribing of their brands. These samples frequently find their way onto the black market, either in original packaging or repackaged, leading to loss of revenue for the supplying company. Using Counterfeit Documentation. Counterfeiting of drugs and packaging allows fake products to enter the supply chain, but in order to sell large quantities of product and to insert it into legitimate sales channels, additional tactics are often needed. Fake, stolen, or substandard products are therefore often accompanied by false documents such as import licenses, regulatory clearances, and quality documents. In the case of counterfeit API or excipients, the true chemical nature of the consignment may be concealed, and false certificates of analysis may be presented. False documents are also used to conceal the origin of products diverted from their original destinations. A common example is the theft and resale of donated pharmaceuticals using forged papers. Unfortunately, much of the supporting documentation used in the certification and transportation of pharmaceuticals is very easy to forge. In many developing countries, this

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step is not even necessary since the relevant permits or certificates can be obtained for a relatively small fee from corrupt officials. Knowingly or Unknowingly Using Substituted Raw Materials. Many of the ingredients used in the manufacture of medicines are highly specialized chemicals that require expensive synthesis or purification from natural materials. Even the basic ingredients used as excipients typically need to be of a higher purity grade for pharmaceutical use than for other commercial applications. This purity comes at a cost, and bulk pharmaceutical materials can be very valuable. There is, therefore, potential profit to be made by criminals who substitute lesser grade materials or similar substances. The adulteration or substitution of API or excipients is difficult to detect at the bulk stage without expensive specialist equipment, which is not commonly available to customs officials or law enforcement officers. If the consignment is accompanied by counterfeited versions of the correct supporting documents, then it may pass into the supply chain. However, once the bulk material is manufactured into finished products, this form of counterfeiting is the one which most frequently makes international news headlines, as it has the greatest potential to cause large-scale tragedies. A consignment of toxic raw materials may be dispersed into thousands of final doses of drug. The adulteration of bulk quantities of food or medicine with impure or toxic raw materials therefore affects many people simultaneously. Although often quickly spotted once, people start getting sick, the discovery of this crime may come too late to save some of the victims. Since the likelihood of adverse events raises the risk that perpetrators of this type of crime will be identified, it seems an unnecessarily reckless criminal tactic. However, the manufacturers of the finished product are not necessarily always complicit in the use of substitute APIs and excipients. The complexity of the international supply chain, and the fact that many bulk raw ingredients in pharmaceutical products may be sourced from non-pharmaceutical companies, adds to the difficulty of detecting and preventing these crimes. For example, sodium chloride and dextrose are used in many medical products but represent only a small fraction of global demand for these commodities. The difficulty and cost of controlling the supply of materials for the manufacture of pharmaceutical products has led to the establishment of an industry consortium, Rx-360, to address this issue.8 The aim of Rx-360 is to “create and monitor a global quality system that meets the expectations of industry and regulators that assures patient safety by enhancing product quality and authenticity throughout the supply chain.”

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Supply chain control is particularly important at the raw material stage, as it is more difficult to use many of the methods that can be employed downstream (adding tracers or using security features on packaging) to differentiate genuine from counterfeit product. The pattern of this type of crime is highly variable. The entire consignment of API or excipient may be counterfeit, or there may be mixing of legitimate and unauthorized sources. Counterfeit documentation and concealment of commercial identity using multiple shell companies are also common factors in cases of API and excipient fraud. “Trojan Horse” tactics may also be used to market bulk products without the correct regulatory paperwork, whereby an authorized supplier with the correct documentation may act as an agent for many unauthorized producers whose products then become mixed into the supply chain.9 The original producer is thus almost untraceable in the event of a quality concern. Diversion

Although the production and supply of pharmaceuticals is now an international business, it is not uncontrolled. The need to provide specific patient information leaflets in the appropriate language, for example, means that most pharmaceuticals are manufactured for a specific regional or country destination and the legitimate sales and distribution channels are set up on this basis. However, the price charged for the same drug may vary between countries quite markedly. A drug sold at a high price in the United States may be donated free to a developing country, to take an extreme example. There is therefore a criminal opportunity to divert the drug from the low-cost market into a high-cost market for profit. Diversion has been defined as “the movement of branded goods across international markets, contrary to the wishes and legal rights of the brand owner.”10 Note that in the case of diversion, the product is genuine but the eventual market destination is not the one intended by the manufacturer. Diversion is therefore often used as a synonym for parallel trade or re-importation but these are not strictly the same thing. Diversion is usually a direct and covert criminal act, and is generally contrary both to the manufacturer’s terms of sale and to the laws of one or both of the markets involved. As noted above, pharmaceuticals that are donated as part of aid packages or preferential pricing schemes for developing countries may be stolen and redirected to markets where they can be sold at a great profit. To maximize profits further, in some cases, the stolen product may be replaced with counterfeits in its original market. The replacement counterfeits are statistically unlikely to be discovered in a resource-limited developing country. Assuming that the packaging is correct for its new

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destination (and it can be easily replaced if not), the stolen genuine product is also unlikely to be impeded on its redirected journey since it will test genuine if the consignment is impounded. Another activity that can drive diversion is widespread off-label use. This occurs where a drug has (or is thought to have) efficacy in an indication other than that for which it is licensed. There may be a market demand for the drug, which cannot be satisfied by the normal channels used for prescription medication. This is typically true of certain product types such as steroids. The profitable gray market for these product types can lead to diversion of product (intended to treat the indications for which it is licensed) from low-price countries to serve the off-label market in affluent countries. Parallel Trade and Re-Importation

As noted above, the manufacturers of pharmaceuticals tend to produce specifically packaged versions of their products for each market or group of markets in which they have a commercial operation. However, when the product is then sold on through distributors, the manufacturer loses control of its eventual destination. Parallel trade or re-importation occurs when product manufactured for and sold to one market is then resold in another market. This is usually for reasons of profit, since—due to exchange rate fluctuations, government pricing caps and commercial requirements—prices are rarely exactly the same between any two countries. It is important to note that parallel trade may not be in violation of the laws in the manufacturing country, the intended destination country, or the final destination country. This is the case in respect of parallel imports in the EU, where the Treaty of Rome11 ensures that internal trade between EU members can proceed unhindered across national borders. This free market allows the supply of drugs to equilibrate with demand but the pharmaceutical pricing systems of EU member countries are not harmonized across the EU and large price differentials exist between different countries for the same product. This is due to state-controlled pricing in many countries, especially those with social healthcare systems. Therefore, there is an active parallel market, which takes advantage of the profit opportunity in the “arbitrage” between these different prices. Product that is manufactured and packaged (with language-specific labeling and leaflet) for a low-cost market and sold to a distributor there may be legally reexported to another country where the price is higher, provided that the patient information and labeling are replaced with new ones in the appropriate language for the new destination.

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The legality and desirability of drug importation (or re-importation) into the United States has been a matter of ongoing intense debate in Congress and elsewhere. In principle, the opening of US markets to international markets to global competition should be beneficial for the American consumer. In practice, the attraction of lower cost drugs may be offset by the potential danger of allowing harder-to-trace, potentially substandard or counterfeit drugs to enter the US pharmaceutical supply chain. At the moment, there are relatively few ways for corporations or governments to control parallel trade, diversion, or re-importation, which can make it hard to differentiate legal and illegal activities. By its nature, parallel trade is commercially complex. There can often be multiple transactions for a single pack before it reaches the final consumer. Although there are a great number of legitimate businesses engaging in the perfectly legal parallel trade of pharmaceuticals, repackaging and the complex supply chains which result from repeated reselling, also provide an ideal environment for criminals to introduce counterfeits. Therefore, the problems of counterfeiting and diversion are often closely linked. Diversion and parallel trade can both lead to difficult-to-control secondary and gray markets, re-importation of donated or export stock, customs frauds, and so on. The existence of legitimate parallel trade channels gives rise to several important policy questions relating to product security. The manufacturer is responsible for packaging the product in a manner fit for purpose, and may also add various security features to deter tampering and counterfeiting or to allow the product to be traced and recalled if necessary. How should the security of the product be maintained if it is reboxed or relabeled? Does the repackager have a responsibility to reproduce security features on the original manufacturer’s box? There are substantial gray areas in responsibility, and the merits and disadvantages of repackaging (where the original container is discarded), overpackaging (where the entire package is placed inside a new box), use of tamper-evident seals, etc., have been extensively debated. A further consequence of this uncertainty is that it provides a disincentive for investment in security features by the manufacturers. Why invest five or ten cents per pack on security features when the original pack can legally be discarded by a parallel trader and the product sold on to a third party in a plain white box? How these issues are addressed by politicians and lawmakers will have a substantial bearing on the effectiveness of anti-counterfeiting activities in Europe. The same issues may also arise if the United States sanctions widespread importation/re-importation.

Chapter

6

Protecting and Educating Consumers As a general principle, the aim of all pharmaceutical anti-counterfeiting strategies should be to protect the consumer. Manufacturing corporations may have other considerations, such as revenue protection and liability reduction. These can be integrated into the overall strategy, but patient safety must be the primary goal. We cannot assume that the consumer is able or willing to take proactive steps to verify the authenticity of their medication. In many cases, people either are simply unaware of the risks of counterfeit drugs or choose to ignore them. Because the consumption of counterfeit medicines is clearly a dangerous activity, it is worth examining why people choose fake drugs or why they choose to ignore the potential risks. CONSUMER BEHAVIOR All substances are poisonous, there is none that is not a poison; the right dose differentiates a poison from a remedy—Paracelsus (physician, 1493–1541).

The fact that most drugs carry risks as well as benefits is generally well accepted by the public. Even in developing countries, with a shorter cultural history of pharmaceutical medicine, everyone is aware of the Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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potentially dangerous nature of medicines. Globally, deliberate overdosing of everyday analgesic drugs such as paracetamol/acetaminophen is a common method of suicide, especially among women.1 To protect consumers, many countries invest heavily in safeguards to ensure that pharmaceutical drugs are properly tested before being authorized for sale and that any remaining risks are minimized through quality control (QC) and restricted supply where necessary. With the exception of suicides and deliberate self-harm, we can safely assume that most people do not knowingly risk their health by consuming dangerous medicines. For counterfeit drugs to exist, other factors must over-ride this caution. The most obvious is the concealment of the true nature of the product—many people who purchase counterfeit medicines believe they are receiving genuine drugs. Another key factor is price—if an affordable but suspect medicine is available and the patient cannot afford the more expensive version, he or she may have no choice but to take the risk. Finally, some people knowingly purchase a counterfeit product because they wrongly and naively believe that it will work in the same way as the original. They assume that a counterfeit drug will be functional, in the same way that a fake “Rolex” watch tells the time or a “Louis Vuitton” bag holds things.2 The counterfeiter feeds off such naivety with a cynical Mundus vult decipi, ergo decipiatur (“the world wants to be deceived, so let it be deceived”).3 To counter this behavior, consumer education messages from governments and brand owners must be consistent: there is no such thing as a good counterfeit. ENGAGEMENT WITH THE CONSUMER

Controlling fake drugs will depend ultimately on the involvement and engagement of the general public. The ability to incorporate the average citizen into an anti-counterfeiting strategy is often hampered by ignorance and fear. The ignorance of the general consumer about the existence and danger of fake drugs is touched upon elsewhere, but the fear comes mainly from the supply side. Whether expressed or implied, fear is one of the most common emotions driving governments and drug companies on the issues of product protection and pharmaceutical crime. There is the understandable and commendable fear for the safety of the consumer. There is also the (often unspoken) fear for the integrity of the “brand”—whether it is corporate or government reputation that is at stake. This latter anxiety is usually on two levels: first, there is the understandable issue of brand damage if something goes tragically wrong and second, there is the worry that even publicizing the existence of a counterfeiting problem will cause adverse public reaction.

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This second fear may link back to the paternalistic, doctor-knows-best attitude that permeated the medical profession in the last century. The medical profession carefully guarded its position of authority in the days when specialist knowledge of all kinds was very hard for the man-in-thestreet to get hold of. With the advent of the Internet, that has changed. The public can find huge amounts of information on almost any topic in seconds. Patients now expect the medical profession to be more engaged with their individual needs and are more prepared to challenge clinical judgments and to seek second opinions. In this new environment, there is an opportunity for the pharmaceutical industry to enhance its reputation, increase customer engagement, and defend its revenues by using product safety as a marketing tool. Of course, this should be on an industry-wide basis: individual companies should not denounce each other’s vulnerabilities in the “attack advertisement” style seen in electoral campaigns. By working together to promote the safety systems that protect the collective integrity of their products, the industry can continue to differentiate itself from the criminal purveyors of substandard and counterfeit drugs.

ENGAGING THROUGH SOCIAL MEDIA

There are many more ways now to interact with customers than there were even a few years ago. With the increasing use of mobile phone and Internet communication, people are becoming accustomed to receiving information on a real-time basis in all areas of their lives. This is providing an opportunity to disseminate messages quickly and help shape customer behavior. Social media services, which are now an integral part of the fabric of daily life for large numbers of people, provide excellent channels for the engagement of customers in a conversation about the dangers of counterfeit drugs and the benefits of safe, tested medicines. The “viral” nature of these media and the ease with which material can be shared also allow information to propagate at unprecedented speeds. This can be a force with both positive and negative effects. Drug companies have historically been reticent about disclosing information on incidents of counterfeiting and drug quality and have preferred to release this information in official channels. In the modern media environment, this can be too slow to prevent the appearance of damaging rumors and, potentially, dangerous and deliberate misinformation. It is therefore advisable to engage fully with social media and to harness the potential of the medium to increase public trust in the integrity of branded drug products. In the fight against fake products, by reassuring customers of the quality

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of the great majority of medicines, drug companies can generate both safety and marketing benefits. Social media activities are different from the usual formal, structured medical communication channels. They are essentially a continuous conversation with the consumer rather than a broadcast to them. This relative informality has obvious consequences for the way in which information is received, used, and responded to. The two-way dialogue that ensues over counterfeit drugs could have paradoxical effects: as the public becomes more comfortable with this information exchange, it is likely that the incidence of fake drugs, or at least the number of reports of suspected counterfeits, will increase. This is a common phenomenon in many fields: the harder you look and the more people you ask, the more there is to see. There may be a higher incidence of false alarms, which will need to be publicly responded to in order to avoid rumor spreading. However, the improved information flow is healthy in the long term, as it is much easier to deal with a problem which is out in the open than it is to eliminate something which is hidden. The study of aggregated information from social media channels, even if the individual components are not fully robust in the sense that medical scientists are used to, could give valuable guidance on buying trends, consumer thought processes, and levels of awareness. Social media marketing is a rapidly emerging subject, and it is clear that it requires a different approach. In the past, when communication was effectively a monologue, information was often out of date by the time it was transmitted. We now have the tools to engage in a twoway conversation with customers, and this can be used to enhance the responsiveness of anti-counterfeiting activities. Some of the approaches below may also require regulatory agencies to show flexibility, particularly in countries where direct-to-consumer (DTC) advertising is not permitted. Like most safety mechanisms, it is important to put them in place and check that they work before they are actually needed. This requires an active engagement of the consumer and social media channels and should be initiated ahead of any crisis.

SOCIAL NETWORKING AND BLOGGING AS ANTI-COUNTERFEITING TOOLS

The representation of the pharmaceutical industry on the social networking scene is very patchy. However, this situation needs to catch up with the outside world quickly. To take the biggest site (as of late 2010) as an example, Facebook4 now has a user base of over 500 million, which

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comfortably exceeds the US population in size,5 and means in theory that 1 in 12 people on the planet has a Facebook account. The penetration in developed countries is probably much higher than that and may be 50% or more in the United States. Together with many similar sites, Facebook is increasingly being used as a source of brand information as well as for social interaction. Referrals of products and services by Facebook friends are becoming one of the most powerful influencing factors for consumers. Maintaining a corporate presence on these sites is relatively inexpensive and can provide excellent customer feedback. In the early stages of an information campaign regarding a counterfeiting incident, for example, attention to such feedback could allow the corporate messages to be fine-tuned for maximum effect. Regulatory authorities such as FDA6 and EMA (European Medicines Agency)7 have also used tools such as Twitter and YouTube8 to disseminate information and highlight product recalls. In the rush to social media, the more effective use of existing websites as a communication tactic should not be ignored. Drug corporation websites can sometimes be formal, product-driven environments that do not engage today’s informed consumer as well as they should. Information is often expressed in legalistic formats and terminology. One of the major advantages of social media is that they are intrinsically “opt-in” approaches to communication. Information is sought out by consumers because it is perceived as having value. It is much easier to spread a message to an established network of customers who have chosen to listen than to try to find those people in a large background of the apathetic or hostile. By making the consumer a part of the ongoing, two-way conversation about the brand and its benefits, both through social media channels and the corporate website and associated blogs, it is easier to broach the subject of counterfeits and potential risks when necessary. The key to a successful corporate presence on social media is to keep the content succinct, interesting, and non-commercial. Links to videos showing a difference between genuine and fake products, or podcasts about suspected incidents, can provide rapid feedback and reassurance to the customer. This not only helps the drug company to deal with an incident, but also reinforces an image of competence in the mind of the public. In today’s world, information sharing is immediate and in many ways uncontrollable. Knowledge of an adverse quality issue or counterfeiting incident is likely to spread very quickly, and therefore the corporate response must be equally rapid. Companies who perceive this as an opportunity, not a threat, are likely to gain public trust in the long term.

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CONSUMER-FOCUSED AUTHENTICATION TECHNOLOGY

If the consumer now has access to more information sources than ever before, surely it makes sense to put them at the center of efforts to control counterfeit medicines by designing consumer-friendly authentication technology? Technology certainly has a key role in protecting the consumer. Indeed, many people—especially vendors of overt authentication technologies—have argued that the consumer is best placed to authenticate medicines. Consumer verification is often cited as the future of anti-counterfeiting. However, in my view, it is not sufficient simply to give consumers the means to protect themselves and then leave the task of identifying fake drugs entirely to them. It is true that rapid increases in mobile phone usage in developing countries are helping to bring technological approaches within reach of the poor for the first time. Indeed, these technologies have a valuable part to play, but we should not expect the patient (whether in Switzerland or Swaziland) to be the sentinel for product quality and authenticity. The advantage of educating the consumer about the risks of counterfeit drugs is that they are potentially the best placed to spot them because they are everywhere. They are the most numerous element of the collective vigilance process, and they are the ones with the most to lose, but involving the customer effectively is not straightforward. Regulatory issues and change controls make the introduction, alteration, or removal of visible packaging features more difficult than for covert features. Customers are also generally suspicious of change, and the potential for confusion should not be ignored. Because the consumer only has the benefit of his own physical senses, any security feature targeted at the consumer will almost always be visible. The combination of these factors has the paradoxical effect that the anti-counterfeiting features most obvious to the public (and therefore most likely to be copied by the criminal) are the ones least likely to be changed on a regular basis. Mimicking of long-standing overt features may eventually make them worthless, even if they are never fully duplicated in all details. The way to combat this paradox is by careful consumer education, but this is an area often neglected during the design and implementation of visible security features. This may be because the pharmaceutical industry does not want to give the impression that fake drugs are a major issue. They do not want to risk a reduction of public trust by being open about the risks and the countermeasures they have implemented. This climate of “less said the better” is steadily changing. For example, a controversial and hard-hitting cinema and TV campaign in the United Kingdom, backed up by print and billboard advertisements and a website, was aimed directly at

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consumers who might be tempted to buy prescription medicines through the internet or via informal channels.9 Graphic imagery highlighted the dangers from fake medicines containing toxic ingredients. The consumer should continue to be discouraged from using unofficial sources to obtain prescription drugs but should not be expected to validate drugs coming through the legitimate supply chain. As well as highlighting the negative aspects and alerting the public to the possible danger of buying counterfeit medicines, it is also important to take the initiative and empower consumers with the knowledge to differentiate genuine products from fakes. Rules restricting direct-topatient advertising can often make it difficult to communicate with users about a specific drug, but there are usually indirect methods that can be employed. This might involve training pharmacists or nurses to check pack appearance and features against reference leaflets or posters before they dispense. CULTURAL SENSITIVITY

What works in Boston may not work in Burkina Faso, and vice versa. In order to maximize the effectiveness of consumer education about the dangers of fake drugs, material should always be presented in culturally meaningful formats. Even seemingly similar cultures can have markedly different outlooks on some issues. There is a (possibly apocryphal) story that sales of a certain product in a Latin American country really took off when the emphasis was switched from curing dysfunction (the marketing approach elsewhere) to enhancing normal function. With the first approach, few men admitted to having a problem. Pharmaceutical supply chains may now be global but culture, thankfully, is not. Authentication technologies need to be tuned to the cultural expectations and technological sophistication of the intended users. All communication material regarding counterfeits should also be screened for its suitability to the intended audience, ideally by local staff or agents, before submission to the regulator or use in the field. Factors which may be important include • Language: The official language of a country may not be the lan-

guage commonly used in the area targeted with information. There may be a need for multiple language versions even within one country. Materials should be translated by a native speaker of the target language where possible, and all translated material should also be “back-translated” into the original language by a second person to check for errors in meaning.

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• Religion: The material used should be sensitive to the beliefs and

taboos of the local population. Religious leaders or tribal elders may also be useful conduits for the dissemination of information. • Ethnicity: In multi-ethnic areas, care should be taken that any material used does not appear to favor or criticize any one ethnic group. • Age and gender: Depending on the product concerned, information may need to be targeted to a specific gender. This may require specific approaches such as group meetings. In all societies, the communication channels that reach young men effectively tend to be different from those preferred by senior women, for example. • Literacy: Even simple material may not be understood in the same way by everyone. In societies where literacy levels are low, the use of posters and leaflets is unlikely to succeed very well—better to use verbal methods such as village meetings or radio stations to get the message across. However, techno-literacy can exceed reading and writing capabilities: mobile phone technology is now pervasive even in poor rural areas. The use of text messaging to warn against counterfeits may be more effective in African countries than in Europe or the United States, where unsolicited messages may be considered as intrusive. Patients have the right to assume that the medicines they are prescribed are safe, and many of them may not be capable of undertaking even simple tests for authenticity. The medical industry is life-enhancing, but the rise of counterfeits is potentially life-threatening, and pharmaceutical anti-counterfeiting strategies must put in place measures to mitigate risks in the same way that other industries manage their risks to users. Airlines do not ask passengers to perform pre-flight engineering checks before boarding the aircraft. The patient should be only the last stage of an integrated vigilance process. All other persons who come into contact with the product, on its journey from raw material to patient, must be partners in the fight against fake medicines.

Chapter

7

Business Risks and Strategy Although the primary responsibility in fighting counterfeits is to minimize the risk to patients, there are clearly also risks to pharmaceutical businesses themselves (society and government issues are addressed separately below). In an ideal world, all of these risks would be reduced to zero, but drug companies have a responsibility to their shareholders and costs must be contained. The need for action against counterfeits must therefore be balanced with the finite resources available. It is simply infeasible for a pharmaceutical company to completely eliminate all potential counterfeiting risks for all their products in all geographical locations. Even if this were technically possible, it would generate major costs, which would have to be passed on as price rises. Ironically, the implementation of such a strategy would therefore have the effect of widening the price differential between real and counterfeit products and could further encourage the spread of fake products among those who cannot afford the genuine items. Therefore, the real challenge is not to allocate ever-increasing budgets to anti-counterfeiting but to marshal appropriate resources in the right places at the right time on the right products, so that risks to consumers are minimized to an acceptable level.

Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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There are many decision tools and business analysis models available, and many of them can be applied to product protection strategy. It does not matter much as to which process is used, so long as it is rigorous, objective, and quantitative. My advice is to use the one that the organization is most familiar with unless there are good reasons not to. To help galvanize the corporate thought processes, I propose the following loose framework of “DRASTIC” actions. D—Definition of what the corporation wants to achieve in product protection (and how it links with corporate ethos and business strategy) and decision to act and commit the necessary resources and budget. This needs to be driven at board level—it is too important to delegate. R—Reality check to thoroughly investigate the current counterfeiting and diversion problem. Make test purchases, use investigators, check all sales channels. Look hard, turn over all the stones, and assume nothing. A—Analysis of the current global situation based on the reality check. Assess the strengths, weaknesses, opportunities, and threats honestly and fully. Remember to be balanced—in many areas, there may be little cause for concern—but avoid complacency. Do not forget legal and compliance issues that may be on the horizon (pedigree, etc.) as well as criminal threats. S—Strategy. Using a risk-adjusted approach based on the analysis above, put together a global product protection plan involving all products, subsidiaries, and operating companies. The strategy should not be too technocentric. Reducing the number of packaging suppliers and distributors may be just as valid as introducing a security feature. T—Tactics. Having defined what needs to be protected and where, decide how . With appropriate confidentiality precautions, involve security vendors in a detailed Request-For-Information/Request-ForProposal process. Enter into a meaningful partnership with selected suppliers. Rank technologies in appropriateness versus the risk levels previously identified as part of the strategy-framing step above. Design roll-out program, ensuring that all technologies are replaceable if subsequently compromised. I—Implementation of the product security program. Roll out and monitor new security features or process changes. Do not assume internal compliance—especially, if there are implications for COGS, changes to manufacturing lines, and so on. Check, elicit feedback,

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and correct as necessary. Allow sufficient contingency time—there will be bumps in the road. C—Communication with law enforcement, customs, and the general public where appropriate. If there is a new overt feature, make sure that people know exactly what to look for. Make sure officials are trained where needed. Do not forget to reinforce the importance of product security with internal staff and trading partners. The DRASTIC process is not a one-time fix for counterfeiting and diversion. The process of analysis and response should cycle around repeatedly as threats and market conditions change. Of course, like all models, the process above is simplistic and represents only a subset of the work that needs to be carried out within a pharmaceutical corporate product protection initiative. Nevertheless, DRASTIC planning may reduce the need for emergency action. The process breaks down into a number of activities, detailed below and in the subsequent chapters.

ESTABLISHING A BASELINE AND PRIORITIZING AT-RISK PRODUCTS

In order to know how to protect products efficiently, the brand owner must first establish the nature and extent of the threats that it faces. A thinly spread, uniformly distributed series of countermeasures, deployed in ignorance of the external situation, will not work. The most efficient approach to a corporate anti-counterfeiting strategy involves assessing the size, type, and distribution of risks and then assigning resources accordingly. To achieve best practice, this should be a formal, rigorous, and data-driven process, conducted on an ongoing basis. The risk-assessment process varies between companies and the exact details are usually confidential for obvious reasons. The balanced scorecard approach provides a useful analytical starting point in developing a measurement tool for assessing risks and countermeasures. It is critical to ensure an international viewpoint. For a multinational company, the products most at risk will vary from market to market and so in order to ensure global consistency, senior executives must sponsor the risk assessment process and must ensure the active involvement and buyin of local affiliate companies as well as all relevant technical functions. Having head office people conduct the evaluation exercise by themselves in a seminar room somewhere risks the emergence of “groupthink” and strategic errors.

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There are many questions that could form the basis of such an assessment and the process will be unique for each pharmaceutical company but there are common themes. Arguably, the following are the three simplest and most important questions, which should be asked about all products and to all local operating companies: 1. Has this product ever (to your knowledge) been counterfeited? 2. Has this product ever (to your knowledge) been diverted (i.e., sold in unauthorized channels or markets)? 3. Have you ever checked your answers to questions 1 and 2 thoroughly (by market surveys, mystery shopping, etc.)?1 The output of question 3 is particularly critical. As Peter Drucker famously said, “What gets measured gets managed.” The market analysis should not be skimped or avoided. Data gathering may well be difficult and the information gained may be imprecise or incomplete. The exercise could lead to difficult corporate politics and expose some uncomfortable commercial truths. However, assessing the extent of the existing problems and potential market issues is an important stage of the vulnerability analysis. Only by defining baseline data, however imperfect, can the effectiveness of countermeasures be accurately quantified.

DOING THE SIMPLE THINGS

Not all actions in an anti-counterfeiting strategy require new budgets to be found. Although implementing security technology is undoubtedly part of the solution to combating pharmaceutical counterfeiting, many improvements in supply chain security can be realized with relatively simple measures, which may cost little or no extra money to implement. • Reducing the number of packaging and print suppliers, especially

those in countries with poor security environments, is often a good first step in increasing product security. In general, the aim should be to have the minimum number of suppliers compatible with guaranteed product supply—probably, more than one source for any given commodity, but not a multitude. A smaller supplier base is easier to audit and monitor. • All suppliers should be audited specifically on their own security procedures. • To try to avoid unauthorized production of counterfeits by suppliers, strict controls should be exerted over suppliers’ production volumes,

DOING THE SIMPLE THINGS

•

•

•

•

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with automatic production monitoring where possible and regular, unannounced spot checks. All usage of security features such as holograms and inks should be fully reconciled with the quantity originally ordered. This should take into account all wastage, priming, dilution, and other operational factors. Not only does this ensure that materials are being used to the correct quality specification but it also helps to avoid the dilution of security inks for use in extra, unauthorized production runs. Attention to detail in the management of waste material can remove a lucrative source of genuine packaging that can potentially be used with counterfeit products. Many prescription drugs are still sold in white, largely featureless boxes. By increasing design complexity, the “barrier to entry” for counterfeiters is raised. By including minor design flaws in the packaging, which do not attract the attention of counterfeiters, a drug company can give itself a cheap and easy tool with which to spot attempted counterfeits.

Used Manufacturing Equipment

It is possible to buy second-hand pharmaceutical manufacturing equipment very easily on the open market. At the time of writing, a search on one of the main industrial equipment auction sites, using the keyword “tabletting,” highlighted more than 30 lots of used pill manufacturing equipment for immediate sale. In many cases, this equipment had previously been used by named drug companies who would regard themselves as security conscious and was being sold off during site rationalization or cost-cutting exercises. Genuine, used equipment is an easy shortcut for criminal counterfeiters. Pharmaceutical manufacturers should make as much effort to control the supply chain and eventual destination of any non-standard machine tools as they do for their drug products. All elements of the pharmaceutical production process are potentially valuable to criminals. The cost savings generated by the resale of a tablet press may be more than offset by the losses incurred because of unauthorized manufacturing, unless the appropriate security precautions have been taken. An interesting, and to my knowledge unexplored, corollary of this observation is that manufacturing equipment could be an additional security tool. By incorporating small design changes into machinery or tool designs that would make a pharmaceutical product from that equipment more distinguishable or identifiable, equipment manufacturers could perhaps help in the identification of genuine drugs. A similar concept, routinely used in forensic science, is the analysis of scratches on bullets

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to identify the weapon from which they were fired. Thinking laterally and getting every supplier on board in the battle against counterfeits is necessary if we are to have success.

LAYERING OF COUNTERMEASURES

There are no magic bullets in anti-counterfeiting. No single security technology, however advanced, is completely effective on all products against all risks in all situations. The security of pharmaceutical products against counterfeiting is therefore greatly enhanced if several layers of countermeasures are used simultaneously. The strengths of one approach can cover the weaknesses of another. By combining multiple overt and covert features on the same product, counterfeiting can be made progressively more difficult. The aim is to make unauthorized copying of all of the product security features impossible or at least impractical or uneconomic. The layering of security features on pharmaceutical packaging is analogous to the layering of security on a domestic property (Figure 7.1). There are some features that are visible (dog, closed windows) and some that are not (intruder detection system). Each component (fence, gate, locks, window bars, alarm, dog, and so on) may not be impregnable to attack in isolation, but together they form an effective deterrent. We should also not forget the deterrent effect of putting a sign up on the fence that says there are one or more anti-burglary devices in use. On a pharmaceutical pack, the simple phrase “This product and its packaging contain one or more authentication elements” may be enough to make the low-level counterfeiter move on. In general, the number of people with the means to identify, access, and view security features is proportional to the overtness of the feature. The most hidden, forensic levels of security are typically only visible in a specialist laboratory but just as we keep our burglar alarm code secret, the very presence of forensic packaging features should only be known to a small number of people.

INFORMATION MANAGEMENT AND ‘‘NEED-TO-KNOW’’

As with any other security protocol, the details of anti-counterfeiting or anti-diversion features should be disclosed only to those who need to know in order to carry out their function. I am aware of cases in which only one person at the drug company and one at the security vendor knew the exact combination of forensic markers on the corporation’s packaging.

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Figure 7.1. Layering of Security Measures. As with domestic security, product security countermeasures do not always have to be impregnable to be of useful deterrent value against counterfeiters.

This “need-to-know” concept also has far-reaching implications for choice of security suppliers, as we shall see.

INTEGRATION WITH CORPORATE STRATEGY

As discussed previously, in many organizations, the addition of product security features onto pharmaceutical packaging is still seen as an extra cost rather than an investment. Purchasing decisions for security measures are often taken on a piecemeal and reactive basis, usually after an outbreak of fake products has occurred. If security features exist, they are often not rotated or renewed on a planned basis. This is not only much more expensive in management time but repeated small procurement exercises significantly raise the unit costs of product security overall. Even in purely procurement efficiency terms, this tactical rather than strategic approach to product security misses an opportunity. Investment in product security is entirely compatible with “lean” processes or cost reduction programs. By taking a positive and proactive approach, and allocating costs and budgets appropriately so that cost

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reduction and product security are not in competition, forward-thinking companies can leverage their investment in anti-counterfeiting. Suppliers can be integrated as partners, making maximum use of their broad and deep expertise. Corporate product security teams are freed from dayto-day crisis management and they are able to take a broader view of corporate risks and countermeasures. Despite the claims of some security vendors that particular products or technologies have proved highly effective against pharmaceutical counterfeiters, quantitative performance metrics based on effectiveness, rather than cost, have often been difficult to establish. However, it may be possible to generate meaningful numbers given sufficient market monitoring for counterfeits before and after the introduction of a new security feature. Such anti-counterfeiting surveillance activities are often clandestine operations using “mystery shopper” tactics—a necessary precaution to avoid alerting sellers, to prevent sampling bias, and to minimize the danger to the test purchasers. A more open approach, in legitimate sales channels, may also give pharmaceutical sales teams another reason to engage with their customers and to promote the image of a responsible and caring drug company. Despite the approaches discussed above, delaying strategic action until perfect information is available is not an option. The impetus for inclusion of product security as a board-level strategy issue for pharmaceutical corporations must come from the company directors themselves. Pharmaceutical executives need to accept that a large-scale counterfeit drugs tragedy is possible and commit the necessary time and resources to minimizing its likelihood. Similar to the Roman testudo tactic,2 the best way to minimize collective danger is to combine effective individual protection measures with a coordinated and well-executed strategy. The DRASTIC process discussed above is not easy, but in the long run, it is less difficult, time consuming, and expensive than doing nothing.

Chapter

8

Government Issues

One of the lessons from the last 10 years of initiatives around pharmaceutical supply chain security and product tracking has been that private organizations are rarely prepared to act and invest strategically in the absence of government legislation. This is not surprising and is arguably a modern day example of the Tragedy of the Commons.1 If no one is specifically responsible for the resource (in this case public safety from counterfeit medicines), everyone will act in their own economic best interests and the resource will eventually become depleted. In a tough financial environment and in the absence of any regulatory clarity, drug companies naturally act in the interests of their shareholders to minimize corporate costs and risks. This prudence has often included not making speculative investments in product security systems that are not legally required. This does not mean that drug industry executives are unfeeling and callous about their customers but illustrates that they need a clear framework of guidance and legislation within which to work. Lawmakers are now starting to address the situation more proactively. Recent consultation and legislative initiatives in Europe, the United States, Brazil, and elsewhere may lead to a more globally harmonized approach. It is encouraging that, although individual countries are proposing their own laws, the issue of international standards is being addressed. The

Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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involvement of organizations such as GS12 and ISO (International Organization for Standardization)3 will help to avoid the proliferation of multiple competing standards.

LEGAL FRAMEWORK

The first and most important government weapon in the war against counterfeit medicines is the legal process. In order to be deterred from their crimes, counterfeiters must face a high probability of being caught and punished. This requires clear, tough, and consistently enforced legislation as well as committed well-trained security services. To encourage greater collaboration in combating counterfeiting and piracy in Europe, the European Commission has created the European Observatory on Counterfeiting and Piracy. This “serves as a platform for consumers, public administrations and industry to join forces, to exchange experiences and information and to share best practices on enforcement.” The Observatory is composed of members of the public and private sectors, and three subgroups address issues surrounding data gathering, existing legal frameworks, and public awareness. Although not specific to pharmaceuticals, this resource sharing approach is a welcome development that will help in the fight against fake drugs. The debate about appropriate legislation against counterfeit drugs has often polarized around related issues of intellectual property (IP) and what constitutes a “counterfeit drug.” The international legal issues around IP are a complex subject in their own right, and I do not propose to discuss them in detail here. The World Trade Organization’s4 Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) provides the main framework.5 It covers issues such as duration of IP protection and the requirement for countries to grant and enforce pharmaceutically based patents, but individual countries are free to set their own patentability criteria. Many countries, although they may have explicit laws or a stated policy on intellectual property, do not have a sufficiently robust or incentivized judicial system to enable these cases to be prosecuted consistently in the courts.6 For a drug company, any unauthorized copying of its products is considered a counterfeit. However, many low-cost manufacturers are based in countries with very limited controls on the use of intellectual property and often with great local need for cheap and effective medicines. The production of so-called generic copies of innovative medicines which enjoy theoretical patent protection elsewhere is therefore not necessarily illegal in many countries. Many of the producers in low-cost countries

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make acceptable or even excellent quality products which often serve a local need. It is when these drugs are exported to a third country that the legal uncertainty may arise—are these copycat products counterfeits or legitimate low-cost alternatives to expensive branded products? The international trade association for drug manufacturers, IFPMA (International Federation of Pharmaceutical Manufacturers & Associations),7 has published a set of principles,8 which it believes should guide policy in this area. Although undoubtedly an important issue in its own right, the focus on intellectual property rights is not necessarily helpful in defining legislation to combat dangerous counterfeit medicines. The World Health Organization definition deliberately avoids discussion of intellectual property and defines a counterfeit drug as . . . a medicine which is deliberately and fraudulently mislabelled with respect to identity and/or source. Counterfeiting can apply to both branded and generic products and counterfeit products may include products with the correct ingredients or with the wrong ingredients, without active ingredients, with insufficient active ingredients or with fake packaging.

The intent to deceive is usually the key factor in determining the potential danger from a counterfeit. The exact international definition of counterfeit drugs vis-`a-vis intellectual property is a side issue in many ways. In order to protect the public, it is clear that the priority should be to control criminal attempts to manufacture and distribute dangerous and unauthorized products disguised as legitimate medicines. In order to do this effectively, the global drug industry would prefer to use interoperable systems so that the technical framework used and the information shared is compatible between companies and between countries. There are some security risks in defining such an open, integrated international system. Based on the need-to-know principle, most technology frameworks designed purely for security are closed systems. These often require specific equipment and may be proprietary technology offered by one supplier. Such approaches have been used successfully for national excise control systems for tobacco and alcohol in several countries and are standard practice in the defense industry. The complex international supply chains and logistics that are involved in the pharmaceutical industry make the use of closed, proprietary systems impractical on an international basis. The adoption of multiple different national systems for drug control would also be very problematic. Manufacturers would be forced to comply with multiple security features, which would raise costs and increase complexity of international supply chain management. Although agreement and implementation will be

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difficult, an international, standards-driven approach to anti-counterfeiting will probably work best in the long term.

LINK WITH REIMBURSEMENT AND SOCIAL HEALTHCARE

As the global burdens of starvation, malnutrition, and infectious disease are gradually lifted, people are starting to live longer. As they get older, they succumb to chronic diseases and have more need for health services and pharmaceutical products. In most countries, the burden of healthcare costs is increasing as the average lifespan increases and as the population ages. These increased costs may be borne by individuals or by the state. In many countries, the government reimburses all or part of the drug costs for at least some of its citizens. This is often accompanied by unwieldy bureaucratic processes designed to reimburse patients for their drugs or to provide free drugs. As noted previously, this provides an excellent opportunity for fraudsters and counterfeiters to make money. The administration systems in many national health programs have not kept pace with the growth in the healthcare industry and its increasing complexity. Therefore, the accountability and control of the drug dispensing process (and of the subsequent reimbursement of doctors, pharmacists, or patients) is often weak. This can lead to wide-scale fraud, ranging from petty opportunist offences by individual patients to systematic defrauding of the state by organized crime syndicates. All of these activities raise the total cost of social healthcare and thus impose a burden on the state and the taxpayer. Implementing better control systems for the distribution and reimbursement of prescription drugs should help to reduce this fraud and to control the cost of public healthcare provision. Such systems are not cheap, as they require the integration of data from millions of transactions involving thousands of points of sale and hundreds of supply points into one or more database systems with a secure method of transferring data between the components. Nevertheless, the savings generated by more efficient management of the distribution of medicines and reimbursement payments to patients and healthcare stakeholders are likely in most cases to exceed (by some margin) the costs of the control system. This means that deployment of drug tracking systems will help both to control counterfeit drugs and to reduce healthcare costs. Even if we set aside the human benefits—reduction in illness and death due to the better control of fake drugs—the financial benefits speak for themselves. Although problematic, time-consuming, and costly to implement and maintain, drug tracking systems will more than pay for themselves in the long term.

DATA MINING

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LAW ENFORCEMENT ISSUES

The presence of the necessary laws themselves, although critical, is only another tool in the fight against counterfeit medicines. Strict anti-counterfeiting laws cannot by themselves provide protection against fake drugs. In order to be effective, the law must be enforced rigorously and consistently. Funds and resources must be made available to law enforcement agencies to enable them to equip, train, and deploy sufficient numbers of personal to be able to monitor and intercept consignments of counterfeit medicines. Given appropriate training, law enforcement personnel usually identify very readily with the issue of fake medicines and are often very motivated to carry out the enforcement tasks. They recognize that this is an issue that affects everyone, including their own families. Usually, the factors that prevent them from doing their work successfully are the lack of suitable tools and training and the sheer lack of manpower to cover the necessary ground. In some cases, corruption is also a problem. This is rarely a simple, black-and-white issue in low-income countries. The bribe received by a poorly paid policeman, in return for looking the other way, may be the difference between him being able to pay for his child to attend school or not. In addition to providing tools and training to enable law enforcement and customs personnel to detect counterfeit drugs, donor governments and NGOs working in developing countries should try to ensure that the officers conducting the checks are sufficiently well paid and motivated to enable them to do their job effectively. At the international level, the establishment of the Medical Products Counterfeiting and Pharmaceutical Crime (MPCPC) unit by Interpol is encouraging closer collaboration between the health sector, law enforcement, international organizations, and non-governmental organizations around the world. This collaboration is starting to bear fruit in the simultaneous and coordinated seizure of counterfeit drugs in neighbouring countries (see Chapters 37 and 38).

DATA MINING

There may be important but under-used information, already available in government or regulatory agency databases, that could give useful clues as to the prevalence and severity of the fake drugs problem. These data may also help to track our attempts to fight counterfeiting. For example, the recording of adverse events that are associated with pharmaceuticals is a standard role for pharmacovigilance systems worldwide, with good

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reason. High-profile drugs that seemed perfectly safe during development are sometimes pulled from the market because of side effects that only become apparent once the product is marketed. However, despite a number of enquiries on this matter with colleagues and regulatory agencies, I am not aware of a systematic and large-scale attempt to map adverse-event data to the known or suspected presence of counterfeit drugs (based on customs seizures, mystery shopper purchases, drug company information, medical records, etc.). As this draft was being finalized, the European Union passed a significant enhancement to its rules on pharmacovigilance.9 It remains to be seen whether future initiatives will encompass the strengthening of the linkages I suggest above. Even if the resulting data were of low resolution and patchy, such information might allow the search for specific batches of fake drugs to be narrowed and consumer education and warning programs to be conducted based on the observed symptoms. Suspected events could then be followed up with targeted toxicology tests, which would otherwise be impractical on a population-wide basis. Similarly, the correlation of cause-of-death data from death certificates with data on the deceased’s recently purchased or prescribed medications could prove interesting. This information could be obtained from medical or insurance records and could be further augmented by requesting or requiring all certifying physicians to list the identity and lot numbers of any medication that the deceased was known to be taking. More controversially, cross-referencing the recent credit card transaction records of deceased or ill patients with the details of known pharmacies or pharmacy websites could identify cases in which recent drug purchases may have been implicated in the cause of death. This would obviously need to be conducted with the consent of the patient or their next of kin. All of the above database cross-referencing processes could, in theory, be largely automated and would not necessarily have to be done for all cases. Although this kind of data mining would be a huge and impractical technical undertaking on its own, it could be more readily incorporated as part of the moves to digital health records that are already underway around the world. Governments and industry should continue to seek more integrated ways to use the data we already have, whilst respecting patient confidentiality, to give a clearer picture of the true extent of the counterfeiting issue. Money Transfer and Credit Cards

In many types of crimes, one of the most effective investigation tactics is to follow the money. Since almost all crime eventually needs money

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as a value transfer mechanism, this financial analysis technique can allow those behind the crime to be identified. Preventing the transfer of money is also a good way to suppress illegal trade. Since many purchases of counterfeit drugs involve credit cards used by individuals over the internet, governments should continue to put credit card issuers under pressure to identify and prevent transactions involving known bogus pharmacy sites.

INTERNET SERVICE PROVIDERS AND SEARCH ENGINES

Governments can (and have) put pressure on internet service providers (ISPs) and the major search providers to limit the online commercial activities of fake pharmacy sites and suspected counterfeiters. By preventing search listings (paid or otherwise) and sponsored links from known bogus sites, search engines can at least reduce the online visibility of known offenders. By rapidly closing down identified fake sites and remaining vigilant for the same or closely related registrants reappearing, ISPs can also play their role. Although the dispersed nature of the internet makes the task very difficult, since many websites are hosted outside the jurisdiction that they target, governments around the world must continue to apply moral and legislative pressure on those who provide the infrastructure of the internet. The advent of the internet has been hugely beneficial in the dissemination of information to patients and holds great promise in the efficient delivery of drugs and other healthcare services. We should be careful not to stifle trade or discourage commercial innovation, but all stakeholders must also play their part to ensure that only properly verified and regulated pharmacies are able to conduct business online.

Chapter

9

Intellectual Property and Anti-Counterfeiting Although the conflation of IP and patient safety issues has undoubtedly resulted in much international controversy and confusion, intellectual property law remains one of the key weapons in the battle against counterfeiters. The US government has set up an Intellectual Property Enforcement Coordinator1 and announced a multi-agency strategy on IP enforcement in 2010.2 The strategy document notes that approximately 8% of the bulk drugs imported into the United States are counterfeit, unapproved, or substandard and includes measures to control online pharmacies and to establish a Counterfeit Pharmaceutical Interagency Committee. In some countries, defense of IP may be the only viable legal option since counterfeiting is not recognized as a separate criminal act in its own right. The area of IP law is a complex one, and the details vary greatly between jurisdictions, but in general, one or more of the following have to be proved in counterfeiting cases.3 1. The branded goods exhibited by the legitimate rights holder are authentic. 2. The alleged counterfeits associated with the defendant are not authentic. 3. The defendant had knowledge that the goods were not authentic. Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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4. The defendant could and should have known that the goods were not authentic. To categorically prove the first point (and therefore, by extension, the second point), more than just minor visual differences are usually required. The brand owner must provide scientifically robust evidence that allows unequivocal differentiation of real from fake product. The presence of key security features on the genuine product, which are absent from the alleged copy, is the most powerful form of evidence. The best way for the rights holder to ensure that this evidence is available when needed is to undertake prior investment in authentication technologies. If such security features are not present or are not cited, but instead the case relies purely on visual differences or on circumstantial evidence, a legal defense of “reasonable doubt” may be accepted, causing the case to be thrown out. ESTABLISHING OWNERSHIP OF INTELLECTUAL PROPERTY RIGHTS (IPR)

Before raising a case based on IP infringement, the rights holder must prove that they own the brand in question. The most basic legal defense, from a brand owner’s point of view, is therefore to ensure that all patents, copyrights, trademarks, and other legal aspects of the branded product are well documented and protected. This is a highly specialist area, and the detailed examination of this issue is outside the scope of this volume. However, there are certain aspects of intellectual property and its defense that are important for the overall aim of preventing or minimizing criminal activity associated with pharmaceutical brands. Patents

International patent applications can be made relatively simply through the patent cooperation treaty (PCT) of the World Intellectual Property Organization (WIPO).4 However, not all countries are signatories to the treaty, and in many countries the defense of intellectual property rights (IPR) is difficult in practice. Patenting is a trade-off between confidentiality and commercial exclusivity. It is, therefore, important to plan ahead in designing a patent filing strategy, which should include consideration not just of the countries in which the product will be commercialized but also of those countries where counterfeiting may be an issue—even if there are no plans to launch the product in these areas. This will be unlikely to provide complete protection, but will at least provide a basis for investigation of future counterfeiting activity, should it occur. The downside

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risk is that mandatory disclosure of technical information when the patent filing is published may give counterfeiters useful information. There has been controversy in recent years regarding infringement of IPR by goods in-transit, particularly through the European Union. Consignments of drugs, manufactured in countries without patent protection for those molecular entities, have been detained during transit through countries where these molecules are patent-protected, despite their apparent destination being a third country which also does not recognize patent protection. Of course, in these situations it may be difficult to differentiate between goods genuinely in-transit and goods which are about to be offloaded unlawfully into the European Union for illegal sale. The World Health Assembly has condemned the practice of stopping consignments in-transit in this way.5 Patenting of Security Technologies

As noted above, patent protection involves a well-known trade-off between market exclusivity and secrecy. In return for protection from competitors, the applicant must disclose details of the invention which can then be used freely by anyone at the end of the patent term. The problem lies in the enforcement of the exclusivity period, and in many countries this is very difficult. Therefore, as soon as a patent application is published, a vulnerability is created. Some companies therefore prefer not to patent key technologies or formulations. Famously, the recipe for Coca-Cola® is not patented but is maintained as a closely guarded trade secret. Some providers of brand protection technologies also maintain their high level of security by choosing not to patent critical developments or ingredients. This should be borne in mind during due diligence processes when brand owners are selecting security suppliers. Excessive reliance on a box-ticking approach should be avoided in favor of a detailed discussion under confidentiality agreement. If the brand owner has never heard of a particular technology before a supplier shows it to them, and cannot find reference to it in the scientific literature, then that may be a good thing if security is their primary objective. Trademarks

Since defense of IP (as a proxy for anti-counterfeiting) may rely on the appearance of packaging rather than on the chemical constituents of the product, trademarks are an important component of a defensive strategy. They should be protected carefully, as counterfeiters and their legal team

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will exploit any gaps or confusion. Protectable trademarks can include logos, pictures, words, phrases, shapes, etc. Anything designed to differentiate a product from its competition could potentially be designated a trademark, although the details vary between countries. Ideally, since counterfeits can appear anywhere, trademarks should be protected in as many jurisdictions as possible, regardless of whether the product will be sold there. The protection of trademarks is not watertight, but all feasible steps should be taken. There is a central system of international trade mark registration, governed by WIPO and known as the Madrid System,6 but it is not universally recognized. The 60 or so signatory countries include China, Russia, USA, and most European countries, but several significant economies, notably India, are not signed up. The system is defined by two treaties: the Madrid Agreement Concerning the International Registration of Marks and the Protocol Relating to the Madrid Agreement. WIPO maintains the International Register, which records trademark ownership, and also publishes the WIPO Gazette of International Marks. An international registration is valid for 10 years and is equivalent to multiple national registrations. However, although it is a single registration process, protection may be refused by some countries, or the protection may be limited. A granted international registration may also be invalidated later in specific countries if the trademark is not used in those jurisdictions. There is a central registration procedure but not a central arbitration process, so any legal action for infringement of an international registration must be brought separately in each of the countries concerned. The first stage in trademark defense is to register all necessary marks, but the use of trademarks as weapons against counterfeiters also relies on the awareness of brand details by frontline law enforcement officials. US Customs and Border Protection (CBP) website has an online procedure for registering trademarks7 in a process known as “recordation.” The CBP recordation process allows rights holders to electronically record their trademarks and copyrights and makes the necessary IPR information readily available to CBP personnel in the field. Importantly, this process facilitates seizures of suspect goods by CBP since they use this information actively to monitor shipments and to prevent the importation or exportation of infringing goods. CBP enforces both recorded and nonrecorded trademarks and copyrights, but the former take precedence over the latter, so recordation is well worthwhile. According to their website, “as of the end of Fiscal Year 2007, over 21,000 trademarks and copyrights were recorded with CBP.” In addition, it is often worth preparing a specific training manual for customs officials since (by definition) trademark infringements can be hard to differentiate from the real thing. A template and guidance is given at

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the CBP website,8 which also features a joint US-EU brochure on the subject. In general, the more help that the brand owner can give to busy and under-resourced customs officials, the more likely these officials are to intercept counterfeit goods. In 2007, the EU and a number of other WTO members began work on a new international agreement—the Anti-Counterfeiting Trade Agreement (ACTA). The objective of ACTA is to obtain a new treaty improving global standards for the enforcement of IPR, to combat more effectively the international trade in counterfeit and pirated goods. At the time of writing, the agreement was not finalized, but this has been a controversial process because of the high level of secrecy under which the talks were conducted and the potentially wide reach of the agreement. The current negotiating parties of ACTA are a mix of developed and emerging economies: Australia, Canada, the European Union, Japan, South Korea, Mexico, Morocco, New Zealand, Singapore, Switzerland, and the United States. Although ACTA was initially negotiated among a relatively small number of countries, it is hoped that other countries will eventually sign up to the agreement. The main provisions of ACTA are: • International cooperation, including sharing of information and coop-

eration between law enforcement authorities, Customs, and other relevant agencies. Technical assistance will be given to enable lessdeveloped member countries to improve enforcement and to promote best practices. • Enforcement practices to support the application of the relevant legal tools. These might include formal or informal public/private advisory groups, fostering of specialized intellectual property expertise within law enforcement organizations, and measures for raising consumer public awareness about the importance of IPR protection. • Establishing a legal framework to enable law enforcement agencies, the judiciary, and private citizens to bring counterfeiters to justice. This area might include border measures as well as civil and criminal enforcement. The impact of ACTA on the drug industry remains to be seen, but from first principles, any increase in the international coordination of IPR and their enforcement should help to reduce pharmaceutical counterfeiting. Note that the fact that a country is a signatory to an international treaty does not mean that defense of intellectual property will be easy or straightforward in that country. The ability to enforce rights will depend on the involvement of the local law enforcement authorities and the judiciary.

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These bodies may take a different view of the priority of the case than the plaintiff, and cases can take years of investigation and legal process. In order to make the most efficient use of the criminal process, whatever the infringement or jurisdiction, the brand owner should be very proactive in providing materials and support for the case and should not assume that follow-up tasks will be completed by the court or the authorities. Examples of what might be needed include • Helping customs ◦

As discussed above, the resources available to customs officials are very thinly stretched, and they have very little time to focus on individual consignments. Making customs officers aware of product verification features so that suspect packages can be identified, and periodically providing refresher training and update materials, can be an effective tactic. ◦ Providing a point of contact and quickly providing assistance when a suspect consignment is seized is critical. The brand owner may need to rapidly provide genuine product samples for comparison, readers for covert features, etc. This is best done in person if possible, either by a member of a rapid response team or by a local agent. • Helping law enforcement ◦ Assisting in the gathering of further evidence, and supporting raids on property where necessary, will require on-the-ground support with local language skills (or with a reliable translator available). • Helping the court ◦ Conducting further analysis on suspect samples will likely be the primary responsibility of the plaintiff. ◦ Providing translations of key documents, if necessary, can speed up the bureaucratic process. In most countries, without help as well as subtle pressure from the brand owner, the case against the suspected counterfeiter will proceed very slowly, if at all. Online Intellectual Property

With the rise of internet sales of prescription drugs, the defense of online assets has become an ever more important activity for brand owners. The internet is a huge and largely uncontrollable environment where complete protection from fraud is difficult to achieve. However, there are some basic

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precautions that every rights holder must take. Domain names for all likely trademarks and product names should be registered in all appropriate jurisdictions. That means that most, if not all, domain name extensions should be considered, since the internet enables criminals to operate from anywhere in the world. Pre-registration of relevant domains is a relatively negligible cost compared to the cost of trying to evict cyber-squatters later. If this is not done, counterfeiters may even use their ownership of websites containing brand names as evidence of their right to market the infringing product. It is better and cheaper to cover all of the internet domains as soon as the generic and proprietary names are chosen. Likely misspellings or shortenings should also be anticipated and protected. Online surveillance of illegal vendors of counterfeit products is an integral part of brand defense strategy. This involves analyzing internet search traffic and closing down unauthorized websites where possible. Although this does not always provide long-term protection from fraudsters, since closed down sites frequently re-open under another domain name, it does make it harder for them to operate. Internet service providers and domain name registration companies are increasingly sensitive to the need to control the use of sensitive domain names and may help to close down rogue sites when they are notified of them, but the onus is typically on the brand owner to identify the sites concerned and report them. There are specialist internet security companies who can provide this service.

CRIMINAL PROSECUTION VERSUS CIVIL SUIT

As we have already seen, the legal landscape for crimes involving counterfeiting of medicines is complex. The strengthening of criminal sanctions against pharmaceutical counterfeiting is critical, and this requires that firm and well-enforced legislation is in place to punish offenders and that cases be brought to court and vigorously prosecuted. A criminal prosecution is still the default option when pursuing counterfeiters through the courts, but the criminal prosecution process can be a long one, and the burden of proof is high. The civil courts may provide an additional or alternative legal avenue in some cases. In many cases, the burden of proof is lower than for a criminal prosecution, and there is the opportunity for the defendant to settle out of court. Pursuing the financial assets of offenders through a suit for damages provides the potential for financial compensation to the brand owner, is often quicker than a criminal prosecution, and can be a powerful deterrent. This strategy does not preclude launching a criminal case, and a dual strategy involving both criminal and civil actions can be very effective.9

Chapter

10

Traceability or Authentication? The previous sections have discussed the rationale for product security measures and some of the strategic considerations involved in their implementation. In the next section, we will move on to consider the practical aspects of anti-counterfeiting with a focus on authentication technologies. Before we get into the detail, it is necessary to explain the basic principles of the field. Broadly, the two main forms of product security in use today are known by the vague and often misleading terms of traceability and authentication. Each has its proponents and detractors, although in practice, there are large areas of semantic and practical overlap between the two related areas. Later chapters will discuss both approaches in detail. To understand the difference between the two, and in order to investigate suspicious medicines, two of the key questions that need to be asked are “Where has this product come from?” and “Is this product genuine or fake?” These questions also guide the strategies used to prevent counterfeiting and the answers are provided by the two related sets of technologies. By the time a pharmaceutical or medical product (whether pill, bottle, or box) reaches the patient, it has typically passed through many hands and collected a lot of “fingerprints” (Figure 10.1). In the event of a suspected counterfeiting incident, it is difficult to unravel the transactional or geographical history of the product without further information. Like Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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R Ingesta 50 mg 30 capsules

Starma

Figure 10.1. Multiple Fingerprints at the Crime Scene. An average pharmaceutical pack passes through many transactions on its journey to the patient. In the event of suspected counterfeiting, this makes it hard to identify the location of any criminal activity.

any crime scene, the information in front of the investigator can only be interpreted by reference to known information points. This question of origin and provenance (“Where has this product come from?”) is addressed by track and trace technologies (sometimes known as digital authentication), which are designed to identify and monitor individual packages within the supply chain. The units of identification may be of varying sizes from shipping containers in a port to individual vaccine vials in a hospital dispensary (and often there are multiple tracking levels in the same system, for different elements in the packaging hierarchy), but the basic principles of the system are the same in most cases. Confusingly, there are several variations in the terminology used for traceability systems, such as “serialization,” “pedigree,” and “track and trace,” and there are various underlying nuances within the basic concept, which will be discussed below. However, in all cases, information about the origin and history of each tracked container or unit of sale is either carried directly on the product (or its immediate packaging) or held in a database. In the latter case, the database is accessed and, if appropriate, updated using one or more characteristics unique to that individual pack—such as printed codes, serial numbers, or surface features. Each scan of the pack adds another data point to its transaction record. Depending upon the number

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of such data capture points in the product’s journey from manufacturer to patient (the known “fingerprints” in the analogy above), track and trace systems can provide a history of the movements and transactions associated with the product. This is the basis of the systems already used to track millions of items in transit by courier companies such as FedEx and UPS. In pharmaceutical distribution and logistics management, this track and trace information has many uses from improving supply chain efficiency to reducing the number of medical errors. In recent years, the adoption of traceability technology has also been proposed as an effective way to fight counterfeiting and diversion. The use of track and trace as an anticounterfeiting tool as well as a logistics method relies on the premise that the more detailed the “life story” of each pack becomes, the harder it is to copy that transaction record illegally and therefore the more difficult it becomes for criminals to insert fake product (with incorrect information) into the legitimate supply chain. Although traceability has tremendous value in helping to pinpoint the scene of a crime, or at least in helping to highlight that a crime has happened before the drug reaches the patient, it does not provide the whole answer to the problem of product security. In order to ensure the security of tracking systems themselves, it is also important to be able to answer the second question I posed above (“Is this product genuine or fake?”). Codes and serial numbers can be duplicated, mimicked, or subverted by criminals, as can websites, helplines, and databases. Relying on tracking technologies alone without additional (non-digital) technologies, such as physical or sensory authentication, is therefore dangerous. It leaves traceability systems vulnerable to circumvention. In the current enthusiasm for these technologies, it is important not to overlook the need for robust verification technologies that give an unequivocal response to the question of whether the product is genuine or not. This process of determining whether or not the product and packaging are real or fake, regardless of their apparent transaction history, is usually known as authentication. Although more correctly the term should be “sensory or physical authentication” to differentiate it from the digital, information-based authentication technologies used in track and trace systems, authentication is frequently used as shorthand for these physical technologies and references to authentication in this book should be taken to mean non-digital approaches unless stated otherwise. The diversity of authentication approaches is very wide, reflecting the many different product and packaging environments in which they have to operate and the spectrum of criminal threats which they try to combat. Some of the many technologies used will be covered in Part II of the book.

Part

2

Authentication

Chapter

11

What Is Authentication?

As discussed in the last chapter, authentication in the context of pharmaceutical security (and accepting the arguably vague and inaccurate use of the term) means asking the question “Is this product genuine or fake?” It is therefore a binary issue: in theory the answer is either Yes or No. This is not the same question as “Does this product have the correct packaging” or even “Does this product carry a valid code or serial number?” Coding and tracking systems can be excellent authentication methods, but are only effective if they are secure. It is possible to authenticate a product as genuine to a legal grade of proof (“beyond reasonable doubt”) without knowing its life history. We do this every day with banknotes, for example. However, the converse is not true: it is not possible to prove a product’s provenance and route through the supply chain without being able to authenticate it as genuine. Thus authentication complements, and is not replaced by, the tracking technologies discussed later. For reasons of practicality, many of the methods by which we verify genuine products involve proxy indicators of authenticity, such as secure packaging and tracking codes. However, it is not fake drug packaging that harms people. Only if the ingested, injected, inhaled, or implanted product itself is genuine, and of the expected quality, is the patient safe from harm due to fake or substandard medicine.

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DIGITAL VERSUS SENSORY AUTHENTICATION

Despite advances in technology in all areas of life, the human senses are still one of the most effective tools in judging quality. In product security, we can use sensory-based authentication methods to enhance the human capacity to differentiate, by adding physical features to the product or its packaging (or using innate properties), which can be distinguished by sight, sound, smell, touch, or taste. Common examples of sensory authentication features include holograms and colorshift inks. Features that rely on covert physical or material properties, not perceivable by humans but requiring a tool or machine, also fall into the sensory category. Digital authentication, in contrast, relies on the association of the product or its packaging with a unique set of information, rather than with any physical features or properties of the material itself. This digital information is allocated, stored, and processed by computers, although it may also be visibly printed on the product for all to see (as a serial number, for example). The digital authentication concept relies on the fact that only authorized persons can allocate the codes and update the information associated with them. This information (or a subset of it) may be stored either on or with the product, in a remote database, or both. It can usually be updated or altered without making physical changes to the product or its packaging. Radio frequency identification (RFID) is a good example of a digital authentication technology. The use of a computer is not the defining element of digital authentication, but rather the use of pre-determined numbers to identify items or groups of items (Figure 11.1). In recent years, there has been a trend in the pharmaceutical industry toward serialization or track and trace and away from authentication technologies. Although tracking technologies are an important and valuable contribution to ensuring the safety of the international drug supply, they are not sufficient in themselves to prevent unauthorized counterfeiting. Nor are they always a practical, real-time option in some of the challenging environments in which decisions must be made. Rapid differentiation between real products and fakes needs to be carried out by law enforcement officials out in the field. Wireless database access may not be possible in real-time in many countries or in challenging locations such as sea ports. This is where sensory authentication comes into its own. It is important to note in passing that truly effective authentication is usually not “cost-neutral.” There is often pressure in manufacturing organizations to find new or upgraded security features that add zero net cost to the product. There are some very cheap and effective features that can be added at the carton manufacturing stage, for example, but in general, security features add an element of direct cost. If there is a tiny budget,

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DIGITAL

SENSORY

Figure 11.1. Digital Versus Sensory Authentication. Both types of authentication methods may involve examination by eye or by automated means. Digital authentication requires confirmation of the presence of a pre-assigned number (whether printed as text, applied as a barcode or 2D code, or coded onto an RFID tag). Physical authentication identifies characteristics which do not depend on numbers.

there may be little benefit, and indeed a false sense of security may be damaging in the long term. The design, implementation, and maintenance of an authentication strategy are often difficult, potentially costly both internally and externally, and always time consuming. It is also increasingly an inevitable cost of doing business in the pharmaceutical industry, not a choice. No sane CFO (Chief Financial Officer) would decide to forego corporate liability insurance, or decline funds for the repair of broken fencing around their animal research facility. Authentication should be seen as a must-have, not a nice-to-have, if we are ever to start reversing the tide of counterfeit drugs. TYPES OF AUTHENTICATION TECHNOLOGIES

There are a large number of security technologies that can be used for authentication of pharmaceuticals and medical products. Some have

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Technology

Overt

Covert

Design features Special security substrates Recognition of random patterns (innate or applied) Adhesives and closures Taggants and dyes Microparticles and nanoparticles Optically variable devices Security inks Coding and serialization

Figure 11.2. Overt and covert technology types.

been specifically designed for the purpose, and some are adapted from approaches that have been used successfully in other industries. For any individual product security requirement, the choice of technology will depend on a number of factors including price, security level, feasibility, etc. The technologies most commonly used in pharmaceutical product security can be broken down into broad categories (Figure 11.2). These various technologies can be used at different levels of packaging and in different circumstances. As discussed elsewhere, it is usually prudent to use more than one technology to give a layered defense against counterfeiting. The principle is illustrated by the “pyramid of authentication” (Figure 11.3). The vertical dimension (not to scale) represents the number of people involved in authenticating the product at various levels of security features. Two main aspects of authentication become apparent. First, the “alertness to danger” increases greatly if the public (and those in the supply chain who come into customer contact, such as pharmacists) are given simple security features that they can verify visually or with very simple tools. This is simply a function of the number of pairs of eyes available—the public, by definition, is everywhere. The second and conflicting factor is that (in general) the wider a security feature is disseminated, the more it is vulnerable to attack by counterfeiters. A mixture of the technology types above is therefore prudent, to provide stakeholders at all levels of the pyramid with different ways to authenticate the product.

INTERNATIONAL STANDARDS AND NORMS

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One or two people (forensic analysis) Product security team (multiple tools, laboratory) Customs, sales reps (complex tools) Pharmacists, public (simple tools) General public (no tools)

Figure 11.3. The Authentication Pyramid. Overt security features at the base of the pyramid reach the general public and allow a large number of people to be involved in validation. Forensic tools at the apex may only be known to a small group, increasing security but preventing widespread routine monitoring. Most anti-counterfeiting features involve a trade-off between ubiquity of awareness and degree of security.

INTERNATIONAL STANDARDS AND NORMS

A single, uniform, and simple-to-use authentication technology applied across all pharmaceutical products is, at first sight, a useful concept. All law enforcement operatives could be made aware of what to look for, and consumer education would be a simple process. In practice, of course, the technology would be vulnerable by its very ubiquity and predictability and would almost certainly be rapidly circumvented. Therefore, it is better to look for agreed standards, against which the effectiveness of security technologies can be measured, without proscribing individual technology choices. The inherent secrecy of security technologies, and the paucity of data about their true effectiveness out in the field, means that objective evaluation of one approach versus another is rather difficult for brand owners and standards organizations to achieve. The involvement of neutral confidential forums such as the Pharmaceutical Security Institute1 can help pharmaceutical companies to compare notes and to report successes and failures. The international standards development process is still catching up with the technology in this area, but ISO, GS1, the North American Security Products Association (NASPO),2 and other groups are all actively engaging with stakeholders to define workable and secure technology standards. At the time of writing, the main ISO technical committee relevant to this topic, TC246, is looking at standardization in the field of anticounterfeiting tools.3 Importantly, this will include assessment criteria

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for adaptability (including interoperability), upgradeability, robustness and resistance to attack, reliability of the control methods and associated tools, grade of proof, etc. International standards will be designed to provide a valuable benchmark for the performance of security tools and features, without requiring pharmaceutical companies to choose or disclose specific proprietary technologies. Brand owners must retain the flexibility to change their security features at short notice and without public disclosure.

Chapter

12

Authentication of the Person Before we look at product authentication, which is the aspect of pharmaceutical anti-counterfeiting that has received the most attention from regulators and the public, it is worthwhile examining how we verify that the person requesting a prescription medicine is genuine. This is important because prescription medicines are dangerous in the wrong hands and because in many subsidized healthcare systems the access to drugs needs to be controlled in order to monitor costs. Before allowing an individual access to medical products, the answers to the following questions should be known: • Are they who they claim to be? Do they have valid personal identi-

fication? • Do they have an authorized prescription from their physician (where

applicable)? • If they are asking for medicines that are normally given long-term for a chronic condition, are they already “known” to the healthcare system? If the answer to one or more of these questions is “No,” then further checks should be made. Some of these precautions will be impractical in some situations, but by ensuring that healthcare professionals consistently Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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take simple steps to verify their patients’ personal identities and healthcare entitlement and to record details of transactions, much of the unauthorized acquisition and resale of medicines can be prevented. Informal transactions and anonymity are the tools of the criminal in all areas of life, and this is equally true with counterfeit or diverted drugs. The problem is exacerbated where the state provides much or all of the funding for prescription drugs, and reimbursement fraud is common where controls are lax. Therefore, to reduce fraud and to ensure that only those entitled to free or subsidized medication receive it, some governments have begun issuing medical cards. These are identity cards for the specific purpose of validating personal entitlement to subsidized healthcare. The system in the Republic of Ireland,1 for example, uses a credit-card-sized format for medical identification cards. The Irish system is means-tested (only those on low incomes are entitled to support) and is carefully controlled to ensure that only eligible patients are able to receive subsidized healthcare. Using similar methods, some drug companies have also started to develop longer term relationships with their consumers. The aim is to get more information about their patients and thus enable greater control and visibility over who is using their drugs and where they are getting them from. The quid pro quo usually takes the form of a price reduction to the consumer. Such schemes often involve product-specific payment cards, which the patient can present to the pharmacist in order to receive approved discounts on his or her medication, financed by the drug company. Consumers in many markets are already comfortable with the loyalty card concept, and these pharmaceutical schemes seem to be proving successful.2 The added benefit of a closer relationship between the patient and drug company is that it can improve the likelihood that the patient takes the required medication correctly and for the correct period. It provides a mechanism to remind them to take their medication as prescribed—socalled “compliance,” also known by the less-loaded term “adherence”— and to come back at regular intervals for repeat prescriptions (known as “persistence”). By increasing adherence and persistence in this way, additional health benefits can be realized, particularly for chronic, largely asymptomatic conditions such as diabetes, hypertension, and hypercholesterolemia. The reduction in hospitalization rates may also offset the cost of the extra drugs to the state, the insurer, or the patient. Critics would say that these “loyalty cards” are purely profit-driven schemes that put too much sensitive patient information into the hands of drug companies, but with appropriate safeguards, a closer link between the patient and the manufacturer has the potential to provide financial and product security benefits to both sides as well as to improve patient health.

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Counterfeit drugs can never be tolerated, and we must continue to use the full force of the law to stamp them out. However, in my opinion, the most effective long-term approach for a drug company to use when dealing with counterfeits is one of product marketing and differentiation. The more the legitimate products can be sustainably differentiated from the competition (whether legitimate or counterfeit) the easier it is to defend their market position. There is a gradual move toward the delivery of pharmaceutical healthcare as a continual service, with the drug itself as only one component, rather than the current model in which drugs are an intermittently purchased, product-only proposition. This trend toward value-added services will make it harder for counterfeiters to infiltrate and subvert the pharmaceutical system. Identifying the patient and establishing their entitlement to the requested drugs is the necessary first step in anti-counterfeiting. The process of authenticating and verifying the pharmaceutical products themselves is, of course, also critical and needs to occur at all levels, from bulk ingredients to final consignment. The methods appropriate to each level are different and are explained in detail in the other chapters in this section.

Chapter

13

Authentication of Bulk Products To the naked eye, one bag of white powder or drum of clear liquid looks very much like another. The requirement for authentication in the drug manufacturing process therefore begins right at the start—at the raw material stage where API and excipients (everything else in the formulation) are manufactured and combined. Although comparatively rare, at least in terms of the number of separate incidents detected and reported, the use of counterfeit or substandard starting materials to produce API or other raw material for (or by) legitimate pharmaceutical manufacturers is not unknown. This may occur knowingly or, more commonly, the final manufacturer may have no idea that they are using counterfeit raw materials until an adverse incident occurs. After discussions with several manufacturers, it is clear that some feel that the reported and known cases of API adulteration and fraud may be just the tip of a very large iceberg. Since the crime occurs at the raw material stage, it is very hard to detect but has the potential to affect many patients, both directly because of the adverse reactions to contaminated products and indirectly because of the withdrawal of supplies during product recalls. One of the few pieces of analytical evidence about the prevalence of falsified API involves gentamicin sulphate.1 The results of the study indicated that one-third or more of the gentamicin samples that were examined may have been falsified.

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These were not samples taken from street markets in Africa but from European and US locations. One of the best studied incidents in recent years occurred in the United States in 2008. In January that year, Baxter Healthcare Corporation’s pharmacovigilance (drug safety) group, routinely monitoring reports of adverse drug reactions, detected an increase in allergic reactions associated with heparin sodium injection, a commonly used anticoagulant.2 From a monthly baseline of 4 or 5 reported deaths of people taking heparin, the figure for January 2008 went up to 50 reported deaths.3 At that time, Baxter supplied 50% of the US heparin market. Working with the FDA, Baxter quickly recalled of all of its vial-based heparin products in the United States. Baxter scientists developed nuclear magnetic resonance (NMR) and capillary electrophoresis (CE) tests, which detected a contaminant, oversulphated chondroitin (OSC) sulphate, in the crude material used by Baxter’s supplier in China to make the heparin API. The contaminant had been chemically modified and was so heparin-like that it was not detected in standard batch testing. It seems to have been introduced before the material reached Baxter or its immediate supplier. Subsequent animal tests confirmed that the contaminant was responsible for the allergic effects seen in affected patients. The majority of the world’s supply of crude heparin comes from China. Though Baxter was first to recall heparin, after the contaminant was identified and testing protocols were shared with other manufacturers globally, over a dozen other companies in several countries issued recalls, which all linked back to supply points in China. The deliberately added adulterant was much cheaper than heparin, which was in high demand and short supply—the perfect conditions for pharmaceutical crime. The episode was financially expensive for Baxter, which recorded a direct charge in its 2008 accounts4 of $19 million (for comparison, its annual heparin sales were $30 million in 2007) and Baxter may have further legal liabilities pending the outcome of associated lawsuits. More importantly, at least 81 and possibly over 100 people are thought to have died as a result of the episode,5 although FDA notes that “In the majority of [Adverse Event] reports with a death outcome, there was not enough clinical information to assess the relationship between death and the use of heparin.”3 The heparin case is complex and has many lessons for the drug industry, but the main defense against such fraud is a rigorous and ongoing focus on supply chain security, supplier validation, and verification of material received.

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In Europe, the European Directorate for the Quality of Medicines and Healthcare (EDQM) is the body responsible for the quality of drugs and has a particularly critical role in assuring the quality of APIs. It sets and monitors the standards of the European Pharmacopoeia and ensures the application of these official standards to substances used in the production of medicines. EDQM also co-ordinates a network of Official Medicines Control Laboratories (OMCL) and collaborates with national, European, and international organizations in efforts to combat counterfeiting. To gain a Certificate of Suitability to Monographs of the European Pharmacopoeia (CEP), a company must provide a declaration to the EDQM that it is operating in accordance with good manufacturing practice (GMP). Importantly, pre-approval inspection of the manufacturing site is not necessary. Once a CEP is granted, the supplier can sell its product for use in medicinal products sold in the EU. The list of granted CEPs is available online. EDQM carries out periodic inspections of API manufacturing sites (either directly or via recognized regulatory agencies) to ensure compliance. As with most audit mechanisms, the comprehensive and repeated coverage of all manufacturing sites is not feasible given limited EDQM resources. The CEP system simplifies the trade in pharmaceutical substances and ingredients within Europe and is recognized by all Member States of the European Pharmacopoeia Convention as well as US FDA and other major regulatory authorities. A CEP is valid for five years and must then be renewed. It is then valid for an unlimited period unless suspended or cancelled. EDQM can suspend CEPs for manufacturer non-compliance or non-agreement to be audited, and does so on a regular basis. Until 20 or 30 years ago, pharmaceutical manufacturing in the multinational corporations was a relatively simple environment, at least in terms of ownership and accountability. Each producer maintained a network of large plants in developed countries, producing for domestic consumption and export, and local facilities producing some of the simpler products in the larger, distant markets. The production network was usually wholly owned by the parent corporation, providing a high degree of control. However, fluctuations in demand and the difficulty of balancing geographically distant capacity meant that this system often came at the expense of operational efficiency. Corporate mega-mergers, and resulting efficiency programs, have meant that the modern pharmaceutical industry is now very different. Most corporations are now heavily dependent on outsourcing and the use of third-party suppliers, such as contract manufacturing organizations (CMOs), for some or all of their production. These supplier companies may also outsource or subcontract parts of their production process, and so on in turn for several more layers. The modern

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pharmaceutical product may contain components sourced from around the globe. This complexity and flexibility allows supply to be tuned more precisely to demand, and the competition among suppliers has contributed to reduced operational costs for brand owners and thus to better returns for their shareholders. However, the same phenomenon means that many brand owners now have a very diverse and hard-to-manage manufacturing base. The severe price competition, coupled with the difficulty of regular audits and oversight, provides opportunities for unscrupulous operators to cut corners. In order to deter counterfeiting, it is essential that the pharmaceutical manufacturer maintains full control and visibility of all stages in the manufacture of the final product. Since theirs is the brand name on the pack, they will bear by far the largest impact should an incident relating to product quality occur. Many of the simple security countermeasures that can be taken at the raw material stage should be self-evident in any quality-focused organization. However, it is surprising how often corporations rely on factors other than scientific data—trust, previous experience, or unverified business references—when using external suppliers. Even if they conduct appropriate due diligence before using a new supplier, many pharmaceutical companies cannot or do not audit those suppliers on a frequent basis thereafter. As noted by the industry-led Rx360 consortium,6 it is almost impossible for an individual pharmaceutical company to audit all of its many suppliers on a regular basis—due to lack of time and resources. The Rx-360 consortium has therefore proposed a shared audit mechanism, to enable fuller coverage of the pharmaceutical supplier base in a collaborative manner. Audit findings, and the costs of the audit process, will be shared among participating organizations. This may represent a significant enhancement in the oversight of the supplier base. The challenge for individual manufacturers will be to ensure that their own corporate liability issues are addressed adequately by such a shared system. However, the potential of the Rx-360 approach has been enhanced by support from the United States Federal Trade Commission (FTC), which has stated that it will not oppose the shared audit system.6 The Commission is satisfied that safeguards are in place to prevent the concerted misuse of shared information for commercial gain and that only non-competitive information will be shared. This opinion removes a significant potential barrier, since the implementation of the system could have been blocked if the FTC had expressed concerns on anti-competitive grounds. Inbound shipments of bulk material should always have a full supply chain history and clear “chain of custody.” They should also, whenever feasible, be packaged in tamper evident containers during shipment from supplier to production facility. Sealed, transparent, “bulk bags” can be

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used for many solid dosage forms to enable visual inspection of the material without contamination. Some non-invasive, non-destructive measurement techniques, such as near-infrared (NIR) detection, are able to penetrate such double-bagged consignments to analyze the pharmaceutical material inside. See Chapter 15 for a full description of these techniques. For certain high-value bulk ingredients, it may also be desirable to use devices that record the location of the product during transit. Usually based on the global positioning system (GPS), which triangulates the position of the receiving device with reference to a satellite network (in the same way as a car’s satellite navigation system), these tracking devices can be costeffective for large shipments of valuable products and give a detailed history of the product’s position on its journey from supplier to manufacturer. Incoming material should also be thoroughly checked and, if necessary, analyzed before use. The best approach in fighting counterfeit raw materials is to think like a criminal and ask “how could my quality control processes be circumvented?” As well as keeping records of what the analytical profile of the genuine product should look like, the security and quality assurance (QA) groups should keep alert for external reports of substances or processes, which could make a fake product look sufficiently like the genuine one so that it passes the standard quality tests. Such information could be found in the scientific or commercial literature or could come from tip-offs and human intelligence. In the case of the 2008 heparin episode, the analytical tests then in use did not highlight the fraudulent switch of OSC sulphate in place of heparin. The counterfeiters almost certainly knew which analytical tests would be used by Baxter and its suppliers, and had presumably tested their counterfeit material to ensure that it passed those tests. The same phenomenon has been noted for counterfeit artesunate drugs in Southeast Asia7 and for melamine in baby milk formula in China.8 However, using a simple and well-known analytical test on incoming material to identify diethylene glycol (DEG) could perhaps have saved the lives of over 100 people in Panama who were killed in 2006 by DEG-contaminated glycerol in cough syrup.9 Similar incidents involving glycerol have been reported in a number of countries and have been linked to the deaths of hundreds of people including many children. The incidents are related both to accidental contamination of glycerol and to intentional substitution of cheaper alternatives and mislabeling. According to the European Medicines Agency (EMA):10 Recent cases [involving glycerol] show the following similarities: • Pharmaceutical manufacturers of products containing contaminated glycerol did not perform full identity testing or tests to determine DEG on the glycerol raw material.

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• Pharmaceutical manufacturers of contaminated products relied on certificates of analysis (COA) provided by the supplier. • The origin of glycerine was not apparent from the COA. The COA provided with the glycerol raw material may have been a copy of the original on a distributor letterhead. The supply chain for glycerol was not readily known by the medicinal product manufacturer because the glycerol may have been sold several times between its manufacture and the medicinal product manufacturer.

These are the common factors across several cases and multiple manufacturers. It is clear that reliance on the Certificate of Analysis as the only quality check on incoming raw materials is a highly dangerous practice. The principle of caveat emptor must be borne in mind and manufacturers should always conduct their own checks and analyzes. Some structural and legal problems also need to be addressed in tightening the supply chain security for API and excipients. Criminalization of the production and supply of falsified or counterfeit API is inconsistent. Implementation of appropriate legal sanctions and penalties is patchy and poorly enforced. At present, the legal definition of a counterfeit drug does not always include drugs made by legitimate suppliers using components containing counterfeit ingredients, which have been introduced further back in the supply chain. This often leads to buck passing if a quality issue flags up a possible counterfeit incident and can allow criminal intermediaries to escape liability. Global coordination of production facility inspections by national regulators, with audits performed on a risk-assessed basis, would be a step forward. At present, due to lack of such information sharing or coordination across borders, there are often multiple inspections of some very high performing, low-risk sites and not enough attention on critical risk areas elsewhere in the world. This should not be a process restricted to the traditionally strong regulatory regimes such as the United States, Europe, and Japan. Emerging manufacturing countries, such as Brazil, are already competing on a global scale and their pharmaceutical regulators are conducting a large number of site inspections overseas. By establishing a mechanism whereby regulators can join forces, a more even inspection coverage could be ensured. Finally, an improvement in the global traceability of bulk API and excipients is also needed. This will be a technically difficult but vital development. Since a single large API production batch may be used in finished product destined for several countries, full traceability will allow better international notification of unusual adverse event profiles linked to particular batches. Since tracing the origin and final destination of bulk API directly (rather than via paperwork) is still difficult, the next best thing is to verify the finished product or its packaging. The next chapter looks at how the final product can be authenticated.

Chapter

14

On-Dose and In-Dose Authentication Despite the major threat posed by counterfeit API and excipients, it is difficult to mark the product or add tracers at this stage without interfering with its composition. It is also problematic to trace any marker added at the bulk stage “downstream” in the manufacturing process with any geographic or temporal resolution, since a raw material supplier may supply many final product manufacturers. Most approaches to the verification of genuine pharmaceuticals have therefore focused on analyzing or altering the finished product or its packaging, for various reasons of practicality and security. By applying security features at this later stage, a manufacturer can more readily differentiate between finished batches made from the same bulk API at different times or between runs of the same product intended for different markets. In theory, the best place for authentication techniques to be used is as close to the final dose as possible. The patient does not swallow the box, bottle, or blister pack, only the pill. By marking the genuine dosage form in a way that it can be readily differentiated from counterfeit product, the line of association between ingestion of counterfeit product and harm to the patient can be shortened. If the patient reports an adverse reaction and is still in possession of some of the dose, then a lack of the expected security features is a very strong indication that the adverse reaction may be due to counterfeit product. The presence of security technologies on or Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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in the substance that is actually swallowed (or injected, inhaled, etc.) is therefore an important consideration, particularly as the original packaging is often not retained by the patient and may therefore be unavailable in the event of a suspected counterfeit incident. The patient may not even see the packaging: in many countries, pills are sold in small quantities or by other sales routes than those originally intended by the manufacturer. Pharmacists may dispense individual strips, or even single pills from a blister pack. This practice may often be a commercial necessity, allowing the poor to buy their medicines using regular but small payments when they cannot afford the price of a whole pack. It also provides the opportunity for unscrupulous sellers to peddle expired, counterfeit, or substandard medicines. From an anti-counterfeiting perspective, the effect of this practice of separating the product from its original packaging is to make it harder to obtain evidence that fake medicines were involved if the patient suffers an adverse reaction. If an identifying mark or security feature was present only on the secondary box, or in one place on the blister pack, then it may never be found in association with the affected patient. Onproduct or in-product marking means that every pill or every dose can be verified as genuine even in the absence of packaging. The principle differences between on-dose and in-dose approaches are described below.

ON-DOSE FEATURES

The authentication process at dose level can either involve inspection or analysis of intrinsic features of the product, or the addition and detection of extra ingredients acting as tracers or taggants. The careful design and use of intrinsic features is perhaps the simplest method and can provide a useful defense against more unsophisticated copies. By paying attention to the distinctiveness of the pill, capsule, or other primary dosage form, and making those features as hard as possible to duplicate without special tools or equipment, brand owners can raise the bar for counterfeiters without incurring significant extra cost. The use of sophisticated tablet presses1 is one of the key competitive advantages between a pharmaceutical manufacturer or CMO and a low-grade counterfeiter and this advantage should be maximized wherever possible. Aspects such as the shape and tooling of the dosage form should be given thorough consideration very early in the development of the manufacturing process for a new product, and ideally the corporate product security function should be represented when design decisions are made. From a security standpoint, simple, common shapes should be avoided whenever possible. Similarly, the texture and granularity of the product

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Embossing, debossing, etc. Printing, coating, etc.

L

PIL

10 Shape, tooling

Texture, granularity, etc.

Figure 14.1. On-dose authentication features.

may give an opportunity to differentiate its feel, appearance, and (where appropriate) dissolution characteristics, in a way that is difficult to replicate. Embossing (adding raised features) and debossing (adding sunken features) can be included during the pressing stage to give extra distinctive detail on the capsule or pill surface (Figure 14.1). The addition of non-printed surface features can now also be achieved at various levels of resolution using lasers and other proprietary techniques, which modify the outer surface or coating but do not add any additional chemicals to the tablets or capsules. It is even possible to add coded information to each pill or capsule in this way. A useful alternative approach is surface marking. The FDA implicitly recommends this approach where possible, to avoid contact and potential interactions between the marker and the active ingredient or excipients. Surface marking is only applicable for solid dosage forms (although some technologies can also be used to covertly mark vial caps for injectable products), but it can have many advantages over the use of trace ingredients mixed into the API itself. With surface marking technologies, nothing is added to the bulk formulation itself and the composition and stability are (in theory) not changed in any way. The surface of the dosage form is altered by printing or coating it with specific features. There are a number of alternative technologies available, many using closely guarded proprietary methods, but all of these approaches mark the product in some way either using physical means, or by printing (most commonly using inkjet technology and ingestible inks). The possibilities range from allover effects, such as pearlescent or colored inks and coatings, to specific

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logos, text, codes, or other surface effects. With some marking technologies, the addition of variable data is also possible, allowing individual pills or capsules to be identified and traced to an individual production batch. The development of non-contact print technologies means that this individual marking can now be done at full production speeds and at very high resolution. Some marking technologies are also multilevel. There may be a visible element or mark, which gives a yes–no authentication of the product. This is a valuable tool for the quick field assessment of a potential counterfeit. There may also be one or more additional marks or even codes, either visible or (more usually) covert. Visualization of these codes generally requires some form of magnification or visualization device and they give access to more detailed information, either directly printed or via association of the on-product code(s) with information held in a database. These data can include information about the product (dosage strength, expiration date), manufacturing details (location, date, batch/lot number), and possibly even the intended distribution path (country, distributor, wholesaler, chain). These technologies are developing rapidly and provide very interesting opportunities for the future in the protection of solid dosage forms. All of the on-dose techniques, which involve the addition of chemical markers or colorants to the surface of the dosage form, must use materials that are tested and accepted as safe by FDA. The simplest way to ensure this is to use food-grade dyes or other substances already on FDA approved ingredient lists. Some newer products, such as pearlescent inks, have been specifically tested and the safety profile submitted for FDA review and approval.

IN-DOSE FEATURES

Since it is the substances that enter the body—by ingestion, injection, inhalation, etc.—which have the capacity to cause most harm to the patient, it would seem obvious that security features should be fully integral to those elements of the product. Some of the on-dose technologies discussed above are visible and accessible on the surface of the dosage form and could, in theory, be removed by someone determined enough to do so. Full integration of the tracer into the product makes its removal almost impossible. This is the rationale for in-dose marking technologies, which are typically used with oral dosage forms, such as pills and capsules, but they can also be used in liquids, creams, and other dosage forms. However, there are various complications and difficulties in using the final dosage form as a carrier for authentication or tracking information,

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particularly for techniques that require chemical additions to the product. Whether printed on the surface, applied as a coating, or mixed with the active ingredients, all security additives must be tested to ensure that they do not compromise the safety of the product, either directly or by interacting with one or more of the other ingredients. The best substances to use for tracer additives are therefore those which are already approved by regulatory authorities. The US FDA maintains a database called the Inactive Ingredients Guide (IIG),2 which details those inactive ingredients already registered for pharmaceutical use. They also publish information on substances used in food or medicines, which are “generally recognized as safe” (GRAS).3 These two categories of ingredient can be used in formulations with minimal further testing (but see the discussion below) and are therefore potentially the simplest and most cost-effective route to product marking. However, if the approach taken is too simplistic, then these compounds may also be relatively simple for criminals to analyze and identify and therefore may be copied readily. A combination of IIG or GRAS additives, used in a known and carefully defined ratio to make a “chemical fingerprint,” is a more secure option. Whatever marker is chosen, it is important to check that it does not have an effect on the active components of the dosage form itself. This can be tested initially in the laboratory prior to formulation, but must also be tested in the final product, particularly in the case of solid oral dosage forms (SODFs), which are complex or multilayered such as sustainedrelease or delayed-release formulations. Even the constituent that is apparently safe when tested separately could have an unforeseen interaction, perhaps causing degradation products or shortening the shelf life of the product, or altering the controlled release characteristics of the active ingredient. After many years, when the regulatory environment was uncertain and manufacturers were reluctant to incur the potential regulatory burden of including chemical markers in their products, the FDA has recently gone a long way to clarifying the situation. They issued a Guidance document in July 2009 on the inclusion of physical–chemical identifiers (PCIDs) into SODFs.4 In their view: Examples of substances that may be incorporated into SODFs as PCIDs include inks, pigments, flavors, and molecular taggants. Such PCIDs may allow product authentication by their presence alone or may be used to code the product identity into or onto the SODF. There are various available means for presentation and detection of PCIDs (e.g., photolithography, holography, laser scanning devices, and excitation/ fluorescence detection). Many identifying characteristics, such as pigments or flavors, could be easily observed by patients, healthcare practitioners,

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and pharmacies. Some could require the use of instrumental detection (e.g., a scanner or photometric detector). FDA anticipates that many of the ingredients that will ultimately be employed as PCIDs are already used as food additives, colorants, or excipients with established safety profiles.

As already noted above, this last point recommending the use of preapproved substances is important when considering this approach to product protection, and heeding the FDA advice will provide the shortest path to approval. Many suitable anti-counterfeiting additives are already approved for use—do not develop a new one just for the sake of it. The FDA also states: If an applicant incorporates a PCID into a solid oral dosage form, we recommend that the ingredients comprising the PCID be pharmacologically inactive so the ingredients can be treated as excipients. To minimize toxicological risk, FDA recommends using permissible direct food additives including those affirmed as generally recognized as safe (GRAS) or those ingredients listed in the FDA Inactive Ingredient Guide (IIG).

The physical structure of the SODF itself has a strong bearing on what approaches are most suitable for the direct incorporation of anticounterfeiting measures. Many modern pills and capsules have several functional layers. In the view of the FDA: When considering where to place a PCID, the applicant may find it helpful to conceptually subdivide an SODF into sections that differ in composition that may or may not contain active drug substance. For example, a core section in an SODF is likely to contain one or more active drug substances, while the external sections of the SODF may not. If an applicant places a PCID inside a core section of the SODF, that placement may increase the chances of interactions with the drug substance that could result in degradation. If the applicant is concerned the PCID will interact with core components, incorporating the PCID into an external section of the SODF (e.g., in a coating or an ink-imprinted logo) may reduce the possibility of such interaction.

In the case of sustained or modified-release dosage forms: The applicant should also consider whether the presence of the PCID might interfere with control of the release rate of a modified-release SODF (SODF-MR), which includes extended-release and delayed-release dosage forms. Thus, FDA recommends that the applicant consider incorporating

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the PCID into a section of the SODF-MR that does not contain any releasecontrolling excipient.

The welcome FDA guidance on this issue is likely to lead to new product security possibilities, but the interested reader is advised to check the regulatory aspects very carefully before making any decisions. REGULATORY REPORTING

According to the FDA guidelines (consult FDA website www.fda.gov for current versions) depending on the toxicological considerations and SODF design factors, the addition of a PCID must be reported to FDA in one of three ways, in ascending order of potential risk to the integrity and function of the product: Annual Report: If the change would have a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product and the applicant’s evaluation of the drug product containing the PCID finds no adverse effect, then the change may be reported with the next Annual Report. “Changes Being Effected (CBE )” Supplement: If design factors elevate the risk of the change, such as adding a PCID to a core section of the SODF or adding a PCID to a section of a modified-release SODF that contains a release-controlling excipient, the applicant should submit a CBE-30 supplement. Prior Approval Supplement: If the incorporation of a PCID would have a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product, and/or the substance does not appear on the GRAS list or the IIG, the applicant may not market the modified product unless a prior approval supplement is submitted and approved. Recently, the encouragement of quality-by-design (QbD) and risk management5 techniques by FDA and others means that manufacturers are expected to pay special attention to quality processes in the formulation area. QbD aspects of additives for anti-counterfeiting and identification purposes are therefore likely to be an increasing focus of regulatory review processes. Both immediate and future regulatory impacts (see below) should therefore be carefully assessed at an early stage when evaluating any anti-counterfeiting feature that may be in contact with the active ingredients.

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Changing the formulation of a marketed product has many quality, regulatory, and administrative implications. As well as formal notification to the regulatory authorities, it may also require extensive revalidation of manufacturing processes in order to comply with Good Manufacturing Practice. All of these processes can be expensive in both time and resources. It is therefore problematic and potentially costly to add an indose marker to an already approved and marketed product. The use of on-dose (rather than in-dose) methods can be slightly easier to retro-fit to existing products, especially where no overt changes to the product appearance are made. Whenever possible, the best time to consider the addition of security features into the formulation itself is during development. At this time, they can be relatively simple to integrate into the normal formulation development and testing processes. LABELING AND DISCLOSURE OF ON-DOSE AND IN-DOSE APPROACHES

The public disclosure of the presence of an anti-counterfeiting feature (e.g., by including a statement on the product labeling) is generally avoided, unless the feature is aimed at the general public. In this case, the label should clearly state what to look for (e.g., a blue logo on the pill, marbled effect on the capsule, and so on) and not its chemical nature. The FDA states: At their discretion, applicants may decide whether or not to revise the labeling of the SODF to indicate the incorporation of a PCID. For example, applicants may wish to revise the labeling to alert healthcare practitioners and patients that the SODF has a PCID with unique visual features so that the practitioners and patients can verify that the drug product they receive contains the PCID.

As with all labeling changes relating to US pharmaceutical products, any revisions due to the addition of anti-counterfeiting features are subject to the reporting and approval requirements under 21 CFR 314.70.6 CONCEALMENT OF IDENTITY

Unless the feature is specifically aimed at consumer recognition, the ability to conceal the chemical identity of the PCID from counterfeiters is important. Any requirement for full disclosure of all ingredients and impurities during the marketing authorization process, and potential public availability of that information subsequently, can negate the value of

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trace materials and markers. Disclosure is inherently counterproductive– a covert security feature is only useful if it is hard for counterfeiters to discover and reproduce. The potential for disclosure, and its consequences, should also be borne in mind when launching products into new markets. If the national registration process for the new market requires the disclosure of covert markers, which are already in use in the same product elsewhere, then the security of those features is also compromised. Even the inclusion of sensitive product marker information in confidential submission dossiers should be avoided if possible. Government departments, including drug regulators, are not fully secure in many countries and sensitive information can sometimes be bought. Criminals are not slow to put information together and can now coordinate their activities internationally. Careless or inadvertent disclosure by a brand owner in one country can have expensive consequences for their business elsewhere. The same rationale applies when prosecuting cases for IP infringement or defending liability cases in counterfeiting incidents. Disclosure during the trial process compromises the usefulness of covert features, therefore forensic-level features are usually not disclosed unless absolutely necessary. Anecdotal evidence suggest that some companies have dropped cases where they have a low chance of winning, in order to avoid disclosure of their anti-counterfeiting technologies and to prevent wider exposure of their products (and patients) to danger.

ON-PRODUCT AND IN-PRODUCT APPROACHES AIMED AT CONSUMERS

Direct marking techniques can be very effective for certain products. However, the on-product and in-product marking approaches described above can sometimes be difficult for the consumer to interact with. Many techniques, though providing very valuable information to the brand owner, require specialist equipment for verification and can only be conducted by trained operators. Typically, these approaches are reserved for vulnerable or high-value products where the benefits outweigh the disadvantages. If the consumer is to be the primary target of this type of authentication feature, then more accessible techniques, such as visible printing of logos or text onto pills or capsules, incorporation of distinctive scent or flavor, or the use of marbling, metallic, or other restricted-availability coating effects, are more appropriate. Although the simple use of distinctive shape, decoration, and color to differentiate products is a useful and important first step in making products harder to copy, it is no longer enough by itself

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to deter the more determined counterfeiters. Criminals will use anything from road paint to printer ink to approximate the necessary color, and can often replicate tablet dies and stamping patterns quite well. Although not usually perfect replicas, such approximations can frequently be enough to fool the average consumer.

FORMULATION ADDITIVES IN PRODUCTS OTHER THAN SODFs

SODFs, such as pills and capsules, are not the only product type that may be suitable for the integration of tracers and taggants into the formulation. As noted above, the addition of extra, traceable ingredients to the alreadymarketed products can be problematic. If carefully planned, however, the addition of such additives to newly developed products can provide excellent levels of traceability at relatively low cost per unit. Unlike direct marking, which obviously requires a solid surface on which to place the mark, the physical—chemical identifier approach is also applicable to products that are not available as SODFs. These may include injectables, creams, ointments, syrups, suspensions, and inhaled products. An added advantage of PCIDs in liquid dosage forms is that quantitative as well as qualitative analysis of the marker can help to identify unauthorized dilution of the product. The formulation principles and regulatory requirements of using markers in these products are broadly the same as for solid dosage forms. GRAS and IIG substances should be used wherever possible. It is generally more difficult to physically separate the marker from the API in these presentations, so interactions must be anticipated and tested. For this reason, it is usually only practical to add markers to new products rather than to retro-fit them to existing products.

Chapter

15

Analytical Detection of Counterfeit Dosage Forms Since pharmaceutical counterfeiting is primarily a form of visual deception, counterfeiters tend to focus most of their energies on replicating the things that can be easily seen and checked. Therefore, packaging quality is usually high (and fake packaging is often very hard to distinguish from that of the genuine product) but the dosage form itself is often substandard. Even if it has some active ingredient, the product is unlikely to have the same physical or chemical profile as the genuine formulation. One of the most powerful and direct methods to detect counterfeit products, therefore, is to analyze the properties of the product itself. This can either be achieved using laboratory-based testing of purchased or seized samples, or can increasingly be done using portable, non-invasive techniques. These analytical methods can also be applied to packaging (see following sections), but are especially effective when used to validate the active ingredients and chemical constitution of the dosage form itself. Because these techniques rely only on physical or chemical properties of the product, they are extremely difficult for criminals to circumvent using counterfeit materials. Although this section is about analytical techniques, we should not forget the obvious in pursuit of a technological solution. The simplest non-destructive method is visual inspection by a well-trained investigator. None of the methods below should substitute for regular communication Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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and liaison by brand owners with customs officials and law enforcement. The value of such a rapport should not be underestimated. If a suspect product is identified and the brand owner cannot be present in person, then they may still be able to advise based on visual inspection—mobile phone communications allow pictures of the suspect product to be sent round the world very quickly. A crumbly, gritty, off-color copy can be differentiated from the original pill in this way without the need for a corporate investigator to have it in his hand. This allows law enforcement to impound the consignment quickly and gives time for the brand owner to react and put the necessary supporting resources in place to help investigate the event. A wide range of techniques is used in the assessment of pharmaceutical quality during and after manufacture, and I direct the reader to other sources for a fuller discussion of analytical techniques used during production.1 Although not all of the techniques used in the factory QA process are suited to the routine search for counterfeits, there are many which can be adapted successfully. The potential methods that are available can be broken down into a number of categories.

SIMPLE CHEMICAL AND PHYSICAL ANALYSIS METHODS

In a safety-sensitive, highly regulated, and technology-intensive industry like pharmaceuticals, many of the problems and challenges that we face tend to need complex technical solutions. The attempt to control and eradicate counterfeits is no exception. However, it is not always possible to deploy these solutions out in the markets where counterfeit drugs are most common. Nor is it possible to send large numbers of seizures or test purchases of pharmaceutical products to the brand owner’s laboratory in order to identify the minority which are counterfeit. In many cases, some form of triage process is appropriate, with simple, portable techniques used on a wide scale and more complex laboratory tools used when suspicions are raised. Therefore, anti-counterfeiting strategies should not overlook some of the more straightforward ways of looking for fake drugs. Some simple techniques that have been around a long time are still perfectly serviceable as frontline tools. They often have the advantage of being easy to teach, relatively cheap, and applicable to use in developing countries where the counterfeit problem is most acute. These simple analytical techniques can often rapidly differentiate between very similar looking products. Although the techniques below are described individually, in practice they are often used in combination for maximum effectiveness. For example, several of these basic tests have been incorporated by the Global

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Pharma Health Fund (GPHF) into a field kit2 known as GPHF-Minilab®. This provides a basic drug testing capability that is portable (it packs into two suitcases) and provides testing capability for a wide range of active ingredients. The GPHF website3 provides further details of the tests and the drugs covered. Aimed primarily at developing countries, this initiative is a good example of pragmatic, low-cost testing that can be undertaken by local staff. Since counterfeits are often rife in remote areas, the portability of the Minilab increases the area that can be analytically surveyed for fake drugs. Colorimetry

This is a useful and simple field method that involves testing for an active pharmaceutical ingredient (API) using a reagent that reacts with it to cause an observable color change. Such reagents are available for a wide variety of common APIs. Absence of the color change, or a weak reaction, is evidence that the test sample may be a counterfeit. The technique is usually only semi-quantitative, and is best used as an initial test to identify candidates for further testing. However, colorimetry can prove valuable as a triage technique in saving time and resources in the field and helping to prioritize samples for further testing.4 For example, the Fast Red TR colorimetric test, used to test for the anti-malarial drug artesunate, has been combined successfully in this way with laboratory analysis by liquid chromatography combined with mass spectroscopy (LC-MS).5 As with many colorimetric tests, the Fast Red TR test is quick, simple, and inexpensive but not foolproof. Counterfeiters are starting to circumvent it by adding small amounts of artesunate to counterfeit anti-malarial drugs. This makes detection of the fake drugs more difficult, but more importantly it could have a devastating effect on public health in malariaprone areas. The prevalence of sub-therapeutic artesunate could increase the resistance of malaria parasites to this important drug. The addition of sub-therapeutic quantities of API (or masking agents that mimic the expected result) to defeat standard tests means that colorimetric tests should be used with caution, but still have a role to play in the fight against fake drugs. Hardness and Dissolution Tests

These tests can be effective, especially against less sophisticated copies, and are also relatively cheap. A very crude measure of hardness can often be gained by hand: poor quality counterfeit tablets are often crumbly or brittle. Most genuine pills cannot easily be crushed to dust between

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finger and thumb, so a particularly fragile tablet is often the result of poor manufacturing using a simple, hand-operated tablet press. There are also quantitative analytical methods that can be used to test hardness more accurately. These measure the compressive strength of the tablet, or the force (expressed in newtons, N) that it can withstand before failing. The dissolution profiles of pharmaceuticals have a direct bearing on their pharmacokinetics (the action of drugs in the body over time) and their efficacy. The dissolution parameters are therefore carefully designed, tightly controlled by the manufacturer, and closely examined by the regulatory authorities. They are highly predictable and reproducible between batches for a genuine product. By dissolving the suspect counterfeit product in water or a solvent, and comparing the rate of dissolution with that of a known, genuine reference sample, the analyst can determine any differences between the two. The dissolution profiles of two separate formulations rarely match by chance and counterfeiters do not usually spend resources matching the characteristics of the real product. Consequently, anomalies in dissolution profile have been a valuable indicator in identifying counterfeit and substandard drugs, such as anti-infectives.6 Various analytical methods can be used to determine dissolution rates, from visual inspection and the fairly simple tests used in the GPHF-Minilab® to more technological approaches.7 Thin Layer Chromatography (TLC)

Thin layer chromatography (TLC) is a simple, low-cost technique that can be applied to a wide range of drugs and is suitable for use in mobile laboratories and in developing countries. It is conceptually similar to the schoolroom experiment of separating the pigments in a spot of black ink using filter paper dipped in water. Typically, in analytical TLC, the test sample is first dissolved in solvent or a mix of solvents and applied as a small spot or thin horizontal line several centimeters from one end of a silica-coated glass plate. The plate is then thoroughly dried, as residual solvent in the plate affects the resolution of the separation. The dried plate is placed in a shallow pool of solvent in a lidded test chamber. The choice of solvent (known as eluent or the mobile phase) affects the separation characteristics and for new analytes may have to be determined by trial and error. The Minilab kit contains detailed pre-determined standard procedures for common pharmaceutical analytes. For optimum resolution, it is important that the test chamber should contain an environment saturated with solvent vapor—this is often achieved by dipping filter paper into the solvent and allowing the wet filter to sit on the inside wall of the developing chamber. It is important that the sample spot remains above

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the initial level of the solvent. The solvent diffuses upward through the silica plate (known as the stationary phase) and when it reaches the sample application area, it causes the components of the dissolved sample to migrate upward through the rest of the silica matrix at different rates. Before the upward-migrating solvent front (i.e., the edge of the “wet” area of the plate) reaches the top of the plate, the plate is removed from the chamber and is then dried. Since many analytes are colorless, the plate usually then needs to be developed with a suitable chemical to reveal the pattern of spots—potassium permanganate or iodine are often used. The developed plate can be visualized under visible or UV light (depending on the plate chemistry and developer used). Comparison of suspected counterfeits with reference samples on the same plate provides a relatively quick, but not foolproof, field test of authenticity. The separation of products can be converted into a semi-quantitative number called the retention factor (Rf ), which is the ratio of the distance moved by the analyte to the distance moved by the solvent front. This is prone to variation depending on the exact physical conditions of the experiment, therefore is not fully comparable between experiments. It is always preferable to use reference standards on the same plate to provide a direct comparison. The Minilab provides materials and full methods for the TLC analysis of a number of different drugs. Ultraviolet and Visible Spectroscopy

Spectroscopy is the study of the light emitted or absorbed by a sample as an incident light beam passes through it. The simplest and oldest technique is visible spectroscopy, which derives from studies of the effects of prisms on a light beam. Modern instruments typically measure in both ultraviolet and visible areas of the spectrum, hence the technique is often known as UV/visible spectroscopy. Many APIs and excipients have characteristic absorption spectra when examined under ultraviolet or visible light, so this technique provides a useful, simple, and quantitative approach to determining the presence and concentration of the key constituents of a pharmaceutical preparation. The absorbance of a solution is directly proportional to the concentration of the absorbing compound(s) in it and to the distance the light travels through the sample (the path length), a relationship known as the Beer–Lambert law.1 Thus, if a fixed path length is used (typically, a 1-cm cuvette), this relationship can be used to determine the concentration of compounds in a test solution by reference to a calibration curve. In order to maximize the visibility of the signal from the analyte and to prevent background interference, the absorption of UV/visible light by the solvent itself needs to be minimized: ethanol and water are usually

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the solvents of choice since they do not absorb strongly in this region of the electromagnetic spectrum. The spectrophotometer corrects for the absorption of the solvent by subtracting a reference spectrum (obtained using a separate cuvette containing only solvent). This allows measurement of only the residual light due to the absorption of the dissolved molecules, which is usually plotted as a graph of light intensity versus wavelength. UV/visible spectrophotometers are relatively inexpensive and portable pieces of equipment and with simple calibration can be very accurate and quantitative. They can be used on a standalone basis with manual filling of glass or silica cuvettes. Care should be taken in sample preparation to ensure that the test material is dissolved and during removal to ensure that the cuvettes are thoroughly cleaned between samples to prevent contamination and erroneous results. Automated UV/visible spectrophotometers, with continuous flow cells rather than manual cuvettes, are also useful as downstream detectors after separation of sample constituents by liquid chromatography (LC).

LABORATORY-BASED METHODS

The methods described above are all quite portable and lend themselves to field-based testing. However, not all samples are suitable for these techniques and there are often challenges in sample preparation and analysis. This, coupled with the need for greater analytical resolution in differentiating more sophisticated counterfeit products, means that laboratory methods are often needed. The techniques described below represent a cross section of the methods used, but this is not an exhaustive list. Some of them are also available as portable instruments. Note that many brand owners do not disclose their analytical methods, for obvious security reasons. Atomic Absorption Spectrophotometry (AAS)

This method requires the sample to be atomized (usually with a flame) and illuminated by a light beam. The light is then analyzed after passing through the sample to give a quantitative breakdown of the elemental composition of the sample. Modern instruments allow the direct analysis of solids without the lengthy sample preparation required previously. Typically used to detect metals, this technique is not normally used in the first-line testing of suspected counterfeits but may provide useful confirmatory information.

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X-ray Techniques

In contrast to atomic absorption spectroscopy (AAS), X-ray fluorescence spectroscopy8 is a non-destructive technique but one which also probes the atomic structure of a sample. Energy dispersive X-ray spectroscopy (EDX or EDS) is one of the commonly used variants, and uses a beam of either charged particles or X-rays to eject electrons from the inner orbital shells of the constituent atoms of the sample. The return of the atoms to the stable ground state, as the empty inner orbitals are refilled with electrons from the outer shells, is accompanied by the emission of X-rays. The energy of the emitted X-rays is related to the difference in energy between these two electron shells, which is distinctive and predictable for different transitions in different atoms. A plot of the number and energy of the X-rays emitted therefore gives the elemental composition of the sample, which can be compared with known reference standards. In the laboratory, the technique is frequently coupled with scanning electron microscopy (SEM).

Nuclear Magnetic Resonance (NMR) Spectroscopy

Nuclear magnetic resonance (NMR) techniques can also be a very useful, often non-destructive analytical technique. The concept relies on the interaction of a specific class of atomic nuclei with an applied magnetic field. Atomic nuclei that have an odd number of protons and neutrons, such as 1 H and 13 C, have non-zero spin values and therefore interact with magnetic fields, whereas nuclei with an even number of both protons and neutrons (including those of atoms common in pharmaceutical chemistry such as 12 C and 16 O) have zero spin values and do not interact. Importantly, the magnetic interaction of a 1 H or 13 C nucleus with the applied field depends on the electron environment around the nucleus, which in turn depends on the adjacent chemical bonds to other atoms. Each bond gives a characteristic signal, or chemical shift, expressed in parts per million or ppm. NMR spectra therefore give useful information on the composition and structure of complex molecules. The ubiquity of 1 H in organic molecules means that quantitative nuclear magnetic resonance spectroscopy (qNMR) is a highly versatile and important technique with many applications in pharmaceutical science. Although 1 H NMR is by far the most common technique, 13 C is also widely used and given a sufficiently powerful magnetic field, it is possible to use other, rarer nuclei with non-zero spin values. Traditionally used to study compounds in solution, NMR detection can be coupled with many of the sample separation techniques described in this section. Solid phase NMR spectroscopy is

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also an excellent tool for the characterization of the water content, polymorphism, and formulation of solid dosage forms such as tablets and powders. The ability of NMR to differentiate between biochemically and structurally very similar chemicals is an important tool. After the heparin contamination incident of 2008, an NMR method was developed by FDA and Baxter scientists to analyze crude heparin and to identify the closely related adulterant, over-sulphated chondroitin.9 For a fuller description of NMR techniques in pharmaceutical analysis, see elsewhere.10,11 Mass Spectrometry (MS)

Mass spectroscopy (MS) measures the mass-to-charge ratio of molecules and molecular fragments. The sample is vaporized and then ionized and finally its constituents are separated by an electromagnetic field before reaching a detector. This quantitative technique allows the mass of individual molecules or fragments to be determined quickly and accurately and is also useful for isotope ratio analysis of suspect packaging.12 Coupled with various front-end sample preparation techniques, MS can provide an unequivocal fingerprint of a complex pharmaceutical sample or its packaging and enables counterfeits to be readily identified. Especially useful in this regard are techniques such as DART (direct analysis in real time), which allow much easier MS analysis without extensive sample preparation.13 Mass spectrometry can be used as a standalone technique or can be coupled with a preceding sample separation stage such as gas chromatography (GC), LC, or capillary electrophoresis (CE). Gas Chromatography (GC)

GC is a useful, versatile, and widely used technique for pharmaceutical analysis.14 Molecules in the sample are separated on the basis of their migration rate through a thin column containing a stationary phase—a thin layer of liquid on a fixed solid matrix —and a mobile phase comprising a pressurized inert or unreactive gas such as helium or nitrogen. The interaction of the test sample constituents with the two phases determines their rate of progress. The time taken to traverse the column and reach the detector at the other end (the retention time) is distinctive for a given molecule in the same analytical system. The series of peaks in the detector readout therefore corresponds to different molecules exiting or eluting from the column and the presence of the expected constituents of a test sample can be verified by comparison with known reference peaks. Since the mobile phase is gaseous, the test sample must be vaporized before separation. This can be problematic if one or more critical analytes are

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prone to decomposition. GC is often used with a thermal conductivity detector or can be coupled to a mass spectrometer (GC-MS), NMR, or other detection system. Liquid Chromatography (LC)

LC uses a solid supporting matrix, usually in the form of a column, and a liquid mobile phase, which is usually pumped through the matrix under pressure. The test sample is introduced in a small volume at one end of the column and its constituent molecules then migrate through the matrix at different rates according to their molecular size, weight, and charge. As for GC above, the retention time is reproducible for a given molecule in the same system. The technique can be used as a relatively low-technology method, using hand-filled columns, but the more usual form is high-performance liquid chromatography (HPLC) in which the solvent is pumped through a tightly packed stationary phase in a steelencased column at high pressure. This technique allows smaller sample volumes, quicker and more quantitative analysis, and greater sensitivity. The output from the HPLC column is coupled to a detector, which may be a UV/visible spectrophotometer, mass spectrometer, or other detection method (see above). HPLC is an excellent method for the identification of impurity profiles and adulterants in complex mixtures as well as for confirming the presence and concentration of active ingredients. Capillary Electrophoresis (CE)

This technique allows the separation of a mixture of charged molecules on the basis of their size and charge. The sample components move at different rates, under an electric field, along a small capillary filled with an electrolyte. As they elute at the other end, they are detected, usually either by a UV/visible spectrophotometer or a mass spectrometer. The technique only requires a small sample size and can be very sensitive but does not work effectively for many neutral molecules. Samples must be dissolved as the technique cannot be used for solid state analysis. Forensic Palynology

The analysis of naturally occurring and harmless contaminants in pharmaceutical preparations can be a useful adjunct to the measurement of APIs and excipients. Palynology is the study of tiny organic particles such as plant pollen and fungal spores. Originally used to analyze fossil microparticles in rocks to gain evidence of earlier climatic conditions, the same

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techniques can now be used for forensic analysis of suspected counterfeit drugs. Tiny amounts of plant pollen are found naturally everywhere, even in clean manufacturing environments, and become incorporated into both real and counterfeit tablets and capsules. Although pollen can be widely dispersed by the atmosphere, the pollen found in a pharmaceutical sample comes predominantly from the plant species that are common in the nearby region. Under an electron microscope, pollen grains from different plants have distinctive shapes and surface features (Figure 15.1). By reference to known samples, a pollen grain can often be identified down to the species level. Careful analysis of the number and relative abundance of pollen types present in suspected counterfeits can therefore reveal the flora of the area in which the pills were produced. This can help to identify the likely geographic origin of the fake drugs, often pinpointing the likely location within a relatively small geographic region15 . By narrowing the search area, palynology can therefore enable law enforcement activities to be better targeted, and it raises the chances of discovering and closing down criminal production facilities. In most cases, counterfeit drugs are made in a different geographical area to the

L

PIL

10

Figure 15.1. Forensic Palynology. Specific types and mixtures of plant pollen are identified using an electron microscope and compared with the known distribution of plant species.

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genuine product. Therefore, forensic palynology is a potentially powerful technique as it is almost impossible to manipulate the pollen content of the fake product without infeasibly heavy investment in clean room technology.

NON-DESTRUCTIVE METHODS

Many of the methods described above require varying degrees of irreversible sample preparation (removal from sealed container or blister pack, crushing into powder, dissolution with solvent, etc.) and therefore cannot be used in non-destructive mode. This can be a drawback for a number of reasons: there may not be the time or facilities during a field investigation to undertake complex sample preparation; the owner of the consignment to be checked may reasonably object to having their consignment opened so that a sample can be removed for analysis; if the product is packed and sealed in bulk, then opening it for examination could render it unsellable and represents a significant and unnecessary financial loss to the owner if the batch is subsequently confirmed as genuine. For these reasons, and often because of the cost and bulk of the instruments used, most of the above techniques are used for secondary analysis of suspected counterfeits that have been identified in the field by other, usually non-destructive, methods such as those described below. X-ray Diffraction

Portable X-ray diffraction (XRD) instruments are now becoming available, often adapted from instruments used in the analysis of minerals in mining operations.16 These instruments operate under the same technical principles as laboratory diffractometers, but using a small, portable X-ray source. By comparing the observed diffraction spectrum from the test sample with known spectra in a database, the machine can identify the presence or absence of key ingredients or contaminants. The portable XRD machines are not as cheap as the portable infrared machines discussed below, but the technique is versatile and offers complementary capabilities to the infrared techniques. Infrared Spectroscopy

The most common non-destructive approach used to check pharmaceuticals in situ, while still in their packaging, is currently infrared spectroscopy. This technology has several different variations, each with

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their own strengths and weaknesses, which are discussed below. Infrared machines can be very portable and, while also not cheap, are now available at a price that is affordable for regulatory bodies in developing countries. The infrared portion of the spectrum is commonly divided into three sub-regions, termed near, mid, and far based on their proximity to the visible spectrum. Each region of the spectrum can provide different information on the molecular structure of the sample. Infrared analyzers typically consist of an infrared laser and a detection system. Light from the laser interacts with the sample depending on the molecular properties of the various substances within it and is absorbed at specific resonant frequencies corresponding to the energies of molecular vibrations in the sample. These interactions result in a spectrum of transmitted light, which is analyzed to form a spectral “fingerprint” of the sample. Measurements taken in a production facility or in the field, using portable or handheld devices, can be cross referenced to a database of known reference scans to identify the constituents of the sample. Often it is possible to differentiate not only between different products but also between different batches of the same product. This can be particularly useful when investigating cases where batch numbers or expiry dates appear to have been changed. Additionally, the ability of the technique to discriminate between batches of product from the same manufacturer makes it possible to identify when the product manufactured for one destination (e.g., a donation to a developing country) has been diverted and illegally resold in another market. Fourier transform infrared (FTIR) spectroscopy, near-infrared (NIR) spectroscopy, and Raman spectroscopy are related but distinct infrared techniques and all three are commonly used in pharmaceutical applications. Infrared spectroscopy can be highly selective and is well-suited for both raw material validation during manufacture and product identification and verification in the field. Fourier Transform Infrared (FTIR) Spectroscopy

FTIR, or mid-infrared spectroscopy, was the first vibrational spectroscopy technique to be widely used for material identification. It measures light absorption by the sample across a range of wavelengths simultaneously, using the Fourier transform data processing technique to produce a spectrum corresponding to fundamental molecular vibrations within the sample molecules. FTIR has excellent selectivity, but sample presentation can be quite demanding. The sample must usually be in direct contact with the instrument and only the surface of the material can be analyzed.

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Near-Infrared (NIR)

The bands observed in NIR, which as the name suggests uses higher energy, shorter wavelength light than mid-infrared FTIR, predominantly arise from stretching of O–H, C–H, and N–H bonds. The bands are generally much broader than those seen in FTIR. Owing to band broadening and the ubiquity of these molecular bonds in organic molecules, the differences between NIR spectra of different compounds are often very subtle and require greater processing. Thus NIR often gives a lower molecular selectivity than FTIR. However, NIR offers much more convenient sample preparation than FTIR. Raman Spectroscopy

When light is scattered by interaction with matter, most of the light retains the same frequency. However, around one in a million of the scattered photons changes frequency (the Raman effect). This effect, despite its low incidence, can be readily measured and is highly sensitive to molecular structure. Raman spectroscopy can analyze substances through glass and plastic, allowing pills to be analyzed while still in blister packs or bulk API to be analyzed while double-bagged in drums. Since water gives a very weak Raman signal, the technique can also be used to analyze materials in aqueous solutions. An advantage, particularly for portable devices, is that little or no sample preparation is needed before performing a Raman analysis. Scanners are now more portable and easier to use, making infrared techniques ideal for field use by regulatory agencies, customs officials, police forces, etc. Although not cheap (scanners typically cost from 20,000 to 50,000 US dollars), the technology is now also within the price range of developing countries—often, the most severely affected by counterfeit drugs. The Nigerian regulator, National Agency for Food and Drug Administration and Control (NAFDAC), has invested in this technology to combat the high level of fake drugs entering the country.17 Several of the major drug companies have also implemented portable Raman devices (Personal communication 23 September 2010). These are used by company investigators to authenticate their products in the field. The companies concerned have undertaken in-depth development and systems integration, in partnership with instrument vendors, to ensure that causes of variability are eliminated. False positives or negatives can be caused by defects in instrument calibration or inadequate user training. Instrument-to-instrument variability must also be eliminated as far as possible.

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Terahertz Imaging

The region of the electromagnetic spectrum between infrared and microwaves, at frequencies around 1 Terahertz, has recently been exploited for non-destructive (although not yet fully portable) testing devices, which allow imaging of solid dosage forms in three dimensions.18 This allows comparison of coatings and layers in the formulations under examination. This could prove valuable in examining suspected counterfeits that appear to have the correct dosage of API, but which may have different (and potentially) dangerous pharmacokinetic properties because of variations in their structural and release properties.

CONCLUSIONS ON THE ANALYSIS OF DOSAGE FORMS

The prevention of counterfeiting is largely based on deterrence, and a high likelihood of detection increases the risks for the criminals who are producing fake drugs. Although the identification of suspect, fake, or altered packaging is often a useful proxy (and often the only feasible option) when looking for counterfeit medicines themselves, the rapid, nondestructive, and unequivocal detection of the counterfeit dosage forms directly is a much more robust method when available. For law enforcement officials, especially in developing countries, the advantages of portable, non-destructive technologies such as infrared spectroscopy are several: • Spot checks can be made quickly and without warning. • Evidence is provided almost immediately, allowing rapid seizure of

suspect items without recourse to brand owner verification. • It is not necessary to equip every customs post or train every officer. • Expensive equipment can be controlled and monitored securely. • Opportunities for corruption can be minimized.

The encouragement by the US FDA of physical–chemical identifiers in pharmaceutical products will encourage the development of more sophisticated ways to use markers, perhaps tuned to specific detection techniques. By its very nature, though, the physico-chemical analysis of drugs can only ever be a spot-check mechanism, used on a tiny subset of the medicines in circulation. In order to reach a higher proportion of medicines and consumers, we need to look at other methods of applying security. The next section looks at how secure packaging can help to differentiate genuine from counterfeit products.

Chapter

16

The Role of Packaging

Through most of human history, the supply chain for drugs has been very short. Hunter gatherers still make remedies from medicinal plants to treat members of their own family or tribe. This task is usually done as and when required: a perfect example of just-in-time inventory management. The product is freshly gathered and prepared immediately, so no packaging is needed. But for almost all of humanity, the vital job of medicine production is now a highly specialist role carried out by distant strangers. It is not practical, in our urbanized, industrialized healthcare system, to make fresh drugs on demand for each patient, so we make them in bulk and store them for future use. Packaging is therefore a necessary and important component of modern medicine, helping to keep drugs in a safe and stable condition until they are required. As packaging has evolved, from its original function of containing the product and protecting it from the environment around it, it has become a useful platform for branding. Customers have learnt to associate the visual appearance of a pharmaceutical product with brand values and expectations of performance and safety. Branding is a concept as old as vision: the yellow and black stripes of a wasp are a perfect brand statement. Of course, the strong association between appearance and expectation has always led to opportunities for mimics to cheat the system. Criminals dupe consumers into buying fake drugs by copying the packaging of Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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the real ones. Stingless hoverflies gain some protection from their predators by looking like wasps. In the context of our overall aim, to control and eventually eliminate the counterfeiting of pharmaceuticals, the role of packaging is critical. This chapter examines how we can protect the integrity of the product by making its packaging harder to mimic.

PACKAGING DESIGN

Before implementing technological measures to increase the security of packaging, it is worth carefully examining other options. The rise in fake drugs and the increasing need for pharmaceutical anti-counterfeiting measures has given rise to a growing number of technology-based “solution providers”—including entrants from other sectors and some new startups. The pharmaceutical industry is a highly technical business and there is an understandable tendency to look for a techno-fix to the counterfeiting problem. The technologies on offer make an important contribution to product safety and many of them are discussed elsewhere in this book. However, relatively simple, non-technological approaches should not be neglected as they can also be effective. One of the simplest things that can be done, for example, is to make packaging harder to copy by making it visually more complex and by using non-standard form-factors where possible. Pharmaceutical packaging technology and pack design is a very broad subject that has been well covered in its own right1 and I do not propose to address the more general points here. The role of design is discussed below purely in terms of how it can aid anti-counterfeiting strategies. The bank note industry is discussed elsewhere in this book as a paradigm for pharmaceutical packaging. A bank note is packaging with no physical product. It is essentially the visible wrapping for the intangible face value represented by its denomination. Those criminals wishing illegally to access the intangible value of banknotes must first copy the packaging by duplicating the features of the note. As such, the approaches taken to protect banknotes are instructive for the defense of pharmaceutical packaging and products. Treasury departments around the world are well-versed in the problem of fake money, which has probably been around ever since these indirect tokens of value replaced direct bartering in the exchange of goods. The governments and their bankers spend years developing visually complex designs to make counterfeiting difficult, and upgrade their banknotes on a regular basis. Banknote designs always include multiple, specialist, anti-counterfeiting technologies, both overt and covert, but one of the other key techniques

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used is design complexity. Often, an individual note has 7 to 10 overt features alone,2 with many more covert and forensic layers of security hidden out of sight. The central banks also make a lot of effort to inform consumers and merchants about the visible features on an authentic note.3 Nevertheless, the US government department responsible for banknote design and production published a report in 2007 that stated:4 Within 5 to 10 years, advances in image-processing tools and digital printing technology will allow a casual counterfeiter to attain the level of skill of a computer graphics art specialist.

The US government is worried that, even with the introduction of increasingly sophisticated designs, their efforts to develop secure banknotes for the future will be overtaken by the abilities of counterfeiters to reproduce them—at least at the superficial, visual level. In contrast to banknotes, and even when compared to most other consumer items, the graphical design complexity of the average pharmaceutical pack—especially for prescription drugs—is minimal. Many drug packs are simple white boxes with a small amount of text and a company logo, or plain brown bottles with white labels. There are, of course, several reasons for this, including the following: • Regulatory authorities control the appearance and content of pack-

aging and tend to be conservative in their outlook. Medical packaging design is driven by considerations of function, not form. This example of guidance from the UK MHRA is typical:5 Innovative pack design that may incorporate the judicious use of color is to be encouraged to ensure accurate identification of the medicine. In considering the acceptability of a particular pack design it will be necessary to consider the relative distinguishing features compared to other packs in a range (a range may mean all packs bearing a corporate livery or a group of packs carrying the same design theme). The primary aim of innovative design of packaging is to aid in the identification and selection of the medicine. • Clear space (known as real estate) must often be left free for the phar-

macist to attach individual dosage instructions or for the application of other labels, codes, or date stamps. • Most countries, with the United States being one of the major exceptions, do not permit direct-to-consumer advertising, so consumer pack recognition is not a critical marketing element. If the box is destined to sit most of the time in a pharmacist’s store room or hospital dispensary, why spend money on making it look attractive or distinctive?

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• Especially in Europe, the manufacturer’s box or container may not

be the one in which the drug reaches the patient. Legal repackaging activities and parallel imports provide a disincentive to investment in pack complexity. • In the United States, the bulk bottle shipped by the manufacturer (via distributors) to the pharmacist is then broken down into individual patient prescriptions, which are given to the patients in standardized, plain bottles with simple labels. • Customers do not associate pharmaceuticals with sophisticated packaging, therefore they accept (and possibly expect) simple graphics and standard pack designs. • Too often, drug companies still see packaging more as a cost to be minimized than as a value-protecting feature of the product. This is therefore a complex issue with many factors coming into play, such as cost, regulations, patient safety, avoidance of medical errors and anti-counterfeiting. We should, of course, avoid an arms race of packaging complexity as manufacturers strive to stay ahead of the criminals with ever more complex visual designs and counterfeiters quickly learn how to keep up. The US government report cited above concludes that this is not necessarily the right approach. However, attention to packaging design—and particularly its evolution over time—can bring useful benefits with fairly minimal cost. Being Just Slightly Better than the Opposition

The cheetah and the gazelle can both sprint fast, but the cat is quicker in a straight line race. So the antelope’s defensive strategy is not to outrun its pursuer but to make it give up the chase. Gazelles are herd animals: constant collective vigilance often gains the target a small head start and allows it to control the direction of the sprint. It can maneuver better than the cheetah and uses constant changes of direction to deplete the chasing cat’s energy. Antelope’s do not win them all, but much of the time cheetahs give up when the energy cost of the chase exceeds the potential rewards. In this analogy, the pharmaceutical industry controls the direction of the pursuit. Vigilance, sharing intelligence, proactive management of packaging features, and regular minor changes (such as introducing deliberate minor “errors” in packaging) can help to frustrate the activity of counterfeiters by making counterfeits harder to produce and easier to spot. The widespread use of inkjet printers on the production line, to add variable information such as lot and expiry data, gives the manufacturers another

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opportunity to add other minor graphical variations to the pack on very short timescales. This is discussed in more detail on the section relating to track and trace technologies. These tactics are probably not sufficient on their own, but in conjunction with other measures, they may be enough to persuade the counterfeiter that the reward is not worth the cost of the chase. SECURITY FEATURES ON PACKAGING

Pharmaceutical packaging forms a barrier between the product and its environment, preventing damage due to moisture, microbial contamination, light, and so on, and therefore performs many important functions in maintaining the integrity and safety of the product. It is also a logical place to start with anti-counterfeiting strategy. The difference between standard packaging and security packaging is simply that the latter contains or bears one or more additional features that enable the informed person to positively confirm it to be original and/or untampered with. The exception to this generalization is technologies where no additional features are needed: the intrinsic properties of the packaging itself are analyzed for each pack and can be used to identify that item uniquely at a later date. This is the basis of one of the variants of “fingerprinting,” and will be discussed more fully in the section on track and trace technologies. The integration of security features into packaging can be done in a variety of ways. Integration into Packaging: Bulk Packaging Material at Source

The simplest way for a pharmaceutical manufacturer to add security to their packaging is to have someone else incorporate the feature during the production of the packaging. This may be the printer or converter who produces the final packaging, or it may be the corporation that produces the raw material. Suppliers of primary materials used in pharmaceutical packaging (carton board, aluminum foil, plastic film, etc.) can often provide material with integrated security features, which allow the original raw material to be positively identified in the event of a suspected attempt to copy the packaging. These features may not be specific to a particular customer, but can provide at least some protection against unsophisticated counterfeiting attempts. Examples include the inclusion of specific fibers in cellulose products, the use of milling effects in foil, etching of glass, and so on. Generally, although these features can be effective as a first barrier, any lack of exclusivity for security measures makes supply chain control more difficult for the pharmaceutical customer. More

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sophisticated methods, such as the integration of customer-specific microfeatures or holograms into foil, can be much more effective. However, the inclusion of distinctive features at the raw material stage is usually a relatively cheap option and should not be ignored as part of a broader anti-counterfeiting strategy. Integration into Packaging: By Design Complexity

The selection of commonly used, widely available packaging is often an effective cost-saving measure in pharmaceutical procurement, since there is fierce competition among suppliers and prices therefore approach commodity levels. However, if drug companies can obtain standard vials (for example) by the million at very low cost on the open market, then so can a counterfeiter. The selection or design of non-standard, productspecific closures, or unusual packaging shapes can therefore be an effective defense against counterfeiting. The number of available packaging formats has increased in recent years with the advent of integrated packaging. Fold-out labels on bottles allow detailed information to remain with the medication. Folding, wallet-style packs can integrate a blister pack with a carton box to provide a robust pack that provides protection to the blister, retains patient information close to the dose, and gives an element of design complexity that makes the packaging that bit harder (and/or expensive) to reproduce. The same innovative approach to packaging can be taken for most product types. Too often, companies spend a billion dollars developing a high-value product and then use industry standard bottles, vials, or caps (available to anyone, often anonymously over the Internet) to package it. This keeps immediate manufacturing costs down but makes the counterfeiters’ life rather easy. The extra cost of nonstandard pack shapes and materials, unusual die cutting, specialist tooling, and other design features is often minimal when spread over the lifetime of the product, but by denying criminals a simple path to replication, they may be a surprisingly effective deterrent to counterfeiting. Addition to Packaging: Labels, Printed Packaging, etc.

Despite the options discussed in the preceding section, it is not always possible to use innovative pack designs for new products, or to change the look and feel of existing marketed products, without considerable management time, introduction of extra process complexity, and increases in cost. Sometimes, the best option is to modify what is already there by adding something else. The addition of extra features is the most common method of incorporating anti-counterfeiting security elements into pharmaceutical packaging, for various reasons.

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• Simplicity and relatively low cost of introducing or switching security

•

•

•

•

features. Existing packaging and procurement arrangements can often remain largely unaltered if additional “bolt-on” features rather than integral security methods are used. Similarly, if the security feature needs to be changed or withdrawn during the lifetime of the product, only one aspect of the production process need be altered. To enable security features to be added as late in the production process as possible, maximizing supply chain security on the needto-know principle. Additional printed features or labels can be added right at the end of the manufacturing process, with knowledge of the nature of the security feature limited to a very small number of operatives within the pharmaceutical corporation. To concentrate a security feature in one place to make it easier to detect. This minimizes the amount of security feature needed and (since security inks and chemicals are often relatively expensive on a per-pound basis) helps to control costs. It is usually better and more cost-effective to concentrate a taggant on the surface of the packaging (directly printed or on a label) than to distribute it throughout the plastic of a bottle (for example). To enable the manufacturer to use different security technologies in different parts of the world. If security features are added at the stage when the product destination is known, the standard packaging can then remain the same worldwide, minimizing complexity and lowering costs, but specific security features can be added or changed as needed for each market. To keep product security in-house. Using inkjet technology, for example, manufacturers can rapidly vary security features without the need to involve their packaging suppliers.

When considering the addition of printed or applied features, there are some practical factors as well as security issues that must be taken into account. Not all technologies can be applied with any print process, and not all substrates are suitable for all approaches. The next chapter discusses print technology and its applications to pharmaceutical security.

Chapter

17

Printing Technologies

Before we examine the application of anti-counterfeiting features by printed means, it is useful to discuss the various options for the choice of printing technology. The general details of printing techniques and their industrial application are outside the scope of this book: for a fuller description, see elsewhere.1 In terms of anti-counterfeiting, there are specific technical limitations and advantages with each technique. The following section discusses some of these issues, but every situation is unique, and the reader is recommended to seek specific and confidential advice from security vendors and converters before deciding on specific printed features. Often, the choice of the final technology will depend as much on pragmatic operational factors as on cost and security.

OFFSET LITHOGRAPHY

In the offset lithography (or “offset”) process, the image to be printed onto the substrate is represented as a raised area on a cylindrical plate. The plate is then inked, and the image, represented by the raised, ink-bearing areas of the cylinder, is offset (transferred) onto a rubber cylinder and then printed from this cylinder onto the substrate. The film of ink applied is typically quite thin, and this is a commonly used and cost-effective Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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technique for the production of pre-printed packaging. Offset processes can work well with spot application of security pigment onto one existing graphical element (which may require careful registration or alignment of the two image areas) or incorporation of pigment into one of the colored inks. Alternatively, large areas can be covered with flood-coating or varnishing, where a (usually colorless) taggant or marker is applied to all areas of the substrate as a final printing step. Clearly, the latter approach will require a larger amount of security material, which may offset the cost savings of the simple application process. As with flexography (see below), inks with large pigment particles may cause technical problems, particularly during long print runs, for example, because of build up of particulates between the plate and the offset roller. Dry offset lithography is a variation of the technique, which uses special plates where only the printed area is inked and the non-printed area is not dampened. This technique tends to be more expensive than standard offset lithography and is usually reserved for special applications. FLEXOGRAPHY

Flexography, commonly abbreviated to “flexo,” is one of the most commonly used print processes in pharmaceutical packaging. Flexographic printing uses flexible cylinder plates made from rubber or special polymers. As in offset printing, the image area is raised on the printing plate. The print area is coated with ink, and the cylinder deposits the image directly onto the substrate. Multiple color stations (typically four) are often used. The printing occurs in a single-pass configuration, with each color applied by separate print rollers in sequence. The substrate is fed around a larger impression roller, which applies pressure and assists the transfer of the inks from the plate cylinders to the substrate. The inks used in flexography are of two main types depending on the preferred drying method: evaporation or UV light. Drying by evaporation is usually too slow for water-based inks and therefore is accomplished using volatile, solvent-based inks—in the pharmaceutical industry, methyl ethyl ketone (MEK) is often used as the solvent. Flexography is a very adaptable, efficient, and relatively cheap printing process. However, like the offset process described above, it can have some technical limitations for inks with large particle sizes. GRAVURE

In contrast to the printing processes described above, offset and flexo, in which the printing area lies above the non-printing area, gravure printing

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is a type of intaglio process, in which the printing area lies below the non-printing area (i.e., the image is “engraved” onto the cylinder). After the whole cylinder is linked, excess ink is scraped from the non-printing area by a doctor blade. When the inked plate is pressed against the substrate, ink is lifted from the ink cells and deposited onto the surface. Although gravure cylinders are relatively expensive, the process is robust and well suited to long print runs. The gravure process is often used to print aluminum blister foils.

SCREEN PRINTING

Familiar from t-shirt printing and popularized by Andy Warhol, screen printing is a relatively simple process. To make a screen, the negative of the desired image is first applied as a blocking stencil to the porous screen using an impervious material. When ink is then scraped across the screen, the positive image is formed onto the substrate below as ink is pushed through the mesh in the non-blocked areas. Typically, the modern industrial screen printing process involves mesh screens made of polymer or steel rather than the traditional silk. Screen printing can be carried out with flat bed or (more commonly) rotary presses—some modern flexo presses also have an additional screen printing station. The screens themselves can be made quite rapidly and at a relatively low cost but are not suited to very high-volume printing. However, screen printing is still sometimes used for security printing, as the ability to use a very porous mesh gives excellent quality results with relatively thick inks or those with large particle sizes.

LASER PRINTING

In contrast to the “wet” printing processes described above, laser printing uses dry toner powder. The image to be printed is projected by a laser onto a rotating drum, altering the electrical charge of the drum’s photoconductive coating. Toner particles are then electrostatically picked up by the drum’s charged areas as it rolls through the toner reservoir. The drum then transfers the image onto paper, where the toner is fused by direct pressure and heat, leaving a permanent image. Security components can be incorporated into the toner. Laser printing is especially suited to the just-in-time printing of security labels at the pharmaceutical manufacturing site.

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CLICHE´ OR PAD PRINTING

This process uses a carrier, known as a tampon or pad, to transfer the ink directly from an inked pad or well onto the substrate. It is not of especially high resolution or suited to high-volume application, but because it is a direct transfer process, it can be used on irregular, non-planar surfaces. It is also sometimes used directly on the pharmaceutical production line for the application of batch and expiry information.

EMBOSSING AND DEBOSSING

This is not strictly a printing process but is widely used in pharmaceutical manufacturing for the application of data, so it is discussed here. In these stamping processes, metal dies or stamps are used to create surface features which are slightly raised (embossed) or lowered (debossed) with respect to the substrate surface itself. The process is simple, direct and robust, and has the advantage of being harder to erase than printed features, but it is not suited to the application of detailed features. The debossing technique is often used for the application of expiry dates and batch code information to carton boxes during production.

LASER ENGRAVING

Although it uses a laser, this is a process distinct from laser printing. Typically, for carton or label applications, a rectangular patch of black ink is pre-printed onto the bulk packaging or label stock, using one of the standard printing processes described above. The desired image (usually alphanumeric characters) is then etched into the surface of the ink during the pharmaceutical production and packaging process, by laser ablation. This burns off the ink in the image area to reveal the white substrate surface underneath. This technique is used mainly for adding small amounts of variable data—typically batch/lot numbers and expiry dates.

INKJET PRINTING

All of the printing or marking processes described above require contact between the substrate and some form of ink carrier, toner reservoir, or stamp. In the case of laser etching, this contact occurs before the use of the packaging on the production line, so only the final

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laser ablation step can be considered non-contact. By contrast, inkjet printing is a completely non-contact process, which can apply ink to any area—without contact between printer and substrate and without the requirement for pre-preparation or printing of an underlayer. The technique is therefore very well suited to the printing of variable data on the fast-moving pharmaceutical production line. Several different inkjet technologies are available—each has advantages and disadvantages according to the desired application. The continuous inkjet has been the most commonly used inkjet variant for printing variable information on pharmaceutical packs, such as batch number and expiry data, and is now increasingly used for printing 2D matrix codes as part of serialization initiatives. The basis of the continuous inkjet process is that a continuous stream of small droplets of ink is created and then some of the droplets are electronically charged and deflected onto the substrate to form an image. Unused ink is captured in a gutter and reused. Continuous inkjet is especially suited to applications on slow to moderate speed production lines, in which the line speeds are compatible with constraints on printing speed and quality. Very high printing speeds, required for some of the fastest production lines, can result in a loss of image quality and the risk of unreadable codes, although maximum operational print speeds have been steadily increasing as manufacturers optimize the process. By contrast, drop-on-demand inkjet printers, as the name implies, only dispense ink when it is when required for the image. They tend to be more expensive machines but can be faster than continuous inkjet printers. This has led to their increasingly widespread use for the printing of serialization codes and other variable data on high-speed packaging lines. Whichever variant is used, inkjet printing is one of the more widespread technologies on pharmaceutical production lines, and is ideal for the application of security marks or small amounts of variable data at relatively high line speeds that do not impede the production processes. It offers reliable, fast, and high-quality printing and ease of use. Inkjet cartridges are usually very easy to install, and the machines generally require minimal training to operate and maintain. Security materials such as taggants can be incorporated into standard inkjet ink cartridges, allowing application of visible data and covert security in one pass, without pausing the production line. Importantly, since the production lines of a pharmaceutical plant are generally very space-efficient with little spare room for additions, the amount of line space taken up by an industrial inkjet print head is relatively small and all other functions are connected to it by an umbilical attachment. Therefore, inkjet printers can be retro-fitted onto most packaging lines. There is often room for more than one print head to be

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installed onto the same packaging line, allowing more than one ink type to be printed simultaneously on the same pack—two codes, or separate overt and covert features, for example. Since inkjet, laser etching and clich´e printing are used on the production line itself, after the final product packing step, they require downstream quality control and ejection systems to identify misprinted or faulty marks and to remove the affected product. This typically takes the form of a computer-controlled vision system with mechanical ejector. SOME TECHNICAL CONSIDERATIONS

There are, therefore, a number of technologies available for the printing or application of security features directly onto packaging. However, the choice of technology is only one factor in a successful product security feature. In order to implement a new printed security element successfully, several other factors must be considered. How Much Surface Area Is Available for the Feature?

The space available for the addition of security elements on pharmaceutical packaging is often very limited, since there are usually many competing textual and graphical elements that must be accommodated. The problem can be especially acute when an overt feature must be “retrofitted” to an existing pack design (often in response to a security incident with the product) without obscuring any of the existing design elements. The available surface area, or real estate, therefore, often determines what constitutes a feasible security feature. If a covert feature is used, then real estate is usually less critical since the feature can in theory be printed over existing text or graphics. It can also, if necessary, be flood-coated. This process involves incorporating the security element into a varnish which is then applied over most or all of the surface area of the label or pack. This is operationally simple, but note the increased amount of security substance needed for this option versus applying a discrete patch over a small area, and hence the higher cost of materials. The decision on whether to flood-coat or apply as a smaller area depends on the cost; degree of covertness, which can be achieved with a patch (the presence of which can be challenging to disguise on glossy and metallic surfaces); ability to detect a relatively dilute signal across the whole substrate if flood-coated; etc. Converters and security providers are well placed to advise on these details, which will vary from project to project. Their advice should be needed as they have generally seen more scenarios and solved more application problems than the brand owner.

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If the security feature is overt, especially if it is intended for consumer verification, then the print or labeling area used must be large enough for that feature to be seen easily by the untrained human eye, but not so large that cost becomes prohibitive. Also note that features with special visual effects, which change with the angle of view, such as colorshift inks or holograms, generally need to be given a larger area (to enable accurate assessment of their authenticity by eye) than the print area needed to confirm the presence or absence of a simple, static feature. Rules regarding the obscuring of text, data or other existing features on the pack must also be followed—these are likely to differ between jurisdictions, so any security feature that leads to visible pack changes needs to be particularly carefully planned. Real estate also becomes an issue when large codes or other variable elements are called for. The BRIDGE (Building Radio Frequency Identification Solutions for the Global Environment) project2 noted this limitation in its pilot of serialization using 2D codes in the European Union. Until a uniform pack specification for designated real estate is established, this may continue to be an issue in the roll-out of serialization programs. What Is the Budget?

In general, if a feature is intended for evaluation by the naked eye, then the bigger it is the more easily it can be interpreted. However, security materials are relatively expensive because of the IP and supply chain security costs embedded within them and the use of restricted-availability raw materials in the manufacturing process. Therefore, within the available technologies, the surface area of the chosen security feature is usually correlated with price. The optimal trade-off between visibility and cost is unique for every project, but experience has shown that around 1 cm2 (about a quarter of a square inch) is a good minimum area to aim for to get a clear, visible change when viewing a dynamic feature. Sometimes budget or space considerations mean that smaller areas must be used, but for overt features, interpretability, not visibility, is the key metric, so tiny features are not effective. Is the Product Surface Flat or Curved?

Printing onto non-planar surfaces is more technically demanding than onto flat objects and places some limitations on the printing technologies that can be used. In many cases, it is simpler to apply a pre-printed label. The design of the security feature must also take into account the shape of the

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substrate. For example, it can be tricky (though not usually impossible) to print 2D codes directly onto curved surfaces. Small, tightly curved, cylindrical surfaces such as syringe barrels are hard to mark without distortion. When serializing this type of product, a pre-printed label is often a better option. Even for relatively large items, the shape of the object or the accessibility of the area to be printed may make printing awkward. However, what is awkward for the brand owner is also difficult for the counterfeiter. Sometimes it is worth going the extra mile to get a hard-to-reproduce feature. Is the Product Orientation Predictable and Constant?

For pre-printed materials such as bottle labels or carton flats, the substrate can be precisely aligned with the printer quite readily. However, for just-in-time printing directly onto the product, some restrictions and problems arise. On a pharmaceutical production line, the linear speed of the conveyor (discussed above under inkjet technologies) is not the only challenge to printing: continuous and discontinuous linear motion (smooth or stop–start production processes) also present different problems. Depending on the size and shape of the product units themselves, they may roll, spin, or tumble as they move down the line. This may not matter if the exact position of the print is unimportant and the object has rotational symmetry (the lot number and expiry date on a cylindrical bottle, for example). However, in order to make a reproducibly positioned mark or code, each unit must be presented to the printer in the same orientation. This may require computer-controlled vision technology and equipment to manipulate the moving product into the correct position. These are all problems which can be solved, but they will add complexity and time to the process and should be considered carefully at an early stage when choosing appropriate security technologies. How Much Time Is Available?

Feature design, formulation, or production of security features and set-up of the press or application process are not trivial activities. “Slideware” mock-ups and approximate costs can be produced by most security suppliers very quickly, but each project is different, and buyers should be suspicious of glib answers and aggressive timelines from vendors. Unexpected complications frequently arise, and adequate time should always be allowed for optimization. Often, the most awkward problems arise when retro-fitting security features onto existing products—since this is frequently done in response to a counterfeiting issue, time pressure is usually

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present. Expectations should be carefully managed on all sides (pharmaceutical manufacturer, packaging converter, and security provider). The earlier the security vendor and converter are involved and the more time they are given to design, plan, and optimize a feature, the better the results. This is an example where the establishment of strategic and confidential relationships with a small number of trusted security vendors, well ahead of time, pays dividends when disaster strikes. Direct Application onto Packaging Versus Use of Labeling

In general, for the reasons discussed above, the application of a security feature onto a product is most commonly achieved by printing or applying it either directly onto the packaging or via a secondary substrate such as a label. The printing of security features directly onto the substrate of the packaging itself has a number of benefits over the use of security labels. First, it enables the security feature to be integrated with the package design, so that it is less obvious. This is an advantage when the feature is semi-covert or covert and is not aimed at the consumer. Wherever possible, security should be planned well before product launch and security features integrated into package design. This requires forward planning and continued liaison between product security and marketing functions but pays off in ease of implementation, elegance of appearance, and robustness of the solution. In some cases, however, it is not possible to integrate the security feature into the existing design. This often leads to the addition of a security feature as an extra graphical motif, typically a rather obvious rectangle, on the package. Although better than not having a security feature, this solution is less elegant and easier to spot, even when covert. Second, the use of direct printing can avoid creating an extra process on the production line versus the alternative of using a separate security label. Finally, it is very difficult to remove and reuse security material that is printed onto, or integrated into, the package itself—although admittedly the entire package could possibly be reused. The unauthorized removal, exchange, and/or reuse of labels, on the other hand, has been a recurring problem in the industry. However, there are also disadvantages to direct printing. It can be more difficult and costly to change graphic designs for the packaging itself than it is to change security labels. Inclusion of covert security material into varnishes, for example, can be problematic and expensive when a whole package must be coated, whereas it might be feasible to coat a smaller label. Planar carton board surfaces are readily printed using a number of techniques, but plastic and glass substrates are trickier. Curved surfaces

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are generally better suited to labels than to direct printing. Of course, if holograms, diffractive optically variable image devices (DOVIDs), or other pre-manufactured optical effects are selected, then these generally need to be applied as labels. The use of labels is therefore desirable and highly effective for some applications. The technical aspects of security labels are discussed in the next chapter.

Chapter

18

Security Labels

As we saw in the previous chapter, the use of labels has many advantages. They are smaller, cheaper, and easier to modify and change than the packaging itself. They allow the cost-effective use of specialized substrates or materials, such as metallic foils, DOVIDs, and other pre-manufactured optical effects. Labels offer tactical flexibility: the same design and label stock can be used on multiple products if required or specific labels can be used for certain items or key markets. Labels can be added or removed during the manufacturing and distribution processes and can have a dual function as information carriers and tamper-evident features. Four main label types are used in the pharmaceutical industry: plain with added adhesive, pre-gummed, heat sensitive, and pressure sensitive (probably the most commonly used). Pharmaceutical security labels are usually applied, using physical pressure only, by an automatic labeling machine during the final packaging process. Although typically pre-printed and supplied on sheets or rolls, labels can also now be produced by printon-demand (POD) processes, which use inkjet or laser printing processes. This can reduce lead times and allows the incorporation of variable data and other changes. Traditional label printing using offset or flexo processes can be less expensive for longer production runs if turnaround time is not an issue, although for the brand owner this saving may be offset by the costs of buying and holding label inventory. Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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The security of an applied label is assured by a number of different features, discussed below, all of which must be considered during the design of the label. ADHESIVE

Since labels, whether paper, polymer, or metallic, do not adhere spontaneously to most surfaces, they must be affixed with an intermediate layer of adhesive. The selection of the correct adhesive is therefore a critical component of the integrity of a product security label. For some retail applications, such as price labels, the ability to remove the label cleanly and without leaving any residue on the product may be a desirable feature. However, for security labels, the exact opposite is true. They must remain in situ after manufacture to prevent any attempt at relabeling of the product with fake labels or reuse of the genuine labels for counterfeit product. Security labels are therefore designed so that removal of the label damages the label and/or the underlying surface so that neither can be easily reused. The adhesive plays a key role in hampering attempts to remove the label. Typically, pharmaceutical security labels use an “aggressive” adhesive—that is, one that forms a strong bond with the substrate. The adhesive is generally pressure sensitive, requiring neither heat nor moisture to activate the adhesion process. This is convenient for automatic application since the label need only be rolled onto the product after the backing paper has been separated. Removal and recycling of pharmaceutical labels has been a major security issue in the past, with criminals using solvents to remove labels from genuine bottles and vials. The genuine label, once removed, can be reused on counterfeit products or replaced with a fake one on the genuine product. The uplabeling discussed earlier is a variation of the latter tactic and has been used by criminals to increase the apparent dosage strength of a product and therefore to increase its selling price.1 Various levels of tack (immediate stickiness) and adhesion (long-term grip) can be specified. Some adhesives do not adhere strongly initially but build into a strong bond over hours or days. Others are instantly adhesive but remain removable. The initial tack level must also be compatible with the application method (usually by machine) to avoid problems and inconsistencies in placement of the label. Common challenges include ensuring consistent removal of the label from the backing sheet: too easy and label wastage may be high, too difficult and the number of unlabeled packs will be unacceptable. Skewing or slippage of labels during the labeling process can also lead to significant wastage and downtime as mislabeled packs are removed and relabeled.

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It is also important to take into account the temperature and humidity conditions under which the labels and (subsequently) the labeled products will be stored. Some label adhesives can lose their tack and become waxy at low temperatures, allowing the labels to come off their backing or off the product. Conversely, high storage temperatures, for example, in a nonair-conditioned part of the manufacturing facility, can cause an adhesive to become less viscous, allowing labels to slip on their backing paper and leading to misapplication and wastage. Finally, if the labeled product will be exposed to significant humidity then the adhesive must be appropriately chosen and tested to ensure that the label remains attached to the product. One pharmaceutical situation when labels may need to be more easily removable is when they contain personal patient data. However, these individualized labels are usually added by the dispensing pharmacist rather than by the manufacturer and do not generally carry significant security features (although there is no reason why they could not). They are in addition to the existing security elements of the pack and are usually positioned so that they do not obscure those features. These individualized labels contain sensitive information, and in the event of unclaimed prescriptions, the labels should be removed and disposed of with care to avoid privacy violations. In the United States, the removal and disposal of patient-specific labels is subject to the Health Insurance Portability and Accountability Act (HIPAA) of 1996 Privacy and Security Rules.2 The specification of label substrates and adhesive is therefore an important part of any security label project and should not be neglected. The label converter can often advise on the best choice of label stock and adhesive, but if they have not printed security labels before, then caution should be used. Off-the-shelf solutions used in food and consumer goods manufacturing may not be sufficiently secure for pharmaceutical use. As always, the security provided is only as strong as the weakest link. Costly security features that are printed or incorporated onto the label will be worthless if the label can be readily peeled off and reused or replaced.

FRANGIBILITY

In order to prevent reuse of labels, a deliberately brittle or frangible label substrate is often used. When applied with an appropriately secure adhesive, this will cause the label to break up into small pieces if removal is attempted (Figure 18.1) and will render the label useless. Label stock is available in frangible paper or plastic-based substrates of various types.

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60 Tablets INGESTA 50 mg

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Figure 18.1. Frangible Label.The label can only be removed in small pieces, often leaving behind an adhesive residue.

SECURITY CUTS AND PERFORATION

In order to reuse a security label, it needs to be removed intact. Therefore, to reduce further the possibility of unauthorized removal and reuse, labels with security cuts should be used wherever possible. These features are die-cut slits in the label substrate, added after the label has been printed. They are carefully positioned to allow the label to be removed from the backing strip in one piece (and applied to the product automatically using a label applicator) but are designed to cause the label to tear and fragment if subsequently removed from the product (Figure 18.2). Cutting dies are available in various patterns. If the label is to be used between two surfaces to cover an opening as a closure seal (rather than applied to a single flat or curved surface of the product), it is also common to use perforation in the fold area of the label that will sit between the two surfaces. This allows the carton flap (or vial cap, bottle top, etc.) to remain sealed and intact during transit, but it can be opened easily by the consumer. The one-time-use aspect provides evidence of prior opening if tampering is suspected. VOIDING

An alternative to making a label very difficult to remove is to incorporate a mechanism to identify clearly when it has been detached. Void labels

GENERAL CONSIDERATIONS

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Security cuts

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Figure 18.2. Security Cuts. After printing, a pattern of slits is made in the label with a steel die. These are designed to make removal of the label from the product in one piece very difficult. Various patterns of die cuts are available.

leave behind a residue or adhesive film when the label is removed from the product, allowing tampering to be easily spotted and preventing reuse of the label. This is often designed as a partial process, so that specific areas of the adhesive are removed with the label. The area remaining causes a logo or message to be revealed when the label is removed, for example, “VOID.” Sealing tapes with this voiding feature are also available.

ALIGNMENT

As with all security, sometimes the apparently simple measures can still be effective. The specific, reproducible, and exact alignment of labels on the product can be an anti-counterfeiting tool in its own right. If a label supplier is able to offer a complex and reproducible label alignment that is hard to achieve consistently by other suppliers, this may provide a way of identifying attempted counterfeits, even if they bear a similar-looking label.

GENERAL CONSIDERATIONS

There are many suppliers of security labels, some using their own inhouse technologies and some using third-party security inks or features. When outsourcing the production of security labels, it is very important to ensure the security of the label converter. If the supplier has not printed security labels or handled security products before, the drug manufacturer should be wary: cost should not be the driver in the buying decision. If the vendor has a unique technology or capability that cannot be obtained from a more established security vendor, then the buyer performs a full security audit encompassing all aspects of the converter’s operations. In particular,

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it is crucial to ensure the secure storage of the security ink or security feature that will be used on the label and of the labels themselves after manufacture and to reconcile the security material used with the output of labels. Security labels and other security materials are highly portable and valuable and therefore very attractive to thieves and counterfeiters. It is also highly advisable for the converter to perform 100% quality control (QC) checks on the printed labels, ideally during production and certainly before their release to the customer. This is particularly important where covert features are printed since their quality cannot be verified by the press operator directly. Some of the particles used in certain security inks are relatively large and may settle more quickly than other constituents of the ink during storage or use. Therefore, a colored security ink containing an invisible taggant may produce a visibly perfect effect throughout the whole print run, but the signal from the invisible taggant may decrease in strength toward the end of the run as it effectively becomes diluted (Figure 18.3). Visual checks will not pick this up, Visual appearance

Appearance under detector

Overt security feature

Covert security feature Starma

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Problem with covert feature during long print run

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Figure 18.3. Need for Appropriate Validation. The consistency of the visual appearance of an overt security feature may mask problems with a covert feature if the latter is not independently checked during production. In this example, the central (covert) star of the double star feature has become washed out during the run, but the outer (overt) star is unchanged. Only an in-line detector or spot-check QC will pick this up during the run.

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so the use of an in-line validator, calibrated to the security feature, is always preferable to post-production random QC. This precaution will help prevent wasted, misprinted batches of labels. The corollary of this issue is that, to ensure efficient press operation, inks must be individually developed and validated for the specific press and print run length. Settlement and sedimentation can be avoided with stirring, but particulate inks can also eventually cause residue to build up on print rollers, which in turn causes smearing and uneven distribution of the ink. Long print runs with offset processes are particularly prone to this problem. If such a formulation is unavoidable in order to achieve the desired effect, the time needed for stripping down and cleaning the press between print runs must be included in any time estimations and the volume of ink required for wastage and re-priming must be included in usage calculations. Careful QC checking should also be conducted. In addition, whatever the production and QC processes used by the converter, the pharmaceutical manufacturer should conduct their own checks on batches of labels received. Particular attention should be paid to the beginning and end of each reel and to any splice points within it. Security features can be integrated with the standard pack label, if one is present, or can be carried on a separate security label. Some companies may even specify two security labels per pack. One of the labels may be universal, for use on all products and/or in all markets, and the other label may be specific to one or more individual products or markets. Whatever the format used—integrated label or separate security label—a wide variety of possible security features is available.

LABEL RECONCILIATION AND STORAGE CONDITIONS

As noted above, security and storage of all components of the security system should be audited and corrective measures undertaken if necessary. This applies throughout the supply chain and includes inks, holograms, finished labels, and, of course, the labeled product. Labels should be kept under lock and key when not in use, and the numbers of labels used during production should be carefully reconciled with stocks and wastage. The FDA current Good Manufacturing Practice (cGMP) guidelines require full label reconciliation, so the manufacturer must account for all labels, both used and unused. This is usually achieved by numbering the back of each label during label production. Label storage conditions at the manufacturing plant should be controlled and monitored (temperature, humidity, and light). The conditions

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should at all times remain within the storage specifications agreed with the supplier. This is usually straightforward at a major pharmaceutical production facility, but if the label is stored and applied elsewhere then special care should be taken. For example, if a contract manufacturing organization (CMO) is used, or a local affiliate is applying a marketspecific security label to pre-packaged product, then the product security group should audit the label storage conditions and security arrangements.

Chapter

19

Holograms and DOVIDs

One of the key security reasons for using labels is to enable the application of sophisticated visual effects that cannot be directly printed onto the product. The most widely used example of a label-applied security feature in the last 20 years, in both consumer and pharmaceutical applications, has been the hologram. Holograms are familiar to many people around the world and appear on credit cards, currency, music and software CDs, and other everyday authentication applications. They form part of a larger group of related technologies known as diffractive optically variable image devices (DOVIDs).1 The sophistication of DOVID technology has evolved greatly since holograms were first introduced, and they can now exhibit a wide variety of complex images and patterns according to the viewing angle (e.g., if they are tilted or rotated). The underlying effect in all of these devices is based on the diffraction of light. Note that holograms are a type of DOVID, but not all DOVIDs are holograms. Holograms are created through the interference of two laser beams, but there are now different techniques to create similar images, including laser etching and electron beam etching. Proprietary types of DOVIDs, with specific brand names, are available, but “hologram” is still widely used as a general term for various reflective, kinetic images or 3D

Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison.  2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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image devices. References to holograms below should be taken in this wider sense unless stated otherwise.

TYPES OF HOLOGRAMS

The main types of holograms are classified1 according to their perceived effect: • 2D: An image appears in two dimensions, normally on the plane of

the hologram. • 2D/3D: Layered 2D images appear, in which at least one layer seems

to lie behind or underneath the other. • 3D: An image, which has full 3D appearance. • Stereogram: An animation effect is produced using a sequence of

images from a film, video, or computer graphics. The primary function of a security hologram is as an overt feature to allow the consumer to recognize and verify the underlying product and to differentiate it from otherwise similar counterfeit products. However, holograms are now used for both decorative and security applications. They have become very common even on relatively low-cost products and are well recognized worldwide. The visible effects of the hologram can be seen easily by untrained members of the public, just by tilting or rotating the image, or by moving its position or the light source. However, the untrained citizen sometimes finds it harder to differentiate between a real hologram with a complex image and a fake hologram with a different (wrong) image but apparently similar effect. The proliferation of holographic production capability for decorative applications has led to a rise in counterfeit security holograms. Simple, first-generation holograms are no longer a reliable safeguard, and modern security holograms usually incorporate several additional layers of protection. These may include semi-covert features or hidden visual elements that require a non-specific, non-proprietary hand-tool to view them. Examples include laser viewable features (that require a simple, widely available laser pointer) and microtext (visible with a magnifying glass). More fully covert image elements may require a proprietary viewer or decoder and may include optically encoded features requiring a specific paired viewer or watermarks verified with a scanner. Forensic features such as taggants can also be added. These taggants usually require laboratory examination to be positively identified and can provide definitive proof that the hologram is authentic. Holograms can also be serialized

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(given a unique, traceable number) with alphanumeric or other codes by overprinting, printing on adjacent non-holographic real estate on the label, or incorporation within the optical exposure, to provide track and trace capability for authentication and supply chain management. The two most common types of hologram production techniques are surface relief and volume. Surface relief holograms are the most ubiquitous type of hologram and are produced mechanically by embossing or casting the image into a film. They can be made on a variety of substrates to suit the intended use. The hologram is then coated to protect the diffractive effect and usually (but not always) has an aluminum reflective layer underneath to bounce light back through the pattern to reveal the image. Volume, or reflection, holograms are made by optical copying of a master hologram. They retain more optical properties than surface relief holograms and can incorporate three-dimensional color images. In the pharmaceutical industry, transparent, non-metallic DOVIDs are widely used in packaging security, for example, in tamper-evident seals and in shrink wrap. They are sometimes used in this way as additional features on already-marketed products, usually to minimize the regulatory burden of a design alteration. Changes to packaging are not to be taken lightly. Any change that is visible to the consumer has regulatory consequences, which can incur delay, costs, and management time. Design constraints and lack of available real estate on the pack also cause headaches for packaging engineers and product security specialists when choosing security features. Security suppliers are therefore sometimes asked to provide “an invisible overt feature,” which at first glance seems like an oxymoron. However, the meaning is that the technology should be unobtrusive enough to not create regulatory issues, or obscure existing text, but should be obvious to the consumer. A further request is usually that the feature should be applicable within existing production environments and should be readily understood and interpreted by the pharmacist and consumer. In all of these respects, transparent DOVIDs have been found to be useful tools within the anti-counterfeiting repertoire. Printed features can be difficult to fit into this semi-transparent constraint. Typically (but with some exceptions), security features printed directly onto the packaging are either overt but opaque features (such as colorshift inks) or invisible, covert features. Although holograms are now a mature technology, they still have value in an anti-counterfeiting strategy. Modern DOVIDs are much more difficult to reproduce than previous generations of surface holograms. They can be serialized, and additional semi-covert features can be visualized by the consumer before purchase. The second generation of the MediTag system in Malaysia,2 for example, widely seen as a pioneer system in the

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fight against counterfeit drugs, uses serialized DOVIDs. These labels also have secondary features that are visualized with a low-cost filter provided in the pharmacy, enabling the customer to validate their product as soon as they receive it and before they pay for it. Customers are used to associating holograms strongly with authenticity, thanks to their ubiquity on bank notes and payment cards for many years. However, this powerful association can be a disadvantage, since counterfeiters have been known to put holograms on fake products even when none exists on the genuine version. In this case, the customer is reassured by the presence of the hologram on the counterfeit product and sometimes suspects the genuine, non-hologram-bearing product to be a fake. Holograms and DOVIDs, like all visible features aimed at consumers, are largely worthless as anti-counterfeiting features without at least some element of customer education. The range and complexity of holographic effects in use, sometimes with multiple images and effects on the same label, can confuse the customer. If the consumer is not given very specific instructions as to what to look out for, they may be fooled by unrelated counterfeit holographic images or even by shiny, iridescent or metallic but non-holographic labels. The technology required to produce pharmaceutical holograms is now widespread, at least for relatively simple holograms. Some excellent field studies have shown the proliferation of different counterfeit versions of the same hologram on anti-malarial artesunate drugs in Southeast Asia, for example.3 Brand owners who specify a low-cost basic hologram may therefore find that fake holograms appear alarmingly quickly. As with all technologies, care is needed in the choice of supplier and in the design of hologram used. With this proviso, the hologram and its relatives and descendants still have a place in anti-counterfeiting strategy.

OTHER OPTICALLY VARIABLE DEVICES

New optical technologies are now becoming available. These optical films, generally applied in the form of pressure-sensitive labels, give striking three-dimensional effects but are not holographic. One of these technologies uses an effect called synthetic imaging. The effect perceived by the eye is of virtual images appearing in the space above or below the film. Printing at very high resolution allows very clear and detailed images to be produced, which appear to float above or below the film surface, turn on and off, or show simple animated motion. Multiple effects can be combined in one film. Although usually more expensive than many holograms, such novel technologies are often harder to reproduce and can

OTHER OPTICALLY VARIABLE DEVICES

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Fakes

Original

Copy

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Starma Mimic

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Figure 19.1. Copying Versus Mimicking. The general public, unless well informed, does not usually differentiate between similar features. Therefore, it is sometimes enough for counterfeiters to approximate the look of the original, even if they lack the capability to reproduce it exactly.

be attractive for some high-value products. As with all overt features, the public must be carefully informed of the precise nature of the effect to look for, or the sophisticated technology may be imitated by a cheap approximation which lacks the full effect of the original but is sufficiently similar to fool the average consumer (Figure 19.1).

Chapter

20

Specialty Inks

The number of decorative inks and special effects now available to graphics designers and packaging specialists is huge. However, for the purposes of product security, it is important to draw the distinction between an attractive graphic and a secure one. The manufacturers of truly secure inks control their production processes and their suppliers very carefully to ensure a secure supply chain. They make background checks of new customers and monitor their existing customer base very carefully to ensure that security materials do not fall into the wrong hands. Commercial packaging ink suppliers, on the other hand, generally do not ask too many questions. Their products can sometimes be bought anonymously on the Internet using a credit card. Those specifying product security technologies should remember that if anyone can buy the ink then it is not a security feature—however distinctive and attractive it may look on the box. In recent years, there has been a greater diversity of security inks available, for both overt and covert use, some of which are described below.

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COLORSHIFT INKS

The first true specialty security ink used in overt pharmaceutical security applications was probably colorshift ink. This technology, introduced around 30 years ago, gives the type of security printed feature seen on most of the world’s bank notes. The underlying technology used to produce these inks is complex and has been highly successful in protecting the value of currency for many years. More recently, colorshift inks have been used in high-profile pharmaceutical brand protection applications. In contrast to holograms, the physical effect seen with colorshift inks is rather simple. Upon changing the angle of view, the observer notices the ink change its color abruptly and clearly. The color change (i.e., the frequency difference of reflected light at the different angles of view) is large enough to be unmissable even to the untrained eye (Figure 20.1). This effect is familiar around the world and is used in anti-counterfeiting for overt, consumer verification applications. Although the effect is simple, the underlying physics and the required production processes are more complex, and the technology has proven rather resistant to counterfeiting. Colorshift features for banknotes are printed using highly specialist intaglio presses. For pharmaceutical uses, they are usually printed by silkscreen or flexography. As noted above, for any overt feature, the surface area required in order to get a good visual effect is generally at least 1 cm2 . This need not literally be in the shape of a square, although simple motifs are still frequently used, but can be incorporated into existing or additional graphical elements on the pack or label. Two or more colorshift inks can also be combined in designs that can produce different images at different angles. Once again, design complexity and control of security

A B

Figure 20.1. Colorshift Effect. The defining characteristic of colorshift features is that they change color from one distinct color (A) to another (B) upon changing the viewing angle. The effect is abrupt, with few intermediate colors.

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materials are the keys to producing robust features that will resist counterfeiting. Colorshift inks can also be combined with other inks such as machine-readable taggants or polarizing inks. This gives the potential for overt, semi-covert, covert, and forensic features to be combined in one printed feature. Although the colorshift effect is simple, the number of possible color pairs is limited by the nature of the physics involved, and additionally some of the available choices may be reserved by the supplier for highsecurity banknote use only. Therefore, the number of options offered by the manufacturers is relatively limited, but there are still enough possibilities to enable the effect to be harmonized with existing color schemes, for example, even if exact color matching is not possible. Also note that because of the relatively limited options, it may not be possible to obtain exclusive use of a certain color pair. As with holograms, security depends on accurate recognition of the feature by the examining party. Some of the visual features of colorshift inks can be simulated, even if not fully reproduced, using other inks. It is therefore important to undertake consumer education when using colorshift features aimed at the public, so that the buyer or recipient of the medicine can identify the exact and striking color change effect that they should look for in the authentic product. Lately, there have been developments of colorshift inks with additional security properties. This provides a printed feature with both a consumer recognition feature (colorshift) and a semi-covert feature accessible with an inexpensive filter. The latter can be used by pharmacists, customs officials, law enforcement, and others. It also enables additional verification by the consumer in the pharmacy, in the same way as the DOVIDs used in the MediTag® system described above. OTHER SECURITY INKS

Colorshift inks are a security item and are hard to get hold of in the open market. There are some other inks that fall into the middle ground of security—useful to deter the casual counterfeiter but not fully secure on their own. The inks below have all been used for security purposes. They are relatively inexpensive and are useful as part of an integrated and layered security strategy. However, they are too readily available to be considered as truly high-security features. Iridescent

Iridescent inks are available in various forms and give an attractive rainbow effect, with multiple changing colors visible as the observer changes

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position relative to the printed surface. Note the difference between iridescent inks and colorshift inks. The latter have a single shift from one discrete color to another, in a clear flip-flop effect, whereas iridescent effects give a more multi-colored “soap bubble” effect with gradual transitions and multiple colors visible simultaneously. Iridescent inks are available in various color shades and are often used in combination with other inks in complex designs. Metallic

These inks are available in various effects and colors, silver, gold, copper, and so on, and are often combined with iridescent inks to give strikingly colorful and reflective effects. Unfortunately for security purposes, metallic effect pigments are cheap, very widely available for non-security applications (decoration, car paint, etc.), and are easily obtainable by counterfeiters. Fluorescent

Fluorescence is the emission of light by matter after irradiation with light of a different wavelength. In almost all cases, the emitted light is of a longer wavelength than the incident light. The phenomenon occurs widely in nature and has been used in decorative and security printing for some time. The fluorescent inks normally used for security purposes glow visibly under ultraviolet (UV) light. They are sometimes called “down converters” because they shift the energy of the incident UV light down into lower energy visible light, which is then emitted and detected by the eye. The effect is immediately reversible, and fluorescence ends when the UV light is removed. The variety of chemistries available allows the incident and emitted light parameters to be tuned to some degree. These inks are often used on banknotes to allow simple validation (using a blacklight) by vendors at the point of sale. Although not considered highsecurity options, they can form a useful first line of defense and can deter simple attempts at counterfeiting (color photocopying, for example). Bi-fluorescent

The use of bi-fluorescent inks simply involves the combination of two pigments that fluoresce at different wavelengths of incident UV light. This approach is generally slightly more secure than single-wavelength fluorescence. Using either an integrated, dual-wavelength lamp or two separate lamps, the effect can be readily visualized.

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Thermochromic

Thermochromic inks, as the name implies, change color or become colorless at a certain temperature threshold. The reaction is usually reversible, allowing the feature to be checked and reset multiple times. The reversible thermochromic inks revert to their original color after a few seconds when cooled below the critical temperature. These inks can be tuned to a reasonably narrow temperature range, for example, so that they change color owing to body heat from finger pressure. They can also be combined with standard colors to create multiple combinations of changing colors. Irreversible thermochromic inks are also available and are useful in “cold chain” checks to ensure that products have remained below the desired temperature threshold at all times during their transit from factory to patient. Although often regarded as a logistics issue, cold chain verification becomes linked with anti-counterfeiting and anti-diversion issues in many cases. Refrigerated products (such as vaccines and blood products) that are removed from authorized sales channels are frequently not stored in an appropriate manner before being resold. This can lead to loss of efficacy or even potentially toxic effects. An irreversible thermochromic feature can therefore be an important element of an integrated product security approach for such products. Photochromic

These inks change color when exposed to UV light, as with fluorescent inks. However, with photochromic inks, the effect is longer lasting and the color reverts to the original hue only a few seconds or minutes after the UV source is removed. Coin Reactive

Coin-reactive ink changes color when scratched or scraped with a metal object such as a coin. The effect can be combined with other inks, often to reveal another printed image when the coin-reactive ink is activated. The use of this type of ink has been mandatory on pharmaceutical products in Brazil for a number of years. Coin-reactive ink can also be combined with fluorescent features—useful for monitoring the printing process without disturbing the coin reactivity. MICROSTRUCTURED TAGGANTS

Printable microtaggants are tiny particles (typically tens of microns in size) that covertly incorporate customized codes, words, or logos. Although

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invisible to the naked eye, they are easily identified using devices such as a low-cost, portable microscope. Other variants are fluorescent or respond to other forms of input signal in a specific way. They can be supplied pre-formulated, added to other security inks, or applied in a clear varnish. Some microtaggant technologies can also be incorporated into bulk material such as plastic resins (used to make bottles, blister trays, etc.), transparent films, and adhesives. The ability to carry a small amount of corporate or brand-specific information, as well as providing a yes–no authentication tool, is useful in tracing suspected diversion and counterfeiting networks or in identifying unauthorized reuse of materials. Microtaggants are of relatively low cost and constitute a useful weapon in the product security armory.

Chapter

21

Covert Taggants and Forensic Markers Visible security features are important and useful—the consumer provides a ubiquitous pair of eyes—but for more effective product protection, the overt elements need to be supplemented with covert security. Hiding a security feature from view provides a first layer of protection from counterfeiters. It also allows security to be added without the need for referral of visible design changes to regulators. Finally, the selective use of different covert technologies in specific markets can help to identify diversion or insider fraud without alerting distributors, agents, and other supply chain stakeholders to the presence of the new security feature. There are many covert technologies available, each with strengths and weaknesses. The best strategy is to choose several complementary approaches. Some options are given below, although for reasons of security, this is not an exhaustive list. Once again, suitable security vendors will be able to provide more information.

INFRARED-ABSORBING INKS

As the name suggests, these inks absorb infrared (IR) radiation. However, instead of emitting longer wavelength light, as in a standard fluorescence process, they emit shorter wavelength light, usually in the visible range. Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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Therefore, they appear to break the laws of physics by converting lower energy, longer wavelength IR light “up” into higher energy visible light and are sometimes known as up-converters. In fact, the energy of two incident photons is converted into that of one emitted photon, so the first law of thermodynamics remains intact. Although the underlying mechanism limits the number of possible permutations, the absorption and emission characteristics of individual ink formulations can be somewhat tuned. The quantum efficiency of the up-converter process is quite low compared to that for down-converters, so the visualization of up-converter inks often requires a more powerful incident light source and a sophisticated electronic detection device of some sort. These inks are therefore often known as machine-readable features. The readers can be handheld, press mounted, or incorporated into other validation machinery. They are usually calibrated for the specific qualities of the ink formulation, so the detector will give a positive signal only if it confirms that the specific ink is present at the correct strength. Another up-converter or an incorrect formulation will give a negative signal. This gives a powerful lock-andkey security effect, which is important for anti-counterfeiting uses. The ink may be detected by the reader on the basis of a single wavelength, multiple spectral properties, or other physical signatures. Typically, the ink/reader pair is sold as an integrated security system by the supplier. These up-converter systems provide much more secure verification than the more generally available inks described above and are based on closely held intellectual property. This, and the fact that they require sensitive and proprietary readers that may need to be regularly calibrated and serviced, means that up-converters are often significantly more expensive than fluorescent inks. The business model is often based on a unit charge, as with colorshift inks. In this case, the supplier will provide intellectual property, readers, inks, formulation development, press validation, and associated services in return for a fee per unit of product protected.

FORENSIC MARKERS

The “deepest,” most hidden covert features used for product security are known as forensic markers. The definition is inexact, but broadly speaking, forensic markers are those additives or features that usually require analysis using sophisticated laboratory equipment not generally available, such as electron microscopes. The exact materials used as markers in any given product should always remain highly secret, since this level of feature is the last line of defense against copying of the product and may

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form the basis of criminal proceedings against counterfeiters. Forensic markers are (relatively) low-cost additions to a layered security system and should be included where possible. Typically, forensic features are not analyzed on a routine basis unless there is reason for suspicion based on other evidence. They are most typically used during the preparation of litigation proceedings to allow the brand owner security team to differentiate with certainty between the genuine product and alleged counterfeit materials that have been identified by other means. Unless absolutely necessary, the identity of forensic features should never be publicly disclosed—even in court cases or regulatory filings. Information on these markers should also be restricted internally within the brand owner organization on a need-to-know basis. It should not be necessary for more than a very few people in the security supplier and customer organizations to know the detailed composition of forensic markers on the product. Many forensic markers can be used in mixtures of well-defined proportions, giving the material in which they are placed a fingerprint that is extremely difficult to detect and almost impossible to “reverse engineer.” To preserve the security of these technologies, only general information is given below. There are some excellent technologies available from reputable security suppliers who can also offer confidential advice. Isotopic Tags

Typically, these are isotopically altered variants of common molecules already occurring in the product. An example might be the substitution of the stable but heavier isotope 13 C for the more naturally abundant 12 C. The altered isotope composition gives the molecule a slightly different mass without altering the chemistry. Present in very low concentrations (e.g., parts per billion), these taggants are very hard to detect except by mass spectrometry and are almost impossible to remove. Their main drawback is that analysis requires expensive laboratory equipment. DNA Markers

In this technique, short synthetic DNA fragments with a specific sequence of nucleotide bases are included within the matrix of a label or security ink. The DNA “signal” can then be detected at a later date using one of several techniques that take advantage of the capacity of DNA strands to bind to each other in a sequence-specific and predictable way. Typically, the target DNA strand is detected by adding the “opposite” strand, which has a complementary sequence to the original and which has a fluorescent “tag” molecule that is activated when bound to another DNA strand.

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This added reagent then binds to the target sequence on the product, and the interaction causes a detectable fluorescence signal. The addition may be achieved using a detector pen or similar field device, making this a potentially portable technique. If the DNA tag is present in very low concentrations, the use of robust and well-established polymerase chain reaction (PCR) technology can allow it to be amplified (the target DNA is repeatedly replicated and increased in concentration so that it exceeds the detection threshold) prior to detection. Such systems can give a highly sensitive and specific signal, provided that appropriate supply chain security is observed and the DNA sequences are specific enough to be difficult to detect and reproduce by counterfeiters. Antibody Systems

Like DNA marking, antibody-based systems also rely on the recognition of specific chemical markers in the product sample. However, in this case, the signal is identified using binding proteins or antibodies, often packaged into portable field kits. Based on the same principles as some medical diagnostic kits, the antibodies used in product security applications display the same high affinity (sensitivity) and low level of false-positive readings. The possible number of target/antibody combinations is very large, making these systems hard to circumvent. However, the testing method is generally destructive of the sample, and antibodies can be hard to store appropriately in the field in hot climates, as they often require refrigeration. X-Ray Detection of Specific Added Elements

If the sample itself does not contain a sufficiently distinctive forensic feature, it is often possible to add trace amounts of specific marker elements. Excitation by X-rays causes a detectable fluorescence signature from the marker elements. Many combinations and ratios of markers are possible, making the feature very hard to copy. Although the technique has the advantage that it does not require “line of sight” between detector and marker, X-ray machines are large and usually not well suited for field use. Other Markers

Where detail is omitted from the preceding descriptions, it is to protect the integrity of existing systems. Many other proprietary markers are available, and for obvious security reasons, they will not be discussed here. The reader is advised to contact suppliers or trade associations such as the International Authentication Association1 directly.

Chapter

22

General Conclusions on Printed Packaging and Security Labels The preceding few chapters have covered some of the options for adding security features. The choice of security features on packaging and labels is a large and complex subject, and for real-world requirements, the optimal approach will be different for each product, market, and threat. Nevertheless, some general conclusions can be drawn.

LAYERING

A well-designed, integrated security system for direct application onto packaging or a label will usually incorporate more than one of the feature types described above, for the reasons outlined previously regarding layering of security. This multi-level approach is sensible from a security perspective because it involves different constituencies in the protection of the product, from the consumer to the product security specialist. The strategy also helps to protect the investment in time and resources in developing a new security feature or system and to ensure its longevity. Remember the principle of the authentication pyramid (Figure 22.1). Ideally, all layers of the pyramid should be addressed.

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More pairs of eyes but higher exposure of security feature

One or two people (forensic analysis) Product security team (multiple tools, laboratory) Customs, sales reps (complex tools) Pharmacists, public (simple tools) General public (no tools)

Figure 22.1. The authentication pyramid.

GUIDELINES

Product security strategy involves individual choices based on the specific circumstances faced by each corporation. Nevertheless, there is a worldwide paucity of guidance on what is a suitable minimum level of anti-counterfeiting features that should be expected. This situation is now being addressed by ISO and others, but it is critically important that all organizations specifying product security standards—whether international or national organizations, government departments, or independent standards bodies—continue to focus on the desired outcomes (security, robustness, etc.) and do not adopt an overly narrow and prescriptive approach to specific technology choices. Limiting the selection of available anti-counterfeiting technologies will only make counterfeiting easier. Standards should be rigorous but should always be based on performance criteria that can be met by multiple technologies. Not only does this avoid the creation of unhelpful monopolies for individual security suppliers but it also allows flexibility for brand owners to change direction in the event of security breaches.

FLEXIBILITY AND VIGILANCE

It is important to note again that no single anti-counterfeiting approach is secure forever. The resources available to organized crime and the profits available from fake drugs mean that criminals can probably duplicate or mimic most security features eventually, if they wish to do so. Brand owners must beware of leaving security features (especially overt ones) in the market for too long before replacing them. They should always have

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a planned upgrade path for the feature and ideally also an emergency Plan B that can be activated quickly in the event of a major security breach. As discussed elsewhere, security does not have to be absolute and eternal to be effective—it has to prevent the opportunist counterfeiters from succeeding and persuade more organized criminals to look elsewhere for easy profits. The effectiveness of anti-counterfeiting measures as deterrents is separate from their use as proof. Deterrence tends to fade over time as counterfeiters find ways to copy, circumvent, or mimic the feature or the public becomes blas´e about checking it. However, it is rare that a well-designed security element is fully and accurately counterfeited in all its aspects, so it may have some value in allowing trained experts to differentiate genuine from fake products even when look-alike products start to appear in the market. Brand owners should therefore remain vigilant for any security breaches, ideally by conducting regular and unannounced market surveillance using mystery shoppers, but should remain measured and flexible in their response to the findings. Rapidly changing the pack appearance as security features are repeatedly replaced can have the paradoxical effect of helping the counterfeiter, since the consumer uncertainty over the correct current brand identity allows similar fakes to pass unnoticed.

Chapter

23

Security of Primary Packaging Having discussed the application of security features in general terms in the previous chapter, the following chapters look at specific packaging types. Pharmaceutical products generally require a higher standard of packaging than many other products, in order to comply with the key requirements of safety, uniformity, integrity, and shelf life. The first layer of packaging around the active principle, known as primary packaging, forms a protective layer around the product, helping to keep it clean, free from contaminants, and in the appropriate conditions for use. It is thus an ideal site for anti-counterfeiting features, albeit with some limitations and cautions.

CONTACT WITH DOSAGE FORM

The primary packaging is a logical place to examine when thinking about the use of anti-counterfeiting strategies and technologies, since it is the last piece of packaging to remain associated with the product itself and the most likely to reach the patient. However, proximity to the dosage form brings its own challenges. Despite the fact that the anti-counterfeiting feature is applied to packaging and is not present

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on the dosage form itself, in some circumstances, it could still come into contact with the product either during storage or when the product is removed from the packaging, and potentially could be ingested by the patient. Therefore, there are potential toxicology issues that need to be borne in mind when choosing a security technology for primary packaging. The FDA’s Guidance for Industry: Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting, quoted previously in Chapter 21, states:1 If an applicant proposes to affix or incorporate a PCID [physical-chemical identifier] into a primary packaging component for a SODF [solid oral dosage form], the applicant should assess PCID toxicology and the potential for an adverse effect on SODF quality, performance, and stability.

When using an established security technology, the security supplier should be able to supply the brand owner with the necessary documentation on the safety of the product and its suitability for the proposed application. If the product has not been specifically tested or is not on the relevant lists of acceptable materials then it may not come into contact with the ingested product. Processes must then be validated to ensure that placement of the security feature occurs in a way that does not allow contact between the security feature and the dosage form to happen. Typically, the problem is more relevant to unit-dose push-through packaging (PTP), such as blister packs, in which the pill must exit through the printed foil, rather than to bottled pills and capsules. FDA’s recommended reporting procedures for packaging changes that may bring anti-counterfeiting materials into contact with SODFs are outlined as follows: 1. Annual Report If the substance(s) in the PCID is a permitted direct or indirect food additive or listed in FDA IIG, or if the added substance(s) has been previously approved for use in the primary packaging of another CDER approved SODF, an applicant may report the addition of a PCID to primary packaging for a SODF in its next annual report. 2. Changes Being Effected Supplement If the toxicology of the added substance has not previously been established (as provided for in the above paragraph), applicants proposing to use the substance as a PCID in primary or secondary packaging may submit the change in a CBE-30 supplement if the supplement includes data providing assurance that there will be no migration of the PCID into the SODF. The supplement should also include information addressing toxicological concerns.

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3. Prior Approval Supplement If the safe use of a PCID cannot be ensured (i.e., if the toxicology has not previously been established and migration potential exists), the applicant may not market the drug product using the PCID in primary or secondary packaging unless a prior approval supplement is submitted and approved.

This guideline highlights the point that it is mandatory, not optional, to examine the level of likely contact between the anti-counterfeiting feature and active ingredient(s) and, if necessary, to conduct further testing to establish the nature of any potential interactions. Although only applicable to the United States, the FDA sets out clear and sensible principles for the protection of patient safety that are appropriate in all markets. Design of packaging to avoid any such potential contact may thus save much regulatory paperwork. TYPES OF PRIMARY PACKAGING

Since pharmaceutical products come in a multitude of shapes and sizes, there are many different types of primary packaging, ranging from bottles and blister packs to glass vials, pre-filled syringes, inhalers, and other complex delivery devices. Packs may be designed for single use or multi-use. Each pack type has specific opportunities and limitations for anti-counterfeiting. Almost all packaging types, including some relatively complex products such as inhalers, have been the target of attempted counterfeiting.2 It would be unnecessary and tedious to list all of the possible security approaches for all available pack types, since many of the concepts are similar. The selection below covers the packaging used in the great majority of pharmaceutical products and highlights general themes and strategies that can be used for other substrates not mentioned. BLISTER PACKS

In most markets outside the United States, prescription drugs are sealed into their packaging when they are produced and then distributed to the patient without leaving their primary pack. This approach is also increasingly being used in the United States. Most commonly, such unit-dose packaging involves a blister pack or PTP. These typically consist of a molded plastic (or plastic–aluminum laminate) tray, which is filled with pills or capsules and then lidded and sealed, typically with aluminum foil (Figure 23.1). The whole process is usually automatic, with a single

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Inside surface of foil

Outside surface of foil

Aluminum foil

Plastic tray

Inside surface of foil not in contact with dosage form

Inside surface of plastic tray Outside surface of plastic tray

Figure 23.1. Cross-Section of a Typical Blister Pack. The blister format provides a number of distinct surfaces for the application of security features with varying degrees of potential exposure to the dosage form. Contact between security substances and the drug itself, both during transit and storage and during removal of the pill or capsule through the foil, must be considered.

form-fill-seal machine combining the plastic or laminate film, pharmaceutical product, and aluminum foil into the finished blister pack. The pharmaceutical blister pack is well suited to its function of protecting the product (which is usually pills or capsules but could also be vials, ampoules, or other products). The aluminum foil and the plastic tray give some degree of impermeability to gases and provide a good barrier against particulate contamination by dust, etc. For extra protection (in tropical climates, for example), cold-form film is used for the tray. This is a three-layer laminate of oriented polyamide (OPA), aluminum, and polyvinyl chloride (PVC). Blister packs also offer some advantages as substrates for anticounterfeiting features. The lidding foil’s outer surface presents a reasonably large and easily accessible surface area and is flat. The foil can be pre-printed with security inks or other optical effects, such as holography, or specialist rolling can be used to incorporate specific images into the foil itself, before delivery to the packaging plant. However, printing onto foil is not the same as printing onto carton board, and some restrictions apply. The reflectivity and smoothness of the lidding

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foil can affect the adhesion of inks and can be problematic for some machine-readable printed security features. This needs to be assessed during the design phase and tested carefully before full production. Security features can be applied by the foil converter before delivery to the pharmaceutical packaging facility or (with some technologies) immediately before or during the packaging process itself. In all cases, the ink or feature must be resistant to abrasion and peeling when the product is transported and stored in its distribution from factory to patient. If preprinted or pre-featured security foil is to be used, the security feature must also adhere reliably to the foil during production and storage of the foil itself (more on this below) and must also be able to withstand without alteration the temperatures and pressures used in the annealing process (sealing of the foil onto the plastic pill tray during the form-fill-seal process). It is important to check this thoroughly to look for discoloration, flaking, distortion, or other changes, both visible and covert. The temperature and pressure tolerance required depends on the types of blister packaging line used. There are two main types: Continuously Operating: These machines are equipped with continuously sealing rollers. This gives the advantage of higher output rates, but because of the smaller surface area pressing down on the foil at any one time, the heat-sealing process must be performed at temperatures of 200–300◦ C. This means that the foil (and any inks or surface features) is subjected to higher thermal stress. The security feature must be tested and validated under these conditions. Intermittently Operating: These systems work with sealing plates rather than with rollers, in a discontinuous process using a relatively low sealing temperature of 140–200◦ C. They allow the use of wider plastic tray forming films and aluminum lidding materials because of the more even sealing and greater surface contact area of the plate versus a roller. However, intermittent processes tend to have slower operation speeds and tend to require more maintenance because of their stop–start operation. Foil with pre-printed security features can be used on both types of machines, but because of the operating differences, the ink or feature used must be carefully formulated and designed for the specific production process and for the intended position on the blister foil. Printed foils are typically produced using gravure printing (although flexography is sometimes used) and are usually supplied pre-printed by third-party foil manufacturers, who can also supply other security features (specialized milling, etc.) integral to the foil itself. The printed foil must

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be checked and validated during production and printing and before use on the pharmaceutical production line and, it is important to consider a number of factors, including the following: • Appearance of the foil and printed feature during and after production • Continued adhesion of the feature to the substrate, if printed • Abrasion resistance and visible properties in the longer term

If pre-printed foil is used, it is typically printed only on one side, which will become the outside face of the lidded blister. Caution is needed during foil production to ensure complete drying before rolling and storage. Also note that prolonged storage of tightly rolled aluminum foil brings the outside face into intimate contact with the inside face of the adjacent sheet and so on through the roll. It is prudent to check periodically that this has not caused transfer of the security ink or feature onto the opposite face and therefore exposure of the security material to the product side of the lidding foil (Figure 23.2). Printed foil should be wound no tighter than is necessary, but tight enough to avoid slippage on the reel which itself can cause foil wastage. If the security feature will come into contact with the dosage form itself when the pill or capsule is pushed through the foil, there is a potential for it to be ingested. This may happen if, for example, a security mark is printed in a wallpaper pattern over the whole surface of the foil. In this case, the ink or feature used should be tested accordingly. One way to avoid this problem is to enclose a security feature between the plastic tray 1 2 3 4 5

Figure 23.2. Transfer of Feature between Faces of Foil. The figure shows a cross-section (not to scale) of a tightly wound drum of foil with a pre-printed security feature (1) on what will become the outer surface of the blister foil (2). The future inner surface (3) will be in direct contact with the dosage form and should not be printed. On a roll, each printed surface is adjacent to the unprinted surface of the next layer. During storage, it is possible for material to transfer between these adjacent foil layers, leading to contamination of the inner surface (4) and damage to the original feature (5).

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and the foil lid in such a way that it is sandwiched in the space between the pill pockets and is therefore visible only from the underside of the blister. It this case, it does not contact the product itself in any way. The feature is printed on the underside of the foil, and careful registration at the sealing stage ensures correct placement of the security feature—but see the caution above about transfer of ink from adjacent foil layer during storage of foil rolls before use. Flexography can also be used to print blister foils in-line, just before the form-fill-seal packaging process. This can offer increased security over other methods of foil printing because the security printing step is “in house” but adds further complexity to the production line. Another excellent and secure option, if it is not necessary to print all of the foil features in-line, is to use foils pre-printed with all of the non-security graphical and text elements but to ensure that all security materials are managed and printed by the pharmaceutical manufacturer or CMO, not the third-party converter. For blister foils, this is best achieved by printing a security feature onto the foil during the packaging process, after the filling and sealing step, using an in-line inkjet printer. In this case, a validation system and an ejection mechanism must also be added on the line downstream of the printer, if not already present, to identify and remove any misprinted blisters. If foils with holographic features or other intrinsic effects (rather than ink-based features) are used, the foil application process should be checked, during pre-production validation, to ensure that the heat-sealing process does not affect the appearance of the feature. Even after validation, and whichever security technology is selected, no process is ever completely fault-free. It is important to have an in-line vision system and rejection mechanism, or end-of-line QC system, for those blisters in which the security feature has either not been optimally applied or has an unacceptable appearance. It may also be necessary to add an extra security protocol to the processes for waste management and/or de-blistering (removal and reuse of dosage form from misprinted blisters), if used. Even reject security foil has its uses in criminal hands.

WALLETS, CARDED BLISTERS, COMPLIANCE-PROMPTING PACKAGING, etc.

The pharmaceutical wallet pack, and its many variants, is a related form of packaging to the blister pack, but rather than having a separate carton box with the blister pack loose inside, the wallet format combines

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both packaging elements into one. It is an especially useful form for some products, such as contraceptive pills, where the sequence of pills is important or where the printed patient information needs to remain firmly connected to the medication package. For products containing more than one dosage form, the wallet also allows multiple components to be packaged in an integrated way. The wallet format is also often used to make it easier for patients to remember their drug regimen and therefore to increase compliance with their therapy (also known as adherence). Such compliance-prompting packaging contains features to help patients take their medication at the appropriate times and finish the course. Finally, wallets are also useful for packaging that needs to be childproof but seniorfriendly. For anti-counterfeiting purposes, integrated, wallet-style packages are more complex to design and manufacture and therefore are not so easy to copy as standard blister packs. From a practical, security application point of view, they have some of the advantages of both blister foils and carton boxes in that many of the labeling, printing, or marking techniques discussed elsewhere can be used depending on which of the surfaces (card or foil) will carry the security features.

STRIP PACKS, SACHETS, AND POUCHES

These packaging types are also related to the blister pack and are formed in a similar way from heat-sealed laminates of plastic film and aluminum foil. In contrast to blister packs, both sides of a sachet-style pack are made of flexible material. The filling process is usually vertical (somewhat akin to sausage making), and like blister packs, the integrated form-fill-seal process provides great flexibility. This packaging method is relatively cheap and can be used for solid, powder, and liquid products. The proportion of the pack’s surface area theoretically available for printing or application of security features is higher than for blister packs, as both sides can generally be used. However, in practice, the security features are usually pre-printed on one of the two rolls used to form the strip; therefore, the feature is present only on one face of the finished strip. In many developing countries, strip-packed drugs are sold in singles or small numbers. In addressing product protection for these markets, it is therefore important to have a repeating design of the security feature (a “wallpaper” pattern), which places at least one identifiable feature on each unit in the strip. The validation of inks, holograms, and other features used on strips and sachets follows the same principles as those used for blister packs.

BOTTLES OR JARS

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BOTTLES OR JARS

Sealing the dosage form in packaging that remains in place from manufacturer to patient has many advantages for anti-counterfeiting. However, it does restrict the flexibility of the pharmacist to modify the product presentation for specific patient needs or to dispense in quantities other than multiples of the standard pack size. Pharmacist work patterns and processes may often be geared to counting and dispensing loose pills or capsules from bulk, and there is some resistance to change. Therefore, despite the growth of unit-dose packaging, glass or plastic bottles and jars are still used widely. In some markets, most notably the United States, the bottle is still the default method of dispensing oral drugs to the patient. They are also used for the shipment of bulk pills and capsules to the pharmacist. The bottles used for pills and capsules tend to be plastic, whereas liquids, ointments, and creams are often dispensed in glass bottles or jars. Plastic is lighter, but care must be taken (especially with products containing hydrocarbons or solvents) that components of the plastic do not leach out and contaminate the product: glass bottles are generally heavier but more inert. Both glass and plastic containers provide a suitable exterior surface for the adhesion of labels and printed features (Figure 23.3). As for vials (Figure 23.4), there is often a trade-off to be made between cost and security. Low-cost, standard commodity components may save money but are available to anyone. The simplest way to add anti-counterfeiting features to an existing bottle format is generally to use pre-printed security labels (Figure 23.4). These can be sourced in a variety of formats, including fold-out, concertinastyle labels, which incorporate the patient leaflet directly onto the bottle, or RFID labels, which allow automatic identification of the bottle in transit and during dispensing. It is important to try to ensure that the labels cannot readily be removed and replaced, to prevent uplabeling of a low-dose product with a replacement “high-dose” label. The removal of standard labels has been achieved with industrial solvents, and more work is needed by suppliers to try to address this problem. Perhaps one of the avenues to be explored is the wider use of shrink label technology (see Chapter 24), which can incorporate standard labeling information, security features, and tamper evidence in a format that is much harder for counterfeiters to reproduce. Bottles can also be printed or marked directly using a number of techniques such as inkjet printing or laser etching. In this case, if the mark must be in a particular place on the bottle, it may be necessary to ensure that the bottle is presented to the print head or etching device in a consistent orientation. If the bottles can rotate randomly about their vertical axis

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Single-use elements: Snap-off, tear-off elements Induction seals Closure: Materials Uniqueness Surface features: Etching Printing Intrinsic variations

60 Tablets INGESTA 50 mg

Starma

Container: Materials Composition Size and shape Complexity Integration with closure Labeling; Substrate Adhesive Design features Print features Integral features

Figure 23.3. Security features for bottles and jars.

as they pass down the line then a corrective mechanism (vision system and turning device) will need to be present upstream of the print head to ensure that the right area is printed. As discussed above for other pack types, the best solution in practice may involve compromises between cost (both direct costs paid to the supplier and internal costs), engineering feasibility, urgency, and security. As in many areas of product security, the most appropriate approach may not be the most obvious one at first sight. Brand owners should therefore keep an open mind and discuss their needs in detail with a number of trusted suppliers under confidentiality agreements. The bottle must also be protected from unauthorized opening, with appropriate tamper-evident closures and seals. Typically these include induction seals made of foil or paper, which are applied and sealed over the bottle opening during manufacture and are pierced or removed on first use by the patient (or in the case of bulk bottles by the pharmacist). Onetime, perforated collars that detach on opening (as widely used on food and beverage bottles) or flip-tops with removable sealing strips are also common. Finally, shrink sleeves provide a further measure of protection. These are perforated plastic film sleeves that slip over the bottle closure and are then shrunk into place using heat. They can only be opened

TUBES

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Single-use elements: Snap-off Tear-off

Closure: Materials Marking Uniqueness Surface features: Etching Printing Intrinsic variations

INJEXA

Container: Materials Composition Size and shape Complexity Integration with closure

50 mg i/v

Starma

Labeling; Substrate Adhesive Design features Print features Integral features

Figure 23.4. Security features for vials.

once and cannot be reused. Note that all of the physical sealing properties of these features can be duplicated by a determined counterfeiter,3 and tamper-evident components should therefore carry additional security features—ideally visible, covert, and forensic. This makes it more difficult for counterfeiters to replace the shrink sleeve. See Chapter 24 for more details.

TUBES

Squeezable tubes made from metal or plastic are widely used for dermatological creams and ointments. Depending on the security requirements, features are most commonly pre-printed onto the container or applied using an in-line printer or label applicator during the filling and packaging process. Snap-off caps, removable or pierceable foil seals, and shrink sleeves are also widely used as tamper-evident features. It is also possible to incorporate microtaggants, specialized milling effects, or other physical features into the plastic or metal tube or into the cap. These approaches

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are less common because of the potential issue of contamination due to proximity of the security feature to the active product.

VIALS AND AMPOULES

These are one of the oldest and most standardized primary packaging forms for sterile products and are most typically used for parenteral (injectable) products, both in liquid and solid (dried) form. Vial presentations usually consist of a glass body, rubber stopper, and aluminum collar. They may also have a protective shrink sleeve and will usually have secondary packaging of some sort—often a carton. Ampoules are simpler, generally consisting of a one-piece glass construction with a constriction or weak point at the neck, allowing the user to break off the top section and insert a needle into the ampoule or pour out the contents. Both vials and ampoules may be packaged singly or in multi-packs and sometimes in lidded blister trays. Vial-packaged products, especially liquids, are highly vulnerable to counterfeiting. The untrained human eye cannot easily detect the difference between backstreet tap water and a sterile, expensive biotechnology product in buffered aqueous solution. Even the very expense of the product may provide a psychological reassurance of its authenticity. The rubber stopper of the vial-packed product is usually designed to be punctured by a needle, not removed, during administration. Only the closest examination of the stopper will spot a previous needle mark, and medical personnel often do not have time to make the checks or awareness of the need to do so. Because they are often intended for injection (and therefore must be kept sterile) or the product itself is labile and sensitive to heat, many vial-packaged products require sophisticated and expensive manufacturing and supply arrangements. These may often include continuous cold-chain logistics. Surprisingly, however, many of these expensive and delicate parenteral products incorporate cheap packaging and sealing components (vials, stoppers, collars, etc.), which can readily be replaced using materials sourced on the open market. This provides an opportunity for reuse of the original product. After removing used vials from dumped medical waste, or buying them from patients or corrupt medical staff, the counterfeiter can refill them with counterfeit material or water, replace the stopper and collar with new ones, and obtain authentic-looking products with the correct appearance and original (if often a bit scuffed) manufacturer’s labeling. If commonly available vials, stoppers, and collars have been used, and the genuine product bears an easily copied label,

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a well-organized counterfeiter can easily produce a fake version without even resorting to reuse of medical waste. As discussed in Chapter 5, one of the simplest pharmaceutical crimes relates to products in which a variety of dosages, with different prices, use the same vial type. In this case, it is extremely profitable for the criminal to buy a low-dose product, remove the label, replace it with a counterfeit or recycled label showing a higher dose, and sell it back into the drug distribution systems at a higher price. There have been a number of high-profile instances of this uplabeling crime, which have led to suffering and death. Vials are a useful and essential packaging format, and it is infeasible to suggest their complete replacement in the pharmaceutical industry. Nevertheless, the threats to their integrity must be countered. Education is a vital first step. All medical and ancillary staff involved in the handling of parenteral products need to be shown how to look for signs of product tampering or previous use (puncture marks, scuffed appearance, poor-quality label, non-standard or ill-fitting collar, etc.) and encouraged to report any suspicions. Disposal processes for used items should be robust, documented, and regularly audited. One of the simplest technological ways to prevent reuse of vials is to add a one-time, tamper-evident flip cap above the rubber stopper. This does not prevent the refilling of vials, but the flip cap is designed so that, in theory, they cannot be resealed, and so the illegally refilled vials cannot be passed off as new. However, although the flip cap cannot be resealed by hand, counterfeiters have been known to glue the caps back on or to re-crimp seals, and it might be possible to replace the flip cap with another one of similar design. If the end users of the vials are trained to check the appearance and integrity of the one-time cap very carefully then these features can provide some useful protection, but they should be used with caution. Another option is to employ a shrink sleeve covering the stopper before first use. When this is removed, the same sleeve cannot be replaced. In this case, it is important to ensure that the shrink sleeve is itself secured. It must be protected with suitable printed or integral features to prevent simple replacement: plain shrink sleeves are readily available to counterfeiters. Shrink sleeves are only truly effective if the underlying vial label or outer packaging calls attention to the shrink sleeve and informs the user that the shrink sleeve must have a certain appearance and should contain specific security elements that can be verified by the user. Any labeling on the vial itself should incorporate one or more security features (overt, covert, and forensic) so that simple replacement of the label can be detected. The use and selection of these features is discussed in detail in Chapter 18.

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Non-contact glass etching techniques are becoming available, which allow the addition of fine detail, including serial numbers and codes onto the vial itself. New techniques allow subsurface laser engraving without causing microfractures (which can weaken the glass and increase the risk of breakage). Finally, where wide price discrepancies exist between dosage strengths of the same product, consideration should be given to using different and clearly differentiated vial components (color, size, and type) for different doses. This will help to prevent the simple uplabeling crime discussed above. Figure 23.5, although greatly exaggerated for effect, illustrates the potential ways of differentiating between dosage strengths: vial size,

INJEXA 80 mg i/v 1

INJEXA 10 mg i/v

2

INJEXA

80 mg i/v

Figure 23.5. Using Different Vials and Labeling for Different Dosages. If the same vials, closures, labeling, color scheme, and font size are used for all strengths of the same product (1), there is greater opportunity for criminal manipulation (and medical error) than if different dosages are well differentiated (2).

OTHER DOSAGE FORMS

187

shape, and color; label size, color, and positioning; font size; collar type and color; stopper type and color; etc. The additional benefit of clearly differentiated packaging is a reduction in the risk of medication errors due to confusion of dosage strengths.

OTHER DOSAGE FORMS

The continuing growth in drug–device combinations, where the method of administration is integrated and supplied with the dosage form itself, will lead to a greater diversity of packaging types. In general, although the packaging size and shape may vary markedly, the anti-counterfeiting techniques used on these dosage and packaging forms are similar. They can be summarized as shown in Figure 23.6. Syringes

For product protection purposes, pre-filled syringes can be treated in the same way as other cylindrical packaging discussed above. The main limitation is usually the relatively small size, which dictates the amount of available real estate on which to place a security feature. Application of labels or the direct printing of complex motifs such as 2D codes may also be problematic on tightly curved surfaces. As with all sterile products, if the sterilization process occurs after the application or incorporation of a security feature then the ability of the feature to withstand the sterilization procedure (whether chemical treatment such as ethylene oxide or an irradiation process) must be assessed. Prevention of reuse is also a key consideration for the effective protection of these products. Luckily, the trend toward single-use products, driven by the need to minimize the risks to patients and medical professionals, is also helpful for anti-counterfeiting purposes. More complex, one-time use products with complications such as retractable needle designs make it harder for criminals to retrieve the devices from medical waste and reuse them. If standard syringes, with a Luer connection to standard needles, are used for pre-filled products then there is a high danger of unauthorized recycling. Inhalers and Related Devices

Although delivery devices intended for inhaled products can often be relatively complex, compared to a syringe or a vial, they are still regularly counterfeited. These fake products may be complete, de novo copies made by the reverse engineering of an existing design. Alternatively, the genuine

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Device: Materials Composition Size and shape Complexity Integration with dosage form

Labeling; Substrate Adhesive Design features Print features Integral features

Surface features: Etching Printing Intrinsic variations

Single-use elements: Snap-off cap Retractable needle

Figure 23.6. Security features for other dosage forms.

inhalers may be stolen from legitimate supply channels4 or retrieved from medical waste and illegally refilled. The medical consequences of this crime can be immediate and severe, either due to toxicity (wrong ingredients) or to lack of effect (little or no active ingredient). For example, an asthma patient suffering an acute attack may become immediately and dangerously unwell if the β2 agonist product they need is an ineffective counterfeit or expired product. The countermeasures used to deter counterfeiting of inhalers are of the same types as discussed above for other dosage forms. Design complexity helps to reduce the ease with which products can be copied, although if the production of the device is outsourced then the usual supply chain security precautions must be enforced. Unit cost must be balanced against security. An innovative, counterfeit-resistant inhaler design in the hands of low-cost but insecure or unscrupulous third-party device manufacturer may not be effective against fakes for very long. One-time activation mechanisms or seals can provide visual confirmation of whether a product has been tampered with, but once again, the ingenuity of counterfeiters must be

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taken into account. Designers should always think like criminals when incorporating anti-counterfeiting features. Security features on labeling are also advisable, and tamper-evident packaging can also be used—either on the device itself or to seal the secondary carton.

Implantable Drug-Containing Devices

Devices intended for implantation can be relatively simple sustainedrelease drug depots or complicated, multi-component devices, such as insulin pumps. The medical device field is discussed briefly below but falls outside the main scope of this book. In general, the fact that the device is implanted precludes the placement of security features such as inks or holograms integrated within the body or on the surface of the device itself. However, many of the techniques discussed above for pharmaceutical packaging and the application of anti-counterfeiting technologies are equally relevant to medical device packaging.

EQUIPMENT AND CONSUMABLES FOR DIAGNOSTIC PRODUCTS

Although generally not yet subject to the same pressure from fake products as is the pharmaceutical industry, the diagnostic industry is potentially vulnerable. The increasing security of the pharmaceutical drugs environment, due to serialization and other authentication initiatives, may eventually displace the counterfeiting problem into other areas of the medical supplies industry. Some diagnostic products, such as glucose strips for diabetics, are already regularly targeted by counterfeiters.5 This has led to product recalls, the need for increased investment in anti-counterfeiting technology, and an increasing requirement for consumer reassurance and education. However well handled, these incidents cause inevitable brand damage and loss of sales, as customers switch to alternative brands if they have a choice. The danger from fake diagnostics is indirect, as opposed to the direct threat from counterfeit medicines, but it is no less present. Wrongly controlled blood glucose, for example, can have potentially fatal consequences for a diabetic and at best causes potentially long-term damage to tissues. The inadvertent use of erroneous values for a clinical parameter or the mis-identification of a disease based on faulty diagnostic data can lead to inappropriate and expensive action—either unnecessary treatment or missed opportunities for early intervention.

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The anti-counterfeiting methodology for the protection of diagnostic products is the same as for other categories of medical and pharmaceutical products, often with the regulatory advantage that diagnostic products do not come into direct contact with the patient. It is prudent for a brand owner to conduct a risk assessment across all markets and the whole product range, based on real data not assumptions, before designing and implementing an anti-counterfeiting strategy. Many diagnostic products are high-volume items, and expensive mistakes can be made if decisions are based on faulty premises. As with all anti-counterfeiting strategies, brand owners should be open and honest with the consumer. Fake medical products of all kinds have become endemic in our society. If we acknowledge the situation, we can fight it more effectively. When we start to trust and empower those who use and consume our products, then the countermeasures will become more effective with time. On a practical level, the size of the unit to be protected usually dictates the available security technologies that can be used. Individual glucose measurement strips, only a few millimeters wide, do not have sufficient real estate to carry a 2D code, for example. Even colorshift ink or a hologram solution may be difficult to implement at this level. Covert taggants are therefore more often used at the very small unit level, with overt features used on larger secondary packaging elements. MEDICAL DEVICES

Counterfeiting of medical devices is widespread and has been seen in many product types, from cheap surgical sutures to machines costing tens of thousands of dollars. In addition to being a threat in their own right, some counterfeit medical devices have been used in criminal activities such as tax fraud.6 The problem of fake medical devices is largely outside the scope of this book, which is focused on pharmaceuticals, but many of the anti-counterfeiting techniques described are applicable to any packaging, whether pharmaceutical or medical device. The identification and tracking of medical devices has also been the subject of much recent work, led by the FDA and others and now harmonized with GS1 global standards in healthcare data7 (although there are other existing standards in the United States8 ). The development of the FDA’s Unique Device Identifier (UDI) approach will aid the coding of medical devices at batch level with a unique alphanumeric sequence of digits and will allow increased security and easier recalls of faulty or counterfeit products.9 The UDI and its equivalents in other countries will be a useful step forward, but some products will still need further protective countermeasures. The authentication methods for medical devices and consumables

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packaging are similar to those described above for pharmaceutical products. The design uniqueness aspect is often particularly critical for medical devices. The more genuinely “single-use” elements that can be incorporated into the design, the safer the product will generally be. This includes one-time needle mechanisms, secure shrink sleeves, and so on. Labeling and secondary packaging should also contain suitable overt and covert security measures. For higher priced medical device products, there are a large number of security options available depending on the size, location, and nature of the product, but for cheaper products often the limiting factor is cost. For low-cost, low-margin items (sutures, sticking plaster, needles, etc.) it can be difficult to find effective anti-counterfeiting measures that are cheap enough to be viable. For some noninvasive items, the conclusion—after carefully assessing the patient risks, commercial impact of counterfeits, and costs of countermeasures—may be either to pull out the product of that geographical market or to accept a background level of fake product. For other items, the potential risk may demand action, regardless of the low cost of the product, and therefore the relatively high proportional cost of protective measures. Examples may include surgical mesh or sutures, which could cause damage to the genuine brand (and parent corporation) if high levels of post-operative infections or anaphylactic shock were to be associated with the use of counterfeit branded products. ANALYTICAL CONSIDERATIONS FOR PRIMARY PACKAGING

The analysis of primary packaging can be undertaken with a number of different techniques, including many of those discussed above in the section on analysis of dosage forms (Chapter 15). These include examining the innate structural, physical, and chemical properties of the packaging itself and detection of deliberately included taggants or markers. Often, the best choice of analytical technique depends on the context of the investigation. If it is necessary to confirm the authenticity of packaging in the field environment, away from laboratory equipment and support, then handheld scanners are generally required. These may detect specific inks, such as up converters or down converters, or may analyze surface properties of the packaging material. It is also possible to use portable infrared spectroscopic techniques to check the IR fingerprint of the packaging and to compare it to known standard spectra. If there is time to send material for laboratory analysis, a number of other techniques become available. These include the detection of forensic markers, use of optical or electron microscopy (to detect pollen, fibers, or inclusions), or chemical analysis of material samples.

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If packaging material is to be used as evidence in criminal proceedings, it is critical that a verifiable chain of custody is maintained throughout the analytical process. The whereabouts and security of the suspect samples should be known and documented at all times, where practical. Often, this is out of the brand owner’s control, but appropriate encouragement and (if necessary) logistical support should be given to law enforcement authorities to enable the material to be stored appropriately and the chain of custody to be verified. This will help prevent the risk of packaging evidence being disallowed in court on the grounds of a technicality.

Chapter

24

Security of Secondary Packaging From the product security perspective, primary packaging has the advantage of being as close to the dosage form as we can get without interfering with it directly and it may be the only packaging that is retained by the patient. However, for various reasons—protection during transit, need to incorporate other components such as patient information leaflets, ease of bulk packaging, and so on—there may be a need to add additional packaging layers. These secondary layers should also be secured where possible.

ROLE OF SECONDARY CARTONS

In areas of the world where unit-dose packaging is the norm, most oral drug products are packaged in blister packs that are then packed in secondary boxes of some kind. Hospital products for injection are also frequently packed in protective secondary cartons. The relatively large surface area, the flat and printable nature of these boxes (Figure 24.1), and their visibility to the pharmacist and the consumer, makes them the most popular choice for the positioning of anti-counterfeiting features. The disadvantage of using the carton or box as a substrate for anticounterfeiting measures, whatever the type of feature used, is that the Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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Figure 24.1. Net Diagram of a Standard Carton. Note the large, flat surface area available for the printing or application of security features.

box is typically the first thing to be discarded after dispensing. In some countries, the pharmacist may often not even give the box (or its accompanying patient safety leaflet) to the patient. The contents may be split up and sold piecemeal for greater profit or to break the manufacturer’s unit of sale down into quantities that are more affordable for the poor. Even if the box reaches the patient, it may not be retained. The product itself is usually contained within further packaging, e.g., in a blister pack, and the outer box is not needed for functionality—the patient may not even be able to read it. If the security feature is only present on the box, and the box is not with the patient when they get sick because of suspected counterfeit product, investigators will find it much more difficult to prove the existence of fake products. There may be no way to quickly and positively identify as genuine the blister pack or dosage form that is found with the patient. For the reasons mentioned above, the “smoking gun” (if one exists) is rarely an intact carton box in cases where patient harm has occurred as a result of suspected counterfeit medicines. Nevertheless, the sheer accessibility and versatility of the carton has made it popular as a site for anti-counterfeiting features. Figure 24.2 shows a typical secondary pack for a unit-dose product, as used in Europe, but the same principles apply to almost any box. Note that the box in the diagram has two opening ends. This may seem somewhat obvious, but it means that if tamper-evident technologies are used, then both ends must be protected

ROLE OF SECONDARY CARTONS

195

R

Ingesta 50 mg 30 capsules

Starma

EXP 1 2 2 0 2 0 LOT 9 A 9 9 9 9

Figure 24.2. Typical Carton for a Blister Pack. The figure shows the same carton from both sides. Note the openings at either end, and the various areas of space reserved for mandatory features (bar code, expiry and lot data, Braille text, white space for pharmacy label, etc.) leaving little spare area for large features.

equally. An adhesive closure seal on only one end is clearly worthless since the product inside can simply be removed from the other end. However, even if both ends are sealed with a closure but only one seal carries a further anti-counterfeiting feature, this also results in vulnerability. Criminals can use plain closure seals (which are readily available) to replace the non-protected seal after breaking and removing the original seal, removing

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the genuine product, and replacing it with fake product. In this scenario, the genuine box still carries its one genuine anti-counterfeiting seal intact, and the other end is also still sealed. To an inspector, the package looks bona fide but in fact the product inside is now a fake. To prevent this, both ends of the box must carry the same caliber of security device or seal. Sealed secondary packaging should be protected with appropriate anticounterfeiting features, so that the product can be readily and positively identified as genuine without opening any tamper-evident seals. However, the secondary packaging should be only part of a product protection strategy, which should ideally cover all stages of production and all packaging layers of the product. The strategic analysis of risk and the formulation of product protection countermeasures are important issues for all corporations. However, there are also many practical and engineering issues in the application of product security in a manufacturing environment and arguably these technical details and areas of expertise are not core business for pharmaceutical companies. One of the critical decisions to be made by the product security and manufacturing teams, therefore, is the choice between applying security features to the pack in-house or outsourcing the task to someone else.

OUTSOURCED OR IN-HOUSE APPLICATION

Often, the easiest way to outsource new security features on an existing product line is to have the current printer or converter pre-print or pre-apply the feature(s) onto secondary packaging. As discussed above, this is the most visually accessible level of packaging and generally can be modified with minimal regulatory impact. Most pharmaceutical corporations and third-party manufacturers already buy in their carton packs as pre-printed “flats” from print suppliers. Some of these suppliers are highly skilled and specialized companies working only with pharmaceutical companies. Others are more generalist providers of high-volume, low-cost printed packaging to a number of other industries—often using the same presses and operatives. As the problem of drug counterfeiting has grown and the market for product security countermeasures has developed, many generalist suppliers have spotted the commercial opportunity and have started to offer the printing or application of security features as an additional service. The entry of low-cost, generalist converters has also been encouraged by two factors. First, pharmaceutical procurement executives are increasingly implementing “lean” processes and are encouraged to take any opportunity to reduce their number of suppliers. Some may rightly question the need to

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work with an ink or hologram supplier and a printer when the printer can seemingly provide a full service. At first glance, the integrated approach means simpler processes and one less contract to manage but the logic of this simplifying agenda only holds if there is no compromise to security which is, after all, the prime objective. Second, the margins charged by specialist “security providers” for security ink, holograms, and so on. have usually been much higher than the prevailing profit margins charged by packaging converters for the underlying package (carton, foil, etc.). To a purchasing department generalist, not used to dealing with security suppliers, these margins can seem high. Security suppliers have therefore often priced themselves out of business when competing on price with more generalist converters prepared to offer security features at lower margins. New entrants have also sometimes deliberately slashed their prices to win market share. Arguably, specialist security providers have failed both to differentiate the features and benefits of their products sufficiently (from more widely available but less secure technologies) and to justify their higher pricing on the basis of the proven superiority of their offering in preventing counterfeiting. For their part, pharmaceutical customers have not always been sufficiently flexible in their procurement to accommodate the subtleties of security issues and how to address them. Price should only become a valid comparator when equivalent security has been established. Buying decisions have often been taken very quickly, in the wake of a counterfeiting crisis. In this reactive scenario, the urgent need to implement rapid countermeasures (with operational staff often under extreme pressure from upper management) can outweigh the desire to design the best long-term solution. The procurement of security features product-by-product, in a discontinuous way, is expensive in management time and also makes it difficult to achieve any economies of scale, both in the costs of the supplier and therefore in the price charged to the customer. A final confounding factor is the decentralized business structure of many drug companies. In many corporations, the local operating company is charged for the cost of implementing product security, as part of the cost of goods sold (COGS). This means that their local profitability is directly impacted by any additional product security costs. This often provokes internal opposition to centrally recommended security measures, or (if the operating company has purchasing discretion) it leads to costbased, sub-optimal security strategies, which are inconsistent across different geographies. The local procurement of low-quality anti-counterfeiting features from potentially insecure or inexperienced suppliers can be counterproductive for the global brand image both in terms of its uniformity of appearance and its security.

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Uncertainty, confusion, and inconsistency are the best friends of the counterfeiter, so the best solution is to act strategically, not tactically. Most drug companies have now acknowledged the need for a centralized, properly funded, product security strategy and many have earmarked separate budgets for the defense of their brands, which are ring-fenced from the general manufacturing budgets. While it does not solve all of the communication problems inherent in a large corporation, this approach removes at least some of the internal inertia and corporate politics and helps to ensure a more consistent approach. Outsourced Security Features

The printing of security inks or affixing of holograms or other features does not automatically make a generalist packaging converter into a security printer and the security of the drug supply chain is only ever as good as its weakest link. Diverted packaging is the pharmaceutical equivalent of identity theft. All print and packaging suppliers (and their subcontractors, if any) should therefore be audited specifically for their own operational security procedures, even if they do not supply the security features on the finished package. Suppliers providing the “security features” themselves should receive extra scrutiny since (to continue the identity analogy) they have direct access to your brand’s passport. Many printers and converters are excellent security providers, but as with all suppliers, the assessment should proceed carefully and evidence of suitability should be written and verifiable. Membership of industry standards organizations such as (in the United States and Canada) the North American Security Products Association (NASPO) or documented adherence to their required standards1 provides reassurance that the supplier is competent to handle product security contracts. The standards set by the Comit´e Europ´een de Normalization (CEN2 ) provide a parallel in Europe. Every case is different and supplier choice should be examined with an open (and skeptical) mind. One way around the issue of supplier security is to apply security features as late as possible during the packaging process, typically on the production line itself. In-House Security Application

The application of printed features or security labels during manufacture has much to recommend it. In the case of inkjet or laser printing onto labels or packaging, it is possible to add features at the very last moment and with minimal human involvement. In theory, it is possible to set up a system that is remotely controlled and that prints variable information

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known only to a very small number of people, who may not even be based at the manufacturing plant. This information can be covert, such as including taggants in the ink used for date and batch information, or even using invisible codes. Alternatively, the variable marks can be overt design-based variations and visible, serialized codes. The ability to vary the mark designs on a daily or batch basis (or for each individual pack in the case of serialized codes) provides a moving target and makes it harder for counterfeiters to replicate features exactly. The printing of 2D matrix codes and other codes onto packaging is a subset of this concept and is discussed in Part III.

PLANNING AHEAD

The graphical sophistication of pharmaceutical packaging is generally low, compared to that for other consumer products. Some of the reasons for this are regulatory, as discussed in Chapter 16, but there is still much room for improvement in the way we use packaging to defend our products from counterfeiting. The first step is the closer integration of marketing and product protection teams. The brand owner companies, which are operating to best practice in this area, start planning security features at the same time as they develop the branding and packaging design of the product (or earlier if they intend to incorporate security elements into the dosage form itself). Integration of security into existing graphical or design elements can help to camouflage their presence and often provide a more aesthetically pleasing result than post hoc addition of (usually) a plain rectangle with rather obvious security purpose. The financial and resource investment required for the commercial launch of a new brand dwarfs the cost of product security by several orders of magnitude, so there is no excuse for poor anti-counterfeiting features on new products. For a new drug, which has yet to build up a deep layer of post-marketing safety data, it is also commercially and medically dangerous to allow substandard counterfeit product to appear quickly onto the market. Fake drugs can cause unexpected reactions that the patient (and their physician) may attribute to the genuine brand. Reporting of such incidents is likely to be higher in the early life of a product when the adverse event profile is relatively unknown in large-scale use and physicians are less experienced in using the drug. An exaggerated adverse event profile caused by the undetected prevalence of a fake product could (in a theoretical worst-case scenario) lead to the withdrawal of an effective product or to the imposition of a “black box” warning3 restricting sales potential. Investment in product security can and should be made as efficient as

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possible, but must not be neglected or compromised by a nickel-and-dime approach toward the choice of technologies or suppliers. TAMPER-EVIDENCE: SEALS, SHRINK WRAPS, PACK CLOSURES, AND ADHESIVE

It is important to know whether a pharmaceutical package has previously been opened and its contents removed, diluted, exchanged, or exposed to contamination. The traditional use for closure systems was primarily to keep the product intact in its packaging and everything else (moisture, bacteria, etc.) out. With the rise of tampering incidents, both unintentional (such as by children) and intentional (adulteration by criminals as part of extortion attempts) closures acquired new importance. In the last 10 years, the need for resistance to counterfeiting and other unlawful activity has also increased the importance of a secure and tamper-evident closure system. Definitions

It is important to differentiate between tamper-evident and tamper-proof packaging. The former enables any unauthorized interference to be readily detected, whereas the latter seeks to prevent it from happening in the first place. Although it is possible to make products fully tamper-proof, this is usually not a practical solution. If a criminal cannot open the seal on a bottle of painkillers, then it is likely to be even more problematic for the arthritic senior for whom it is intended. Therefore, the usual solution is to make tamper-evident product closure systems that are straightforward to open but are one-time use. As soon as the closure is activated for the first time, it is evident to anyone who subsequently examines the product that it has been opened and therefore might have been tampered with. A common example in the food industry is the pop-up button commonly seen on the lids of glass jars. As soon as the pressure is released, when the lid is unscrewed, the button pops up and cannot be re-set. To obtain tamper-evident closures, several different techniques are used depending on the nature of the closure. Each has its advantages and drawbacks and, like all product security decisions, the advice of vendors should be sought on specific technologies. Snap-Off Caps

Commonly used on vials for injection, the device typically consists of a plastic collar and removable cap, which may be hinged to the collar

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or attached by breakpoints. The removable part of the cap is taken off from above the rubber seal just before use. Although it can be effective, this type of closure can often be mimicked or the removable part can be re-glued. This type of device is only useful in conjunction with education campaigns alerting clinical staff to the need to check for the integrity of the feature (and other security measures on the same pack) before they use the product. If a nurse is used to seeing “traditional” unprotected vials for low-cost competitor products, she may not realize that she needs to check the presence and integrity of the snap-off cap on a more expensive (and atypical) vial. If she does not know what to look for, a vial that has already been used and refilled without a protective cap may pass unnoticed. Glued End-Flaps

One of the simplest methods of closing the end of a box is to glue the flaps together and this method has often been used on pharmaceutical carton boxes. It requires a relatively large amount of aggressive glue, often “hot-melt” adhesive that requires heat to start the adhesion process. One-time, perforated tear-off strips are sometimes incorporated into the end flap(s) to facilitate the re-opening of the pack by the patient once sealed. The weakness of gluing is that the glued flap can often be carefully opened (e.g., with a razor) and re-glued with minimal visible evidence. In markets where the patient information leaflet may need to be replaced during (legal) parallel trade activities, a glued end flap or tear-off design is usually not used for reasons of practicality. Seals

For boxes with non-glued flaps (the majority of modern pharmaceutical packs), the most common solution for a tamper-evident feature is a closure seal. Once the box is filled and the flaps are closed, the closure seal is placed over the opening edge of the end-flaps using an automatic labeling machine. The material used in the seal can be either paper or plastic, but both the substrate and the adhesive must be suitable for the storage conditions (temperature, humidity, etc.). It is important to seal both ends of the pack, and to ensure that both seals carry suitable security features (Figure 24.3). Serial numbers can also be added to the seals, allowing individual units to be traced4 . It is important that the seal is firmly fixed across the end flap in such a manner that it cannot be removed without leaving evidence. This is usually accomplished with aggressive adhesive that damages the underlying carton

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R

Ingesta 50 mg 30 capsules

Starma

EXP 1 2 2 0 2 0 LOT 9 A 9 9 9 9

Figure 24.3. Application of Security Seals. Note that text and other mandatory pack features must not be obscured by the seal, and a secure seal must be used at both ends (although not necessarily the exact same design).

when the label is removed. Seal substrates are also often friable, that is they crumble when removal is attempted and will only come off in small pieces, or voiding (i.e., they leave a clear residue). See Chapter 18 for further details. If the label is removable intact, then it is reusable, and it becomes worse than useless. All labels, including those placed across the end of the pack as security seals, must not obscure the underlying text. This can present problems if lack of available real estate on the pack conflicts with the need for a minimum area of security feature in order to get the desired effect.

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Induction Seals

These are used to seal the top of bottled items, such as pills and capsules, forming a seal across the opening of the bottle and underneath the cap. The seal acts as a barrier and as a tamper-evident seal. Once removed, the same seal cannot be replaced, although a new seal can potentially be added. For this reason, induction seals are typically protected with additional security features such as holographic features or printed elements. In some counterfeiting cases, the difference in induction seals is one of the key identifying features.5 See Figure 24.4 for a theoretical example with a minor difference (the repeating motif is “Security Sealed” or “Security”). Shrink Wrap and Tear Tape

Widely used for consumer-oriented packaging in other areas with counterfeiting problems, such as the tobacco industry, shrink wrap is less common on patient packs in the pharmaceutical environment. However, it is more commonly used for higher level packaging and for hospital products and there is no conceptual reason why these approaches could not become more widely used in the pharmaceutical industry. In the shrink wrap process, the entire package is wrapped in translucent polythene film, which is then shrunk down onto the pack using mild heating. The wrap typically also incorporates a secure tear tape which is used for one-time opening of the wrap. Tape and wrap are discarded after opening and cannot be reused. However, the security of the tear tape element is essential because standard shrink film is readily replaceable and in theory, a pack could be opened and rewrapped. Both shrink wrap and tear tape can be secured

ity Secur Sealed y it r cu u e c S Se aled it rity Se u c Secur e d S le led ity Sea r u d c e le S Sea Sealed ecurity l aled S e S y ity Sea r it Sur Secu d le a y e ity S ecurit Secur aled S rity Se u c e S aled

urity ity Sec Secur y it r u Secu c Se curity ecurit rity Se u c e S urity S led ity Sec r u c e urity ity S ity Sec Secur Secur y it u r u Sec ity Sec Surity Secur y it r u c y ity Se ecurit Secur urity S ity Sec r u c e aled S

Figure 24.4. Induction Seals. The figure shows a top view of two bottles with induction seals. They are very difficult for the consumer to tell apart, even though the ‘‘counterfeit’’ one on the right has a slightly different wording.

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with covert features such as microtaggants, microtext, security inks, and holograms. They can also carry overt features for consumer recognition, providing that these do not obscure critical areas of the underlying pack. Tear tape is very noticeable to the patient or the medical professional using the product, since it must be manually removed before opening. It is therefore an excellent medium to carry printed messages (subject to regulatory approval) to prompt the consumer to check for specific authentication features in verifying that the pack is genuine.

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Analytical Methods for Packaging As discussed earlier, fake packaging is not usually what actually causes harm to the patient—excluding glass breakage, substandard needles, or other physical hazards. The direct analysis of dosage forms rather than packaging is therefore the most direct way to demonstrate the link between a fake drug and the potential or actual harm it causes. The ability to confirm, unequivocally, whether packaging is genuine or not is, nevertheless, very useful for several reasons. First, if the patient has already used all of the medication, then they may only have the packaging as evidence of what they have ingested. This is common for short-course therapies, such as antibiotics, where lack of efficacy after taking the full course may be a sign of counterfeit or substandard medication. Secondly, modern criminals frequently source internationally and ship fake packaging separately from the counterfeit drugs, to try to evade detection at customs. Packages are then made up into finished product at a separate location and shipped to the final consumer. In this case, seizure of suspect packaging may occur without the drug consignment itself ever being traced. Finally, analysis of packaging is often critical in cases of sophisticated IP infringement where the product itself is a very close copy of the branded product. This can happen, for example, where an API subcontractor is performing unauthorized

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production runs to make extra profits by distributing counterfeit copies of the genuine product. In addition to the various analytical techniques discussed earlier for dosage forms, various methods can be used to discriminate between two visually similar packages.

VISUAL INSPECTION (VISIBLE LIGHT)

Careful examination by eye and with low-power magnification can detect small errors made by the counterfeiters. Often, there are small differences in font style or size, for example, which are a good first indicator of counterfeiting. This logic can also be reversed by incorporating minor imperfections into the genuine product. Visual examination and comparison with a reference sample can then confirm the absence of any deliberately introduced “errors” or subtle intricacies in design or text that may not have been noticed or fully copied by the counterfeiters. Computerized image analysis and digital subtraction techniques1 can also provide evidence of counterfeiting. Additionally, these techniques can give important clues as to the origin(s) of fake material found in multiple different markets. By subtracting the real graphic from the suspected counterfeit graphic, a characteristic pattern of small “residual” marks is revealed. This pattern is usually unique to the individual counterfeiter. Therefore, the presence of the same residual pattern when samples obtained in different markets are compared with the same reference sample gives important clues about the distribution and sales channels of the counterfeiter. More sophisticated techniques, such as 3D topomicroscopy,2 can highlight small differences between apparently similar 3D forms. There may also be differences in the composition of the materials used, which can be spotted visually—different grades of carton board, for example. Counterfeit packaging is not always of inferior quality. Often, suspect packaging actually looks a little “too good,” and more than one drug company has identified counterfeits with higher quality packaging than they use for their own product. This is probably sometimes inadvertent on the part of the counterfeiters, but it also plays into consumer psychology. Consumers probably assume that the quality of the product inside the pack will be proportionate to the quality of the packaging. Counterfeiters therefore devote most of their efforts to packaging rather than product. Sometimes, they may even add their own “security” features (such as holograms), which are not present on the original, in order to dupe customers into thinking that the fake product is an improved or updated version of the real thing.

OTHER METHODS

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OTHER OPTICAL METHODS (UV, IR, POLARIZED LIGHT)

Many overt features aimed at consumers (colorshift inks, holograms, other visible effects) can be paired with semi-covert elements such as UV or polarization features. This allows quick verification of the packaging in the field using small lights or filters. It may even be possible to check products covertly in the pharmacy or at a market stall, without the need for a test purchase. However, there are personal safety implications in this tactic and it is not advised. Inspections with the retailers’ knowledge and cooperation, or anonymous test purchases (by local staff) for subsequent analysis, are preferable approaches. The advice of the corporate security function should always be sought before conducting retailer surveys of any kind. Retailers in many countries often already use a polarization filter or UV “blacklight” at the point of sale to identify some of the basic semi-covert features on banknotes. Such features can also be useful on pharmaceutical packs as a first-line defense and they help to identify poor quality counterfeits. Even if the ink has been counterfeited, more detailed laboratory analysis of emission and absorption spectra can reveal subtle differences in apparently similar features on counterfeit and genuine packs. In particular, IR-absorbing features are much less common than UV inks, and therefore more secure and more specialized in their use. They are hard to counterfeit since the supply of the necessary raw materials is limited and controlled. Laboratory analysis of the exact characteristics of the IR ink used on a suspected counterfeit could therefore help to identify its likely source.

OTHER METHODS

All of the analytical methods for dosage forms, discussed in Chapter 15, can also be applied to packaging. The exact combination of methods used will be unique for each product and will depend on the intrinsic and added properties of the original reference sample and the suspected origin and nature of the counterfeit. As discussed previously, if a legal action is undertaken, the exact analytical methods to be disclosed as evidence in court should be carefully evaluated beforehand. In regard to the overall product security strategy, it is important to avoid revealing sensitive information, which may affect the security of other products.

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Security of Other Packaging Types Although the most common areas for anti-counterfeiting features are either on or in the dosage form or its primary and secondary packaging, there are a number of other important situations that must also be considered.

DRUG–DEVICE COMBINATIONS

Pharmaceutical products for parenteral administration, which usually require a needle of some type, often come in kit form, including a separate or integrated means of administration. With these products, the potential for harm comes from both the drug component and the delivery device. This type of product is often used for serious acute or chronic conditions, which require the administration of parenteral drugs. Counterfeits of these types of products are therefore especially dangerous as they have direct access to the bloodstream. There have been instances of kits being re-manufactured with used or non-sterile needles and counterfeit drugs. The contamination present on these needles can lead to many disease outcomes ranging from instant allergic reactions to hepatitis C, which may take years or decades to develop.

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The FDA defines1 a drug–device combination as: A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity; Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products; A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose; or Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect.

The many types of combination product can be summarized in the following most common categories: • Convenience kits or co-packages • Pre-filled drug or biologic delivery device/systems • Devices coated/impregnated/otherwise combined with drug or bio-

logic • Drug/biologic combinations.

One of the most frequent problems encountered with pre-filled delivery systems is the unauthorized reuse of the device portion of the product. This is typically in conjunction with a counterfeit replacement for the drug component. This is highly dangerous, as the device may have become contaminated during first use, for example, with blood or other body fluids. The counterfeit drug used to refill the device may be ineffective or actively harmful. The reuse of medical devices is a longstanding and global problem. It has been estimated that 30–50% of used syringes in India are retrieved by waste scavengers and, after washing and wrapping, find their way back into the supply chain.2 The protection of pre-filled drug–device

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combinations is therefore best achieved by ensuring that the device itself cannot be used more than once (if it is intended as single use) or by designing the drug–device interface to prevent reuse. Stents (mesh tubes used by cardiovascular surgeons to keep blood vessels open after angioplasty), are a widely used example of a drug-coated device. Originally, the stent was simply a metal mesh tube, carefully designed and manufactured to expand in a controlled manner and to perform its function in situ with minimal damage to the blood vessel wall. Counterfeit stents typically had poorer quality components and (presumably) inferior surgical performance. The need to minimize the growth of scar tissue within the stent (which can lead to blockage of the blood supply or restenosis) has led to the gradual replacement of the original bare metal stents with more advanced drug-eluting versions. These drugreleasing stents are now the therapy of choice. The advance in technology and the incorporation of drugs into the device has led to stents becoming much more expensive. This is turn has attracted a new wave of counterfeiters, with a new range of life-threatening fake products. The genuine stents can be fraudulently relabeled to increase the shelf life of expired stock and allow it to be resold3 or bare metal stents can be packaged and sold as drug-eluting stents. Counterfeit stents that contain expired, substandard, or poorly tested drug ingredients and polymers are very difficult to differentiate from genuine stents by appearance alone. In the same way as for pharmaceuticals, for all drug–device combinations, the product security team must learn to think like the enemy and ask “how many different ways could someone illegally make money from recycling, relabeling, or counterfeiting this product or its packaging?” For most products, there will be many theoretical vulnerabilities—some feasible, many not very likely. Senior management need to empower the team to close off as many of the more likely avenues as is reasonably practical. PATIENT INFORMATION LEAFLETS AND LABELS

The amount of information that accompanies the average pharmaceutical product is substantial. Dosage recommendations, possible interactions with other drugs, potential side effects, drug corporation contact details, and other mandatory information must be somehow associated with the pack. This is most easily done by printing a separate paper leaflet and including the leaflet with the primary pack inside a secondary box or carton. Alternatively, the information can be printed on a fold-out label and affixed to the bottle directly or incorporated as part of an integrated wallet design. Although not as frequently counterfeited as dosage forms themselves, patient information leaflets (PILs) are a critical component of the

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safety of drug products and some thought should therefore be given to their protection. A more common problem is that the PIL is lost or inappropriately replaced during legal repackaging operations. Anti-counterfeiting measures can therefore also be useful in ensuring that the correct, countryspecific, or language-appropriate PIL is present, thus helping to avoid repackaging errors. Suitable anti-counterfeiting technologies to consider are those commonly used for other paper and board products—DOVIDs, security inks, and so on. These would generally be pre-printed or applied onto the PIL by the printer. The adoption of fully sealed patient packs may improve the protection of PILs by removing the possibility of unauthorized substitution. The further development of integrated, fold-out information labels on bottles and wallet packs will provide an extra layer of complexity and cost, which may help to deter the counterfeiting of some products. OTHER DOCUMENTATION Certificates of Analysis, Import Licenses, etc.

The globalized pharmaceutical industry has a complex supply chain and generates a lot of paperwork (virtual and real) as materials and products move around the world. At the moment, these isolated “dots” of information are not joined up to form a full picture of product history and quality. The systems that might enable us to do this are discussed later in Part III. In the meantime, we have disparate systems of certificates, licenses, and other vulnerable but valuable pieces of paper, which can instantly add value to a pharmaceutical cargo. As noted previously in Chapter 13, failure to check or validate bulk manufactured products and raw material has led to several well-publicized tragedies. The root causes of these incidents can be traced, in many cases, to forged or altered documents. If a shipment of materials for pharmaceutical use, whether it be API, excipient, or finished dosage form, is effectively worthless without appropriate documentation verifying its authenticity and provenance then, by definition, the paperwork that validates it has a value in itself. The technologies needed to protect other “value documents”—checks, bonds, passports, and so on.—from falsification or duplication are well established. Anti-counterfeiting techniques are available for use on almost any substrate from paper to plastic and metal and reputable security suppliers can provide the necessary advice and services. As a minimum precaution, the circulation of hard copies of any blank document templates should be restricted if they are pre-printed. If the

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forms are downloadable, then security procedures should prevent unauthorized access and use. Once issued, the document should be able to be readily verified as genuine and should be resistant to fraudulent alteration. This may involve some of the covert technologies used for check security, such as invisible inks that bleed when wetted (during attempted alteration) or security fibers. Prescriptions

The term prescription medication is used to mean those drugs that are powerful or dangerous enough that the medical profession needs to intervene in their supply and use. The medical prescription is therefore a permission slip from the physician, authorizing the pharmacist to dispense the medication to the patient and in some cases, authorizing the cost of the drug to be charged to a third party such as an insurance company or state medical scheme. Despite the fact that similar systems exist almost everywhere, the reality on the ground is very different. In some countries, pharmaceutical drugs can be legally purchased without a medical prescription issued by a qualified and registered physician, and in many others, the mandatory prescription requirement is routinely ignored or circumvented using fake documents or bribery. The forgery of prescriptions is thought to be a major problem worldwide, but hard evidence is difficult to find. The prescription documents themselves are often relatively unprotected from counterfeiting—especially when compared (for example) to checks or similar value documents. In some countries, the prescription is not even a standardized form and may vary from one doctor to the next. Often, the prescription pad, even if it is a specific format or layout, is simply printed on standard paper and can be easily duplicated or amended. Even if the prescription pads are consistent and carry security features, they can often be obtained with few background checks. For many governments, implementing and enforcing relatively simple security measures for the design, printing, distribution, use, collection, and reconciliation of prescriptions would go a long way to controlling the medical fraud problem. The protection of similar value documents is well established and various security features, from simple to sophisticated, are suitable for the task. Reputable vendors can advise on appropriate security measures in more detail. Reimbursement

Related to the problem of prescription fraud is the problem of reimbursement control. Most countries with state-sponsored healthcare have

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a system to offset some or all of the cost of drugs: the state refunds the money to the patient. Sometimes, this reimbursement is direct and the patient pays nothing upfront. Alternatively, there may be a flat rate “prescription charge” or a graduated “co-payment” system. In other cases, the patient pays for the drugs in full and is reimbursed subsequently upon presentation of the necessary paperwork. All systems involving transfer of money from the state or the insurer to the physician, pharmacist, or patient can lead to fraud unless properly secured. Forgery, or multiple representation of the same paperwork, can impose huge burdens on already expensive health systems. The best solution to reimbursement fraud is to use system-based countermeasures to validate and record all transactions, so that any individual prescription or drug can only be dispensed or used once. As the worldwide medical industry becomes digitized and networked, interactions between doctors, pharmacists, and patients will become less paper-based. This provides opportunities to improve the security of the prescription and reimbursement processes as well as to reduce healthcare costs. The systems that might enable this are discussed later in Part III.

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Bulk Packaging and Transport Security The previous few chapters have discussed how to add security features at various levels of product and packaging, and how to analyze products to separate genuine items from counterfeits. We now come to the highest level of packaging used to move pharmaceuticals around the world in bulk. Investment in secure manufacturing facilities and anti-counterfeiting packaging features at the unit level is necessary but not sufficient to prevent criminal activity. The money spent by a brand owner on these elements is wasted if the supply chain vulnerability is simply displaced to outside the perimeter fence. The resale of stolen, genuine pharmaceutical products is on the rise and is one of the most profitable criminal activities. It is very damaging for pharmaceutical companies both in financial terms and in reputation. Therefore, drug companies are starting to pay close attention to the security of their products in storage and in transit and to the processes and technologies that can help them to prevent theft. Transport security is not exclusively a technology issue. As logistics arrangements get more demanding and complicated, some simple management steps can be used to keep control. The first of these is the choice of transport providers. The drive to strip away non-core activities from pharmaceutical corporations means that very few drug companies now haul their own drugs. Rather than maintain a fleet of vehicles and hire their own Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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truck drivers, most manufacturers now use third-party logistics providers (3PLs) to get their product from production plant to market. Similar to all service industries, there is great variation in quality, capability, and experience between logistics providers. If a simple tender process is used, and low price is the main decision driver, there is a risk that an inexperienced or corrupt supplier could be inadvertently chosen and security could be compromised. As always in product security, cost should be only one element in the decision process—if transport suppliers are not chosen, audited, and trained with the same level of care as other aspects of the supply chain, the results can be expensive and damaging.

THEFT OF CARGO FROM TRUCKS AND WAREHOUSES

Counterfeiting a complex product, such as a prescription drug, is not easy. It may sometimes be easier to steal the real thing. In many countries, one of the key tactics used by criminals targeting the pharmaceutical industry is now the theft of genuine product, either directly from warehouses or during shipment as cargo. Truck theft is a growing problem for haulers in all industries. A spate of incidents in the United States in 2010 prompted the FDA to issue a letter to all stakeholders, requesting them to step up their efforts to combat the theft of pharmaceuticals.1 The drug industry has established the Pharmaceutical Cargo Security Consortium to work together to combat this growing issue.2 The theft problem is present in most countries and is a multi-billion dollar business that results in financial loss to manufacturers and potential disruption of the supply chain for patients. Although not strictly a counterfeiting activity itself, cargo theft of pharmaceuticals is almost always linked with other organized crime activities and aids counterfeiting in several ways. First, it creates a gray market into which counterfeits can more easily be inserted. Second, it leads to greater expectations of low prices and a blurring of quality expectations—the product is genuine but stolen and can therefore be very profitably sold on at well below market prices. Unless it is coded in some way, it can be very hard to trace. Pharmaceuticals make up just 5% of reported cargo theft incidents. However, the average value of a pharmaceutical theft is very high at around $4 million and one major incident alone was estimated at $75 million.3 Even lower value, over-the-counter drugs can be worth tens of thousands of dollars per load. Pharmaceutical manufacturing plants generally have security features such as perimeter fencing, closed-circuit television, and guards. Technology is often used to verify employee identity and to monitor activities

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within the facility. Prevention of theft from fixed facilities is a general security issue rather than an anti-counterfeiting one, with the exception of ensuring that stolen material can be traced if it is re-inserted into legitimate sales channels—a consideration that will be discussed in Part III. The site security aspects of this problem are therefore outside the scope of this book and will not be discussed specifically: my discussion begins at the gate. Drug companies take anti-theft measures and yet security can sometimes slip when the products pass from the custody of the drug company or contract manufacturer to that of a haulage company, for shipment from the plant to a distribution center and then to the local pharmacy. Thefts of pharmaceuticals are not random robberies. The ability first to identify and then to steal or hijack a truck and then finally to remove quickly, disperse, and resell the contents for profit requires organization. These events are usually very well-planned and have involved the complicity of insiders in some cases. There have been some spectacular thefts from fixed facilities such as manufacturing plants and warehouses, but the most common method worldwide is to hijack a truck carrying finished products after it has left the manufacturing plant. The cargo is then often quickly broken up and sold—either on the black market or sometimes back into the legitimate supply chain. However, it may also be exported abroad to other markets, repackaged, or just stored until the media interest in the theft wanes and the level of public vigilance for the stolen products decreases. Combating such a well-planned crime requires similar forethought and care on the part of the brand owner. Transportation should therefore not be seen as purely a commodity service, to be purchased at the lowest available price. Freight companies should be audited for security, and employees at both the hauler and the manufacturer should be appropriately trained. The contractor should not have the right to subcontract to third parties without the manufacturer’s permission, and if this is necessary then these companies should also be checked out. Careful thought should also be given to “just in time” logistics practices, which may minimize inventory but can pose avoidable security risks. This is a particular problem when goods are transported or stored at weekends. Not all depots are open seven days a week. A delivery for a distribution center scheduled for Monday morning can mean that consignments are sent out from the manufacturer on a Friday afternoon. If the center is shut at weekends, the valuable shipment may then be parked in transit for the weekend at an insecure location. There are various ways to combat theft. The most obvious first steps to take are the standard security precautions used to deter other threats to facilities and vehicles, such as terrorist attack.

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Vigilance

Since pharmaceutical robberies require advance planning, reconnaissance activities are usually needed. Manufacturers and distributors should therefore stay alert for surveillance being conducted on their production and logistics operations. Signs of suspicious activity could include • unauthorized vehicles parked outside site entrances; • unauthorized use of cameras (by staff or outsiders) within or near

the facility; • unknown personnel inside the facility or loitering around the perimeter; • vehicles that appear to be following freight drivers when they exit the site or during transit. In some cases, cargo theft is perpetrated with inside help. Drivers, security guards, and logistics staff should therefore be security vetted before employment or acceptance as contractors. Information Management

To minimize the spread of sensitive information, vehicle and cargo movements should not be shared with anyone except on a need-to-know basis. This includes historical information (which may be useful for pattern analysis and prediction of future routes) and planned activities. Drivers and routes should also be varied regularly and randomly, so that drivers are not aware of their itinerary very far in advance. Site security should also liaise with logistics personnel—unauthorized entries or attempted break-ins should be noted and followed up as they could be due to criminals testing the security system with a view to subsequent theft of drugs. License plates of unknown vehicles seen repeatedly around the facility with no good reason should also be noted so that they can be traced in the event of a subsequent cargo theft. Training

Although some transport crime is perpetrated with insider help, the great majority of truck drivers are honest and hard working and their help should be enlisted. Security training of drivers, whether by the brand owner or as provided and documented by the logistics supplier, should include instruction in identifying and reporting security incidents as well as in hijack avoidance tactics and defensive driving. If the itinerary is at the

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driver’s discretion, the route and time of departure from the manufacturing facility to the destination(s) should be varied where possible. The driver should not make predictable stops, e.g., always using the same place to refuel or rest, and should be appropriately prepared for the journey. Even a simple precaution, such as having the numbers of emergency contacts and local police (in case the vehicle breaks down or is stolen), can help the driver to prevent a crime or to aid its detection by alerting the police more quickly. Other Factors

Where local laws permit, the use of armed guards may be an option. However, although this may deter opportunistic attack, it may fatally escalate any conflict situation that involves organized crime or militia groups and should be used with extreme caution. The use of technologies, such as global positioning system (GPS) tracking to monitor vehicles in real time, is a better option and significantly improves the vehicle recovery process.

TECHNOLOGY APPROACHES: RFID AND GPS

In addition to the process-based precautions against theft described above, there are a number of technological approaches to the protection of bulk products after it has been manufactured. Although these should not substitute for a rigorous review of existing security procedures, they can form a valuable adjunct. By knowing where your product should be, and tracking where it actually is, any deviations can be quickly spotted and reacted to. The available tracking technologies operate at two main levels. Radio Frequency Identification (RFID) Technology

Radio frequency identification (RFID) is a relatively old technology that derives from the development of radar. The technical aspects are discussed more fully under product tracking in a later chapter. It relies on two-way radio communication between an RFID chip on the tracked item and a receiver or scanner within range of the item. RFID tags can either be active (constantly emitting a signal) or passive (only emitting a signal when queried by a scanner). They can be detected by spot checks (e.g., by police, customs, etc), but their relatively short range means that they cannot be used for remote tracking. The RFID approach is well suited for use on bulk freight. The relatively high technology cost per unit has been a barrier to the universal implementation of RFID in the pharmaceutical industry,

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but this is less of an issue when the unit is a high-value bulk carton or container than it is when RFID is used for individual patient packs. RFID tags are very compact—small enough to be placed in selected individual packs as well as on shipping cartons and/or on groups of items such as pallets. By using a hierarchy of tags in this way, it may be possible to trace and recover some of the load even if it is stolen and split into smaller consignments. Global Positioning System (GPS) Technology

In order to go from yards to miles (or meters to kilometers) in the tracking of pharmaceuticals, we need to switch technologies from short-range RFID to long-range GPS systems. The technological basis of GPS tracking for freight is the same as for the satellite navigation systems, which have become familiar in cars and on smart phones. A GPS freight tracking system uses information derived from satellite signals to triangulate the position of the cargo in real time. The satellite signals are received by small devices concealed in the truck or the freight. The information is then transmitted back to a control center over cellular (mobile) phone networks. The same technology can monitor vehicles and large cargo items, such as pallets or shipping containers as well as smaller items if needed. Real-time monitoring by asset management software highlights when items deviate from expected routes or if there are unplanned stops in their itineraries (Figure 27.1). Although radio waves can pass through some materials, GPS satellite tracking systems require reasonably direct line of sight from the tracking device to the satellites in order to receive the satellites’ signals. Therefore, they may not function properly in the holds of shipping vessels, or in container yards, or if signal reception is otherwise impeded. Typically, an external antenna on the truck or container is used to maintain line of sight. Note that the GPS receiver interacts passively with the satellite network. Positional information derived from the satellite signals is not beamed back up to the satellite, but is transmitted by the tracker device back to the control center over cellular networks. This has the advantage or requiring much cheaper transmitters and lower power, but cellular network signals are not necessarily secure and in theory can be detected and either jammed (so that the control center receives no positional information) or emulated (to give a false position). To determine its position accurately, a standard GPS tracking device needs to establish contact with at least four satellites. Searching for these signals can take some time and requires processing power, limiting the minimum size of these devices. However, with the development of assisted

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1

2

3

Internet 4

Figure 27.1. Typical Configuration of a GPS Tracking System. The GPS devices fitted in the truck and its cargo pick up multiple GPS satellite signals (1) enabling them to pinpoint their location. The information is transmitted over cellular networks (2) and relayed securely via the Internet (3) to a monitoring facility. If the truck or its load deviates from the planned route, then law enforcement authorities can be rapidly directed to the site of the GPS transmitter(s) (4).

GPS tracking, this requirement can be simplified. An assisted GPS system can use mobile phone signal data to calculate the tracking device’s current approximate position in the cellular network. It then obtains the location of the closest satellites to that position and the device searches specifically for those satellite signals. The development of assisted GPS has simplified the data processing requirement and has led to smaller tracking

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devices—currently about the size of a cellphone—and therefore enables covert tracking of cargo as the devices can be hidden within the shipment. For high-value pharmaceutical cargoes, the classic layering approach should be used for transport security: covert tracking devices should ideally be hidden in individual packs within a shipment, on the outer container, in the cargo trailer, and in the cab of the truck itself. This may not prevent all thefts, but will certainly provide a deterrent and can help in the tracking and rapid recovery of bulk cargo. The tracking and tracing of individual unit packs requires additional approaches, which are discussed below in Part III.

Part

3

Product Tracking

Chapter

28

Rationale for Pharmaceutical Tracking So far, we have mostly looked at the protection and authentication of the pharmaceutical product and its packaging in three dimensions: what security features to choose, where to put them on the pack, and how to protect different packaging layers. This approach can help answer the “how” and “what” questions in a counterfeit investigation, but often gives little information on the “who,” “where,” and “when.” In order to enhance pharmaceutical security further, it is necessary to add the fourth dimension: time. Drugs undergo a complex and sometimes long journey from factory to bloodstream, passing through many hands and often across international borders. In many cases, the intermediaries involved only know limited transactional information about what they buy, sell, or ship. They may know where the drug has just come from and where it is immediately going, but often not much more. This lack of visibility and oversight allows criminals to operate more easily. The ability to track drugs cheaply, securely, and efficiently across the globe—from manufacturer to patient—would dramatically improve the safety of medicines. At first glance, this seems like a problem which should be addressable with current technology, but in practice, the solution to this issue has proved complex and difficult. Figure 28.1 shows a highly simplified supply chain from factory to pharmacist. It does not convey the billions of unit items involved worldwide or the thousands of transactions at each distribution Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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1

2

3

5

4

7 6

Figure 28.1. Simplified Diagram of Pharmaceutical Distribution. The individual packs (bottles, vials, blister packs) are produced and packed into shipping cartons. These in turn are packed into pallets for dispatch (1). The destination of the pallet could be anywhere in the world, and it will be handled by multiple logistics partners (2). During its journey, the pallet may be unpacked and broken down into smaller units (3), which are repacked with other manufacturers’ products into mixed consignments (4) before further logistics steps. This process may repeat multiple times (5) before the consignment reaches the inventory of various pharmacists (6) and the individual drug packs are dispensed to the patient (7). Dispensing of loose pills or capsules from bulk bottles into patient bottles adds a further layer of complexity (not shown).

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center every day or the multiple mixing and repackaging steps that an individual pack may undergo. Any tracking technology for pharmaceuticals must be able to cope with this complexity or at least find ways around it while retaining integrity. The proposition that drug tracking is vital to the future security of medicines is taken as a given by many, but this assumption should first be tested since it leads to considerable cost for all concerned. Before we examine the ways in which pharmaceutical products can be tracked and monitored as they move from the manufacturer to the patient, it is worth looking in more detail at the reasons why traceability is a good idea. The life of a pharmaceutical product begins with the supply of raw materials, whether it is the active pharmaceutical ingredient (API) or any other component of the formulation (excipient). Depending on the product, these may be from natural sources or they may be produced by industrial chemical processes. A typical product will have several different ingredients, each of which have different and critical roles in the function of the final product. These raw materials, especially the common excipients such as starch or dextrose, may come from suppliers for whom the drug industry is a relatively minor customer. Some of the worst mass poisonings due to medicinal products have occurred after accidental or deliberate substitution of products at the raw material stage. Poor documentation in many cases may have meant that the link to an original batch was not quickly made and therefore unnecessary lives were lost. Therefore, it is important to have full traceability of supply for all constituents of the final product and to have all necessary records regarding the provenance of those raw materials and their storage and use in the manufacturing facility. However, it is only when these raw materials are manufactured into the finished drug and packaged that it becomes practical to track small quantities of the product. As the required resolution of the tracking becomes finer, for example, tracking a single box anywhere in the world, the complexity involved in the tracking process increases. If a ton of bulk API is delivered by truck, then it is relatively straightforward to check and monitor the origin and use of that consignment. However, that ton of API is finished and packed into perhaps millions of unit items that are then distributed and dispersed from the manufacturing facility through multiple layers of distribution (perhaps crossing several borders in the process) to pharmacists and finally to the patient. It becomes very difficult to maintain the accuracy of tracking without considerable investment. If the tracking of drugs was a simple and cheap activity, it would have been done by now, so why should we persevere with that aim? The benefits of a universal, or at least universally accessible, tracking system will be significant. By monitoring the transactions of all drug packs, we make it harder for

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criminals to insert huge quantities of fake drugs into the supply chain undetected. Tracking systems aid the protection of legitimate drugs from counterfeits and help raise the alarm quickly when fakes are found. Accurate knowledge of where each drug pack is, and where it has been, also radically improves our ability to undertake accurate recalls of products in the event of quality issues that have nothing to do with counterfeiting. Finally, the least discussed but potentially greatest benefit of drug tracking and coding systems will come when these tracking systems are extended right to the patient’s bedside. Medication errors are surprisingly common and many are preventable with better systems. In principle, then, how can we maintain the visibility of an individual pack anywhere in the world and at any point in the distribution system? A typical pharmaceutical supply chain is complex, and there are many professional disciplines involved. The details of logistics management are outside the scope of this book except where they impact on product security. Security issues arise because there are usually many changes of custody during the journey from factory to patient. Each of these transactions is a potential break point in the supply chain and a possible vulnerability for theft, diversion, or counterfeiting. In developing nations, the distribution system may be further complicated by the informality of much of the drug market, the high prevalence of donor-derived medicines, and the frequent diversion of official stocks for resale. In theory, it is possible to generate a manual record of every transaction and to update and send that physical record onward with the product at every stage. However, paper-based systems quickly become unwieldy (how to store all those hard copy records?) and are notoriously prone to human error and deliberate falsification. The only practical way to track billions of drug packs around the world is to use technology to automate some or all of the data capture, transfer, and storage steps involved. Ideally, the same standard framework should be used worldwide, but the choice of which technology to use has been controversial. For a long time, this uncertainty was a barrier to implementation since nobody wanted to make the wrong call on the big investments necessary. This situation is now slowly resolving, at least in some regions, but it is useful to discuss the technology alternatives. These are detailed in Chapter 29. As a final note in passing, although the details are outside the scope of this book, any automated technology that impacts production line processes should be carefully validated in its own right (i.e., from an engineering standpoint as well as for security). The International Society for Pharmaceutical Engineering1 (ISPE) publishes the Good Automated Manufacturing Practice guide, which is highly useful in this regard. At the time of writing, GAMP® V is the most complete, widely applicable, and

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up-to-date guide on the design, installation, validation, and routine use of computerized systems in pharmaceutical manufacturing. Many older pharmaceutical plants contain one or more legacy computer systems that are often too difficult or expensive to replace. Getting these systems to work with track and trace systems may require extensive and expensive tailoring of “off-the-shelf” vendor systems. This will require either in-house engineering time or additional service fees to the vendor. The impact of serialization or pedigree on technical areas other than product security is always significant and should not be neglected when assessing the cost and business impact of implementing these initiatives.

Chapter

29

Tracking Technologies

Authentication, as discussed in Part II, is the process of answering the question: “Is this product genuine?” However, non-digital authentication technologies (colorshift ink, holograms, taggants, etc.) provide no information on the path that the product has taken from manufacturer to the patient (or the point of seizure). This is the domain of tracking technologies, which go by a number of potentially confusing names: track and trace, pedigree, and serialization. A brief digression on definitions is in order (see Chapter 30 for a fuller explanation of each technology). Broadly, “serialization” is simply the process of assigning a unique number to a unit of production (which can be a whole batch or an individual pack) such that it can be identified later. It does not imply or require the recording of particular transactions. “Pedigree,” on the other hand, is the process of recording most or all of the product history (transaction dates, ownership details, destinations, etc.) in such a way that the life story of the pack can be reconstructed in full. Pedigree can be paper based or computerized (known as ePedigree). “Track and trace” can incorporate either serialization or pedigree or both, and simply implies an ability of the system to know where a product went (track) and where it came from (trace). These and other digital authentication methods are primarily logistics control systems for following the progress of drugs from production to consumption. They establish the transaction history of each item, or more Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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accurately, the history of recorded transactions since not every journey or change of ownership is captured. To take a slightly simplistic analogy, serialization and most track and trace systems are similar to taking snapshots of a surgical operation: you cannot always reconstruct every detail if something goes wrong, but you can narrow down the causes and timing quite well depending on how many shots you took. Pedigree is more like time-lapse video, with more detail recorded for posterity, but it comes at the expense of complexity and cost. Knowledge of a pharmaceutical item’s journey can give clues to what went wrong in the event of an incident, whether counterfeiting, theft, quality issue, and so on. It can also help pinpoint other products that may be similarly affected and can help to remove them from the supply chain more efficiently. However, the fact that a product has an apparently genuine transaction record is only one element of its authentication—these records can (in theory) be faked. Tracking technologies should always be used in conjunction with the other physical authentication methods discussed previously to provide full protection. Technology choices are difficult and important decisions in this field. There are many ways to send a valuable item around the world, and given sufficient resources, almost anything is possible. For example, Air Force One does a very good job, albeit at great expense, of getting the President of the United States safely and securely to where he needs to go. Where budgets are more limited, compromises need to be made. Dispatching each drug pack directly to the patient by armed convoy is not an option, so instead, we focus on technologies that can monitor the position and status of the pack at various intervals so that security breaches can be identified and dealt with. The main technologies that might be feasible for global drug-tracking systems can be broken down into several types.

SERIAL NUMBERS

Widely used in many industries for over a century, serial numbers are simple and robust. A unique string of printed or stamped digits describes the item type (e.g., the stock-keeping unit or SKU) or a subset of production (e.g., batch number) or the unit itself. As the number of items to be included in the number system increases, the serial number format must get longer in order to maintain a unique number for every item. With the growth in international trade and the increasing number of items that need to be tracked, the numbers can quickly get unmanageably long. Numerals (0–9) can be used on their own, but more commonly, combinations of letters and numbers (0–9 plus A–Z) are combined to give alphanumeric

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codes. Each digit in an alphanumeric code can therefore be one of 36 possible values versus 10 possibilities for a numerical code. The larger number of possible permutations allows more data to be encoded in the same number of digits, or the use of shorter data strings, and therefore quicker and easier printing than if numbers are used alone. Typically, serial numbers have some hierarchical structure rather than being fully random or following on in series in the strict numerical sense (see the later section on GS1 GTIN (Global Trade Item Number) codes, for example). In the United States, by far the largest market for branded drugs, all drug products must display a unique number called the National Drug Code (NDC)1 as a universal product identifier. The NDC system is coordinated by the Food and Drug Administration, and the NDC data for all products are listed in a database together with product attributes. The NDC is a 10-digit, 3-segment number that identifies the labeler, product, and trade package size (but not the batch number or individual pack identity). The first number segment, the labeler code, is assigned by the FDA. A labeler is any firm that manufactures (including repackaging or relabeling) or distributes (under its own name) the drug. The second number segment, the product code, identifies a specific strength, dosage form, and formulation for a particular corporation. The third segment, the package code, identifies package sizes and types. Both the product and package codes are assigned by the manufacturer. There are detailed requirements for the format and type of NDC data—see the FDA website for details. Note that the Health Insurance Portability and Accountability Act (HIPAA) 1996 also applies where appropriate: HIPAA-compliant data identifiers are 11 digits. The same number can be used for both applications, but careful formatting is required to avoid ambiguity and potential confusion. In Europe, a patchwork of different numbering systems has evolved. These have varying degrees of interoperability, which causes complexity when drugs are traded within different countries of the European Union. Serial number formats range from 7 to 16 digits, including some that are compatible with the 13-digit international GTIN standard. There is also variation around where and how the number should be displayed. In only three EU countries, at the time of writing, does the code contain elements that permit pack-level traceability, although several more governments have plans to upgrade their numbering systems. The advantage of serial numbers is that they can be read by eye and input into a tracking or verification system by hand. This is useful in the event of technology failure but is a slow and potentially error-prone method of data capture. The need for speed and accuracy led to the development of linear bar codes.

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LINEAR BAR CODES

Since the 1970s, the linear bar code has dramatically improved the accuracy and speed of retail transactions and warehouse processes. A bar code goes one stage further than a serial number by providing information about the product in a machine-readable form, encoded as a series of black lines (bars) and white spaces. Both can be of varying widths depending on the barcode type. A scanner, consisting minimally of a light (usually a laser) and a photosensor, is used to read the pattern and to relay the message to an output device, which may be a point-of-sale cash register, computer system, and so on. The laser beam sweeps across the barcode, reading a slice of the barcode pattern. A configuration of mirrors in the scanner usually allows flexibility in the angle at which the code can be presented. The relationship between the coded information and the barcode itself is known as a symbology. As with any language, there are defined rules of grammar and syntax within each symbology. The symbology choice is more important for 2D codes (see below) than for bar codes. The code format may be specified by the local regulator. An important limitation of linear bar codes is that the information can be encoded and read only in one dimension; therefore, adding more data makes the code longer. This can quickly lead to quite large codes, such as the 16-digit code used in Belgium,2 and becomes impractical for the storage of long data strings. Linear bar codes are therefore generally only used to identify SKUs rather than production batches or individual packs, although there is no theoretical reason why they could not be used for full serialization. An advantage of using bar codes at the SKU level is that the code can be pre-printed onto the packaging by the converter since it is the same for all items of the same type. Linear symbologies were originally designed to be read by laser scanners, but camera-based, charge-coupled device (CCD) imagers are now becoming the preferred code-reading method. These have the advantage that they can read both linear and matrix codes.

MATRIX CODES

Most products have limited real estate on which to print bar codes, and the demand for on-pack data keeps growing. With the advent of more versatile, camera-based scanners, one of the obvious ways to increase the coding capacity of bar codes printed on flat surfaces was to use two dimensions instead of one, and this led to the 2D code in its various forms. The greatly increased amount of data that can be encoded in a small unit area means that serialization of every unit pack became a feasible

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proposition for the first time. The trade-off is that 2D symbologies cannot be read by a laser scanner, which can be problematic in countries where only laser scanners (for linear barcodes) are readily available. There are now many 2D symbologies available, with various code shapes and data encryption schemes. The most common formats are matrix codes, which feature black square or dot-shaped modules arranged in a grid pattern on a white background. However, it is not necessary for the code to be printed in visible ink. Covert codes printed with invisible security inks of various types are available. Other visual formats include circular patterns, non-matrix or random patterns, and the use of steganography techniques to hide an information array within another image. From an initial diversity of symbologies, the industry-standard3 2D matrix symbology for pharmaceuticals is emerging as ECC200.4 Standards for data formats,5 syntax,6 and printing quality7 are ISO/IEC 15418:2009, ISO/IEC 15434:2006, and ISO/IEC 15415:2004, respectively. The ECC200 code uses a unique perimeter pattern, with a solid line at the left and lower edges of the code and a broken line at the right and upper edges (see diagram below), which helps the barcode scanner to determine cell locations and to decode the symbol. The QR code,8 one of many alternative formats, uses three concentric squares to locate the corners. Figure 29.1 shows an ECC200 matrix code with QR code for comparison. The small size of the dots in a code, and the ease with which an individual point could become damaged or erased, means that redundancy must be built into the system. No single data point should be critical to the reading of the code. In fact, the error-correction algorithms for the ECC200 standard allow the recognition of barcodes that are up to 60% damaged or illegible. This is critical, since 2D codes usually incorporate real-time data specific to an individual batch or unit and are therefore typically printed by high-speed inkjet printers on production lines. On some fast-moving lines, the printers may be working near the limits of their print speed capabilities, but the error-correction function helps prevent line stoppages due to illegible codes. External pharmaceutical packaging

(a)

(b)

Figure 29.1. ECC200 code (a) and QR code (b).

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may easily become scuffed during transit. For accurate reading, it is also important to have sufficient white space or “quiet zone” around the code itself, so the code must not be printed over or near existing text or graphics. This requirement for sufficient white space, also called real estate, on the pack has proved to be problematic for some smaller pack formats9 in pilot studies. It is not necessary for the code to be visible, if a suitable reader is available. Covert (invisible) codes, sometimes used for proprietary, closed systems, can often be printed with special security inks over colored text or graphical elements. However, the readability must be tested carefully before use to ensure that the ink used for printing the visible background does not quench (absorb) the light signal needed to read the invisible code or interfere with the signal by fluorescing. Visible, open standard 2D codes such as those promoted by GS1 can be read by any suitable code reader and are the preferred format for any application in which data must be shared because they allow anyone to read the code and to extract the information without contacting the person who printed it. For some closed-system applications, such as additional brand owner security systems, encrypted codes may be used. These may be printed with visible or covert inks, but the data they contain are pre-encoded before they are converted to a matrix. Therefore, the matrix itself (if visible) can be decoded by a standard scanner, but this will yield only a meaningless number unless the viewer has access to the necessary decryption keys. ECC 200 barcodes support various size formats (the total number of cells in each dimension). Although bigger matrices allow the coding of more information than smaller ones, which would appear to be a good thing, they also take longer to print and verify. This can be an issue in pharmaceutical serialization programs where the code is printed in real time on the production line, since the print time for the code can become the rate-limiting factor on fast lines, thereby slowing the production process. The code format chosen should therefore be no bigger than necessary to encode the required information. A matrix size of 22 × 22 cells is quite common, but there are several alternative options, and specialist advice should be sought. For a detailed discussion of technical requirements and limitations of 2D codes, the interested reader is recommended to contact their local GS1 organization or one of the major technology vendors. 2D Codes and Mobile Phones

With the growing availability of cameras on mobile phones, it is now possible for the ordinary consumer to read standard (unencrypted) visible 2D codes using readily available software10 without using a dedicated scanner. Already used in retail applications as a direct-to-consumer marketing technology on price tags and product information, this development

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may eventually open up drug-tracking technology to end users. It is also potentially suited to use in developing countries, where mobile phone use is growing rapidly. Technical Issues with 2D Codes

In terms of efficiency of use for pharmaceutical serialization, 2D codes are an obvious improvement over linear barcodes. They are easy to generate, can be printed at high speed on production lines, and can be read with very low error rates by fairly simple scanners. The whole system is relatively cheap (at least in terms of direct costs) on a cost-per-coded-unit basis. However, there are also some technical drawbacks with matrix codes. The major limitation is the need for line of sight between the scanner and the code. Detection of the standard, black-and-white 2D code requires visible light; therefore, the code and scanner must be placed in close proximity, with nothing obstructing the light path between them. This limitation is not a concern during application of the code, on a pharmaceutical production line, since the codes are printed (and then visually verified by a camera reader) individually for each pack as it travels down the line. Similarly, when the product is finally dispensed, it is in a single-pack form in the pharmacist’s hand and the code can be readily accessed. However, the need for line of sight becomes a problem at all intermediate stages of the supply chain, where unit packs are typically aggregated into shipping cartons or larger pallet consignments. This is exacerbated by the fact that 2D code readers can only scan one code at a time, unlike RFID readers, which can read multiple tags simultaneously. There are workarounds for these issues, which will be discussed later, but the line-of-sight issue limits the ability to capture all transactions. On some lines, the speed of code printing may be an issue. On lines with very high linear speeds, the inkjet print head may not be able to move quickly enough across the product to print the code without blurring. This problem can often be addressed with the correct choice of technology (drop-on-demand printers are generally faster than continuous inkjet types) but may sometimes be difficult to solve. An alternative is not to code variable data into the matrix at all. It is possible, in theory, to pre-print codes onto packaging or to apply pre-printed, coded labels before the pack is filled. At the time of application on the pack, these are either “dumb” codes carrying no product information or they carry all of the information that is known in advance but not variable data such as lot number or expiry date. The final step is then to “activate” the code, that is, to associate it with the pack identity in the database, as it moves past the code scanner. Note that this is only a valid option if the code does not need to contain

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any real-time data, since anyone reading the code will not be able to access the variable data unless they have access to the database. Pre-application gets around the problem of how to apply a complex code at high speed onto a moving pack without blurring or distortion. However, most of the proposed pharmaceutical coding schemes will require data such as batch/lot number and expiry data to be hard coded, that is, readable offline from the pattern of dots themselves and not just by reference to a database. If the code needs to contain this real-time data, which can be known only at the time of packing, then pre-printing of codes is not an option. Inline printing is the only way forward. On some lines, the need for in-line code printing may arise because an existing continuous inkjet printer, previously used only to print batch and expiry dates, cannot be upgraded to print the 2D codes but must be replaced with a drop-on-demand model instead. Despite the many technical issues and the practical problems that must be resolved in the implementation of pharmaceutical serialization programs using 2D codes, they are still the preferred technology for most in the industry, as they provide a pragmatic balance of price, coding capacity, and functionality. They are likely to be the dominant technology until RFID or a variant of it becomes sufficiently cost-effective to take over. RADIO FREQUENCY IDENTIFICATION (RFID)

RFID uses radio wave technology to read, and in some cases write, information on printed chips that are placed on the product to be tracked. RFID has long been discussed11 as the ideal solution for track and trace systems for pharmaceuticals and medical devices, even at the unit pack level. It is regularly touted as the ultimate anti-counterfeiting tool, although in reality, it is perhaps a supply chain management method with security benefits rather than a security technology per se. Its widespread adoption by the pharmaceutical industry at pack level seems to be perpetually five years into the future, for a number of reasons discussed below. RFID is intuitively the most promising of the currently available technologies for drug tracking, for a number of reasons. First, it is one of the few data-carrying technologies available that do not require an unobscured line of sight to the product. Radio waves, unlike visible light, can penetrate some opaque materials. In theory, it is possible to read the RFID tags of multiple unit items packed in larger containers (such as shipping cartons or pallets) simultaneously and without unpacking and repackaging the individual units. This is a major advantage in the logistics of reading and recording codes in high-volume environments, such as distribution centers. Major pharmaceutical distributors have rapid turnover of

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huge inventories. They may receive, stock, pick, and dispatch millions of items every night and use highly automated processes. RFID potentially provides a way of recording product codes as they flow through the system, without slowing that process down. By contrast, the use of a system requiring the reading of 2D codes on every pack requires each pack to be presented to a reader with clear line of sight and in the correct orientation with the coded side of the pack facing the reader. This involves a whole new inventory and picking processes, and with present drug distribution systems, is more or less impractical. There are ways around this limitation by aggregating data, which will be discussed in Chapter 30, but these do not have the conceptual simplicity of the RFID approach. Another key advantage of RFID is that, depending on the technology used, the read distance (maximum effective recognition distance between RFID tag and reader) can be quite large. The RFID chips and antennae themselves are small and flat enough to be incorporated into labels and affixed onto individual packs. Although these labels need to be of a minimum size to accommodate the antenna, this only becomes a limiting factor for very small packages. The radio frequencies and the type of tags used in an RFID system determine the range of the chips and the applications that can be used. The specific details of transmission and reception of radio signals, and the benefits and drawbacks of different RFID formats, should be discussed with a qualified vendor. From a drug-tracking strategy point of view, these issues are an important detail, but the fundamental principles are similar across all RFID types. For a fuller technical description of this field, see elsewhere.12 RFID tags come in various types and operate in various frequency bands, but the main distinction for anti-counterfeiting purposes is “active” versus “passive.” An active tag has its own power source (battery) and is generally larger and more expensive than a passive tag. It also usually has a read–write capability. That is, the information that is held on the chip itself can be both read and updated. Therefore, the tag can hold genuine pedigree information that is directly associated with the product: the full transaction history can be read offline without reference to a database. This enables a full pedigree (see Chapter 30 for a fuller discussion of what this is) to be written onto the tag and transported with the product. Active tags can have a read range of up to 100 meters. Passive tags, by contrast, do not have their own power supply. They use the power of the incoming radio signal from the RFID reader to transmit a simple message back over a short distance (typically up to around 3 m). They are read-only, so pedigree information in these systems is held and updated in a database, not on the tag. The data standards for RFID are well established,11 and system interoperability is not likely to be a significant problem.

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However, despite its many technical advantages, RFID does have some well-known drawbacks that have limited its uptake in the pharmaceutical industry. These include cost, both for the infrastructure needed to read the tags and for the tags themselves. The tag manufacturing technology is advancing, and the eventual goal is to use tags that are fully printable, ideally using a standard printer, rather than prefabricated ones. At present, the chips are the limiting factor, although printed antenna technology is available. Tags have yet to come down in cost to a level where RFID becomes a feasible proposition for unit-level packaging of all pharmaceutical products, including relatively low-value items. Marginal costs are therefore still significant: at the time of writing, the typical cost of an RFID tag is around 25¢. The general consensus in discussing these issues with colleagues seems to be that a unit cost of 5¢ per tag or less is needed before RFID becomes viable as a data carrier on all item-level packaging. There are also significant one-time hardware costs for all actors in the supply chain, who will be required to purchase RFID readers and associated equipment. For these reasons, RFID has generally been limited to the tracking of the higher levels in the packaging hierarchy, such as shipping boxes and pallets, or to high-value items such as controlled drugs. Related to the cost of RFID is the relative technological complexity of the infrastructure required. To fully automate a warehouse for RFID requires a heavy investment in hardware (receivers in loading bay arches, etc.) and large amounts of management time. Current technology, although rapidly improving, is not yet fully plug-and-play in the sense that it can be installed from the box with minimal configuration. Each installation typically requires a site survey and fine-tuning of signal reception. It is important to get this stage right, as mis-reading of tags is both expensive and time-consuming to correct. RFID labels can be more difficult to read in proximity to liquid environments (e.g., when used on biological products), but there does not appear to be any evidence that they can cause degradation of the product.13 Even with the best systems, 100% error-free tag reading is still difficult to achieve in all situations. Privacy and data security have also been raised as potential issues for RFID, and there has been some vociferous consumer opposition in some quarters to the use of RFID on pharmaceuticals. These concerns are not unique to pharmaceutical applications of RFID, but do raise some industry-specific issues. For an RFID-tagged medicine, it is possible, in theory, for the information contained on the RFID chip to be read remotely by unauthorized persons after the drug has been dispensed. Patient groups have expressed concerns that sensitive information on the medication status of individuals could thus fall into the wrong hands. However, in practice, this seems to be largely a theoretical issue. As a

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final precaution, it is possible for the RFID tag to be removed or deactivated by the pharmacist before the product is dispensed to the patient. A more serious security concern may be the potential to alter or corrupt data about the history or pedigree of the product. In the case of active tags, it may even be possible to re-program the tag with a bogus pedigree. In most security systems, the people and processes matter at least as much as the technology, and RFID is no exception. By appropriate design, training, and implementation, many of the vulnerabilities discussed above can be minimized. The early pilot implementations of RFID by large drug companies have typically been problematic and have often had a poor cost-benefit ratio. Poor return on investment is often an issue for technology “islands” set up by one early adopting stakeholder in the absence of full integration with business partners, so this should not be a surprising finding. A more positive experience was reported in 2009 by the EU-funded “Building Radio Frequency Identification Solutions for the Global Environment” (BRIDGE) consortium.9 The project pulled together multiple stakeholders including pharmaceutical manufacturers and distributors. The project team drew some interesting comparisons between the merits of 2D codes and RFID, and the final report states: An over-arching conclusion of the pilot is that full supply chain traceability systems in the open, cross border supply chain in the European Pharmaceutical sector (and undoubtedly other continents too) is entirely feasible.

The BRIDGE project found that the use of open information standards together with two data carriers (2D matrix codes in ECC200 format and RFID tags) enabled maximum interoperability. In their view, the GS1compatible data set used for the project (product code, serial number, batch number/lot code, and expiry date) not only offered the required traceability for electronic pedigree but would also be suitable for recall systems, inventory management, and financial reconciliation systems. The BRIDGE team observed not only that significant investment in technology and training is required by all of the individual parties in the supply chain but also that significant effort and focus on trading partner collaboration and stringent adherence to robust processes and their management is critical. This requires sustained executive commitment as well as training, education, and communication at all levels from senior management downwards. These “soft” costs should not be underestimated when budgeting for the implementation of a track-and-trace system, whatever the data carrier.

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The project used mixed data carriers, with each one used as appropriate for pack size and packing hierarchy. However, there were often difficulties locating appropriate physical space for the 2D code or RFID label on the patient pack. This was mainly due to the lack of appropriate white space for the code to be applied in a quality manner with an appropriate white zone to allow effective reading. Future packages will need to be designed to allow codes to be easily accommodated by allocating space for printing. In order for processes to be harmonized properly, the pharmaceutical industry needs to agree on the most appropriate space (e.g., on the top, edge, or side of the carton) for placement of codes on different forms of packaging. Ideally, this space should be unvarnished to avoid subsequent smudging of the printed code. An unvarnished white area is already left on many packs for the lot and expiry data to be printed. Finally, and as noted by many distributors previously, the BRIDGE project found that high-speed picking and tote assembly at the distribution center is a fundamental bottleneck for processes based on 2D codes. The need to read codes individually and at close proximity to the reader makes automation difficult. The BRIDGE project report is an excellent case study for the implementation of the complex, multi-stakeholder systems that will be needed to tackle the growing problem of counterfeit drugs; it also contains warnings (based on real experiences) about the likely cost and complexity.

MOBILE PHONES

The use of mobile phones as authentication tools has been widely promoted as the ideal solution to pharmaceutical counterfeiting.14 Improved technology and falling costs mean that the use of these methods is increasing in both developed and developing countries. As the costs of wireless telephony in general have decreased massively in recent years, this has led to its increasing penetration in almost all countries. This may eventually allow, for the first time, a ubiquitous, consumer-led, technology-based authentication method to emerge. Those who have traveled in Africa in the last few years will have noticed the greatly increased prevalence of mobile phones. Even among the poor, possession of a mobile phone (or at least access to a shared one) is becoming almost ubiquitous. By contrast, the penetration, reliability, and quality of landline networks and broadband communication in Africa are typically very poor. Many developing countries, rather than laying and upgrading fixed lines, have deliberately leapfrogged landline technology and have instead prioritized mobile phone networks. As a result, signal quality is often excellent even in relatively remote areas. Since the mobile

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phone places modern communication technology in the hands of almost anyone, it is logical that it should be considered as a means of verifying information on packaged products such as medicines. The simplest use of mobile phones in drug verification is to ally them with a simple existing technology such as human-readable serial numbers. Many of the current systems incorporate a specific and unique piece of information from the pack—such as an alphanumeric serial number. The pack information requests that the user phone a helpline or send an SMS text message containing the number. The operator or automated response system can then check the serial number against a database and send a message back confirming the authenticity of the product or identifying it as a possible counterfeit. In countries with a higher prevalence of more sophisticated camera phones, it may also be possible to scan and verify bar codes or 2D matrix codes using the camera function of the phone. Many cameras now have the capability to do this, potentially bringing a sophisticated digital verification tool into the hands of the general public. However, although mobile phone technology may be attractive, it is also very simple for anyone to download software to generate their own alphanumeric codes or 2D codes, which could then be printed onto bogus products. A false but reassuring verification message can lull the unwary into believing that their product has been authenticated when in fact it is a fake (Figure 29.2), therefore robust safeguards are needed. The systems, controls, and processes are more important to overall success than the security technology in most product security applications. There have been pilots of mobile phone verification systems for pharmaceuticals in several African countries,14 with technologies designed specifically for emerging markets. In these systems, using any cell phone, customers can send a text message containing the unique code printed on the item and receive a rapid response confirming the product’s authenticity. The message is free to the consumer. In operational systems, it will most likely be paid for by a small per-item levy on manufacturers. The coding system employed is single-use and uses scratch-off technology to conceal the code until the point of sale. The customer first checks the integrity of the metallic covering, before scratching it off to reveal a unique code and then texting the code to the appropriate number. Scratch-off technology is used around the world in many applications. Importantly, for consumer acceptance, it is already well recognized in emerging markets, where scratch cards are widely used in pay-as-you-go mobile phone payments. In addition to sending the verification message, such a system could allow participating brand owners to send targeted offers to their

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“Call: 800-999-0909 Web: www.ingesta.com SMS: 99099”

S tarm

“Call: 800-909-9909 Web: www.myingesta.com SMS: 9990999”

aSrt m

Figure 29.2. Parallel Universe Issue. Verification systems that use the Internet, SMS, or telephone-based methods (left) should always be protected with additional authentication features. Otherwise, the counterfeiter can create a ‘‘parallel universe’’ (with fake versions of help lines, SMS systems, or websites) that ‘‘validates’’ the fake codes on their counterfeit products (right).

consumers. This may be controversial and whether it adds to or detracts from the authentication capability remains to be seen, but it will clearly have some commercial attractiveness to brand owners. Although the privacy and data protection aspects of direct-to-consumer communications are potentially problematic in many markets, by providing the participating brand owners with a clearer return on investment, these systems may represent a useful incentive for the rapid implementation of anti-counterfeiting systems. This type of phone-based system could also give enforcement agencies useful new information. Large-scale data on drug authentication and movement could allow authorities to target pharmacy inspections more accurately and to make better use of their limited resources.

OTHER TRACKING TECHNOLOGIES

Various other formats for product coding and tracking have been proposed, often based on random physical properties of the packaging itself or on

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added random features or marks (which can be printed or applied using a label). During production, the unique random features of each pack are recorded and stored on a database. Transaction information can be added to the database whenever the product is scanned using a suitable device, and those unique features are detected and verified. The limitation of most of these proposals is that they are largely proprietary and not interoperable with other systems. They are thus likely to remain adjunct systems, used for internal security purposes by brand owners, rather than universal tracking and logistics systems shared between business partners.

APPLICABILITY OF TRACKING SYSTEMS WORLDWIDE

It is a tragic irony that the burden of counterfeit drugs falls most heavily on those societies who are least able to fight it. We have discussed technology-heavy approaches such as RFID and 2D code systems as potential universal tracking networks. Although difficult and costly to implement, these approaches may be supportable and affordable in the major developed countries. However, such systems place a heavy load on poorer countries, and it is precisely these countries that have the greatest need for efficient countermeasures. In Africa, where the problem of counterfeit medicines is arguably the most acute, the national gross domestic product (GDP) of some countries is below the annual revenue of a mid-sized drug company. Government officials know the problems of counterfeits. They face an influx of fake products of all types, from ballpoint pens to shoes to razor blades to aircraft parts. Counterfeits hurt their own domestic industries as well as their people. Fake drugs are a critical threat and kill many Africans everyday, but many countries lack the expertise and finances to implement countermeasures on their own. In order to secure the global drug supply, which is in all our interests, it may be necessary for developed countries, multinational drug manufacturers, and NGOs to allocate sufficient funds to support the deployment of drug tracking in less-developed nations as well as in the rich world.

Chapter

30

Data Format, Generation, and Storage The technology arguments in the previous chapter are important, but on a world scale, the biggest practical challenges in drug tracking are generally in the areas of data format, data sharing, and data storage. As we have already looked at in Chapter 28, there are a number of closely related terms that are commonly used in discussions regarding product tracking. Although often used interchangeably, there are subtle differences, and we now need to take a closer look at these seemingly nuanced distinctions and their real-world implications. Ultimately, the choice of tracking scheme affects the likelihood of success, so these factors need to be thought through very carefully by legislators and their advisors. The types of tracking systems and data formats used in drug tracking fall into the following broad categories.

SERIALIZATION

The first step toward the differentiation of large numbers of similar things is to assign each of them an individual identity. Serialization involves assigning a “name”—in this case a unique serial number—either at the batch level or at the unit level. Strictly, these are nominal numbers (i.e., they assign a unique identity) not serial numbers (since sequential integers Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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are not necessarily assigned to consecutive items on the production line). However, “serialization” is the universally used term, and the meaning will be taken to mean assigning a unique number. Most of the systems now under discussion involve full serialization right down to unit level, although some product security professionals argue that most of the key benefits could be achieved by the much simpler step of serialization at the batch level. There is a large diversity of possible data formats for serialization. Without appropriate standardization, the benefits of serialization would be lost because of the cost and complexity of reconciling multiple parallel systems. Fortunately, there is an emerging global consensus on the structure of serialization data in healthcare. This process has been led by healthcare industry users themselves and coordinated by GS1, a not-for-profit standards organization, and has led to agreed numbering rules.1 The GS1 system of standards incorporates a set of Identification Keys—numbers identifying products and services and providing access to information held in computer databases. These numbers have been designed to have certain key characteristics: Unique: Every variant of an item is allocated a separate unique number. This prevents duplication and confusion. Non-significant: The number identifies an item but contains no information about it. This is important for security purposes. International : GS1 Identification Keys are unique across all countries and all sectors, so only one number is needed for each item. Secure: GS1 Identification Keys are of fixed length and numeric and include a standard check digit. Such open, technology-independent standards are critical to permit full cross-talk and compatibility between systems—known in the jargon as interoperability. Open standards mean that users are not locked into incompatible, proprietary solutions. Global standards are a vital factor in protecting pharmaceutical supply chains, which are frequently international. The basis of the GS1 System is the GTIN (Global Trade Item Number) Identification Key. GS1 Identification Keys can be carried on any type of data carrier of sufficient data capacity, including linear bar codes, 2D matrix codes, or RFID tags. The numbers are allocated by the manufacturer according to the GTIN Allocation Rules and include a GS1 company prefix assigned to each individual company by GS1; an item reference, assigned by the company itself; and an automatically generated check digit.

SERIALIZATION

GS1 Company Prefix N1 N2 N3 N4 N5 N6 N7

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Item Reference

Check Digit

N8 N9 N10 N11 N12

N13

When a GTIN is assigned, the producer must transmit the information linked to this number as well as the packaging hierarchies. All units (individual packs and secondary logistic units) carry a GTIN. The GS1 system also incorporates a number of other identification keys appropriate to various situations. The Global Location Number (GLN) is a 13-digit number that identifies any physical or legal location involved in a given transaction, such as the manufacturer, the product shipping location, the unloading location, and the final delivery destination (medical care unit, etc.). The Serial Shipping Container Code (SSCC) is an 18-digit number that uniquely identifies a logistic unit. In the United States, GS1 Healthcare members signed up to “sunrise dates” for implementation2 of GLNs by December 2010 and GTINs by December 2012. The GTIN is unique to a trade item or SKU but not to each pack. The addition of a serial number, which is unique to each unit pack, leads to a serialized GTIN (SGTIN), which can uniquely describe any box or bottle of product anywhere in the world. This is therefore the basis of a potential universal tracking system. The FDA guidance on numerical identifiers3 specifies that pharmaceuticals in the United States should carry a serialized National Drug Code (sNDC), allowing any individual item to be uniquely identified. The data structure is adapted from the existing NDC code with the addition of a serial number of up to 20 alphanumeric characters. The sNDC format is compatible with the SGTIN data structure, which will allow the US drug numbering scheme to be compatible with GS1 standards worldwide. For a serialization system to be effective, data sharing standards are also needed. EPCIS (Electronic Product Code Information Service) is a standard4 developed by the EPCglobal offshoot of GS1 and is used to track the progress of coded objects as they move through the supply chain. EPCIS provides the standards necessary for the storage, communication, and dissemination of serialization data. It provides standard event capture and query interfaces for obtaining and sharing data about unique objects in the supply chain within and across organizations. Therefore, EPCIS provides a way for supply chain partners to share and exchange information efficiently, even though they may store the information in different types of underlying databases. As the draft of this book was being finalized, GS1 released5 the EPC Tag Data Standard Version 1.5. This clarifies and enhances a number

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of areas of standardization and also removes the previous confusion in terminology between RFID and EPC. The latest version makes clear that the Electronic Product Code format is carrier independent and RFID is only one of several options for encoding the data onto products. In conjunction with the earlier Pedigree Ratified Standard, this new tag data standard will make it easier to ensure that data capture, transfer, and storage processes are fully interoperable across vendor platforms and between corporations. The reader is advised to check www.gs1.org for recent updates to standards. In addition to requiring data to be shared between business partners, most tracking systems—including serialization—also require some of the data to be securely segregated. There is potentially a lot of commercial value in the output from such a large-scale dataset, including useful and detailed knowledge on real-time sales patterns, competitor activity, and so on. To avoid information falling into the wrong hands, systems are designed with appropriate safeguards and access controls. Corporation A cannot see the tracking data for Corporation B and vice versa. A further complication arises when multiple countries are involved in the same system, as could potentially be the case in a future European system. The pharmacy organizations and drug regulators in some companies have privately expressed reservations about data from patient transactions in their country being accessible in another country. However, given the possibility that a pack can be re-routed around Europe before its eventual sale, there may have to be a practical solution to this issue. A final and important footnote to the subject of open standards in healthcare tracking is the need for material security to accompany the system security measures. Visible codes can be duplicated and should be protected with additional measures to verify their authenticity. As a general rule, proprietary security tracking systems are easier to protect from criminal activity than open ones since readers and marking materials are not available on the open market. The GS1 standards trade-off absolute security for the benefits of international compatibility and interoperability, which is a necessary pragmatic step in the development of tracking systems that are globally effective.

RANDOMIZATION

This is a less frequently heard term that is often used as a synonym for serialization, but, in fact, the strict meaning is subtly different. In order to maintain the security of a tracking system based on serial numbers, it

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is important that the numbers are not actually completely “in series” in the literal sense. That is, the next serial number in a given production batch should not be predictable from a knowledge of existing numbers. Therefore, although certain elements may be common to all related units, the best practice in serialization systems is to include at least one random alphanumeric string in the overall number format, which uniquely describes the unit item to which it is attached and is independent of any predictable factors such as date, time, or batch number. “Randomization” describes this process of assigning non-sequential, non-predictable numbers as part of a serialization scheme. Note that the number assignment process must be very robust to avoid the possibility of repeating any of the previously used numbers.

PEDIGREE/ePEDIGREE

The use of the term “pedigree” in healthcare is broadly analogous to its use in dog breeding. A pedigree verifies the provenance and prior history of a product and therefore acts as a guarantee of authenticity. Pedigree (or “ePedigree” for electronic systems) and serialization are the two main types of traceability systems. In pedigree-based systems, information regarding all of the transactions associated with the product unit is retained and is available for inspection. The information is usually directly carried with the product, either on paper or in electronic form, or accessed via a database. The pedigree becomes an official life history of the product, showing its path in detail through various commercial transactions from manufacturer to patient. Each stakeholder in the supply chain is obliged to update the pedigree information as it passes through his or her hands. The alternative mode of traceability, discussed under serialization, involves recording some of the transactions associated with each serial number in one or more databases. At the simplest level, the serial number and product attributes are recorded only during production. Authorized users are able to query the database based on the serial number of the product, but the full pedigree information and transactional history of the product does not travel on or with the unit itself. In many cases, the detailed transaction history is simply not known. In many serialization schemes, many transaction types are deliberately not recorded in order to simplify the system and reduce costs. The advantage of having a pedigree physically associated with the product is that it is not necessary to have access to an online database. This makes pedigree systems useful for situations in which real-time access to a

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remote database would be problematic, for instance, in remote pharmacies without broadband access or in developing countries. The costs of recording and transmitting data are shared between the actors in the supply chain, since each actor is responsible for updating only the information pertaining to his transactions. However, the data recording burden can be significant for pedigree systems—particularly if paper based. If electronic recording methods, such as RFID, are used then all actors in the supply chain must be equipped with RFID read/write capability, which is costly and complex. Typically, the manufacturer bears the highest marginal costs, since they need to affix the information carrier to each item. In the case of RFID, this cost can be quite significant, although for 2D codes, the marginal cost of printing a code is small. Whatever the data carrier, the application process also carries significant hardware costs and requires a lot of optimization and management time to get right. Pedigree systems present certain practical challenges, which have hindered their implementation. If the pedigree must be physically associated with the product, there is the need for a data carrier that can be modified once the product has left the manufacturer. In the past, this has been achieved using paper-based pedigrees, which are updated after each transaction. However, these are bulky, inconvenient, error-prone, and vulnerable to fraud. In the future, it may be possible to build efficient pedigree systems using rewritable electronic technology such as RFID, although at present, the cost and complexity of these systems is proving to be a barrier to implementation. The bigger problem for pedigree is the need to record all transactions. This places a heavy burden on distributors and other intermediaries who need to process thousands of transactions quickly. Over the last few years, the state of California has driven many of the debates about the merits and problems of pedigree drug tracking systems. The California Board of Pharmacy, attempting to implement California State law, has sponsored many meetings between technology providers, drug manufacturers, distributors, and pharmacists. It has become increasingly clear that there are no easy answers to these questions and that compromise is necessary on all sides. With the postponement of the implementation of California’s requirements until 2015, some of the heat was taken out of this debate. The likelihood of a major, gamechanging technology breakthrough in this time is, in my opinion, unlikely. Therefore, it is prudent to begin the implementation of strategies that are based on current technological capabilities and existing limitations, with a view to migrating to more complex capabilities and full pedigree in due course.

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TRACK AND TRACE

The two elements of track-and-trace systems (“track” and “trace”) are related but distinct. In the forward direction, the “track” component of the system enables goods to be monitored as they progress through the supply chain from manufacturer to patient. This is done by collecting information at some or all of the transaction points along the way and uploading the data to one or more databases. These databases can then be queried by authorized users in order to determine the status of any given unit item in the system. Tracking is therefore the ongoing downstream data process, which collects baseline transaction data for authorized shipments in the normal supply chain. Tracing is the process that occurs when a query is made or an exceptional event occurs. Examples of these events may include suspected counterfeits, but tracing is also used for quality-related problems. The tracing process queries the existing database of previous transactions and therefore relies on the tracking data that are already in the system. Therefore, in order to be optimally useful in the fight against fake drugs, track and trace systems rely on all stakeholders fulfilling their obligations to record details of transactions as each code passes through the supply chain. The more detail that is recorded in the track (forward) mode, the easier it is to pinpoint the location of any problem or unauthorized event in the trace (backward) mode. Track and trace systems do not require any particular technology. However, recording of all the possible transactions for each unit can become technically rather onerous, as discussed in earlier chapters. This is particularly true for data-carrying technologies such as 2D codes that require line of sight, which effectively means that the code location must be visible to the operator as well as the scanning machine. The code itself may be invisible to the naked eye, as used on highly secure proprietary systems, for example, but there must be an uninterrupted path from the reader to the code in order for it to be read. Systems that use RFID to carry the information on the individual packs do not, in theory, suffer from this limitation. However, experience has shown that caution must be exercised since the achievable read rates for RFID chips may not be close enough to 100% to be relied upon in the qualitybased environment such as pharmaceutical distribution. If the product unit information is stored as a human-readable serial number, linear barcode, or matrix code, all of which require line of sight in order to be read, then each transaction may, in theory, require the unpacking of all coded units from their shipping containers. This is impractical in the high-throughput environment of pharmaceutical distribution. A number of approaches have been devised to overcome this limitation and are discussed in Chapter 31.

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FINGERPRINTING

As discussed above, most of the commonly proposed and implemented methods for recording and tracing pack identities use codes that are artificially generated from an algorithm and therefore have some degree of man-made structure. An alternative approach is to use innate physical characteristics of the product, or random features applied or printed onto the product, to derive a unique data set that can be converted to a numerical code and stored in a database. These features may be the distribution of paper fibers in a label or carton or the surface imperfections of a plastic bottle. Equally, they could be artificially derived from a randomly printed pattern of tiny bubbles6 or other surface features (Figure 30.1). The key advantage of such techniques is that they are based on chaos. The chances of two natural surface patterns being the same by chance are vanishingly small—typically 10−20 or better even on apparently “smooth” surfaces such as metal and plastic and less than 10−72 for paper.7 In the case of inherent features, a further advantage is that no additional application step is necessary—the product produces its own fingerprint,

Unique digital signature 1

Unique digital signature 2

Figure 30.1. Digital Fingerprinting. Surface features of the packaging are analyzed and converted to a unique digital file for that pack unit.

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which can be expressed as a relatively small dataset of less than one kilobyte. These data can be further associated (either directly by coding or by association in a database) with another product identifier, such as a 2D code, or it can be encoded onto an RFID tag. The validation tools are also relatively low cost and portable. Since there are no known processes that would allow the fabrication of copies of the fingerprint, these approaches have the potential to be very secure. There are some drawbacks of using such surface fingerprints as a primary identification tool. The first issue is that they are not manually readable. This can be problematic in the event of equipment failure or for offline use, but this limitation also applies to other technologies such as 2D codes and RFID. A further limitation for innate surface features is that the technique relies on matching a pattern taken in the field with the pattern recorded and stored in a database during manufacture. This requires careful alignment of the recording device with the correct part of the pack. If the registration is inaccurate and the wrong part of the pack is measured then the results will be wrong. In fact, this will generate a false alarm because the database does not recognize the pack as part of legitimate production. Avoiding this problem requires careful training of the staff who will perform the validations, which may limit the technique’s usefulness and widespread use. Conversely, if the correct registration point is made too obvious (by marking the spot, for example), then it may become a target for counterfeiters—not for duplication but for disruption. A legitimate pack with an obscured or defaced fingerprint area may not be readable and might be flagged as a potential counterfeit. If it can be subsequently authenticated by other features, there is potential for confusion. Counterfeiters do not have to integrate their activities with a security system to render the system functionally inoperable. Disruption leading to disuse is a usually much easier and cheaper tactic. Frequent false results quickly undermine the confidence of users in any security system—witness the apathy of those in earshot when a car alarm sounds. Despite these cautions, fingerprinting techniques represent an excellent avenue for further development. Their inherent robustness and randomness make them potentially very useful. In the short term, fingerprinting is likely to be a secondary tracking tool, perhaps with 2D codes as the primary data carrier. In this role, they can perform an excellent backup function. The relatively low implementation costs and low marginal cost per item make fingerprint technologies attractive for some brand owners who wish to supplement compliance-driven serialization with proprietary tracking information.

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PHYSICAL AUTHENTICATION + DIGITAL TRACKING = ENHANCED SECURITY

As with all digital systems, the value of data output from a drug tracking system is proportional to the quality of data input. It is therefore vitally important to ensure that only authentic data can be entered into a track and trace system. High levels of data security are required, and there are many established secure data storage mechanisms and vendors available. Drug tracking data are both potentially sensitive (especially if it includes patient identifying data) and highly valuable. The ability to edit and retrieve data must also be carefully controlled and any activity within the system monitored. A criminal hacker or fraudulent insider able successfully to penetrate a drug tracking system could duplicate, erase, or alter records and would have the means to insert untold quantities of fake product into the legitimate supply chain. All of these counterfeit products would be identified as genuine in subsequent checks, in the absence of other authentication methods. Whatever is the format of tracking system used, whether for compliance with government mandates or for brand owner security purposes, the digital systems must be backed up with physical security. As discussed in Part II, authentication of the people using the tracking system, and of the products flowing through it, is a critical component of the overall security and should not be neglected in the drive for systems implementation.

Chapter

31

Management of Packaging Hierarchy As already noted, the currently proposed drug-tracking systems have a high impact on existing logistics processes and budgets. RFID, although potentially allowing full automation, is not yet fully reliable or costeffective enough at item level. The main alternative strategy—using 2D codes—also has its potential showstoppers. Unpacking and repacking shipping containers at each trans-shipment or warehousing point right down to unit packs so that item-level 2D codes can be recorded is both time consuming and error prone. In reality, it is usually not a practical proposition even for small consignments and is totally impossible in very high-throughput environments, such as those of major distributors. The search for ways around this limitation has led to two possible solution types.

INFERENCE APPROACHES

The concept of “inference” is quite simple: code and electronically link every level of the packaging hierarchy and do not read item level codes unless there is no alternative. In an inference system, all individual items are first coded on the production line in the normal way and then sent for packing into shipping boxes and finally pallets. The codes of all the unit Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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packs going into a specific shipping carton are recorded at the time it is packed; then, a secondary code is affixed onto that outer container and associated in a database with those unit pack codes. This can be repeated at higher packing levels (e.g., pallets) to give several layers of nested codes. Thus, when the outermost code is subsequently scanned (and assuming the container has not been opened or its contents altered), it is possible to infer the codes of the individual unit codes contained within it (without the need to scan them individually) by reference to the database. When a transaction is recorded for an outer carton, the records for all of the constituent units packaged within the box will be automatically updated without further scanning. This hierarchy approach (sometimes known as a “parent–child relationship”) has been used in industries such as tobacco, where the product is shipped in bulk and then broken down in stages into several packaging layers but different products are not usually mixed (Figure 31.1).1 The inference approach is a pragmatic tactic, which partially addresses the problem of unpacking and repacking in pedigree systems, but is not a full solution to pharmaceutical track and trace issues with 2D codes. Unit items or shipping cartons containing a small number of items are often unpacked from larger consignments and repacked several times during their progress through the supply chain. The pharmaceutical supply chain is also unusual in that multiple products, from different manufacturers, are made up into mixed shipments, for example. This is the basis of overnight delivery systems in the major distributors (Figure 31.2). After analyzing many distribution systems and receiving extensive input from its stakeholders, GS1 has identified the following core processes in pharmaceutical forward logistics (the shipment of product from manufacturer to patient). I have expanded and adapted the terms for clarity and to explain the actions relating to the coded products. Not all of these steps will apply in the United States or in all situations, but in other scenarios, the requirement may be yet more complex. See www.gs1.org for more information on the logistics simulation process. Manufacturer Processes • Label product: apply and record the primary codes on each unit pack. • Build and label case: check and record unit codes, pack units into cases, apply and record secondary codes at case level, and associate secondary codes with unit pack codes contained within. • Build mixed pallet: check and record case codes, pack cases onto pallet, apply and record tertiary code at pallet level, and associate with case codes and unit pack codes contained within. • Inventory a pallet: assign all codes on and within the pallet to inventory and record transaction.

INFERENCE APPROACHES

1

259

2

3

Database

4

Distribution ?

Figure 31.1. Inference. This simplified diagram shows the recording of unit pack codes (1) and their association with subsequent codes on higher level packaging (2). During distribution (3), only the outer code is read, but the database record for all the contained codes is also automatically updated. Assuming the higher level packs are not repacked during transit, it should be possible to monitor the location of any required unit pack by tracking the outer codes only (4).

• Pick pallet from inventory: assign all codes associated with the pallet

as leaving inventory. • Ship pallet to warehouse or inventory area: record transaction details for all codes associated with the pallet. Wholesaler Processes • Inspect shipment: check pallet identity. • Receive shipment: check if pallet contents match EPCIS data transmitted from manufacturer and correlate with documentation such as purchase order. • Inventory shipment: record transaction for all associated codes.

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2

1

3

4

?

5

Figure 31.2. Complexity of Distribution and Effect on Inference. Distributors receive bulk consignments from multiple manufacturers or from other distributors and split these down into inventory. When orders are fulfilled, packs are picked from multiple manufacturers and combined into the customer order. Great care is needed if inference is the basis of pedigree data—dissociation of outer and unit-level codes can easily cause loss of inference capability, which means loss of pedigree for the affected unit packs.

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• Move to forward logistics site: record transaction for all associated

codes. • Break down pallets and cases and move into inventory: record transaction for all associated codes. • Pick inventory: record which codes are taken from inventory. • Build and label totes: check and record which codes enter the tote, label tote with a secondary code, associate secondary code with individual codes within. Pharmacy Processes • Inspect shipment: check tote identity. • Receive tote: check if codes and contents match expected consign• • • •

ment. Break down tote and move into inventory: record transaction for individual codes or case codes. Pick product from inventory: record codes taken from inventory. Dispense product: record codes dispensed. Deliver product to customer/patient: apply traceable label to allow patient bottle to be associated with bulk bottle received to inventory (not necessary for unit-dose packaging, which already has a code from the manufacturer); in reimbursement systems, it may be necessary to associate the patient’s identity with the drug code.

Even this highly simplified process highlights the number of steps involved and the various manipulations that each piece of data must undergo. Unless the corresponding code hierarchies and data records are very carefully maintained and updated during the distribution of the bulk product, the inference approach has scope for much complexity, confusion, and error. This leads to a further complication relating to legal compliance and corporate liability. If and when unit-level pedigrees become mandatory, whether in a Californian system or US Federal system or elsewhere, systems will need to be foolproof. The fact that an upstream stakeholder made an error may not be a permissible defense for the owner of a consignment if the product does not have a full pedigree when checked by a law enforcement official. Rigorous process standards and very high levels of trust, as well as the agreement of corporate insurers, are needed between supply chain actors if inference is to be a successful approach in simplifying the tracking process.2 Apart from the obvious costs to supply chain stakeholders (since product without pedigree could be unsellable and therefore effectively worthless), a high level of false data in a tracking

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system could lead to reduced user acceptance and eventual disuse, therefore giving an opportunity for counterfeits to enter the supply chain. The inference of “parent–child relationships” between levels in the packaging hierarchy may be a usable solution that enhances efficiency and simplifies the tracking process for large quantities of product in transit. However, in the real-world distribution environment, a product may not stay in its original shipping container all the way through the supply chain. During repackaging, the original outer carton may be discarded or replaced. Several different products, perhaps even from different manufacturers, may be repacked into a new container. With each repackaging step, the potential for error increases, so the accurate management of parent–child relationships in the coding of shipping boxes is a very complex problem. ‘‘BOOKEND’’ APPROACHES

The legitimate parallel trade of drugs in the European Union is a good example of the potential complications faced by a drug tracking system. Reliance on secondary inference information from codes on packing cases rather than primary information from each unit code creates complexity and is a potentially major vulnerability when repackaging is the norm and not the exception. The search for alternative, pragmatic, workable but robust tracking solutions has led some to propose the so-called “bookend” approach. This was the model used by the EFPIA in their Swedish pilot project3 of 2009–2010. See Chapter 32 for a fuller discussion of this project. The bookend scheme is so-called because the key supporting elements of the tracking system are at either end of the drug manufacturing and distribution process, in the same way that a pair of bookends supports the volumes on a shelf. This concept involves recording data at the two points where unit pack codes can be most easily read, namely, during code application at the point of manufacture and at the point of dispensing from pharmacist to patient. In a pure bookend system, all intermediate transactions are ignored. Each unit of product is coded during or immediately after production with a unique number, which may in principle be encoded as a 1D (linear) bar code, as a 2D matrix code, or on an RFID tag or other data carrier. At this point, the information is uploaded on to a central database and stored. The product is then shipped and distributed in the normal way. The coded information is not read or updated at the intermediate points in the supply chain, and the database is not queried or modified with any transaction information. Once the product is finally received at the pharmacy, the code is read and verified by the pharmacist using the appropriate

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Manufacturer

Database

Starma

R

Ingesta 50 mg 30 capsules

Starma

Figure 31.3. Bookend Systems. The manufacturer uploads information to a database when packs are coded during production. These codes are unchecked during distribution until they reach the pharmacy. The pharmacist checks the code against the database record before dispensing the drug to the patient.

reader. Depending on the pre-existing equipment, pharmacies may need to be equipped with an appropriate reader during project implementation. The coded information on the pack is checked against the original stored information in the central database, usually in real time via a secure internet connection, and a pass/fail message is received by the pharmacist. Note that the system is entirely blind to the intermediate transactions, of which there may be many more than are shown in Figure 31.3 but none of which are recorded in the database. The bookend scheme, although it is imperfect and involves major compromises, is probably the most practical option we have available today for implementing a worldwide drug-tracking scheme without fundamentally changing the distribution processes for medicines. Its main benefit is that it uses available technology and existing business methods and can be implemented in a relatively short time span. It also places verification tools in the hands of the last professional interface between the drug industry and the patient, namely, the pharmacist. The other advantage of this system is its scalability—it can be expanded in future to include other levels in the supply chain, such as distributors.

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Those countries considering the adoption of a drug-tracking scheme based on the bookend design should also be aware of its possible limitations. One of the potential problems arises from the fact that criminals are opportunistic and quick to exploit inefficiencies or delays in supply. If the codes on a legitimate consignment of product are illegally duplicated during its journey through the supply chain, and those duplicated codes are applied to counterfeit product, then the two products become effectively indistinguishable in a bookend system. Criminals have a much shorter supply chain than legitimate suppliers and may be able to get their fake coded product to a pharmacy before the original. Whichever code reaches the pharmacy first will be checked against the database and will be verified as a genuine product. The second copy of the same code will not be accepted by the system, which will send an alert to the pharmacist, manufacturer, and regulator about possible fake product (Figure 31.4). In the absence of any other authentication technologies, bookend systems could provide an initial false sense of security but eventually lead to confusion. This is an unlikely scenario, and difficult for criminals to pull off without insider collusion, but we should remain vigilant. I need to reinforce my recurring theme one more time: to defeat pharmaceutical crime we need to think like criminals as well as like scientists and engineers. Whether this remains a theoretical risk to bookend systems or eventually becomes a problem, only time will tell. At the moment, the available data on the bookend approach stem from controlled trials in small geographical areas and with relatively limited inventory. There are legitimate arguments to suggest that serialization in the bookend mode, although not guaranteed to stamp out all counterfeiting, totally disrupts the business model of organized criminals by making it difficult to infiltrate large volumes of illicit pharmaceutical products into the supply chain unnoticed. Only small, opportunistic incidents will slip through the net. However, it is important to remember that, in order to break a system, the criminal does not have to integrate his activities into it. He merely has to decrease the confidence of the users in the output of the system so that it becomes an unreliable burden to the pharmacist rather than an invaluable tool. User resistance will then accomplish the rest of the task. The pharmaceutical supply chain is sufficiently unwieldy and (even in the bookend scenario) unmonitored that we should not assume that bookend systems will solve security issues by themselves. One of the ways around this problem is to ensure that drugs are protected with robust non-digital security measures as well as serialization. Drug tracking is potentially expensive, requiring millions of dollars in capital outlay and with significant recurring costs. Some corporations may

‘‘BOOKEND’’ APPROACHES

Manufacturer

265

Counterfeiter

Data theft, code duplication [

[

Database

Figure 31.4. Bookend System: Need for Caution. The legitimate supply chain (left) is sometimes slower than the opportunistic criminal (right). If genuine codes can be obtained and placed on the fake product, and if that product can be inserted into the legitimate supply chain, a potential vulnerability arises. If the counterfeit reaches the pharmacy before the genuine manufacturer’s product, the pharmacist may unknowingly validate it (since it has a valid code recognized by the database) and dispense fake product to the patient. When the real product is subsequently checked, perhaps at another pharmacy, it will be flagged as a potential counterfeit because the code it bears has already been dispensed on another pack.

be tempted to take a zero-sum approach to budget allocation between serialization initiatives and other authentication projects. That is, money spent on complying with the requirements of national serialization systems could be subtracted from existing product security budgets at the expense of non-digital authentication technologies. This may be shortsighted: authentication should not be neglected in the push for track and trace, or we may simply create new vulnerabilities.

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BATCH LEVEL TRACEABILITY VERSUS FULL SERIALIZATION

It has been argued by some that tracking every unit of product around the world is overkill and that most of the safety and commercial benefits of serialization could be achieved if the “resolution” of the tracking system was at the batch level rather than at the pack level. The French CIP 13 system,4 which is compulsory from January 1, 2011, on all pharmaceutical products marketed in France, uses batch level information, including a 13-digit alphanumeric code, encoded into an ECC200 matrix code. Batch level serial numbers provide some of the benefits of full unit-level serialization, with less complexity and reduced costs. Although the full benefits of track and trace may only be realized with unit-level codes, CIP 13 is based on standard 2D code formats and the printing and scanning equipment needed is therefore compatible with other likely serialization initiatives. Some companies have therefore used the CIP 13 deadline to become serialization-ready for other markets.5 DIGITAL SIGNATURES

Whatever the underlying tracking system, verification of the identity of stakeholders and the veracity of the information that they upload is a critical security component. In the case of pedigree systems, digital signatures will be required in order to prove compliance with legal obligations at each stage of the supply chain. These are not the same as the “digital signatures” produced by fingerprinting of surface features (Figure 30.1). They are produced with a set of algorithms that allow unambiguous verification of the sender of a piece of data. Crucially, they enable the concept of “non-repudiation”— critical for pedigree. Non-repudiation means that the receiver has “proof of postage”: the sender cannot subsequently deny the sending of the data. The pedigree concept relies totally on upstream stakeholders compiling and passing on accurate information. Digital signatures can help establish what went wrong (and who was to blame) in the event of a problem. The existing standards for digital signatures are well established in the United States.6 For the non-pedigree systems being piloted in Europe and elsewhere, these issues are still important and prudent data security precautions have been taken. SUPPLY CHAIN BENEFITS

Whatever the name tag—serialization, pedigree, track and trace, and so on—a pharmaceutical tracking system brings more than security and

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safety benefits. There are major advantages to other business processes as well, and these may be easier to quantify. As noted above, standardization of data transfer is a critical issue if all of the potential benefits of drug tracking are to be realized. If all data are open standard and all systems are interoperable (i.e., data sharing between systems is independent of hardware and software), tracking data enables supply chain stakeholders to do the following (adapted from the GS1 Healthcare website7 ). • Comply with regulatory requirements on recalls and manage the pro• • • • •

cess more efficiently and cheaply Reduce business risks above and beyond legal compliance Ensure efficient logistics and quality management Provide information to end users and trading or traceability partners Support patient safety and increase brand protection Implement product authentication and anti-counterfeiting policies

Therefore, the benefits and commercial opportunities of track and trace systems extend well beyond anti-counterfeiting. Although the detailed discussion of these additional benefits is not within the scope of this book, they should be clearly assessed and articulated when drawing up the business case for these systems. Many of the early attempts to demonstrate the return on investment for serialization were based predominantly on patient safety or on brand protection and anti-counterfeiting arguments. Patient safety should always be the prime motivation for a pharmaceutical corporation, but these arguments are notoriously hard to quantify. By establishing a fully rounded and business case, focused on commercial gains as well as safety, the quantifiable benefits become clearer. A major obstacle for global tracking systems is the wide range of environments in which the system must operate. Complex systems requiring sophisticated information technology are often not feasible in many of the countries where counterfeit drugs are the biggest threat. However, systems that are too simplistic are vulnerable to circumvention and criminal attack. Getting the right balance between cost, practicality, and functionality has proved problematic. The approaches taken by the legislators in different countries are discussed in Chapter 32.

Chapter

32

Geographical Perspectives

In the preceding chapters, we have looked at the theoretical aspects and practical implications of tracking drugs. The translation of that theory into reality has been a long and twisting path. The development of drugtracking systems has proceeded somewhat independently at various political levels around the world. Even within the United States, both state and federal legislation have taken turns to drive the agenda. To understand where we are today (late 2010) and where we might go tomorrow, we need to examine some of these state, federal, and international initiatives in more detail. U.S. STATE LAWS

Multiple U.S. states have seen a rising threat from fake drugs, and many of them have enacted or planned to enact drug pedigree legislation of various types. One of the early adopters was Florida,1 with a statute enacted in 2006, although it is now widely seen as a flawed and unwieldy system.2 The Florida law takes a paper-based approach and does not require package serial numbers (or indeed involve the manufacturer in any way). Since the Florida law and many of the other proposed state initiatives will likely be superseded by Federal legislation, I will only discuss one of the states in detail here. Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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California

California is the most valuable segment of the U.S. pharmaceutical trade—which in turn is the world’s largest and most profitable market. What happens in California therefore matters a lot—not only to businesses in California but also on a U.S. Federal level and internationally. The necessary law was enacted some years ago in 2004, but the struggle by the California Board of Pharmacy to enforce the California statute (SB 1307) on drug pedigree is a long-running story in the world of drug tracking and pharmaceutical security. According to the Board’s own submission3 in response to an FDA request for information in May 2008: The California pedigree law was first enacted in 2004, with an initial effective date of January 1, 2007, and then modified and extended in 2006 by additional legislation that pushed the effective date to January 1, 2009. Recently, the Board exercised authority delegated to it by the 2006 legislation to further extend the effective date for implementation of the pedigree requirements to January 1, 2011.

The attempt by the Californian legislature to impose a pedigree system, whereby all drug transactions from manufacturer to patient could be recorded and checked, was vigorously opposed by some industry stakeholders. Some of the objections related to feasibility, others were about timescale, and many focused on cost. The lobbying campaign against the implementation of the pedigree statute was sustained and well organized, and the implementation date has been gradually pushed out. In 2008, an amendment4 was proposed, the first part of which I include here (bolded text and strikeouts as per original): THE PEOPLE OF THE STATE OF CALIFORNIA DO ENACT AS FOLLOWS: SECTION 1. Section 4034 of the Business and Professions Code is amended to read: 4034. (a) ‘Pedigree’ means a record, in electronic form, containing information regarding each transaction resulting in a change of ownership of a given dangerous drug from the point it leaves the accredited distribution chain, from sale by a manufacturer, through acquisition and sale by one or more wholesalers, manufacturers, or pharmacies, until final sale to a pharmacy or other person furnishing, administering, or dispensing the dangerous drug. The pedigree shall be created and maintained in an interoperable electronic system, ensuring compatibility throughout all stages of distribution.

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Note the change of emphasis from full transaction recording in the original version, to limiting the need for pedigree only to those transactions outside the accredited supply chain. See also the removal of the need for full system compatibility and interoperability at all distribution stages. The history of pedigree legislation worldwide is littered with such amendments and insertions by special interest groups. The California law is not perfect, but it differs from the Florida statute in that it requires a fully electronic, item-level serialization system rather than paper-based records, and the pedigree obligation starts with the manufacturer—not the first wholesaler as in Florida. The California requirement has now been pushed out again to an implementation date of 2015–2017 and is therefore likely to be superseded by federal regulations from FDA, but the tenacity and commitment of the California Board of Pharmacy to implement the modified 2004 statute—despite the technical difficulties—has helped to galvanize many pharmaceutical companies, distributors, and pharmacy chains. California’s pedigree law is potentially a huge change to the business operations of manufacturers, wholesalers, and retailers.5 They are now confronting this change and starting to solve the supply chain issues surrounding pedigree and serialization.

FEDERAL INITIATIVES IN THE UNITED STATES

As the world’s most profitable pharmaceutical market place, and home to many of the “big pharma” corporations, the United States has always had a central position in international pharmaceutical policy. In particular, the Food and Drug Administration is seen as the primary global arbiter of quality in the assessment and regulation of new drugs and the control of their manufacturing quality. Therefore, although the incidence of fake drugs in the United States has historically been low compared to that seen in some developing countries, the pharmaceutical industry has looked to the FDA for guidance in the anti-counterfeiting area. The need for coordinated action is growing, as healthcare costs rise and as some U.S. consumers turn to the internet and other alternative supply channels in search of cheaper medicines. The FDA has been involved in developing anti-counterfeiting strategies for pharmaceuticals and medical devices for over 10 years, but the roots go back to 1988, when the Prescription Drug Marketing Act (PDMA) was enacted. PDMA introduced safeguards into the drug distribution system to provide assurances through paper records of the source and distribution history (pedigree) of a prescription drug. PDMA’s reliance on

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paper records was potentially costly, especially for small and mediumsized wholesalers, and paper records can be easily forged. At that time, PDMA did not envision the use of modern technologies to track or verify the authenticity of prescription drugs. The practical problems in implementing the pedigree provisions in PDMA have therefore meant that they have never been enforced. In 2003, the FDA set up a Counterfeit Drug Initiative to better identify the risks and threats from counterfeit drugs, to coordinate public and private efforts to fight counterfeiters, and to identify technologies and tools to aid in identifying, deterring, and combating counterfeiting. A new internal FDA Counterfeit Drug Task Force was asked to explore measures to be taken to prevent patients being exposed to counterfeit drugs. The Task Force was asked to investigate low-cost technologies that could be used to assure product and package integrity and to track legitimate products through the distribution chain. They were asked to recommend ways to educate consumers about counterfeit drug and to explore the effects of stiffer legal penalties for counterfeiting. At the time, for example, the jail sentence for counterfeiting a drug label could be up to 10 years, but for counterfeiting the actual drug it might only be 3 years. On September 27, 2007, President George W. Bush signed into law H.R. 3580, the Food and Drug Administration Amendments Act of 2007 (known as FDAAA). Section 913 of this legislation created section 505D of the Federal Food, Drug, and Cosmetic Act. Among other things, the new law required the FDA to develop or adopt a standard numerical identifier (SNI) structure, to facilitate a federal system for the tracking of prescription drugs, within 30 months from that date. The resulting FDA guideline was issued in draft form in January 2009 and confirmed in March 2010. The non-compulsory guidance6 addresses numbering at the package level, which the FDA defines as the “smallest saleable unit placed into interstate commerce by the manufacturer or the repackager for sale to the pharmacy or other dispenser of the drug product.” Other issues such as higher packaging levels, repackaging, track and trace, authentication, and validation are not included in the guidance. According to the guidance: The SNI for most prescription drug packages should be a serialized National Drug Code (sNDC). The sNDC is composed of the National Drug Code (NDC) (as set forth7 in 21 CFR Part 207) that reflects each corresponding manufacturer or repackager, combined with a unique 8-digit numerical serial number generated by the manufacturer or repackager for each individual package. An example is shown below with a 10-digit NDC.

EUROPE

National Drug Code (NDC) 55555 Labeler code +

273

Serial Number 666 Product code +

77 Package code +

11111111 Unique 8 digits

Expiration date and/or lot or batch number are not part of the sNDC because FDA regulations already require this information to be included on the label of each drug product. Manufacturers or repackagers may choose to include this information [in their numbering systems], provided that the resulting number still permits users to distinguish the sNDC. The sNDC is compatible with, and may be presented within, a GS1 serialized GTIN (sGTIN) format.

The FDA does not specify a particular means of incorporating the SNI onto the package but expects that it will generally be applied to each package in both human-readable and machine-readable forms. The location on the package where the SNI should be placed is not specified, but the FDA notes that it must not obstruct other legally required labeling. The legal process is always subject to rapid change or indeterminate delay due to political factors, so what follows should be viewed only as a snapshot of the types of legislation under consideration. Details may alter, but two further bills look likely, at the time of writing, to be pushed through or reintroduced8 to Congress. The FDA Globalization Act9 of 2009 (H.R. 759) deals largely with the risks of importation and the inspection of overseas manufacturing facilities. The second bill is an updated version of the Safeguarding America’s Pharmaceuticals Act of 2008. This legislation, if introduced and passed, would have superficially similar provisions to the California statute described above. It would require a federal electronic pedigree system with interoperable technologies and would mandate that the Standardized Numerical Identifier discussed above be used on all individual packages. The FDAAA simply instructs the FDA to define the characteristics of the SNI, which they have now done, but does not require companies to use it. One, both, or neither of these bills may eventually be signed into law, but if not, then it is likely that the themes that they include will reappear in subsequent proposals. EUROPE

The United States may be the world’s biggest pharmaceutical market by value, but it is arguably not the most complex. The European Union comprises 27 member countries with a total population of around 500 million people speaking 23 official languages. Parallel trade of pharmaceuticals

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between any two EU nations is entirely legal, and the European Union is effectively a single market, but not all members use the Euro as their currency. Most, but not all, of the European nations are members of the European Union (Switzerland is not, for example), so the European Union represents by far the majority of the European pharmaceutical market. The ease of internal trade and the porous geographical borders of the European Union to the east and south have made it vulnerable to an influx of fake drugs. At the time of writing (late 2010), the European Union is about to pass the Falsified Medicines Directive10 to amend existing directives to strengthen protection against counterfeit medicines. As currently envisaged (but like all legislative proposals, subject to amendment or cancellation), this initiative will require all prescription medicines sold in the European Union to have one or more of the following attributes, based on a risk assessment: 1. Covert, overt, and forensic features 2. Individually identified packs 3. Tamper-evident closure of packs. It is envisaged that lower risk products may only require tamper-evident closures, but higher risk products will require all three security elements. The directive will also prohibit the removing, replacing, or covering of safety features on packs by actors in the supply chain unless the repackager reapplies functionally equivalent safety features as on the original pack. This is a sensible move, as it ensures that equivalent security features are retained throughout the life of the pack. However, the detail may be harder to pin down. The guidelines for functional equivalence are not yet clear and will require very careful thought. The generally accepted data carrier for the identification of individual packs within a future European tracking system is the 2D matrix code based on the GS1 ECC 200 standard. The mandatory information to be carried will likely consist of the following four components: Product Code (GTIN): Unique Serial Number (randomized): Expiry Date: Batch Number:

14 digits Up to 20 alphanumeric characters 6 digits (YYMMDD) Up to 20 alphanumeric characters

The EU approach is highly controversial, particularly the potential ban on repackaging that affects the business model of many distributors. However, it is expected to come into force around 2013 and will have farreaching implications for all supply chain stakeholders from manufacturer to pharmacist. The current European framework of coding and serialization systems is complex and diverse, including the “bollino” system in

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Italy (a coupon-based reimbursement system) and various incompatible numbering systems. The exact technical provisions that eventually come into force may well be watered down from those described above, but any harmonized EU-wide approach is to be welcomed. THE CONCEPT OF ‘‘MEDICRIME’’

The ability to combat counterfeit drugs has been hampered in many countries by the lack of a clear criminal framework. In many cases, the same laws used to prosecute those selling unauthorized T-shirts must also be used to deal with those peddling potentially lethal counterfeit drugs. The evolution of the concept of pharmaceutical crime or “medicrime” is an attempt by the Council of Europe to address this shortcoming by framing clear and specific offenses in law, in the so-called Medicrime Convention11 . The draft Convention was published in late 2009 and seems likely to be ratified by the Council of Europe and eventually by individual member states. The Convention is careful to reference the other relevant work of the Council of Europe and others such as IMPACT. The Convention aims to strengthen Europe’s ability to combat counterfeiting and similar crimes involving threats to public health by introducing “new offences and penal sanctions relative to these offences.” The specific and incontrovertible criminalization of the acts of counterfeiting and knowingly supplying counterfeit drugs will be a big step in the enforcement of sanctions proportional to the seriousness of the crime. The Convention seeks to frame a “comprehensive international instrument which is centered on the aspects linked to prevention, protection of victims and criminal law in combating all forms of counterfeiting of medical products and similar crimes involving threats to public health”. In particular, the authors rightly note the pharmacist’s critical role in the framework of health security. The document provides some useful background on framing such legislation and on the definition of terms, so I have given it in some detail below. The following excerpts are adapted (and simplified for clarity) from the draft Convention and are not legally in force at the time of writing. EUROPEAN COMMITTEE ON CRIME PROBLEMS (CDPC)

Draft Council of Europe Convention on counterfeiting of medical products and similar crimes involving threats to public health, Strasbourg, 9 November, 2009

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Purpose

The purpose of the Convention is to prevent and combat threats to public health by • providing for the criminalization of certain acts • protecting the rights of victims of the offences established under the

Convention • promoting national and international cooperation In order to ensure effective implementation of its provisions by the Parties, the Convention sets up a specific monitoring mechanism. Scope

The Convention concerns medical products (whether or not they are protected under intellectual property rights or whether they are generic or not), including accessories designated to be used together with medical devices, as well as the active substances, excipients, parts, and materials designated to be used in the production of medical products. Definitions

For the purposes of the Convention • the term “medical product” shall mean medicinal products and med-

ical devices; • the term “medicinal product” shall mean medicines for human and veterinary use, which may be ◦ any substance or combination of substances presented as having properties for treating or preventing disease in humans or animals ◦ any substance or combination of substances which may be used in or administered to human beings or animals either with a view to restoring, correcting, or modifying physiological functions by exerting a pharmacological, immunological, or metabolic action, or to making a medical diagnosis ◦ an investigational medicinal product; • the term “active substance” shall mean any substance or mixture of substances that is designated to be used in the manufacture of a medicinal product and that, when used in the production of a medicinal product, becomes an active ingredient of the medicinal product;

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• the term “excipient” shall mean any substance that is not an active

•

•

•

•

•

substance or a finished medicinal product, but is part of the composition of a medicinal product for human or veterinary use and essential for the integrity of the finished product; the term “medical device” shall mean any instrument, apparatus, appliance, software, material, or other article, whether used alone or in combination, including the software, designated by its manufacturer to be used specifically for diagnostic and/or therapeutic purposes and necessary for its proper application, designated by the manufacturer to be used for human beings for the purpose of ◦ diagnosis, prevention, monitoring, treatment, or alleviation of disease ◦ diagnosis, monitoring, treatment, alleviation of, or compensation for an injury or handicap ◦ investigation, replacement, or modification of the anatomy or of a physiological process ◦ control of conception ◦ and which does not achieve its principal intended action in or on the human body by pharmacological, immunological, or metabolic means, but which may be assisted in its function by such means; the term “accessory” shall mean an article, which, while not being a medical device, is designated specifically by its manufacturer to be used together with a medical device to enable it to be used in accordance with the use of the medical device intended by the manufacturer of the medical device; the terms “parts” and “materials” shall mean all parts and materials constructed and designated to be used for medical devices and that are essential for the integrity thereof; the term “document” shall mean any document related to a medical product, an active substance, an excipient, a part, a material, or an accessory, including the packaging, labeling, instructions for use, certificate of origin, or any other certificate accompanying it, or otherwise directly associated with the manufacturing and/or distribution thereof; the term “manufacturing” shall mean ◦ as regards a medicinal product, any part of the process of producing the medicinal product, or an active substance or an excipient of such a product, or of bringing the medicinal product, active substance, or excipient to its final state

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◦

as regards a medical device, any part of the process of producing the medical device, as well as parts or materials of such a device, including designing the device, the parts or materials, or of bringing the medical device, the parts or materials to their final state ◦ as regards an accessory, any part of the process of producing the accessory, including designing the accessory, or of bringing the accessory to its final state; • the term “counterfeit” shall mean a false representation as regards identity and/or source; • the term “victim” shall mean any natural person suffering adverse physical or psychological effects as a result of having used a counterfeit medical product or a medical product manufactured, supplied, or placed on the market without authorization or without being in compliance with conformity requirements.

Manufacturing of Counterfeits • Each Party shall take the necessary legislative and other measures to

establish as offences under its domestic law, the intentional manufacturing of counterfeit medical products, active substances, excipients, parts, materials, and accessories • As regards medicinal products and, as appropriate, medical devices, active substances, and excipients, paragraph 1 shall also apply to any adulteration thereof • Each State or the European Union may at the time of signature or when depositing its instrument of ratification, acceptance, approval, or accession, by a declaration addressed to the Secretary General of the Council of Europe, declare that it reserves the right not to apply or to apply only in specific cases or conditions in paragraph 1, as regards excipients, parts, and materials, and in paragraph 2, as regards excipients

Supplying, Offering to Supply, and Trafficking in Counterfeits • Each Party shall take the necessary legislative and other measures to

establish as offences under its domestic law, when committed intentionally, the supplying or the offering to supply, including brokering, the trafficking, including keeping in stock, importing, and exporting of counterfeit medical products, active substances, excipients, parts, materials, and accessories.

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• Each State or the European Union may at the time of signature or

when depositing its instrument of ratification, acceptance, approval, or accession, by a declaration addressed to the Secretary General of the Council of Europe, declare that it reserves the right not to apply or to apply only in specific cases or conditions in paragraph 1, as regards excipients, parts, and materials. Falsification of Documents • Each Party shall take the necessary legislative and other measures

to establish as offences under its domestic law, the making of false documents or the act of tampering with documents, when committed intentionally • Each State or the European Union may at the time of signature or when depositing its instrument of ratification, acceptance, approval, or accession, by a declaration addressed to the Secretary General of the Council of Europe, declare that it reserves the right not to apply or to apply only in specific cases or conditions in paragraph 1, as regards documents related to excipients, parts and materials. Similar Crimes Involving Threats to Public Health • Each Party shall take the necessary legislative and other measures

to establish as offences under its domestic law, when committed intentionally ◦ the manufacturing, the keeping in stock for supply, importing, exporting, supplying, offering to supply, or placing on the market of medicinal products without authorization, where such authorization is required under the domestic law of the Party or medical devices without being in compliance with the conformity requirements, where such conformity is required under the domestic law of the Party ◦ the commercial use of original documents outside their intended use within the legal medical product supply chain, as specified by the domestic law of the Party. 



Aiding or Abetting and Attempt • Each Party shall take the necessary legislative and other measures to

establish as offences when committed intentionally, aiding or abetting

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the commission of any of the offences established in accordance with this Convention. • Each Party shall take the necessary legislative and other measures to establish as an offence an intentional attempt to commit any of the offences established in accordance with this Convention.

Jurisdiction • Each Party shall take the necessary legislative and other measures

•

•

•

•

•

to establish jurisdiction over any offence established in accordance with this Convention, when the offence is committed ◦ in its territory or ◦ on board a ship flying the flag of that Party or ◦ on board an aircraft registered under the laws of that Party or ◦ by one of its nationals or by a person habitually residing in its territory. Each Party shall take the necessary legislative and other measures to establish jurisdiction over any criminal offence established in accordance with this Convention, when the victim of the offence is one of its nationals or a person habitually resident in its territory. Each Party shall take the necessary legislative and other measures to establish jurisdiction over any offence established in accordance with this Convention, when the alleged offender is present in its territory and cannot be extradited to another Party because of his or her nationality. Each State or the European Union may, at the time of signature or when depositing its instrument of ratification, acceptance, approval, or accession, by a declaration addressed to the Secretary General of the Council of Europe, declare that it reserves the right not to apply or to apply only in specific cases or conditions the jurisdiction rules laid down in paragraph 1, sub-paragraph d, and paragraph 2 of this article. Where more than one Party claims jurisdiction over an alleged offence established in accordance with this Convention, the Parties concerned shall consult, where appropriate, with a view to determining the most appropriate jurisdiction for prosecution. Without prejudice to the general rules of international law, this Convention shall not exclude any criminal jurisdiction exercised by a Party in accordance with its domestic law.

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Corporate Liability • Each Party shall take the necessary legislative and other measures to

ensure that legal persons can be held liable for offences established in accordance with this Convention, when committed for their benefit by any natural person, acting either individually or as part of an organ of the legal person, who has a leading position within it based on ◦ a power of representation of the legal person; ◦ an authority to take decisions on behalf of the legal person; ◦ an authority to exercise control within the legal person. • Apart from the cases provided for in paragraph 1, each Party shall take the necessary legislative and other measures to ensure that a legal person can be held liable where the lack of supervision or control by a natural person referred to in paragraph 1 has made possible the commission of an offence established in accordance with this Convention for the benefit of that legal person by a natural person acting under its authority. • Subject to the legal principles of the Party, the liability of a legal person may be criminal, civil, or administrative. Such liability shall be without prejudice to the criminal liability of the natural persons who have committed the offence. Sanctions and Measures • Each Party shall take the necessary legislative and other measures

to ensure that the offences established in accordance with this Convention are punishable by effective, proportionate, and dissuasive sanctions, including criminal or non-criminal monetary sanctions, taking account of their seriousness. These sanctions shall include, for offences committed by natural persons, penalties involving deprivation of liberty that may give rise to extradition. • Each Party shall take the necessary legislative and other measures to ensure that legal persons held liable in accordance with Article 11 are subject to effective, proportionate, and dissuasive sanctions, including criminal or non-criminal monetary sanctions, and may include other measures such as ◦ temporary or permanent disqualification from exercising commercial activity; ◦ placing under judicial supervision; ◦ a judicial winding-up order.

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• Each Party shall take the necessary legislative and other measures to ◦

permit seizure and confiscation of medical products, active substances, excipients, parts, materials, and accessories as well as goods, documents, and other instrumentalities used to commit the offences established in accordance with this Convention or to facilitate their commission; proceeds of these offences, or property whose value corresponds to such proceeds. ◦ permit the destruction of confiscated medical products, active substances, excipients, parts, materials, and accessories that are the subject of an offence established under this Convention; ◦ take any other appropriate measures in response to an offence, in order to prevent future offences. 



Aggravating Circumstances • Each Party shall take the necessary legislative and other measures

to ensure that the following circumstances, in so far as they do not already form part of the constituent elements of the offence, may, in conformity with the relevant provisions of national law, be taken into consideration as aggravating circumstances in determining the sanctions in relation to the offences established in accordance with this Convention: ◦ the offence caused the death of, or damage to the physical or mental health of, the victim; ◦ the offence was committed by persons abusing the confidence placed in them in their capacity as professionals; ◦ the offence was committed by persons abusing the confidence placed in them as manufacturers as well as suppliers; ◦ the offences of supplying and offering to supply were committed having resort to means of large-scale distribution; ◦ the offence was committed in the framework of a criminal organization; ◦ the perpetrator has previously been convicted of offences of the same nature. Criminal Investigations • Each Party shall take the necessary measures to ensure that persons,

units, or services in charge of criminal investigations are specialized in the field of combating counterfeiting of medical products and

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similar crimes involving threats to public health or that persons are trained for this purpose, including financial investigations. Such units or services shall have adequate resources. • Each Party shall take the necessary legislative and other measures, in conformity with the principles of its domestic law, to ensure effective criminal investigation and prosecution of offences established in accordance with this Convention, allowing, where appropriate, for the possibility of carrying out financial investigations, of covert operations, controlled delivery, and other special investigative techniques. Cooperation and Information Exchange • Each Party shall take the necessary legislative and other measures

to ensure that representatives of health authorities, customs, police, and other competent authorities exchange information and cooperate in accordance with domestic law in order to prevent and combat effectively the counterfeiting of medical products and similar crimes involving threats to public health. • Each Party shall endeavor to ensure cooperation between its competent authorities and the commercial and industrial sectors as regards risk management of counterfeit medical products and similar crimes involving threats to public health. • With due respect for the requirements of the protection of personal data, each Party shall take the necessary legislative and other measures to set up or strengthen mechanisms for ◦ receiving and collecting information and data, including through contact points, at national or local levels and in collaboration with private sector and civil society, for the purpose of preventing and combating the counterfeiting of medical products and similar crimes involving threats to public health; ◦ making available the information and data obtained by the health authorities, customs, police, and other competent authorities for the cooperation between them. • Each Party shall take the necessary measures to ensure that persons, units, or services in charge of cooperation and information exchange are trained for this purpose. Such units or services shall have adequate resources. Measures for Prevention • Each Party shall take the necessary legislative and other measures to

establish the quality and safety requirements of medical products.

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• Each Party shall take the necessary legislative and other measures to

ensure the safe distribution of medical products. • With the aim of preventing counterfeiting of medical products, active substances, excipients, parts, materials, and accessories, each Party shall take the necessary measures to provide, inter alia, for ◦ training of healthcare professionals, providers, police, and customs authorities as well as relevant regulatory authorities; ◦ the promotion of awareness-raising campaigns addressed to the general public providing information about counterfeit medical products; ◦ the prevention of illegal supplying of counterfeit medical products, active substances, excipients, parts, materials and accessories. Measures for Protection • Each Party shall take the necessary legislative and other measures to

protect the rights and interests of victims, in particular by ◦ ensuring that victims have access to information relevant to their case and necessary for the protection of their health; ◦ assisting victims in their physical, psychological, and social recovery; ◦ providing, in its domestic law, for the right of victims to compensation from the perpetrators. International Cooperation • The Parties shall cooperate with each other, in accordance with the

provisions of this Convention and in pursuance of relevant applicable international and regional instruments and arrangements agreed on the basis of uniform or reciprocal legislation and their domestic law, to the widest extent possible, for the purpose of investigations or proceedings concerning the offences established in accordance with this Convention, including seizure and confiscation. • The Parties shall, without prejudice to their internal reporting systems, designate a national contact point, which shall be responsible for transmitting and receiving requests for information and/or cooperation in connection with the fight against counterfeiting of medical products and similar crimes involving threats to public health. Monitoring Mechanism • The Committee of the Parties shall be composed of representatives

of the Parties to the Convention.

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• The Committee of the Parties shall be convened by the Secretary

General of the Council of Europe. Its first meeting shall be held within a period of one year following the entry into force of this Convention for the tenth signatory having ratified it. It shall subsequently meet whenever at least one-third of the Parties or the Secretary General so requests. • The Parliamentary Assembly of the Council of Europe, the European Directorate for the Quality of Medicines and Healthcare (EDQM), the European Committee on Crime Problems (CDPC), as well as other relevant Council of Europe intergovernmental committees, shall each appoint a representative to the Committee of the Parties in order to contribute to a multisectoral and multidisciplinary approach. Many of the legal and technical areas covered by this comprehensive document would serve as useful templates for other nations seeking to criminalize the production, distribution, and sale of counterfeit pharmaceuticals and medical products. In particular, the acknowledgment that this is a problem that needs international, multidisciplinary, and multisectoral approaches is critical. The Medicrime Convention (assuming that it is eventually approved by the European Parliament) will not solve all of the issues of pharmaceutical crime overnight, but it will provide a stronger and more uniform legal framework within which other product protection initiatives are likely to be more successful.

EFPIA PILOT CODING PROJECT

The European Federation of Pharmaceutical Industries and Associations (EFPIA) is the trade body for the pharmaceutical industry in Europe. The organization has long been active in highlighting and combating counterfeit medicines and in lobbying state governments and the European Union to strengthen legal countermeasures. In September 2009, in collaboration with the Swedish pharmaceutical retail chain, Apoteket AB, and several technology partners, EFPIA launched a pilot project to test a pharmacybased verification system using 2D codes.12 The pilot ran for four months in 25 large pharmacies in the greater Stockholm area with a total of 180 dispensing points and more than 200 pharmacists. EFPIA’s approach is a classic “bookend” system (as described in the previous chapter). More than 95,000 specially coded packs from 14 pharmaceutical companies were placed into inventory at the test pharmacies. The items were scanned and verified before they were dispensed to the patients. To simulate future operational systems, the pilot verification system was designed to be fully

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integrated into normal pharmacy workflow. By scanning the data matrix code with a 2D code reader, linked to a central database over a broadband internet connection, the pharmacists were also able automatically to detect the product expiry date and the batch number. Deliberate errors, miscoding, recalls, and suspicious events such as test attacks were introduced to test the system’s ability to detect these in a normal working environment. The cost of the pilot system was not disclosed. The results of the pilot project showed that such a 2D code system allows effective identification of fake packs as well as expired or shortdated packs and recalled products. The metrics for system availability (uptime) and performance (response time) were as specified and allowed pharmacists to work at a normal pace and without significant additional effort. The system was reported to be easy to use when fully integrated into the pharmacy workflow, leading to very high user acceptance. Other interesting findings of the project relate to user acceptance issues highlighted by interviews with the participants in the pilot. EFPIA’s report recommends that to achieve sustained credibility, such tracking systems must provide the correct answer to all transaction requests (i.e., have a low rate of false positives and false negatives). The report also notes that integration of the system with existing pharmacy workflow as well as local conditions and regulatory requirements is critical. Finally, and importantly from a practical viewpoint, the study found that the presence of more than one code on the pack caused confusion for the user and had the potential to jeopardize user acceptance. Even in such a controlled environment, there were small issues that could “cause severe damage to the overall system in the long run as it can cause the user not to trust the system response and thus render the whole system useless.” From a technical and security perspective, the pilot demonstrated that data segregation and privacy issues could be successfully addressed. For example, it is important that data are available only to those who need to see it and that patient privacy or commercial confidentiality is not compromised. The report’s authors are also confident that the security of the system was maintained against the deliberate test attacks. The EFPIA pilot, even though it involved pharmaceutical corporations who compete commercially, was based on cooperation between these and other stakeholders. In EFPIA’s view, such voluntary collaboration is not scalable. A defined legislative framework is required to enable a largescale system, one based on voluntary participation may not be used everywhere and could allow the introduction of illicit products onto the market via the weakest point. The scale-up of this pilot project across the European Union will be challenging. By EFPIA’s own admission, the technical environment of the project was not typical of the wider EU context. The

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healthcare system in Sweden is very modern—approximately 80% of prescriptions are electronic. The same point-of-sale system is installed in all pharmacies and has links to other systems for real-time reimbursement management and automatic product ordering. The Swedish pharmacies all had an existing broadband data network connection and established workflows involving regular scanning of bar codes during the dispense process, which enabled rapid integration of the EFPIA front-end application. The pharmacy environment across the rest of Europe is financially, culturally, and linguistically diverse and will present much greater challenges to an EU-wide system than were faced in Sweden. EFPIA believes that any future system should be harmonized across Europe, requiring all national coding systems to be interoperable with each other based on common standards. They note, however, that when implementing a full system, it will be necessary to run carefully monitored pilot projects in each market to identify and eliminate any flaws before the system is fully rolled out. A harmonized system across Europe would allow any pharmacist in any country to verify whether a pack with the same code has been dispensed before, independent of its country of origin. Accredited wholesalers could also have access to the database to check the status of the product at any time, either before sending a product to the pharmacists or upon return of the product by the pharmacists. The European Union represents a unique challenge with its combination of diverse national regulations and free trade environment, but the successful EFPIA project with its potentially scalable “bookend” architecture shows what might be achieved with planning, investment, and cooperation.

INDIA

The Indian government has come under some criticism for its seemingly ambivalent attitude to IPR and its downplaying of the size of the problem of counterfeit and substandard drugs. As the draft of this book was being finalized, reports emerged13 that the Indian government was planning to implement a 2D code system for exported pharmaceuticals. Designed to address what the Indian government called the “controversies and blownup apprehensions about the export of spurious drugs from India’” the 2D code technology will apparently be compulsory for all exports of pharmaceutical products from the country. The Indian Commerce Secretary has accepted the recommendations of the Pharmaceuticals Export Promotion Council (“Pharmexcil”), which had been asked to identify suitable new technologies to eliminate the counterfeit drugs problem “repeatedly

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highlighted by the foreign media.” The consultant appointed by Pharmexcil suggested three technologies: “barcoding, digital mass serialisation (DMS)/unique number, and hologram technologies.” The Commerce Ministry apparently felt that the hologram was too widely available and insufficiently secure and therefore opted for a combination of bar coding and serialization. The ministry plans to issue a public notice in 2011 then to make coding compulsory for all exports of pharmaceutical products in the first phase. The use of serialization will apparently be introduced later. The Indian pharmaceutical industry has asked for at least a one-year transition period before implementation.

MALAYSIA MEDITAG™ SYSTEM

Malaysia is an Asian country of 27 million people with relatively prosperous economy and high life expectancy according to United Nations statistics.14 Faced with an increasing threat from counterfeit drugs, the government developed a multi-tiered strategy to combat them. The starting point was a strong political will to do something about the issue. Sound legal foundations already existed, and these were strengthened with new and revised laws where necessary. Malaysia has a reputable drug regulatory system for registration, licensing, surveillance, testing, adverse drug reaction monitoring, and information dispersal. There is an established enforcement system for inspection of factories and warehouses, investigation of incidents, prosecution of suspected counterfeiters, and confiscation of fake drugs. Importantly, there is also a good network for consumer education. The anti-counterfeiting initiative used all of these existing frameworks and also involved collaboration and networking with national and international industry organizations, consumer groups, and professional bodies. The final part of the strategy was to implement a technological approach to protect legitimate drugs. The government mandated, as a Directive under Regulation 8(1) of the Control of Drugs and Cosmetic Regulations 1984, that a security label with defined safety features should be placed on all drug packs. The project was rolled out in two phases to include first non-parenteral products and then parenteral/injectable products. Over-the-counter products, external personal care products, vaccines, and biologicals were exempted from the scheme. The technology chosen was an adhesive security label. After an open tender process, the label eventually chosen and developed was named Meditag™ and is supplied exclusively by a local company, Mediharta Sdn Bhd, using the technology developed by Hologram Industries SA of France. It is a holographic, self-adhesive label that can be easily attached on the outer packaging.

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Only government-licensed, GMP-compliant manufacturers and importers are allowed to purchase the labels. They are sold in roll and sheet form at a (2010) price per label of RM 0.068 (around 1.8¢) plus delivery.15 The current Meditag™ has been updated from the one introduced in 2005 and also contains other security features. Each label has a unique serial number to help authenticate and trace pharmaceutical products in the marketplace. The various features allow different levels of authentication for consumers and enforcement teams to verify the product’s authenticity. Active consumer education has focused on reducing the demand for, and tolerance of, counterfeits through public awareness talks, exhibitions, pamphlets, press release, media coverage during enforcement operations, and so on. An important aspect of the Malaysian strategy is a strategic approach to the counterfeiting problem as a whole, focusing on demand reduction as well as controlling the supply of counterfeits. An integrated National Task Force to fight illicit drugs is headed by the Enforcement Division of the Ministry of Domestic Trade and Consumer Affairs and includes the Royal Malaysian Police, Royal Malaysian Customs, the Immigration Department, Pharmacy Enforcement teams, Ministry of Health, and so on. The Malaysian strategy is not reliant on a technological “fix” but uses many of the existing state resources and augments them with the necessary enforcement tools. It provides a potentially useful model for similar countries to follow. TURKEY

Turkey is a large and geographically diverse country at the gateway between Europe and Asia. It has a population of around 78 million.16 The country has a social healthcare system that has seen its costs skyrocket. Some of this has been due to the fact that the system for distributing prescription drugs to patients has been heavily defrauded by “repeat reimbursement” scams. A lack of effective safeguards, on who was paid for what and when, meant that the state was often paying for the same medicine several times as the same pack or prescription was “recycled,” or non-existent drugs were being reimbursed. It was also possible, although technically illegal, to obtain drugs without a prescription. The fraud problem was estimated to cost the state around $150 million a year.17 The Turkish government decided to implement a drug-tracking scheme,18 known as ITS (˙Ilac¸ Takip Sistemi) to combat the reimbursement fraud issue. Securing the public against counterfeit, substandard, and diverted medicines was an additional stated goal. The system was designed to track prescription drugs, over-the-counter medicines, and dietary supplements from production or importation through to dispensing, using

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2D bar codes in a GS1-compliant format. It was originally scheduled to become operational at the start of 2009, but this was postponed and is being implemented at the time of writing in 2010. Unusually, the Turkish regulations as formulated required the tracking of all pack levels, including pallets and shipping boxes as well as unit-level packs. Data are to be uploaded and stored on a centralized database managed by the Turkish Ministry of Health. The pharmaceutical tracking system is entirely separate from the previously installed alcohol and cigarette tracking system (see Chapter 33). The system works in a similar way to the EFPIA pilot discussed above. At the time of dispensing, the pharmacist checks the database online by scanning the pack code with a handheld reader. If the code has been dispensed before, or if the product is known to be stolen, expired, or recalled, this will be identified before dispensing. The additional requirement to track multiple levels in the packaging hierarchy caused delays in implementation and resistance from manufacturers and distributors as the complex nature of this issue became clear. Opposition also came from pharmacies, which had to buy the scanners needed for the system at a cost of around $150 per device. The pharmacy opposition may also stem from the disruption of previous practices. There was known to be a widespread and unrecorded barter system for prescription drugs between pharmacies before the implementation of ITS.17 The benefits of ITS have yet to be quantified, but an investigation by researcher Roger Bate uncovered local claims of an implementation cost exceeding $200 million.19 Despite the problems in its implementation, the ITS has had the same effect in Europe that the California legislation had in the United States. It has catalyzed action and forced all members of the supply chain to address, and start to solve, the complex issues around drug tracking.

BRAZIL

Brazil is fast emerging as a world player in many industries, including pharmaceuticals. It has had a problem with pharmaceutical crime including counterfeiting and cargo theft. To counter this, the government introduced legislation in 2009 (Act Number 11.903) to control the distribution of pharmaceuticals. This Act has a proposed implementation date of January 2011 (although this date is likely to be put back) and requires “data capturing, storing, and electronic transmission technology.” The proposed system specification is unknown at the time of writing, but it looks likely that it will be GS1 compatible.20

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Product Tracking in Other Industries The problems of counterfeiting, smuggling, theft, and diversion are, of course, not linked exclusively to pharmaceuticals. Any class of commodity that can be copied, diverted or stolen, and distributed at a profit is now vulnerable.1 The control of this trade by organized crime2 has led to the development of tracking systems in other industries to try to prevent or at least control counterfeiting and illicit trade. Some of these are described in brief below to illuminate themes that are also common to pharmaceutical crime.

EXCISE PRODUCTS: TOBACCO AND ALCOHOL

In many countries, prescription medicines are zero rated for tax. However, the taxation of pharmaceutical products (usually at retail level in the form of a General Sales Tax or Value Added Tax) is not uncommon worldwide. The tax is not usually at a level that becomes a major driver of pharmaceutical crime or smuggling. Alcohol and tobacco, on the other hand, are almost always heavily taxed around the world. Governments rely on the revenue that they collect from these sources. The serialization and tracking of heavily taxed products such as alcohol and tobacco therefore Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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has very different motives from those involved for tracking pharmaceuticals. There is certainly a consumer safety benefit in preventing counterfeit tobacco and alcohol from reaching the public. Fake alcohol, in particular, kills thousands every year.3 Fake tobacco may also contain higher levels of toxic impurities, although since even legal tobacco has long-term deleterious health effects, the effect of this is harder to prove. Generally, however, the key economic driver for alcohol and tobacco control systems is the efficient collection of excise duty. This makes track and trace systems easier to sell for tobacco and alcohol than for pharmaceuticals. In government terms, money talks, and so the purely financial return-oninvestment for tracking tobacco and alcohol is easier to articulate than for items such as medicines, which are usually low tax or zero rated. It is not surprising, therefore, that some of the pioneering track and trace systems have been in the tobacco and alcohol sector. Countries such as Turkey, Malaysia, and Brazil and US states such as California and Massachusetts have been leading the way. For example, in 2006 (well before the pharmaceutical ITS system was proposed), the Turkish Ministry of Finance sought proposals for a nationwide product tracking system for locally manufactured and imported tobacco, alcohol, and beer products. The government’s stated threefold objective was to introduce improved enforcement measures to prevent tax evasion, reduce unfair competition against local manufacturers arising from illicit trade, and provide additional protection to consumers. A Turkish–Swiss joint venture, SICPA-Assan, was chosen as the technology provider to install and maintain the new system,4 which included security inks, hardware, and software. Turkey was the first country in the world to implement a singletechnology framework to monitor securely all excisable tobacco, alcohol, and beer products nationwide. According to the government’s own figures, over seven billion items are protected per year. Tobacco companies have also developed their own tracking systems, often in response to anti-fraud initiatives.5 The adoption of the WHO Framework Convention on Tobacco Control (ratified by over 170 countries to date)6 may eventually increase the uptake of such systems worldwide. However, although the technology has been proved, these projects are still often controversial and politically sensitive—usually because the cost of the tax stamp or marking system is passed on to the consumer in the form of price rises. FOOD AND BEVERAGE

The rationale for track and trace in tobacco and alcohol is revenue enhancement, whereas for lower tax products (the majority of ingestibles),

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the driver is consumer safety. The ability to track food and drink is highly beneficial in the event of contamination events, suspected adulteration, or other health scares. Counterfeiting is not yet such a high-profile issue in food as it is in pharmaceuticals, probably because of the lower profit margins, bulkier nature, and shorter shelf life of fresh food. In North America, the Produce Traceability Initiative,7 sponsored by several fresh produce trade bodies, aims to develop a standardized industrial approach to enhance the speed and efficiency of traceability systems. The group’s vision is to achieve electronic traceability for every case of produce by 2012. Existing commercial solutions such as the HarvestMark® in the United States already protect over a billion items per year.8 President Obama set up the Food Safety Working Group9 in 2009, which is charged with examining options to improve food safety and traceability. The key traceability issue for many areas of the food industry is cost. Some products such as fine wines and specialty items such as caviar can command very high prices because they are only available in low volumes. These categories are vulnerable to a version of the “uplabeling” problem seen in pharmaceuticals, where a fake premium label is placed on a similar-looking but inferior and lower cost version of the product. In these cases, it may be financially imperative for the owner of a premium brand to invest in appropriate product protection technologies. However, for many items that are not luxuries but daily commodities, such as milk, the situation may be quite different. The number of unit packs in circulation is often huge, and the profit margins for most of the stakeholders in the supply chain, especially the producers who would have to apply the traceability information, are usually small. Any practical solution for these industries must therefore be very cheap and must be capable of use on very high speed production lines. So far, a single technology has not emerged to address these issues, and so the uptake of traceability in the food and beverage industry is patchy.

TOYS

Although toys are not ingestible products, small children do their best to chew anything and therefore are in potential danger from shoddily made toys. In addition to physical hazards from sharp edges and small, loose components, there are chemical hazards from paint and other components. In recent years, the drive to reduce costs has led many toy companies to outsource production, often to distant countries. Despite oversight procedures, there has been an inevitable loss of control. Safety issues and major product recalls in the toy industry10 have put consumers at risk and have

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cost brand owners tens of millions of dollars. These events have also led to an increased legal requirement for traceability. For example, the European Union implemented traceability requirements in its 2009 Toy Safety Directive.11 These state that Every manufacturer must ensure that their toy can be identified. This can be done by using a type, batch, serial/model number or other element allowing the toy to be identified. The toy must also bear the manufacturer’s name, registered trade name/mark. A single contact point address for the manufacturer must also be provided. If the size or nature of the toy does not allow it to bear the identification element and the manufacturer’s information, the manufacturer must place the required information on the packaging or in a document accompanying the toy.

The European regulations do not specify the type of identifier or the technology to be used. In the United States, the requirement for a General Certification of Conformity, as part of the Consumer Product Safety Improvement Act,12 is the functional equivalent of a limited pedigree system, albeit at batch level rather than for each toy.

CONCLUSIONS

The challenges faced by the pharmaceutical industry in tracking and authenticating its products are not unique. Other industries are addressing the same issues, and although the cost environment and the motivation for each of these traceability projects may be different, there are many common factors. In looking for answers to the practical problems and engineering difficulties encountered in implementing a traceability program, pharmaceutical manufacturing engineers could benefit from some benchmarking among their counterparts in other fields.

Chapter

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Supply Chain Security Processes Many of the anti-counterfeiting and physical authentication approaches reviewed in this book require specialist technology or scientific analysis, either during application or during interpretation. The drug tracking systems discussed in this section also rely on finding technical solutions to difficult security and logistical issues. Technology is not the only approach to increasing drug security, although I would argue that it is an important component of an integrated product protection strategy. There are many benefits to be gained by examining simpler measures to increase supply chain security. Many of these can be found by monitoring and upgrading human interactions and work processes. These enhancements can often be part of ongoing continuous improvement processes and do not always require specific corporate initiatives.

GENERAL SECURITY

For brand owners and distribution partners, employee involvement and empowerment is critical to improving product security. By training staff involved in the quality, security, supply chain logistics, and manufacturing functions to think about counterfeit drugs as they go about their daily tasks, Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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it is possible to instill the culture of increased vigilance and continuous security improvement. Two mindsets need to be actively incentivized: • How could I make this process better and more secure?

Encourage all staff to look hard at what they do and how it could be made more robust, more cost-effective, and so on. Ask for suggestions. Reward good ideas. • How could a criminal subvert this process? Everyone should be a detective in their own environment. Just because a process is lean, elegant, and well-established it does not mean that it is secure. Do not encourage “experimental sabotage” or other unauthorized or dangerous activity, but ask all employees to think how an insider or outsider could penetrate the security of the product or the facility. The ideas and information that result from this initiative may need to be treated more discreetly than the standard process improvement suggestions discussed above, but there should still be recognition and reward. Given the involvement of insiders in some pharmaceutical crime, the more loopholes and vulnerabilities that the brand owner is aware of in their supply chain, the better their vigilance can be targeted.

FORWARD LOGISTICS

The transport of goods from manufacturer to consumer is known as forward logistics. This is the direction of most of the flow of goods through a logistics system and can involve many different transport systems and changes of ownership. One way to reduce the complexity of the pharmaceutical distribution system (and therefore to reduce the number of points at which security breaches can occur) is to shorten the chain from factory to patient by removing some or all of the intermediaries. Some corporations have taken measures to truncate their supply chains by supplying directly to pharmacies rather than through distributors or by selecting a small number of preferred wholesalers to handle all of their business. The logic is that the fewer hands a product passes through on its journey from factory to patient, the lower the risk of diverted or counterfeit products entering the supply chain. Other pharmaceutical companies are thought to be considering the selective use of this approach, although it may be impractical for very large markets, developing countries, or low-value products. Some distributors feel this direct-to-pharmacy process is a potential breach of fair competition. Manufacturing companies

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are also challenging the standard commercial processes by looking at “fee-for-service” distribution, whereby the distributor is paid to deliver the product but ownership of the product remains with the manufacturer. This is designed to offer tighter control of the supply chain by reducing the number of financial transactions involved and therefore limiting potential entry points for counterfeit, diverted, or stolen products.

REVERSE LOGISTICS: RETURNS AND CUSTOMER COMPLAINTS

Although forward logistics operations carry the majority of pharmaceutical goods in circulation, many of the most time-consuming, hard-to-integrate, and (per-unit) expensive issues are actually in “reverse logistics.” This is the process whereby goods are returned to the manufacturer, for whatever reason. Returns may be due to technical reasons such as overstocking, product expiry, recalls, and so on. Alternatively, individual items may be returned because of customer complaints. Many pharmaceutical companies see returns and complaints as primarily financial and quality issues. The customer is compensated, the product is destroyed, and the quality control issue is addressed as appropriate. All of these actions carry a direct cost to the business. However, the management and investigation of complaints and product returns is also an often neglected area of security management and is a great opportunity to find out what is going on out there in the market place. The function involves the product moving against the general flow of outward distribution, similar to salmon swimming upstream in a fast-moving river. Since it represents a small fraction of product movements, the returns process can be difficult to incorporate into inventory systems. Similar to salmon, some of the product probably does not make it all the way upstream to the source. Typically, expired or returned products are sent from retail and wholesale outlets back to manufacturers or a contracted returns processing center. The sender receives credit for the item—often for the full value of the item—and the product is then usually destroyed. Careful analysis and management of the returns channel is of paramount importance for security reasons. Most of the attention and financial commitment of the organization is focused on the forward logistics operation, so there is potential opportunity for fraud and for the introduction of counterfeit product in less-scrutinized returns areas. In a poorly managed environment, a counterfeit product could be inserted into the reverse logistics system, with its authenticity unchecked. It could then be destroyed by a contractor, who has not been asked to verify authenticity. Proof of

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disposal could then be used to generate an automatic refund from the manufacturer for all of the items destroyed. All of this could take place without the product being examined by the manufacturer for authenticity and without leaving a trace of physical evidence behind since the packs and contents have been destroyed. Although, in theory, this is a crime that does not expose patients to harm, since counterfeits have been inserted into the system only to be immediately destroyed, it is nevertheless financially damaging to the brand owner and potentially dangerous in the context of other counterfeiting activity. Customer returns can be an excellent source of other intelligence information in the fight against counterfeiting. Reports of unusual tastes, strange smells, crumbly pills, and so on should all be sent to the product security team and followed up where appropriate. These are often signs of poor-quality product. Each incident may or may not be due to counterfeiting, but unless the reports are followed up, important information on counterfeit incidents may be mis-filed as miscellaneous quality complaints and the valuable insight they give into criminal activity may be lost. Sometimes a large organization defeats itself, through lack of internal awareness or poor communication channels. The detailed knowledge of all distribution channels, expected packaging, routes to market, pricing, and other variables should be a standard data set when planning and operating corporate product security systems. However, the supply chain for an international pharmaceutical company is large and complex. In many cases, headquarters may not even know about some of the business practices at distant subsidiaries. These are often not criminal acts (although insider fraud is not unknown: see below) but just pragmatic solutions to local business needs, implemented without reference to head office. Something as simple as a local re-boxing step that removes a covert security element could wreck a carefully constructed product security strategy for that market.

INSIDER FRAUD

In addition to targeting counterfeiters, security executives must also look out for the enemy within. Insider fraud and theft occurs in almost all businesses, ranging from widespread petty offenses (such as taking office stationery for home use) right through to rarer but damaging crimes (such as unauthorized funds transfer and long-term embezzlement). The drug industry has the same vulnerabilities as other corporations, with the additional aspect that pharmaceuticals and the chemical intermediates used in

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their production are often potentially useful or dangerous chemicals that have alternative uses. The production of controlled substances is an obvious example, but some seemingly innocuous pharmaceutical drugs can be used as starting points for the manufacture of illegal street drugs, for example. The theft of small quantities of product, or waste materials, can go undetected for years unless rigorous procedures are in place. This type of theft or diversion has serious consequences well beyond the immediate financial loss to the owner. In one major case,1 the manufacturing process generated a waste powder, which was of pharmaceutical grade but unusable for pharmaceutical production. An environmental services business was contracted to remove and dispose of the waste material. The waste material concerned, although a benign material in itself, was also a key ingredient in the manufacture of an illegal narcotic. Around 500 kilos were taken from the facility over a 10-year period, leading to the manufacture of more than $40 million worth of illegal drugs. During that 10-year period, the same key person at the environmental services contractor was responsible for removing the waste. The long-term diversion was only uncovered after the criminals stepped up their activities, perpetrating an armed robbery and kidnapping at the facility to enable the theft of a 50-kg drum. This case has clear lessons for supply chain security management. First, the value of waste products from pharmaceutical production is not nil. They may be worthless (or even represent a disposal cost) to the drug company, but they can have a street value—either to manufacturers of illicit narcotics as in the case above or to counterfeiters. Impure versions of drugs can potentially be used as API in fake drugs or as masking agents to allow counterfeit products to pass screening tests. The potential value of chemicals, solvents, intermediates, packaging, and old equipment is also surprising. All drug companies have waste management procedures, but insider involvement in diverting this material to criminal use is harder to battle against. However, as in other areas of counterfeit prevention, managers should adopt the same mindset as the financial services industry and assume that all processes may have the potential for fraud and should be monitored accordingly. To avoid diversion of pharmaceutical waste for criminal purposes, the waste stream needs to be managed almost as if it contained used banknotes. The diversity of possible fraudulent activity is very wide, but four basic elements are necessary for a fraud to occur:2 • People to carry out the fraud: Most of the time, a successful fraud

requires one or more persons inside the organization, or with internal access to it, plus one or more accomplices outside the organization to receive and disperse the materials.

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• Assets that are available to acquire fraudulently: The key word is

available. Any time an asset is able to pass through one person’s hands without supervision from another, it is available to acquire fraudulently. Some crimes involve multiple insiders, but most do not and are perpetrated by lone individuals. • Intent to commit the fraud: The great majority of staff are loyal, law-abiding employees. Those who commit serious fraud tend to be either disgruntled with the organization or have a need for money to feed their lifestyle or are being blackmailed. • Opportunity: A potential fraudster in a tightly controlled environment is little threat, but if processes are lax and the prospect of being caught is unlikely then the potential crime may turn into a real one. Since these crimes almost invariably require the help of an insider, the identification or placement of the necessary person is a vital first step in a criminal plot. There are various common mechanisms of obtaining insider help for fraud,3 of which the following are the most relevant to theft and diversion issues in the pharmaceutical industry: • CV fraud: using a falsified resum´e to get a job with access to con-

trolled areas • Bribery and corruption: paying employees to provide information or materials • Blackmail: using information to force people to commit fraudulent acts. Once there, the fraudsters can do their work. Insider fraud, by its nature, is a highly secretive activity, but it is almost impossible to commit serious crime leaving absolutely no trace. For the vigilant investigator, there can be some warning signs.2 • An apparently stressed employee (working late or skipping vacation) • • • • •

without a high workload Employees with external business interests Resistance by the employee to a proposed change of vendor Employee who insists on being the sole contact for a supplier Rising costs or wastage rates with no obvious explanation Missing or altered documents.

None of these factors is diagnostic on its own, but if several are present then checks should be made. Consider activities such as • Analysis of long-term patterns of costs and waste

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• Random spot checks of vehicles and individuals, subject to local laws • Periodically re-tendering contracts for waste management • Staff rotation so that individual contractors and staff members do not

hold the same fraud-sensitive position for long periods • Using staff changeover and vacation periods to look for changes in

waste levels or other indicators of potential fraud • Requiring management review of fraud-sensitive authorizations

Insider fraud, by its very nature, involves trusted employees and can be difficult to eradicate completely. However, simple, unobtrusive steps can be taken to lessen its likelihood. Whatever the precautions, fraud can appear in any situation, sometimes with amazing chutzpah. In India, the government implemented a reward-based whistleblower scheme for the reporting of counterfeit medicine producers by those with inside knowledge. However, the system was rapidly targeted by fraudsters reporting false counterfeiting incidents in order to claim the reward money.4

SECURITY OF SECURITY MATERIALS

When looking at logistics and its related security issues, the use of security technologies is often very helpful. However, it is also very important to maintain a secure supply chain for anti-counterfeiting materials themselves. Security materials have an inherent value much greater than their catalogue price. When a consignment of pharmaceutical products is examined in the field, the security feature is the key material difference that allows law enforcement officials to distinguish between legitimate, fullprice goods and almost worthless suspected counterfeits. This intangible security value can amount to tens of dollars per pack. Incidentally, this is one of the reasons that some suppliers charge per unit of product protected, using a “click charge” model, rather than per kilogram or pound of ink (see discussion in Chapter 35). Security materials are worth more than their weight in gold and should be treated accordingly by both in-house manufacturing facilities and outsourcing partners. For example, simply by reconciling the amount of security ink used during a printing process with the amounts actually ordered from the supplier, it is possible to prevent diversion or theft of the ink. This monitoring process can be delegated to the security supplier, who should be able to account in detail for all materials used by the printer, including material used for priming the press, press returns, wastage, etc. Similar reconciliation should be carried out for holograms or other applied features.

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SECURITY OF EVIDENCE

The identification and seizure of counterfeit materials is only the first step in a long legal process. Whenever possible, the brand owner should remain involved after the raid. Unless the suspect material is immediately and securely impounded when arrests are made, accomplices may remove it later, whether by stealth, bribery, or force. Once the evidence has been removed to a law enforcement facility or agreed storage location, it is then important to ensure that the material is securely and appropriately stored until needed in court, which may take months or even years. Finally, once the case has been dealt with and the perpetrators convicted, it is important to ensure that the counterfeits are securely and verifiably destroyed. The destruction process should be recorded on paper and on video by the brand owner. If local law enforcement is corrupt or inept, the counterfeit material could otherwise quickly return to the supply chain.

Chapter

35

Implementing Anti-Counterfeiting Initiatives—Practical Issues Some of the anti-counterfeiting approaches described in this book can be taken without the need for external resources. However, frequently the involvement of one or more external partners is necessary in order to implement a product security program, especially if technology is involved. As with any business interaction, there are many areas where things can go wrong. The following section tries to distil some of the practical aspects of product security operations involving technological approaches, gleaned from personal experience and from discussions with colleagues around the world.

HOW TO WORK TOGETHER: GETTING THE BEST FROM SECURITY PARTNERSHIPS

One of the major barriers to the effective implementation of product security programs is the high degree of coordination required between multiple parties. In order to design, develop, and implement such a program, three or more companies may be involved in discussions. If these interactions sometimes become strained or downright painful, there are generally identifiable reasons. In the following scenario, I assume the involvement of a pharmaceutical company, a converter, and a security supplier in a product Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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security project and examine some of the needs of each party in reaching a successful collaboration. What Do Pharmaceutical Companies Need? • Return on Investment: Cost constraints are a fact of life in all areas

of today’s pharmaceutical industry and likely to remain so. Therefore, one of the key requirements for a successful proposal from any supplier is to address issues of cost, value, and return on investment. The first two are easier to elaborate, but the last one is the most critical. Verifiable data on actual results with previous implementations of the system are worth a thousand fancy slides. Hard numbers on reducing the incidence of fakes using anti-counterfeiting technologies are very hard to get hold of, but the supplier should be creative in making a good business case. It may be that an increase in operational efficiency or a decrease in stock “shrinkage” (the logistics euphemism for loss or theft) has been noted by previous customers. Maybe the publicity and associated consumer awareness with the launch of a new overt feature caused an uptick in sales revenue for that brand. Anything with hard financial numbers, which helps the product security team to sell the project to their own management, is welcome. • Expertise: In general, pharmaceutical product security teams are small in number and often resource limited. Individuals may have global responsibilities and heavy travel commitments. Any technical support that the supplier(s) can give them is therefore welcome. This should include expertise in the choice and design of security technologies and systems, but it may also include sharing non-confidential material or intelligence from similar projects or the ability to provide local support at multiple international locations. • Discretion: An efficient supplier representative will have widespread penetration of their customer accounts. They may know more people within the corporation than some of their customer contacts do. Inertia is a fact within all large corporations, including drug companies, so suppliers can often add value by using their multiple relationships within the customer account to pull together a large or international project. A word of caution here: nobody likes to be bypassed. Suppliers should be very discreet in their activities and avoid playing off different departments or trying to influence decisions in indirect ways that undermine the primary contact. • Adherence to Procedure: Large organizations need procurement control mechanisms, or the process gets out of hand and costs

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spiral. There is usually a stepped procedure whereby suppliers are first pre-qualified using a Request-for-Information (RFI) process. This may take the form of a long and detailed questionnaire that often takes significant effort on the supplier’s part to collate and return. Once the replies to the RFI have been received and collated, the brand owner may issue a Request-for-Proposal (RFP) to those suppliers who have demonstrated that they are qualified to deliver the project. This also takes quite a lot of preparation by the supplier, often including pre-submission meetings with the brand owner, and has associated costs. The RFI and RFP processes may sometimes seem restrictive and time consuming to suppliers, but they are often part of mandatory corporate quality and audit systems. Those who adhere to the procurement process stand a vastly improved chance of winning business. Those who submit incomplete or invalid responses may find themselves automatically disqualified regardless of the merits of their technology. What Do Security Suppliers Need? • Time: The most effective security programs are rarely off-the-shelf.

Most technologies require some tailoring to the customer here and there. The earlier that contact is made by the brand owner with a security provider the better the outcome will be. Reactive “we-need-security-features-on-production-packs-within-two-weeks” projects are sometimes unavoidable, but short deadline initiatives do not give the most satisfactory or cost-effective outcomes and should be avoided whenever possible. Better risk analysis, prioritization, and implementation of pre-planned strategies can reduce the need for expensive reactive measures. Security providers can often provide lots of added value if you involve them early. • Trust: Many security suppliers work not only in pharmaceuticals but also in other highly secure industries and are very sensitive to client confidentiality and secrecy issues. In addition to keeping customer information secret, they also expect the customer to reciprocate by being discreet about the details of their security technology. Under suitable non-disclosure agreements, involving preferred suppliers as trusted partners will bring dividends, but do not be offended if the supplier refuses to show you the “recipe.” The technology or its constituents may not even be patented, in order to preserve the necessary secrecy. Seek evidence of the effectiveness and applicability of the technology, but do not expect to see chemical formulae.

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• Security: Most of the serious security providers, if providing their

services to the brand owner in conjunction with a third party such as a converter, will require a security audit of that third party. This is to protect all parties, since a supply chain is only as secure as its weakest link. If the converter has not used security products before, they may need to modify procedures or install extra equipment. • Flexibility: Sometimes, the most appropriate solution to a product protection problem is not the one first suggested by the customer; therefore, brand owners should avoid being too closed in their RFP approach. Security providers will respond to specific enquiries with the requested information, but they may be able to offer more secure and cost-effective alternatives. They may be aware of new developments—either in technology or in the prevalence and nature of counterfeits. By focusing on the desired outcome—secure products—not on particular technologies, rights holders can make the most of supplier expertise. • Budget: It is an unavoidable truth that authentication and product security almost always cost money. Despite the skepticism of some, there is generally at least a rough correlation between the level of security and unit cost. Both sides need to be honest and realistic about what can be achieved with the given budget. The most successful brand protection projects tend to have independent budgets that are not directly linked to other commodities such as packaging. This allows both sides to focus on the cost and value of the security feature itself and prevents poor decision making based purely on cost. Comparisons of security costs with prices for more commodity items such as carton board and blister lidding foil can be particularly misleading, as the components are not performing comparable functions.

What Do Print and Packaging Suppliers Need? • Clarity: In some cases, the converter may also be the security

provider. There are some advantages to this arrangement since it simplifies communication, and some converters have the technical capability to provide very good product security features. However, if a non-specialist converter is used in conjunction with a separate security provider then it is important to establish clear responsibilities and communication lines between all parties. The technical aspects of printing, or the application or incorporation of

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a non-printed feature, during the converting process should not be neglected. Solutions that look good in a presentation or on the lab sample do not always translate well onto the press. Changes may be needed from the original assumptions, either in formulation or even in printing or production processes. These are best discovered early to avoid delay, so once they have been audited and placed under non-disclosure agreement, all sides should meet as soon as possible (typically at the converter site) and should be open and honest about expectations and capabilities. • Understanding of cost drivers: Press trials and machine modifications cost money, and the profit margins on packaging are much smaller than those on security features. If the converter has won a packaging project after a bidding process on the basis of price, and only then is requested to work with a third-party security provider, then it seems only fair for reasonable and unseen additional costs to be reimbursed by the customer. As in all industries, there is a gray area called “business development costs,” and most suppliers are expected to absorb some costs that they would prefer to charge for. However, common sense should prevail here. If the converter has nothing to gain financially from the incorporation of the product security feature, then they will be less motivated to ensure efficient progress of the security project.

GENERAL OBSERVATIONS ON BUSINESS MODELS FOR PRODUCT SECURITY

The growth in pharmaceutical counterfeiting over the last 10 years has spawned a whole industry of security product vendors. There has been much innovation in product security technologies but arguably not enough attention to the business model and the return on investment for the customer. Some of the security vendors are highly specialist with one technology that addresses a specific issue, and others can integrate multiple technologies from both in-house and external sources to provide a full service offering. Owing to the difficulty in demonstrating financial benefits to brand owners because of the scarcity of accurate data on counterfeits, the pricing of product security has been difficult to underpin with a hard, rational basis other than cost of materials plus varying degrees of embedded IP and exclusivity value. The cost of product security to the brand owner is clear, but the payback in financial and brand value often is not well characterized. Since procurement executives are generally incentivized on quantitative metrics, and usually the only hard number

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in a product security deal is cost, this situation has occasionally led to a focus on pure cost reduction rather than value creation. Excessive focus on cost rather than value tends to commoditize any industry. It increases price competition and brings in new market entrants but can drive out innovation and eventually reduce the technology choices available in the marketplace. Some of the various pricing models that are currently used are discussed in the following sections. Unit Fee Pricing

Many of the most successful projects in pharmaceutical product protection involve the unit fee or “click charge” business model, where a fixed fee is levied for each unit of product that carries the security feature. Some or all of the upfront costs incurred by the vendor in setting up the project may be rolled into the unit fee. This arrangement has cash-flow benefits for the brand owner and entails risks for both the buyer and the vendor, which must be managed. Typically, the main risk for the vendor is that the brand owner’s production volumes, on which the unit price calculation is based, are lower than anticipated, leading to a revenue shortfall. Conversely, if the brand owner is locked into a fixed price contract and their production volumes turn out to be many times the level predicted then the vendor will make a large profit. To avoid these situations, which can lead to financial and customer relationship difficulties on both sides, it is usually prudent to agree on a minimum charge or minimum production volume. Especially in the case of security features on new products with unknown market demand, the brand owner may also wish to negotiate a sliding, decreasing scale of unit charges based on increasing production volume. Despite the care with which they must be framed, these projects can offer easy predictability of costs for the pharmaceutical manufacturer and give a predictable income stream to the supplier. This encourages longer term partnerships and tends to lead to greater sharing of information. Such contracts should also have built-in upgrade mechanisms that ensure that security features are kept under review by both sides on a regular basis and that the vendor is offering their best technology. If the relationship is long-term, the contract may also have either static (with no annual rise for inflation) or declining unit prices over time, independent of production volumes. This reflects the gradually reducing costs to the supplier of servicing the contract as their initial and fixed costs are amortized. Commodity Pricing

High price does not always correlate with high security value in anticounterfeiting, but the converse is often true. Some effective and cheap

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technologies exist, especially for forensic marking, but in general, a very low-priced technology may indicate that there are multiple suppliers in the market, which in turn implies easier availability of these security features to counterfeiters. Vendor selection procedures that are appropriate and cost-effective for procuring commodity items like toilet tissue are not usually a good idea when buying business-critical product security technologies. Practices such as online reverse auctions or similar purely price-based sourcing methods should be avoided unless all participants have been pre-screened for security or are already known to the purchaser. Insurance Premium

As noted in the early chapters of this book, the reality of counterfeiting is that the genuine brand is always associated, however unfairly, with the damage caused by fake versions and knockoffs. This has a negative impact on the consumer image of the brand and increasingly may lead to lawsuits from customers or regulators who feel that the rights holder did not differentiate their product sufficiently from look-alike versions. As corporate liability issues therefore become more strongly linked with product integrity, it is interesting to speculate about new brand protection business models. For example, an integrated product protection strategy (and the associated technology spend) may eventually be seen as another form of corporate liability insurance. This may lead to a more holistic view of corporate brand value and the reduction of risks to which that value is exposed. Perhaps an alliance between a large insurer and a major security organization could bring benefits for both vendor organizations and their customers. Full outsourcing of product protection on a corporate scale has never, to my knowledge, been attempted by any pharmaceutical company. However, although it would be a challenging proposition, there is no reason in principle why this should not be possible. Other Pharmaceutical Service Industries

In my view, anti-counterfeiting technology suppliers and other product security vendors should always position their offerings as services, not as products. When examining potential business models, the best comparisons may therefore come from other service industries in the pharmaceutical space. If we look at the evolution of the contract research and contract manufacturing industries, as comparators, we see that most of the larger contract research organizations (CROs) and contract manufacturing organizations (CMOs) have co-evolved with their customer base. As the level of outsourcing of clinical trials, development services, and manufacturing

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has increased, the business relationships between CROs/CMOs and pharmaceutical companies have changed radically. The industry and its customers were initially very input-focused: time-and-materials contracting models were the norm. Since pharmaceutical development projects such as clinical trials involve many unknowns, this frequently led to (sometimes disputed and relationship-damaging) contract revisions because of “out-of-scope” activities that were required to keep the project on track. As the growth of outsourcing brought more competitors into the market, the industry went through a period of price pressure and commoditization, with some providers slashing charge-out rates to gain market share. The development of fixed price contracting followed, allowing larger providers to differentiate themselves as they gained more experience in predicting their costs and risks. This meant that the vendor absorbed much of the project risk (over-runs, unseen events, etc.) in return for guaranteed revenue and a chance to bring the project in more efficiently to increase their profit margin. Although still very competitive, the CRO/CMO industry has now evolved again and has become much more operationally integrated with its customer base, leading to long-term financial and operational partnerships that benefit both sides. Certainty of revenue has enabled vendors to expand and specialize to fit their customers’ needs, whereas the stability and expertise of the major vendors has allowed pharmaceutical companies to outsource non-core business. In some pharmaceutical corporations, whole therapeutic areas are handled using this type of third-party relationship. The closer integration of vendor services with customer operations could also be the future of product security in the drug industry and, in my view, would be the best way to generate economies of scale without rapidly commoditizing security features and destroying their value.

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4

Conclusions and the Future

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36

Where Do We Go from Here? In this book, I have tried to cover some of the key challenges, opportunities, and technologies in pharmaceutical anti-counterfeiting, as they currently appear. However, this is a fast-moving field and in this chapter I will try to look forward to what might happen over the next few years in the implementation of anti-counterfeiting technologies. The celebrated physicist and Nobel prizewinner Niels Bohr1 famously said “Prediction is very difficult, especially about the future.” What seems sensible at the time of writing (2010) can be embarrassing with hindsight. The next section therefore comes with the “Safe Harbor” proviso used by drug companies when presenting their R&D pipelines to investment analysts. These are the author’s personal views and some of these scenarios may not come to pass: what follows should not form the basis of investment decisions.

FUTURE SCENARIO: RISK OF INACTION

Counterfeit drugs are on the increase. Although there is wide discrepancy between estimates of the prevalence of fakes, and hard data is scarce, the consensus seems to be that this upward trend is likely to continue over the next few years. Death due to counterfeit drugs is still very rare Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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in developed countries, where almost all major drug producers are headquartered. If the low incidence (or at least low detection) in these markets continues, then the adoption of technological countermeasures may be relatively slow. Although the United States (more accurately, worldwide) heparin tragedy of 2008 has catalyzed some action, we in the pharmaceutical industry are still not adequately protecting our customers. If there is another large-scale tragedy caused by fake drugs somewhere in one of the major economies, this is likely to provide an impetus for much faster action, but the disaster is already happening out of sight in other parts of the world. The annual death toll because of fake or substandard drugs is probably higher than the number of fatalities caused by the great Indian Ocean tsunami of December 2006 or the Haiti earthquake of January 2010. Both of these natural disasters cost the lives of over 200,000 people and led to changes in the way that earthquakes and tsunamis are predicted and monitored. Counterfeit drugs are a preventable yet recurring disaster for the people of poor countries.

FUTURE SCENARIO: RISK OF INCOMPLETE ACTION

Although recent progress is encouraging, it will be some time before systematic and widespread digital countermeasures such as drug tracking have been implemented. During that time, there will still be a need for increased vigilance by drug companies, customs officials, and the law enforcement community. However, track and trace technology is not a “silver bullet” that will kill off counterfeit drugs and may itself have vulnerabilities. Physical and sensory authentication tools will still be needed both during and after the development of track and trace systems around the world. In my view, if we do not integrate both digital and non-digital (physical and sensory) authentication methods into our collective pharmaceutical security approach, then we risk wasting the major investments that are about to be made in track and trace. Fake drugs are hugely profitable and we should not expect criminals to give up easily.

FUTURE SCENARIO: RISK OF INAPPROPRIATE ACTION

As we move forward, the fight against counterfeits must not be confused with the protection of intellectual property, which is an important but separate issue. Some of the unauthorized drugs that are found in developing countries are of perfectly acceptable quality. They are often produced by generics companies with modern production facilities, low labor costs,

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and shorter supply chains to their markets. Whether or not they are in violation of the original rights holder’s intellectual property is often a legally disputed gray area. However, one of the possible concerns is that such generic product is then placed in fake packaging simulating that of the original brand owner, giving a counterfeit product that is good quality but at a much lower price than the original. If buyers source these products and distribute them as low-cost “originals,” this has potential negative implications in promoting the view the pharmaceutical industry is overcharging with its standard pricing. The welfare of the patient, not the elimination of unauthorized generic competition or the defense of intellectual property rights, must remain the primary philosophical focus of anti-counterfeiting initiatives. Counterfeiting is primarily a global health issue not an international IP law issue. It requires a coordinated, worldwide, health-based response—precisely the raison d’ˆetre of the World Health Organization (WHO). Although the WHO has no legal powers over member states and is therefore not able to drive decision making at national level, it does constitute the most appropriate neutral international organization to deal with the pharmaceutical counterfeiting issue. In recent years, the controversy surrounding the International Medicinal Product Anti-Counterfeiting Taskforce (IMPACT) initiative has allowed some organizations with vested interests to deflect attention away from patient safety by blurring the definition of what constitutes a fake drug. If we are to maintain the focus on health and patient protection, rather than IP issues and legal definitions, any future attempts to move responsibility for fake drugs from the WHO to the World Intellectual Property Organization (for example) should be resisted.

FUTURE POLICY APPROACHES

In my personal view, if the world is serious about fighting counterfeit drugs, then there is only one viable policy option. Mandatory regulations—internationally harmonized—are the only way to ensure widespread uptake of drug tracking technologies and an appropriate level of non-digital authentication. Many international industries have had a debate about the merits of self-regulation versus legislation, but the political taste for state intervention tends to vary between countries. Controversial issues have often led to patchy voluntary standards and eventually to piecemeal legal requirements. If consumers are aware of their choices about what they consume, then one can perhaps make a case for voluntary codes of practice. Given adequate publicity for the voluntary standard, an informed customer is able to make choices about what they

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buy. For fake drugs, the consumer often is usually not aware of the danger they are in. Generally, the patient has no choice in the product that he or she consumes as it is dispensed by a pharmacist who in turn probably only stocks one brand of each prescription medicine. The only safe policy approach is to impose a minimum security requirement. As noted elsewhere, lack of ownership of the counterfeiting issue will otherwise lead to the “tragedy of the commons” scenario where everyone recognizes the problem but nobody takes the lead and little is done about it. Therefore, legislative impetus from governments around the world is critical in generating society’s response to this potentially dangerous threat to our health. Some of these changes do not require new technology. Simply by implementing policies that reduce the number of manual operations involved in the transport of drugs from factory to patient, legislators can help minimize the opportunities for counterfeits to enter the legitimate supply chain. For example, the mandatory use of tamper-evident closure seals and unit-dose packaging during manufacture, and the prohibition of opening of the seal before the medicine is dispensed to the patient, would go a long way to improving the security of the drug supply. The European Union is contemplating these measures, although there is currently some resistance from distributors and re-importers. In the United States, the continuing gradual conversion from pharmacy-dispensed bottles to unit-dose packaging will have an impact on the workflow of pharmacists. This is being resisted by some pharmacists who fear that their professional judgment and input will be removed from the dispensing process. However, sealing the product during manufacture and maintaining that seal intact until the patient chooses to open the pack would seem a logical way forward from a purely security perspective. Sealed packaging has long been the norm in the US food industry, and we do not expect our local grocery store to dispense flour from a sack or milk from a vat. An alternative, albeit radical, policy option would be to make the original rights holder legally and financially responsible for any harm done to those who believe they are buying that brand. In other words, those who unknowingly buy lookalike products, thinking they are getting the real thing, would have means of redress against the genuine manufacturer. This would put the onus on the original rights holder to unequivocally differentiate their brand and to educate their customers about how to spot potential counterfeits. This approach is liable to be legally contentious and difficult to enforce. It may not work well in isolation, but would at least ensure that counterfeiting is acknowledged as a risk for all products and would perhaps drive the development of appropriate business models. Whatever the legislative tactics chosen, governments of all nations have a responsibility to their citizens to ensure that mandatory legal processes

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are put in place to protect the drug supply. The WHO, through its IMPACT initiative, has developed some model legislation to aid countries wishing to strengthen their laws in this area.2 The rich world also has a responsibility to help developing countries to bring their drug supplies up to a safe standard. This is not only a moral imperative, to help save some of the thousands of lives lost annually because of fake drugs in poorer countries, but it is also an enlightened self-interest.

FUTURE AUTHENTICATION APPROACHES

In addition to having the standard problems of looking into the future, this is a difficult section to write without giving ammunition to those who wish to profit from counterfeit medicines. There are many solution providers, industry associations, and pharmaceutical security consultants who can advise on specific technology choices and on appropriate investments for the future. For these reasons, I do not propose to address future technologies in specific detail but only to highlight some likely themes. On the basis of the discussions with colleagues, listening to presentations at conferences, and reading the product security literature, it seems to me that there is a clear need for a new phase of technology development in the authentication of many products. Counterfeiters are learning how to reproduce (or at least mimic) the effects of existing technologies—especially overt features such as holograms and colorshift inks—with increasing effectiveness. This is true across all industries, not just for pharmaceuticals. The product security industry needs to fight back. However, the development of new security technologies, especially those overt features designed for consumer recognition, is a difficult and prolonged process. Of necessity, the methods and materials used to generate visible features which are both striking and difficult to copy are complex and often expensive. Development times are measured in years. Rather like drug development, the costs involved in developing a new overt feature have to be recouped in a limited time period before counterfeiters can catch up or at least develop a technology that looks superficially similar. Consumer confusion is the friend of the fake drug manufacturer and we need new technologies to clearly differentiate the genuine from the fake product. Security suppliers are working hard to come up with new authentication approaches for many different industries. However, it may also be prudent to ask the suppliers to reserve some of these new technologies for the protection of pharmaceuticals rather than allow them to be used on all product classes, and to restrict their supply accordingly. In the same way that powerful new antibiotics are often reserved for specific

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diseases in order to preserve their potency, maybe it is right to consider the same approach for product security. Although these types of approaches may be difficult in practice, vendors and buyers need to think more imaginatively about how we work together to exclude the counterfeiters from new technologies for as long as possible. The development of covert and forensic technologies, although technically challenging, is generally less problematic than for overt features since things that cannot be seen by naked eye are often less heavily targeted by counterfeiters. We will continue to see innovative new approaches that will aid in the process of providing technical confirmation and legal proof in suspected counterfeiting cases. It is tempting to dismiss covert authentication technologies as mere “fire alarms”—able to report the existence of a problem but unable to prevent it—but this is still a very valuable function. Similar to fire alarms, covert technologies can help prevent small problems from turning into bigger ones, and they undoubtedly save lives. In the future, I expect to see technologies that lessen the need for laboratory analysis by using portable instruments or by using cryptic elements that can be recognized by consumer devices. The growth in the number and popularity of specialist consumer applications for “smart phones” may also trigger a wave of innovation in the product security area. Today, the cost of the security features on a higher denomination bank note greatly exceeds the typical investment made in security features for a pack of drugs of the same value. The currency industry has learned that to stay ahead of determined counterfeiters, it is necessary to invest significantly and continuously in countermeasures. Maybe it is time for the drug industry to think in the same way. FUTURE TRACEABILITY APPROACHES

The recent history of drug tracking has been dissected at length in earlier chapters and I expect the current, country-by-country roll-out process to continue. However, although the serialization of drugs in multiple separate jurisdictions is a necessary first step in protecting our drug supply, it is not sufficient protection on its own. The scope and success of drug traceability will depend on the collective efforts of governments and international organizations. Global Standards, Worldwide Tracking

It seems likely that global drug tracking systems will become feasible within the next few years. The pharmaceutical industry’s efforts to

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coordinate individual company activities, with the support of organizations such as ISO and GS1 as well as pressure from the European Union, US FDA, and others, seem to be bearing fruit at last. The consensus that is forming around the use of two-dimensional bar codes as the primary data carrier for track and trace technologies at the item level is encouraging. Major challenges remain in the implementation of these systems, particularly in developing countries, but it is better to start something flexible and scalable and improve it over time than to procrastinate in search of perfection. RFID

If we make sensible choices regarding database infrastructure and interoperability, it should be possible to upgrade the coming first-generation, 2D-code-based track and trace systems without entirely starting over. The next logical step in their development is to use the powerful capabilities of radio frequency identification. At least at the unit pack level, RFID has hitherto been the drug industry’s equivalent of nuclear fusion in the power industry—it will be revolutionary and hugely beneficial if it ever becomes universally available but its everyday use seems to be perpetually in the future. The relatively high costs of RFID have prevented its adoption as a unit-level approach. As the technology becomes more widespread across a number of industries, the costs are likely to fall in the future to within the range that makes the use of RFID (or a technology derived from it) feasible for drug tracking at the pack level. Developments in miniaturization and the use of printable components such as antennae, circuitry, and even batteries could allow low-cost RFID labels on all unit packs. The use of electronic prescriptions and electronic patient identity systems—perhaps both employed via the almost ubiquitous mobile phone—could eventually marry with RFID to form a robust and hard to penetrate security layer around the pharmaceutical product. GPS

If the miniaturization and cost reduction of global positioning technology continues, driven by innovation in the mobile phone market, then it may be feasible in future to use individual positioning chips for high-value packs of medicines. This would in theory allow localization of these products anywhere on the globe (or at least anywhere with cell phone reception). In practice, there may be environmental issues regarding the disposal or recycling of the components in the chips, but with the right processes these could be addressed. This approach is already used at shipping carton level by some companies.

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Combined with GPS tracking of authorized personnel and key assets (such as trucks) in the legitimate distribution chain, the use of passive RFID tags may provide a halfway house to the universal use of GPS technology. A GPS device with an additional inbuilt RFID reader, carried by an operative or mounted on a truck, could report the position of any passive RFID tags within range. The result would be ever-changing clouds of positional data as each operative conducts their work or as goods are packed and shipped on. This is a foreseeable development of current mobile phone technology and would allow the automatic gathering of data on the whereabouts of all items as they flow down the distribution channels. Any items that go silent and are no longer visible to the system can be flagged and followed up with a message to the nearest operative to the last known location. It may simply be that the items have been placed in a rarely visited part of a storeroom, or stock may have been stolen or diverted. By placing RFID chips in every nth unit pack, the total cost of the chips can also be divided by n compared to a system with chips in every pack, but the usefulness of the tracking information gained is reduced by a much lesser amount. Most thieves do not steal or divert one item or pack: they steal a carton or a truckload. Therefore some of the items will have tags and their disappearance from the data cloud will be noted by the system. Although it will take some imagination and process development as well as an expansion of existing technology, the use of RFID, GPS, and related technologies in item-level pharmaceutical product protection does not need to evolve in one huge leap from impractical to ubiquitous.

Chapter

37

New Models, New Approaches As technology evolves beyond the known areas discussed above, entirely new possibilities for the authentication or tracking of pharmaceuticals will become available. The constant reduction in the costs of computing power and the growth of internet applications, cloud computing, and mobile telephony will have profound effects on our ability to track individual packs of medicines as they are distributed around the world. Evolution, in technology as well as nature, tends to work with what materials it has to hand, changing things gradually over time with few radical jumps. As well as looking for incremental improvements to current drug security paradigms, such as those techniques discussed in this book, we should remain alert to other options in the battle against counterfeiting. Lateral thinking in the application of new technology may lead to new, safer business models in healthcare. The discussion of new ways of delivering drugs to patients is largely outside the scope of this volume, although there is tremendous potential to make the process more direct. In principle, though, the shorter and faster the supply chain, the more secure it is likely to be. The convergence of devices to aid patient compliance (or adherence) and product verification technologies seems a productive avenue to follow. Adherence to prescribed medication regimes can often be very poor,

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for a number of reasons1 . Many patients simply forget to take their medication, and this can be a major cause of adverse events and poor clinical outcomes. Counterfeit drugs are difficult for the patient to detect and few people check their medication and its packaging thoroughly unless they experience an unexpected reaction. A low-cost device that automatically checks the authenticity of the drug, dispenses the correct dose, and reminds the patient to take their medication would be a great advance in the care of patients in their own homes. The same technology could also be used in hospitals to remind busy nursing staff. Technology to automatically replenish drugs when depleted would also reduce drug wastage and increase the efficiency of the drug supply system. It may even be possible for direct, producer-to-patient supply to become the norm, in the same way that many consumer goods are now produced to order. Low-cost biometric input devices could verify specific patient information such as fingerprints or iris scans. This information could be sent securely to the producer, along with the prescription, directly from the physician’s office. The patient-specific information could then be encoded onto the product or its packaging before dispatch, to be verified by the patients’ device on arrival. The reduction in the cost of genomic sequencing has been as spectacular as the increase in speed. It will soon be a normal and inexpensive clinical practice to sequence a person’s genome as part of their medical history2 . By analyzing derivative information such as the transcriptome (the set of genes that are being expressed rather than all of those in the genome) in various tissues and at various points through the patient’s life, it may be possible to detect early changes in gene expression, which might be associated with cancers or late-onset diseases. This huge stepchange in the personalization of medicine will open up whole new areas for authentication to explore. How can we link product characteristics to individual patient data so that drugs are only usable by one specific person? There will be many hurdles along the way, but with open minds and lateral thinking, there will be lots of new opportunities to make the pharmaceutical industry safer and more tuned to individual needs.

NON-TECHNOLOGICAL APPROACHES

There are other possible approaches to the reduction of counterfeit medicines that do not involve specific anti-counterfeiting technologies or advances in medicine. Some of these may seem impractical and would require great changes in the way we think about health and disease. They might alter the shape of the drug industry and of society itself. However,

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prevention is almost always better and cheaper than cure. Focusing on prevention rather than treatment of the drug counterfeiting problem is more likely to provide long-term security for our global health system. The increasing prevalence of counterfeit drugs is probably driven by several factors: lack of availability and/or high cost of genuine medicines, huge profit potential, relatively low entry costs, low likelihood of counterfeiters being caught, and minimal legal penalties for pharmaceutical counterfeiting in many jurisdictions. By addressing all of these factors, the incentive for counterfeiting is reduced.

Lack of Availability of Genuine Drugs

Despite large international donor programs, there is still a major global problem of access to medicines for the poorest and most vulnerable. Even those in developed economies such as the United States can struggle to afford the price of the medicines they need. Should we consider distributing medicines free or at cost price to all who need them, regardless of their income? Of course, this would be very controversial and we would still need to charge for global health services, albeit in an entirely different way. However, if the current disparity between the drug supply and the demand for medicines creates the opportunity for pharmaceutical crime, then removing the problem of access should have a beneficial effect.

Huge Profit Potential

Counterfeit drugs are a massively lucrative criminal activity. This is due to the high cost of genuine medicines versus the cost of making copies (let alone the even lower cost of products with no active ingredients at all). In the current drug industry business model, the drug pack must carry, in its unit price, all of the hidden and sunk costs involved in its research, development, and manufacture (and the R&D costs of all the company’s failed drug candidates). The sale of drugs is almost the only way for a company to recoup its investment, and it has only a limited time before its patent runs out and its earning potential is reduced. This often leads to a relatively high price versus the production costs of the product itself. There are few ways around this limitation except state ownership of the pharmaceutical industry, which is only likely to cause stagnation and to stifle innovation. Nevertheless, individual states and the international community should seek ways to reduce the profit potential of pharmaceutical crime.

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Low Entry Costs

As we have already seen, the design complexity of pharmaceutical dosage forms and packaging is still comparatively low. This makes it relatively easy for counterfeiters to acquire or develop the technology needed to copy (or at least approximately mimic) a new product even before it is launched. Furthermore, the easy availability of second-hand pharmaceutical production equipment aids this process. Many drug companies sell-off old production equipment via auction sites when they install new machines, or when mergers and site closures cause a surplus. This lack of direct connection between seller and buyer is an inadvisable practice that could be easily and quickly stopped, in my view. Equipment manufacturers could also increase their due diligence on their customers and should work toward a position where production machines, their users, and their output are readily identifiable. To take the currency example one more time, the manufacturers of specialist printing presses for banknotes do not allow their equipment to be sold to just anyone or to circulate on the open market3 . Law Enforcement Issues

The resources available to police counterfeit pharmaceuticals will always be less than we would like. However, in most cases, the police and customs authorities are motivated to identify and eliminate fake drugs and are eager to receive the necessary tools and methods to make their role more effective. By working consistently with existing law enforcement authorities, and educating them about the dangers of counterfeit drugs and how to spot them, brand owners can generate many quick wins. It is generally easier and quicker to enhance existing systems than to invent new ones. Legal Approaches

The lack of effective legal sanctions against the production and sale of fake drugs has allowed criminals to operate almost with impunity. The international application of a consistent system of deterrents and penalties for pharmaceutical counterfeiting is therefore an obvious requirement if we are to control the problem. Legislators have been slow to wake up to the dangers of fake drugs but they are now starting to catch up. By closing more legal loopholes, increasing the penalties for those convicted, and making it harder and riskier for criminals to make profits from counterfeits, the supply side can be more readily controlled.

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CONCLUSIONS

The scourge of counterfeit drugs poses difficult but not always unique technical and political problems. The drug industry and those who regulate it should therefore gather experience and best practice from other industries. Many governments already have (or are planning) national excise control programs involving track and trace systems for tobacco and alcohol products, and in some cases other taxable products. They use very similar technology to that being assessed for pharmaceutical security purposes. Although they are tracking non-medical products, the lessons of these programs for the pharmaceutical industry are clear. Firstly, a large-scale tracking system has a much greater chance of success if it is mandatory for all concerned. Voluntary systems requiring significant initial investment do not get funded when finances are tight, and struggle to find friends even in the good times. When able to make individual choices, companies act in their own best interests and do not implement discretionary systems. When strong government legislation is in place to force the adoption of a tracking system, there will still be resistance from some quarters. However, clear legislation makes the playing field level again and compliance with the new system is no longer a competitive advantage or disadvantage. Ironically, anecdotal evidence suggests that many of the manufacturers who resist the tracking system initially are able to make considerable savings and efficiencies in their supply chain control when they finally implement it. The second lesson from excise control systems is that economies of scale can bring down the costs of track and trace systems significantly when they are fully implemented across whole corporations and countries versus the inefficient piecemeal processes and small-scale operations used at the pilot phase. The unit costs of track and trace are not likely to distort the availability of medicines, either in the major markets or in the developing world. A final learning from the control of tobacco and alcohol is that different configurations may be necessary in different countries. What works in pharmaceutical producing countries may not be so appropriate for drug importing countries, for example. Many developing countries have almost no domestic drug industry and rely totally on imported medicines. They wish to increase the control and traceability of their drug supply, but they are not a sufficiently large market to be able to insist that drug companies apply specific security features during the manufacturing process. An alternative scenario is to have an import control mechanism to inspect the drugs when they arrive into the country, then add a security label or other seal of approval before releasing the drugs for distribution and sale. For small- and mid-sized countries, this approach is feasible as it is

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possible to restrict the number of entry points into the country. Even just taking the simple step of restricting the ports of entry for medicines can have a beneficial effect on the control of counterfeiting. Nigeria, a country almost 1 million square kilometers in area with a population of over 150 million, limits the authorized entry points for medicines to just six. This has enabled them to concentrate their customs resources and has helped to improve anti-counterfeiting efforts. The systems that are being designed for the United States and Europe should not be forced upon developing countries that lack the necessary funds or infrastructure. Rather we must design scalable global standards that allow different systems to operate in parallel. The sophistication of counterfeits is rapidly increasing and large-scale counterfeiting is now controlled by organized crime, which has established entire parallel criminal industries. These often use many of the same modern printing and production techniques as the legitimate manufacturers. Even when a product carries a highly sophisticated security feature, some degree of imitation by counterfeiters is often seen within weeks or months of its introduction. This may not be a perfect reproduction but it may be close enough to fool the consumer. It is no longer feasible to expect a single anti-counterfeiting feature to function as an effective deterrent for many years. Brand owners must therefore present a moving target to counterfeiters. To continue the earlier analogy of the cheetah and the gazelle, the package development process is similar to evolution between predators and prey. • Whenever one side gains a temporary advantage, it forces the evo-

lution of a response (security labels and lookalike fake labels). • If the other side cannot respond to the changed circumstances, it may cause the extinction of the species (individual counterfeiters may decide to move to other activities). • The presence of predators may discourage prey species from entering a territory (some companies choose not to launch key products into some markets, for fear of rapid counterfeiting). Only by constant vigilance and by taking regular proactive steps to update security technologies and procedures can the legitimate brand owner stay ahead of the criminals. Much of this book focuses on product protection technologies— additional security elements such as codes and markings, which are added to the existing pharmaceutical industry framework. These are one of the only feasible options in fighting counterfeiters at the moment, and will still be needed as we move forward. However, in the longer term, we

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need to find and start implementing business models and administrative structures, which inherently exclude (or at least make increasingly difficult) any large-scale criminal activity. Petty crime and small-scale fraud will probably always occur, but by planning our corporate activities and legal frameworks so that organized crime finds it much harder to integrate its parallel business practices, we may be able to prevent the worst of the damage caused by fake drugs.

Chapter

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Selected Examples from Around the World The following short summaries are intended to give an overview of the variety of criminal methods used and the geographical spread of pharmaceutical counterfeiting activities. This is not intended as an exhaustive list but merely represents an illustration of the scale and diversity of the problem at the time of writing. Individual studies are chosen for example purposes only and are from public sources. No judgment is implied, either about the relative seriousness of the incidents or the guilt of those involved. For up-to-date news items on seizures of counterfeit pharmaceuticals, see www.securingpharma.com.

ARGENTINA

In January 2010, almost 400,000 counterfeit pills for the treatment of erectile dysfunction were seized by Argentinian customs officials in a raid conducted in the port of Buenos Aires.1 A shipping container was detected with 398,000 Viagra® and Cialis® counterfeit pills, with a total market value of US $235,000. The container was reported to have started its journey in China and was declared as containing “lamps.” Such crimes are very difficult to detect since it is physically impractical to inspect every

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container arriving at a major port. The port of Buenos Aires handles over 1 million containers per annum. Opening and checking several thousand containers per day with limited customs resources is impossible.

BRAZIL

From January to June 2009, the Brazilian National Health Surveillance Agency (ANVISA) and the Federal Police seized 316 tons of fake pharmaceutical products, an eightfold increase over the same period of 2008.2

CANADA

Canada has been at the center of the re-importation controversy over drug importation into the United States. Although there are many legitimate Canadian online pharmacies, Canada’s proximity to, and friendly relations with, the United States makes it the most used proxy location for internet sales of counterfeit drugs. Drugs are sourced from anywhere in the world (often China) and routed through several destination countries to launder their true origin before finally being posted to individual US consumers who believe themselves to be buying Canadian drugs from a genuine Canadian pharmacy website. According to Canadian Border Security Agency officers at the Vancouver International Mail Centre, they intercepted over 10,000 packages of suspect health products in six months during 2009.3

CHINA

Although China has often been vilified as the main global source of counterfeit products, and specifically implicated in major fake drug scandals, it should be remembered that the Chinese people are also major victims of counterfeiting.4 Thousands, perhaps hundreds of thousands, of innocent Chinese patients are poisoned or killed every year by counterfeit medicines. In 2007, China sentenced the former head of the State Food and Drug Administration (SFDA) to death5 after he was convicted of corruption for accepting more than $850,000 in bribes to approve hundreds of drugs. The Chinese government announced a review of about 170,000 medical licenses that were awarded during his tenure at the agency.

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EUROPEAN UNION

The European Union (EU) recently apprehended 34 million fake medicines in only two months, in a coordinated action called MEDI-FAKE.6 INDIA

In 2009, the Indian health ministry collected more than 24,000 drug samples across the country and tested them for counterfeits. It reported that only 0.04% of drugs it surveyed across the country were counterfeit. There are doubts over the methodology used and the validity of the results amid claims that pharmacies were told in advance that they would be surveyed.7 The World Health Organization estimated in 2006 a 20% prevalence of counterfeit medicines in India.8 Work by independent researchers, published in a peer-reviewed medical journal, evaluated pharmacy drug quality in the major Indian cities of Delhi and Chennai.9 They found a substandard rate of 12% and 5%, respectively. Although the sample size was smaller than the Indian government survey (562 samples of 5 drugs from 52 pharmacies), in this case, the pharmacies did not know they were being investigated as the survey was conducted by covert shoppers. LAOS AND SOUTHEAST ASIA

Malaria is endemic in Laos and the surrounding area of Southeast Asia and, worryingly, treatment-resistant forms of the parasite seem to be emerging here. Evidence is coming to light that low-dose and substandard counterfeit pills may be at least partly to blame.10 A tropical medicine research group has uncovered the extent of the fake anti-malarials circulating in the region.11 A study of 391 samples of genuine and counterfeit artesunate packs collected in Vietnam, Cambodia, Laos, Myanmar (Burma), and the Thai/Myanmar border, found 16 different fake hologram types. Laboratory analysis confirmed that all specimens thought to be counterfeit on the basis of packaging contained less than 25% of the labeled dose of artesunate, and in some cases none at all. Evidence suggested that at least some of the counterfeits were manufactured in China. NIGERIA

The National Agency for Food and Drug Administration and Control (NAFDAC) seized $3.3 million worth of fake drugs in one seizure in

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2010.12 Officials said the consignment of fake drugs came into the country by air from Hong Kong and China.

RUSSIA

An operation in 200613 by police and inspectors from the Russian Federal Agency for Monitoring Health and Social Development, Roszdravnadzor, uncovered an estimated $2 million worth of fake drugs. Corruption is widespread in Russia and many pharmaceutical companies have links with Russia’s bureaucracy—whereas previously the production of fake drugs was on a small scale, much is now thought to come from non-declared production (so-called third shift activities) at legitimate factories.

UGANDA/EAST AFRICA

In mid-2010, a combined international operation14 across East Africa targeting counterfeit medical products and pharmaceutical crimes resulted in the seizure of at least 10 tons of counterfeit and illicit medical products. More than 80 arrests were made of individuals suspected of involvement in the illegal manufacture, trafficking, or sale of counterfeit and diverted medical products. The operation involved police, customs, and drug regulatory authorities across Burundi, Kenya, Rwanda, Tanzania, Uganda, and Zanzibar. It was conducted in July–August 2010 and was coordinated by Interpol and undertaken under the umbrella of the World Health Organization’s International Medical Products Anti-Counterfeiting Taskforce (IMPACT). Forensic assistance was provided by the laboratories of the Singaporean Health Science Authority, and the operation also included support from the World Customs Organization. Operation Mamba III was the third such operation in as many years aiming to curb the manufacture and distribution of counterfeit medical products in East Africa. Interpol has a dedicated Medical Products Counterfeiting and Pharmaceutical Crime (MPCPC) unit, which is encouraging close collaboration between the health sector, law enforcement, international organizations, and non-governmental organizations. The two-month-long operation saw 300 premises checked or raided across the participating countries. Together with follow-up investigations, this led to the seizure of counterfeit essential medicines such as vaccines, anti-malaria drugs, and antibiotics as well as significant quantities of government or donated medicines that were diverted to illegal resale markets.

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UNITED KINGDOM

In 2007, an investigation by the Medicines and Healthcare products Regulatory Agency (MHRA), codenamed Operation Stormgrand, led to the conviction of four men15 of offences concerning the conspiracy to smuggle and supply counterfeit medicines into and out of the United Kingdom. The crimes involved millions of pounds and the investigation traced a complex network of individuals, companies, and bank accounts. The men were part of the United Kingdom distribution arm of a global counterfeiting ring, operating from China, India, and Pakistan, and extending to the Caribbean and the United States. MHRA has issued nine product recalls because of counterfeit products in the period from 2005 to 2009.

UNITED STATES

Many of the examples quoted in the main text of the book occurred in the United States (I will not repeat them here), but this reflects the strength rather than the weakness of the US supply chain, since these incidents only come to light by continuing vigilance. The system is not perfect, though, and the Timothy Fagan affair is a well-known case, which illuminates many features and weaknesses of the US drug supply. See “Dangerous Doses” by Katherine Eban16 as an excellent and detailed overview of the complexity of the case and the nature of the criminal deception involved. The very sophistication and complexity of the US healthcare system provides opportunities for criminals. On October 17, 2008, a shipment of Carbatrol® and Adderall XR® that was traveling from Shire Pharmaceuticals’ manufacturing facility in North Carolina to their Distribution Center in Kentucky was stolen. The shipment was never entirely recovered, despite prompt action. It is thought that around 35,000 units of 200 mg Carbatrol capsules, with expiry dates in April and May 2010, were taken by the thieves. Out-of-date Carbatrol® from the stolen lots started to appear in expired returns in mid-2010 (the stolen Adderall XR® lots were still in date when the issue emerged, so have not yet resurfaced in this way). US pharmacies can receive credit or refunds if they return expired, unused medicines to the manufacturer. As explained in Chapter 34 (reverse logistics), this presents an additional route for criminals to infiltrate the legitimate supply chain. As there may have been more stolen product still on the market, Shire suspended the issuing of credit for the affected lots17 .

Part

5

Further Resources

A Patient’s Guide to Avoiding Counterfeit Drugs This book examines the scourge of pharmaceutical counterfeiting mainly in terms of the big picture: policies and technologies to combat fake drugs and to help catch the criminals who produce and supply them. But it is also useful to think about practical actions that we can all take, as patients and members of the public, to reduce the market for fake drugs by becoming better informed and more discerning consumers. What can we all do to spot counterfeit medicines before they cause harm? Are there any steps that almost anyone can take, with no special training or tools? As with other threats to our safety and well-being, such as terrorism, workplace hazards, or communicable disease, the key behavior is vigilance. Many people do not give their medication a second thought, but by being more observant about what drugs look like, where they come from, and so on, we can help eliminate at least the more obvious counterfeits. Here are some of the things patients should think about when buying and consuming drugs.

DO I NEED THIS PARTICULAR MEDICATION?

Many chronic medical conditions are accompanied by internet myths and legends regarding supposed new treatments or cures or perhaps new uses Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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for established drugs. The desperate or incautious patient can be lured by online advertising into putting their faith in these untried and off-label drugs, often in conjunction with their existing prescribed medication. In the event of an adverse reaction, perhaps caused by the new “remedy” or by its interaction with the existing medications, it is very difficult for the physician to disentangle cause and effect. Alternatively, for those who suspect they have a serious or embarrassing medical condition but have not consulted a doctor about it, the desire to avoid a diagnosis can be a strong motivator to seek anonymous, unauthorized channels for their medication. The reason for avoiding their physician may be simply shyness or it may be the wish to avoid having something on their medical record that may be a perceived disadvantage in obtaining insurance or employment. Both of these reasons for seeking medication without a prescription are highly dangerous and should be strongly discouraged. The first step in avoiding counterfeits is to seek the advice and endorsement of a qualified medical practitioner for any medication you wish to take, and to buy drugs only from approved channels.

IS MY DESIRED DRUG APPROVED AND AVAILABLE IN MY COUNTRY?

The blunt fact of the matter is that if a patient lives in a developed country and their national regulator has not approved the medication the patient wants (and the drug is therefore not for sale or obtainable locally), there is likely a very good reason. If that patient resides in the United States, they are part of the world’s most commercially attractive and profitable medical marketplace. Usually, legitimate manufacturers want FDA to approve their drugs so they can gain access to the US market. There may be good commercial or strategic reasons why a genuine manufacturer does not commercialize a particular product in the United States but, in general, if an American patient’s desired drug does not appear on the FDA approved drugs database, known as “Drugs@FDA”1 then this is a major warning sign. The database lists both approved drugs and approved manufacturers.

ARE MY DRUG SOURCES AND METHODS OF PURCHASE SAFE?

Some buying behaviors are more risky for patients than others, and buying prescription drugs over the Internet is the riskiest of all. There are many reputable internet pharmacies, but unfortunately on a global basis

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these are in a small minority. The genuine sites are crowded out by a large number of bogus sites, many of which may be controlled by organized crime groups involved with various other illegal activities including money laundering, selling counterfeit products, credit card fraud, and identity theft. The following sentence should be a sticker on all new computers: USE EXTREME CAUTION IF ORDERING DRUGS VIA THE INTERNET!

Setting up a professional-looking pharmacy website is quick, easy, and relatively cheap—in addition to being very profitable. Consequently, however, many sites get closed down by the good guys; there are always far more crooks and charlatans selling medicines online than there are genuine pharmacies. Unless the website shows a physical location and a phone number, which can be fully verified (by making a call to a pharmacist, for example), it is safer to assume that it is not a genuine site. Patients should also check the site’s accreditation. In the United States, the National Association of Boards of Pharmacy (NABP) operates the Verified Internet Pharmacy Practice Sites™ scheme,2 which certifies and approves online pharmacies. Similar schemes operate in some European countries. Buyers should beware, though: counterfeiters will also fake online accreditations. Nothing should be taken at face value and everything should be checked out. A bona fide pharmacy site should also ask for a medical prescription or other documentation before dispensing. If the patient is seeking medication that normally requires a medical prescription in the jurisdiction in which they live, and they have not been asked by the pharmacy site to provide any such paperwork, then they should ask themselves why not. The risk of fake drugs is not limited to online pharmacies. Those buying drugs abroad should also take care when in unfamiliar surroundings or when buying unfamiliar brands. Even when getting medication from wellknown chain drug stores, a little vigilance never does any harm. WHAT DOES THE PACKAGING LOOK LIKE?

The external appearance of a product can often give some important clues to its authenticity, especially if it is an unsophisticated copy or a refilled pack. Does it look as though it has been opened or tampered with? If there is a closure seal, has it been slit or does it look like it might have been replaced (glue residues, ripped area on package)? If there is a plastic shrink sleeve around the neck of the bottle, check that it looks like an original and has not been resealed in any way. If it is a liquid product

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for injection, check the rubber seal for needle holes and look for apparent damage or alteration to the aluminum collar or the flip cap. Does the package or bottle look scuffed or dirty, like it has been recycled? Genuine pharmaceutical products from legitimate supply channels should normally arrive at the consumer in pretty good shape having been carefully transported. Criminals frequently reuse medical packaging scavenged from waste, or the products may have been stored and transported frequently leading to abrasion. If the patient has used this drug before, does the product and packaging received this time look exactly the same as the previous ones? Look for small differences—different fonts, changes in text size, mis-spellings, color changes, logo not being quite right, and so on. Many counterfeits are very good copies of the original but few are perfect. Patients should check new packaging against previous packs and take the product to a pharmacist if unsure. Is the manufacturer’s label on straight? Genuine drugs are usually machine-labeled by the manufacturer to strict quality controls. If the label is poorly applied or not straight, the product may have been labeled by hand. This may have a simple explanation if the bottle has been made up to order by a busy pharmacist, but if the product was labeled by the manufacturer, then this may be a warning sign. WHAT DOES THE PRODUCT ITSELF LOOK LIKE?

Does the shape and size of the pill look right? Manufacturers are not allowed to change the appearance of their products without a formal regulatory process and therefore it is not done lightly. If the appearance is not the same as the last time the patient received this medication, then there could be an innocent explanation (substitution of a generic equivalent product, change by the manufacturer with an accompanying explanatory note, and so on). However, an unexplained change could indicate either an unidentified quality issue or a counterfeit. In either case, the patient’s pharmacist should be informed. Do the pills (or vials, etc.) in the consignment all look the same as each other? Genuine drugs are manufactured in bulk by automated, quality-controlled processes and have a consistent appearance. If there is noticeable variation between individual pills or capsules this is a warning sign. Are the pills cracked or chipped or crumbling? Some counterfeit drugs are made with machinery identical to the original and are therefore very difficult to tell apart. However, often the fakes will be made with a different tablet press and using different bulk materials. These will not have the

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same physical characteristics as the original machinery and ingredients and often counterfeit drugs are coarse-grained, gritty, or crumbly compared to the genuine product. Has the pill color changed compared to previous prescriptions? Manufacturing of genuine medicines is highly controlled and they should look the same every time. Even subtle changes from the usual appearance, or differences between pills in the same batch, can indicate fake product. If the product is a clear liquid, check for precipitates, cloudiness, or color. If it is a white powder, check for grayness or specks. If there are any features that are not usually present, then seek advice.

WHEN TAKING THE DRUG

Does it feel, smell, or taste different? Genuine manufacturers’ product will usually be consistent, so changes could indicate a counterfeit—especially if there seems to be a strong “masking” flavor or smell present, which was not in previous batches. Sometimes an unusual or unpleasant taste or odor may reflect a quality issue at the manufacturer, rather than a counterfeit. However, this should still be reported to a pharmacist as strange odors and tastes can be an indicator of fungal or bacterial contamination or a tainting of the product during manufacture. Does the product behave unexpectedly (e.g., dissolve differently)? The differences in manufacturing processes and ingredients between genuine drugs and counterfeits mean that there will almost always be differences in their behavior. The fake drug may dissolve badly or not at all when it should be soluble, or it may crumble on the tongue when it should be swallowed whole. For injectable drugs supplied as powder or freeze-dried, any remaining particulates after reconstitution are a strong indicator of a quality problem or a counterfeit.

AFTER TAKING THE DRUG

Any unexpected adverse reactions (side effects) should be noted and followed up with a pharmacist or physician. Many drugs have well-known side effect profiles, which are explained on the patient information leaflet. However, if the patient has taken the drug before without problems, minor symptoms (headache, nausea, dizziness, etc.) after starting a new batch of the medication may be a sign of fake or substandard drugs. Major adverse events (palpitations, shortness of breath, etc.) should be followed up with immediate medical consultation. Often, these events are explainable by

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other factors, but in some cases, counterfeit drugs may be to blame. If the patient has any unusual adverse event relating to their medication, they should keep all drug packaging as evidence. It is important that if the patient has bought additional drugs, vitamins, supplements, and so on off the Internet, then these should be included in the discussion with the doctor—whether the physician authorized or recommended the product or not. Polypharmacy (patients who are taking a variety of medications at the same time) is already a problem for physicians to manage, as many drugs probably interact with each other in ways that have not been fully tested. If the patient hides the fact that they are taking something else on top of what their doctor is aware of, it only makes investigating potential counterfeiting or quality incidents harder and could put other people at risk.

Information Sources

The following works are loosely split into general and specialist works.

GENERAL READERSHIP

Eban, K. (2005) Dangerous Doses: A True Story of Cops, Counterfeiters and the Contamination of America’s Drug Supply. Harcourt, New York. [A classic, thorough, and readable work on the human side of fake drugs in the United States.] Naim, M. (2005) Illicit: How Smugglers, Traffickers and Copycats are Hijacking the Global Economy. Doubleday, New York. [An international perspective on illicit trade from the Editor of Foreign Policy magazine.] Phillips, T. (2005) Knockoff: The Deadly Trade in Counterfeit Goods. Kogan Page, London. [Exposes the links between counterfeiting and other organized crime.]

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Glenny, M. (2008) McMafia: Seriously Organised Crime. The Bodley Head, London. [Fascinating and entertaining account of global investigations into organized crime by distinguished BBC journalist.] As this book was being finalized (mid- 2010), Nature Medicine published a very useful focus on Counterfeit Drugs, with contributions from various authors. Nat. Med. 16 (4), 358–66. doi:10.1038/ nm0410-358a.

SPECIALIST READERSHIP

Satchwell, G. (2004) A Sick Business: Counterfeit Medicines and Organised Crime. The Stockholm Network, London. [A useful, short overview of the key points.] Pitts, P. J. (ed.) (2006) Coincidence or Crisis? Prescription Medicine Counterfeiting. The Stockholm Network, London. [European, policy-focused review.] Hopkins, D. M., Kontnik, L. T., & Turnage, M. T. (2003) Counterfeiting Exposed: Protecting Your Brand and Customers. John Wiley & Sons, Inc, New York. [An excellent overview of the counterfeiting problem across various industries.] Dean, D. A., Evans, E. R., & Hall, I. H. (eds.) (2000) Pharmaceutical Packaging Technology. Taylor & Francis, London. [A detailed and very clear reference work on packaging.] LeParc, M. (ed.) (2002) Protecting Medicines & Pharmaceuticals: A Manual of Anti-counterfeiting Solutions. Reconnaissance International, Egham, Surrey, UK. [A more technical approach with input from technology vendors.] The Economic Impact of Counterfeiting and Piracy OECD (2008) OECD Publishing, Geneva. [Full of statistics and independent research.]

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NEWS

For news articles and updates relating to counterfeit drugs and pharmaceutical security: www.safemedicines.org www.securingpharma.com For broader coverage of authentication issues and technical developments in anti-counterfeiting, across all industries, see “Authentication News,” a monthly newsletter available by subscription: www.authenticationnews.info. There is also a wide range of useful special interest groups on anti-counterfeiting, serialization, GS1, and other security-related topics at www.LinkedIn.com.

EDUCATION

Michigan State University has inaugurated the Anti-Counterfeiting and Product Protection Program (A-CAPP). This inter-disciplinary program teaches the skills needed to protect brands and customers. www.a-cappp.msu.edu/index.html There are a number of conferences in this field, of which the biennial Global Forum on Pharmaceutical Anti-Counterfeiting is arguably the most international and broad-based. www.reconnaissance-intl.com.

ORGANIZATIONS

Some useful trade associations, industry networks, patient groups, international organizations, and so on, are listed below: Anti-Counterfeiting Group (ACG) www.a-cg.org Association of European Trade Mark Owners (MARQUES) www.marques.org Business Action to Stop Counterfeiting and Piracy (BASCAP) www.iccwbo.org/bascap

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Canadian Anti-Counterfeiting Network (CACN) www.cacn.ca Coalition Against Counterfeiting and Piracy (CACP) http://www.theglobalipcenter.com/pages/coalition-against-counterfeitingand-piracy European Alliance for Access to Safe Medicines (EAASM) www.eaasm.eu European Association of Pharmaceutical Full-Line Wholesalers (GIRP) www.girp.eu European Federation of Pharmaceutical Industries and Associations (EFPIA) www.efpia.org European Generic medicines Association (EGA) www.egagenerics.com Global Anti-Counterfeiting Group (GACG) www.gacg.org GS1 Healthcare www.gs1.org/healthcare Healthcare Distribution Management Association (HDMA) www.healthcaredistribution.org Health Industry Business Communications Council (HIBCC) www.hibcc.org Health Industry Distributors Association (HIDA) www.hida.org International Alliance of Patients’ Organizations (IAPO) www.patientsorganizations.org International Anti-Counterfeiting Coalition (IACC) www.iacc.org

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International Authentication Association (IAA) www.internationalauthenticationassociation.org International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) www.ifpma.org International Federation of Pharmaceutical Wholesalers (IFPW) www.ifpw.com International Hologram Manufacturers Association (IHMA) www.ihma.org International Medicinal (IMPACT) www.who.int/impact

Products

Anti-Counterfeiting

International Trademark Association (INTA) www.inta.org Interpol www.interpol.int National Association of Boards of Pharmacy (NABP) www.nabp.net National Association of Chain Drug Stores (NACDS) www.nacds.org North American Security Products Association (NASPO) www.naspo.info Partnership for Safe Medicines www.safemedicines.org Pharmaceutical Cargo Security Coalition (PCSC) www.pcscpharma.com Pharmaceutical Group of the European Union (PGEU) www.pgeu.org

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INFORMATION SOURCES

Pharmaceutical Research and Manufacturers of America (PhRMA) www.phrma.org Pharmaceutical Security Institute (PSI) www.psi-inc.org Rx-360 www.rx-360.org Union des Fabricants (UNIFAB) www.unifab.com World Customs Organization (WCO) www.wcoomd.org World Health Organization (WHO) www.who.int World Intellectual Property Organization (WIPO) www.wipo.int World Trade Organization (WTO) www.wto.org

Drug Regulators

Websites of various national regulatory authorities are listed below. See www.ema.europa.eu/exlinks/exlinks.htm for a fuller list. Argentina National Administration of Drugs, Food & Medical Technology www.anmat.gov.ar Australia Therapeutic Goods Administration www.tga.gov.au Austria Austrian Agency for Health and Food Safety www.ages.at Belgium Federal Agency for Medicines and Health Products www.fagg-afmps.be Brazil National Health Surveillance Agency www.anvisa.gov.br Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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DRUG REGULATORS

Canada Health Canada www.hc-sc.gc.ca Chile Ministry of Health www.minsal.cl China State Food & Drug Administration www.sfda.gov.cn/eng/ Colombia National Institute of Food and Drug Monitoring www.invima.gov.co Denmark Danish Medicines Agency www.dkma.dk European Union European Medicines Agency www.ema.europa.eu Finland Finnish Medicines Agency www.fimea.fi France Agence francaise de s´ecurit´e sanitaire des produits de sant´e www.afssaps.fr Germany Federal Institute for Drugs and Medical Devices www.bfarm.de Ghana Food & Drugs Board www.fdbghana.gov.gh Greece National Organization for Medicines www.eof.gr

DRUG REGULATORS

Hungary National Institute of Pharmacy www.ogyi.hu India Central Drugs Standard Control Organization www.cdsco.nic.in Indonesia Ministry of Health www.depkes.go.id Ireland Irish Medicines Board www.imb.ie Israel Ministry of Health www.health.gov.il Italy Italian Medicines Agency www.agenziafarmaco.it Japan Pharmaceuticals & Medical Devices Agency www.pmda.go.jp/english/index.html Kenya Pharmacy & Poisons Board www.pharmacyboardkenya.org Malaysia National Pharmaceutical Control Bureau http://portal.bpfk.gov.my Mexico Ministry of Health www.ssa.gob.mx Morocco Ministry of Health www.sante.gov.ma

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DRUG REGULATORS

Netherlands Health Care Inspectorate www.igz.nl New Zealand Medsafe www.medsafe.govt.nz Nigeria National Agency for Food and Drug Administration and Control www.nafdac.gov.ng Norway Norwegian Medicines Agency www.legemiddelverket.no Pakistan Drugs Control Organization, Ministry of Health www.dcomoh.gov.pk Philippines Bureau of Food & Drugs www.bfad.gov.ph Poland Office for Medicinal Products www.urpl.gov.pl Portugal Infarmed www.infarmed.pt Russia Rozdravnadzor www.roszdravnadzor.ru Saudi Arabia Saudi Food & Drug Authority www.sfda.gov.sa/En/Home South Africa Medicines Control Council www.mccza.com

DRUG REGULATORS

Spain Spanish Medicines Agency www.agemed.es Sweden Medical Products Agency www.lakemedelsverket.se Switzerland Swiss Agency for Therapeutic Products www.swissmedic.ch Turkey Ministry of Health www.iegm.gov.tr Uganda National Drug Authority www.nda.or.ug United Arab Emirates Ministry of Health www.moh.gov.ae United States of America Food and Drug Administration www.fda.gov Vietnam Ministry of Health www.moh.gov.vn

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Notes and References

CHAPTER 1 1. World Health Organization (2010) Counterfeit Medical Products: Report to the Secretariat, Document A63/23 . WHO, Geneva. http://apps.who.int/gb/ebwha/ pdf_files/WHA63/A63_23-en.pdf (accessed 2 May 2010). 2. Harris, J., Stevens, P., & Morris, J. (2009) Keeping It Real: Protecting the World’s Poor from Fake Drugs. International Policy Network, London.

CHAPTER 2 1. The point is not that shamanism and other faith-based healing traditions are invalid, rather that the claims are untested, and sometimes untestable, in the scientific sense. 2. Kunin, R.A. (1989) Snake oil. West. J. Med . 151 (2), 208. It seems that there may indeed be active ingredients in the original Chinese snake oils. 3. A randomized, double blind, placebo-controlled trial is a design that allocates patients randomly and without bias to treatment groups, and where neither the

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4.

5. 6.

7. 8.

9.

10.

11. 12. 13.

14. 15. 16. 17. 18. 19.

NOTES AND REFERENCES

physician nor the patient knows which of two or more possible options (active treatments or placebo) is being given to each group. It aims to remove the possibility of false results due to placebo effects or psychological suggestion, active or inadvertent, from physician to patient. Newton, P.N., Fern´andez, F.M., Planc¸on, A., et al. (2008) A collaborative epidemiological investigation into the criminal fake artesunate trade in South East Asia. PLoS Med . 5 (2) e32. doi: 10.1371/journal.pmed.0050032. DiMasi, J., Hansen, R., & Grabowski, H. (2003) The price of innovation: new estimates of drug development costs. J. Health Econ. 22 (2) 151– 85. GMP = Good Manufacturing Practices. See for example: www.fda.gov/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ucm064971.htm (accessed 18 June 2010). FDA (2010) website: www.fda.gov/ForIndustry/UserFees/PrescriptionDrug UserFee/default.htm (accessed 4 April 2010). European Commission (2006) Commission warns about fake drugs on the internet. EC Press Release, 27 March 2006. http://europa.eu/rapid/pressReleases Action.do?reference=IP/06/375 (accessed 30 March 2010). Bogdanich, W. & McLean, R. (2007) Poisoned toothpaste in Panama is believed to be from China. New York Times, 19 May 2007. www.nytimes.com/ 2007/05/19/world/americas/19panama.html (accessed 24 May 2010). Full text is available free from the US Government Printing Office (2010) http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=111_cong_bills& docid=f:h759ih.txt.pdf (accessed 16 June 2010). Council of Europe (2010) website: www.coe.int/t/DGHL/StandardSetting/ PharmaCrime/ (accessed 18 June 2010). IMPACT (2010) website: www.who.int/impact/en/ (accessed 15 July 2010). FDA (2010) The possible dangers of buying medicines over the internet. www.fda.gov/ForConsumers/ConsumerUpdates/ucm048396.htm (accessed 15 July 2010). EAASM (2008) The counterfeiting superhighway. Report available from the EAASM website: www.eaasm.eu (accessed 15 July 2010). NABP (2010) website: www.nabp.net/indexvipps2.asp (accessed 16 June 2010). Phillips, T. (2005) Knockoff: The Deadly Trade in Counterfeit Goods. Kogan Page, London. McCartney, S. (2005) The Fake Factor: Why We Love Brands But Buy Fakes. Cyan, London. Gessler, C. (2009) Counterfeiting in the Luxury Industry: The True Cost of Counterfeit Goods. VDM Verlag Dr Muller, Saarbrucken. Glenny, M. (2008) McMafia: Seriously Organized Crime. Vintage, London.

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CHAPTER 3 1. The total size of the market depends on the definition used. To obtain a “prescription” drug, the patient should require a formal consultation and signed prescription from a doctor although in many countries informal dispensing can and does happen. Prescription drugs can be branded (usually patented) or generic. Non-prescription medicines can be “over-the-counter” or pharmacistcontrolled remedies. No class of product is immune from falsification. 2. IMS (2010) IMS forecasts global pharmaceutical market growth of 5–8% annually through 2014; maintains expectations of 4–6% growth in 2010. IMS Press Release, 20 April 2010. Available at www.imshealth.com (accessed 24 May 2010). 3. WHO (2006) Counterfeit medicines: an update on estimates. WHO IMPACT Press Release, 15 November 2006. http://www.who.int/medicines/services/ counterfeit/impact/TheNewEstimatesCounterfeit.pdf (accessed 6 July 2010). 4. MHRA (2010) website: http://www.mhra.gov.uk/Safetyinformation/General safetyinformationandadvice/Adviceandinformationforconsumers/Counterfeit medicinesanddevices/CON019608 (accessed 15 July 2010). 5. PSI (2010) website: www.psi-inc.org/incidentTrends.cfm (accessed 15 July 2010). 6. Porter, M. (1980) Competitive Strategy. Free Press, New York. 7. OECD (2008). The Economic Impact of Counterfeiting and Piracy. OECD Publishing, Paris. 8. Kontnik, L. (2002). Corruption: state involvement in the problem. In: LeParc, M. (ed.) Protecting Medicines and Pharmaceuticals: A Manual of Anticounterfeiting Solutions. Reconnaissance International, Egham, Surrey, UK. 9. Warwick, J. (2010) Officials fear toxic ingredient in Botox could become terrorist tool. Washington Post, 25 January 2010. www.washingtonpost.com/wpdyn/content/article/2010/01/24/AR2010012403013_3.html?hpid=topnews&sid =ST2010012403382 (accessed 26 January 2010). 10. www.wcoomd.org. (accessed 30 August 2010) 11. Irish, J. (2010) Customs group to fight $200 bln bogus drug industry. Reuters.com, 10 June 2010. http://www.reuters.com/article/idUSTRE65961U 20100610 (accessed 18 June 2010). 12. www.rollbackmalaria.org. (accessed 30 August 2010) 13. White, N.J., Pongtavornpinyo, W., Maude, R.J., et al. (2009) Hyperparasitaemia and low dosing are an important source of antimalarial drug resistance. Malaria J . 8, 253. doi:10.1186/1475-2875-8-253. 14. WHO (2009) World Malaria Report 2009 . WHO, Geneva. www.who.int/ malaria/world_malaria_report_2009/mal2009_rep_chap3_v2.pdf (accessed 26 May 2010).

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15. Harris, J., Stevens, P., & Morris, J. (2009) Keeping It Real: Protecting the World’s Poor from Fake Drugs. p 24. International Policy Network, London.

CHAPTER 4 1. Chaubey, S.K., Sangla, K.S., Suthaharan, E.N., & Tan, Y.M. (2010) Severe hypoglycaemia associated with ingesting counterfeit medication. Med. J. Aust. 192 (12) 716–17. 2. Nugent, R., Back, E., & Beith, A. (2010). The Race Against Drug Resistance. Center for Global Development, Washington, DC. 3. Bogdanich, W. & McLean, R. (2007) Poisoned toothpaste in Panama is believed to be from China. New York Times, 19 May 2007. www.nytimes.com/ 2007/05/19/world/americas/19panama.html (accessed 24 May 2010). 4. BBC News (2010) Timeline: China Milk Scandal. http://news.bbc.co.uk/1/hi/ world/asia-pacific/7720404.stm (accessed 24 May 2010). 5. Ipsos-MORI (2009) Annual Survey of Public Trust in Professions. Royal College of Physicians, London. www.ipsos-mori.com/researchpublications/ researcharchive/poll.aspx?oItemId=2478 (accessed 24 May 2010). 6. Aegate (2009) Study validates benefits of drug authentication. Aegate Press Release, 23 September 2009. http://www.aegate.com/aegate-news/studyvalidates-benefits-of-drug-authentication.html (accessed 14 July 2010). 7. OECD (2008) The Economic Impact of Counterfeiting and Piracy. OECD Publishing, Paris. 8. Akerloff, G.A. (1970). The market for ‘Lemons’: quality uncertainty and the market mechanism. Q. J. Econ. 84 (3) 488–500. 9. Rehak, J. (2002) Tylenol made a hero of Johnson & Johnson: the recall that started them all. New York Times, 23 March 2002. http://www.nytimes.com/ 2002/03/23/your-money/23iht-mjj_ed3_.html?pagewanted=1?pagewanted=1 (accessed 25 May 2010). 10. The heparin scandal that affected Baxter Corporation is a recent example. For an overview, see: Powell, B. (2008) Heparin’s deadly side effects. Time, 13 November 2008. www.time.com/time/magazine/article/0,9171,18588701,00.html (accessed 25 May 2010). 11. Margolies, D. (2003) Payments set for courtney victims. Kansas City Star, 9 February 2003, Sect A: 1. The newspaper reported that, in an out-of-court settlement, arbitrators assessed $48.55 million against Eli Lilly and $23.55 million against Bristol-Myers Squibb in a case involving unauthorized and criminal dilution of their products by a pharmacist. Both companies denied liability. Article available for a small fee from the newspaper archives at www.kansascity.com/archives. 12. Commission of the European Communities (2008) Accompanying document to the proposal for a directive of the European Parliament and of the Council amending Directive 2001/83/EC as regards the prevention of the entry into the legal supply chain of medicinal products, which are falsified in

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relation to their identity, history, or source: impact assessment. Commission Staff Working Document, 10 December 2008. http://ec.europa.eu/health/ files/pharmacos/pharmpack_12_2008/counterfeit-ia_en.pdf (accessed 16 June 2010). 13. Sharfstein, J.M. (2010) Statement of Joshua M. Sharfstein, M.D., Principal Deputy Commissioner, Food and Drug Administration, Department of Health and Human Services, before the Sub-Committee on Health, Committee on Energy and Commerce, U.S. House of Representatives. FDA Press Release, 10 March 2010. http://energycommerce.house.gov/Press_111/20100310/Sharfstein .Testimony.3.10.10.pdf (accessed 16 June 2010).

CHAPTER 5 1. Felson, M. & Clarke, R.V. (1998) Opportunity Makes the Thief. Police Research Series, Paper 98 . Home Office, London. http://rds.homeoffice.gov.uk/ rds/prgpdfs/fprs98.pdf (accessed 16 June 2010). 2. WHO (2009) website: www.who.int/medicines/services/counterfeit/overview/ en/ (accessed December 2009). 3. FDA (2010) website: www.fda.gov/RegulatoryInformation/Legislation/Federal FoodDrugandCosmeticActFDCAct/FDCActChaptersIandIIShortTitleand Definitions/ucm086297.htm (accessed 25 May 2010). 4. Nagarajan, R. (2009) Chinese passing off fake drugs as ‘Made in India’. The Times of India, 9 June 2009. http://timesofindia.indiatimes.com/articleshow/ 4633377.cms (accessed 25 May 2010). 5. Diaz Cote, A. (2010) Presentation at 5th Global Forum on Pharmaceutical Anti-Counterfeiting, Miami, FL, February 2010. 6. Werner, J. (2010) Presentation at 5th Global Forum on Pharmaceutical AntiCounterfeiting, Miami, FL, February 2010. 7. Eban, K. (2005) Dangerous Doses. Harcourt, Orlando. 8. www.rx-360.org (accessed 30 August 2010) 9. Pitts, P. (ed.) (2006) Coincidence or Crisis? Prescription Medicine Counterfeiting. The Stockholm Network, London. 10. Satchwell, G. (2004). A Sick Business. The Stockholm Network, London. 11. http://europa.eu/abc/treaties/index_en.htm (accessed 25 May 2010).

CHAPTER 6 1. Krug, E.G., Dahlberg, L.L., Mercy, J.A., Zwi, A.B., & Lozano, R. (eds.) (2002) World Report on Violence and Health. Chapter 7: Self-directed Violence. WHO, Geneva. www.who.int/violence_injury_prevention/violence/global_campaign/ en/chap7.pdf (accessed 25 May 2010). 2. My thanks to David Teale for this observation.

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3. Attributed to Petronius, Roman writer, 1st century A.D. 4. www.facebook.com (accessed 30 August 2010) 5. CNN.com (2009) Facebook nearly as large as U.S. population. http:// edition.cnn.com/2009/TECH/09/16/facebook.profit/index.html (accessed 21 June 2010). 6. www.twitter.com/fdarecalls and www.twitter.com/fda_drug_info (accessed 25 June 2010). 7. www.twitter.com/ema_news (accessed 25 June 2010). 8. www.youtube.com/user/USFoodandDrugAdmin (accessed 25 June 2010). 9. www.realdanger.co.uk/get-real-get-a-prescription (accessed 24 May 2010).

CHAPTER 7 1. I am indebted to David S. Howard, of Johnson & Johnson and past Chair of the International Authentication Association, for this insight. 2. The testudo or “tortoise” formation involved individual soldiers holding their shields together all around and above an infantry formation to form a barrier to arrows and other missiles. It required coordination and training but was highly effective. See Plutarch’s Life of Anthony, Ant. 45, for the primary source. For more detail on Roman tactics see Rance, P. (2004) The fulcum, the Late Roman and Byzantine Testudo: the Germanization of Roman infantry tactics? Greek, Roman Byz. Stud . 44, 265–326.

CHAPTER 8 1. Hardin, G. (1968) The tragedy of the commons. Science 162 (3859) 1243–48. doi: 10.1126/science.162.3859.1243 (accessed 15 July 2010). 2. www.gs1.org/healthcare (accessed 30 August 2010) 3. www.iso.org (accessed 30 August 2010) 4. www.wto.org (accessed 30 August 2010) 5. WTO (2006) TRIPS and pharmaceutical patents: fact sheet. www.wto.org/ english/tratop_e/trips_e/factsheet_pharm00_e.htm (accessed 9 June 2010). 6. Mertha, A. (2005). The Politics of Piracy: Intellectual Property in Contemporary China. Cornell University Press, Ithaca, NY. 7. www.ifpma.org (accessed 30 July 2010) 8. IFPMA (2010) The IFPMA ten principles on counterfeit medicines. IFPMA Press Release, 12 May 2010. www.ifpma.org/fileadmin/webnews/2010/pdfs/ 20100512_IFPMA_Ten_Principles_on_Counterfeit_Medicines_12May2010. pdf (accessed 25 May 2010). 9. Grogan, K. (2010) European parliament endorses drug monitoring rules. PharmaTimes.com http://www.pharmatimes.com/Article/10-09-23/European_ Parliament_endorses_drug_monitoring_rules.aspx (accessed 23 September 2010).

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CHAPTER 9 1. www.whitehouse.gov/omb/intellectualproperty/ (accessed 25 June 2010). 2. US Intellectual Property Enforcement Coordinator (2010) Joint strategic plan on intellectual property enforcement. June 2010. www.whitehouse.gov/omb/ assets/intellectualproperty/intellectualproperty_strategic_plan.pdf (accessed 25 June 2010). 3. Adapted from: Tillery, M.K. (2006) The Legal Framework for Authentication. Authentication News, July 2006. (accessed via www.international authenticationassociation.org 19 December 2009). 4. www.wipo.org (accessed 30 August 2010) 5. Europolitics (2010) Generic drugs: eu criticized. 20 May 2010. www. europolitics.info/business-competitiveness/generic-drugs-eu-criticised-art2724 64-7.html (accessed 25 May 2010). 6. www.wipo.int/madrid/en/ (accessed 30 July 2010) 7. https://apps.cbp.gov/e-recordations/ (accessed 15 July 2010). 8. www.cbp.gov/xp/cgov/trade/priority_trade/ipr/ (accessed January 2010). 9. Bennett, S. (2010) Pfizer: Civil Suits for Drug Counterfeiters. Business Week , 8 July 2010 www.businessweek.com/magazine/content/10_29/b4187021988297 .htm (accessed 14 July 2010).

CHAPTER 11 1. www.psi-inc.org (accessed 30 August 2010) 2. www.naspo.info (accessed 30 August 2010) 3. www.iso.org/iso/iso_technical_committee.html?commid=572293 (accessed 25 May 2010).

CHAPTER 12 1. www.hse.ie/eng/services/Find_a_Service/entitlements/medical_cards/ (accessed 9 February 2010). 2. Jack, A. (2010) Pfizer launches e-payment system. Financial Times, 8 February 2010. www.ft.com/cms/s/0/503e764c-1414-11df-8847-00144feab49a.html (accessed 9 February 2010).

CHAPTER 13 1. Wienen, F., Deubner, R., & Holzgrabe, U. (2003) Composition and impurity profile of multi-source raw material of gentamicin—a comparison. Pharmeuropa 15 (2) 273–279. See also: Hopkins, D.M., Kontnik, L.T., & Turnage, M.T. (2003) Counterfeiting Exposed . John Wiley & Sons, Inc, New York, pp 72–73 for a summary of the gentamicin case in the USA.

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2. Baxter (2010) website: Heparin sodium injection—background information. www.baxter.com/information/safety_information/heparin_background_infor mation.html#case_study (accessed 25 May 2010). 3. FDA (2010) website: Information on adverse event reports and heparin. www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsand providers/ucm112669 (accessed 22 June 2010). 4. Baxter International, Inc. (2008) Annual Report. www.baxter.com/downloads/ investors/reports_and_financials/annual_report/2008/PDF_files/BaxterAR_ 2008.pdf (accessed 25 May 2010). 5. Richwine, L. & Heavey, S. (2008) Families tell U.S. Lawmakers of Heparin Deaths. Reuters.com, 29 April 2008. www.reuters.com/article/idUSN29333077 (accessed 25 May 2010). 6. www.rx-360.org/AboutRx360/Objectives/tabid/103/Default.aspx (accessed 25 May 2010). The Federal Trade Commission response to the Rx-360 proposals can be found at http://www.ftc.gov/os/2010/09/100916bloomletter.pdf (accessed 20 September 2010). 7. Newton, P.N., Fernandez, F.M., Green, M.D., Primo-Carpenter, J., & White, N.J. (2010) Counterfeit and substandard anti-infectives in developing countries. In: Sosa, A. de, J., Byarugaba, D.K., Am´abile-Cuevas, C.F., Hsueh, P.-R., Kariuki, S., & Okeke, I.N. (eds.) Antimicrobial Resistance in Developing Countries. pp 413–443, Springer, New York. 8. FDA (2009) Guidance for Industry: pharmaceutical components at risk for melamine contamination. www.fda.gov/downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/UCM175984.pdf (accessed 22 June 2010). 9. Beatty, A. (2008) Panama cough syrup death toll rises further. Reuters.com, 14 February 2008. www.reuters.com/article/idUSN14497747 (accessed 22 June 2010). 10. EMA (2009) website: What is the background regarding international incidents of glycerol contamination? www.ema.europa.eu/Inspections/gmp/q16.htm (accessed 7 December 2009).

CHAPTER 14 1. See the following animation for an excellent view of how a modern tablet press works: http://en.wikipedia.org/wiki/File:Tablet_press_animation.gif#file (accessed 23 June 2010). 2. FDA (2010) website: Inactive ingredient search for approved drug products. www.accessdata.fda.gov/scripts/cder/iig/index.cfm (accessed 25 May 2010). 3. FDA (2010) website: GRAS substances (SCOGS) database. www.fda.gov/Food /FoodIngredientsPackaging/GenerallyRecognizedasSafeGRAS/GRASSubsta ncesSCOGSDatabase/default.htm (accessed 25 May 2010). 4. FDA (2010) website: Guidance for industry: incorporation of physical-chemical identifiers into solid oral dosage form drug products for anticounterfeiting.

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www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/ guidances/UCM171575.pdf (accessed 15 July 2010). 5. FDA (2010) website: Guidance for industry: (R2) pharmaceutical development www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfor mation/Guidances/ucm073507.pdf (accessed 17 June 2010). 6. Electronic Code of Federal Regulations website: Title 21: Food and Drugs http://ecfr.gpoaccess.gov/cgi/t/text/text-idx?c=ecfr&tpl=/ecfrbrowse/Title21/ 21cfr314_main_02.tpl (accessed 23 June 2010).

CHAPTER 15 1. Watson, D.G. (2005) Pharmaceutical Analysis: A Textbook for Pharmacy Students and Pharmaceutical Chemists (2nd Edition). Churchill Livingstone, London. 2. GPHF (2010) website: The GPHF-Minilab® —protection against counterfeit medicines. www.gphf.org/web/en/minilab/index.htm (accessed 23 June 2010). 3. www.gphf.org. (accessed 30 August 2010) 4. WHO (1999) Counterfeit Drugs—Guidelines for the Development of Measures to Combat Counterfeit Drugs. WHO, Geneva. http://whqlibdoc. who.int/hq/1999/WHO_EDM_QSM_99.1.pdf (accessed 25 May 2010). 5. Hall, K.E. (2006) Characterization of counterfeit artesunate antimalarial tablets from Southeast Asia. Am. J. Trop. Med. Hyg. 75 (5), 804–11. 6. Kelesidis, T., Kelesidis, I., Rafailidis, P.I., & Falagas, M.E. (2007) Counterfeit or substandard antimicrobial drugs: a review of the scientific evidence. J. Antimicrob. Chemother. 60 (2), 214–36. 7. Wang, Q., Ma, D., & Higgins, J.P. (2006) Analytical method selection for drug product dissolution testing. Dissol. Technol . 13 (3), 613. 8. Goldstein, J.N. (2003) Scanning Electron Microscopy and X-Ray Microanalysis. Springer, New York. 9. Keire, D.A., Trehy, M.L., Reepmeyer, J.C., et al., (2010) Analysis of crude heparin by 1H NMR, capillary electrophoresis, and strong-anion-exchange-HPLC for contamination by over sulfated chondroitin sulfate. J. Pharm. Biomed. Anal. 51 (4), 921–26. 10. Holzgrabe, U., Deubner, R., Schollmayer, C., & Waibel, B. (2005) Quantitative NMR spectroscopy—applications in drug analysis. J. Pharm. Biomed. Anal. 38 (5), 806–12. 11. Wawer, I.H. (2005) NMR Spectroscopy in Pharmaceutical Analysis. Elsevier, Amsterdam. 12. Santamaria-Fernandez, R. & Wolff, J.-C. (2010) Application of laser ablation multicollector inductively coupled plasma mass spectrometry for the measurement of calcium and lead isotope ratios in packaging for discriminatory purposes. Rapid Commun. Mass Spectrom. 24 (14), 1993–99.

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13. Cody, R.L. (2005) Versatile new ion source for the analysis of materials in open air under ambient conditions. Anal. Chem. 77 (8), 2297–302. doi:10.1021/ ac050162j. 14. Alvarez, J.G. (2004) Clinical and pharmaceutical applications of gas chromatography. In: Grob, R.L. & Barry, E.F. (eds.) Modern Practice of Gas Chromatography (4th Edition), pp. 739–68. Wiley, New York. 15. The Wellcome Trust (2008) Fake antimalarial drugs analysis highlights threat to global health. Press release 12 February 2008. http://malaria. wellcome.ac.uk/doc_WTX047603.html (accessed 7 June 2010). 16. Taylor, P. (2009) inXitu brings portable XRD analysis to pharma counterfeit fight. Securing Pharma, 9 October 2009. www.securingpharma.com/40/articles /247.php (accessed 25 June 2010). 17. Taylor, P. (2010) NAFDAC praises TruScan role in Nigerian counterfeit fight. Securing Pharma, 15 April 2010. www.securingpharma.com/40/articles/443 .php (accessed 27 May 2010). 18. TeraView (2010) website: www.teraview.com/terahertz/id/27 (accessed 25 June 2010).

CHAPTER 16 1. Dean, D.A., Evans, E.R., Hall, I.H. (eds.) (2000) Pharmaceutical Packaging Technology. Taylor & Francis, London. 2. Bank of England (2010) website: Banknote checklist. www.bankofengland.co. uk/banknotes/kyb_lo_res.pdf (accessed 29 June 2010). 3. U.S. Bureau of Engraving and Printing (2010) website: The new $100 note. www.newmoney.gov/newmoney/default.aspx (accessed 29 June 2010). 4. Committee on Technologies to Deter Currency Counterfeiting, National Research Council (2007) A Path to the Next Generation of US Banknotes: Keeping Them Real . National Academies Press, Washington, DC. 5. U.K. Medicines & Healthcare products Regulatory Agency (2003) Best practice guidance on labelling and packaging of medicines. MHRA Guidance Note Number 25 . www.mhra.gov.uk/home/idcplg?IdcService=GET_ FILE&dDocName=CON007554&RevisionSelectionMethod=Latest (accessed February 2010).

CHAPTER 17 1. Dean, D.A., Evans, E.R., Hall, I.H. (eds.) (2000) Pharmaceutical Packaging Technology. Taylor & Francis, London. 2. BRIDGE (2010) Project website: www.bridge-project.eu (accessed 29 June 2010).

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CHAPTER 18 1. Eban, K. (2005) Dangerous Doses. Harcourt, Orlando. 2. U.S. Department of Health & Human Services (2010) website: Health information privacy. www.hhs.gov/ocr/privacy (accessed 27 May 2010).

CHAPTER 19 1. International Hologram Manufacturers Association (2010) website: www.ihma.org (accessed 27 May 2010). 2. Mediharta (2010) website: About Meditag ®. www.mediharta.com.my/benefits. shtml (accessed 27 May 2010). 3. Newton, P.N., Fern´andez, F.M., Planc¸on, A., et al. (2008) A collaborative epidemiological investigation into the criminal fake artesunate trade in South East Asia. PLoS Med . 5 (2) e32. (doi: 10.1371/journal.pmed.0050032).

CHAPTER 21 1. International Authentication Association (2010) website: www.internationalauth enticationassociation.org (accessed 17 July 2010).

CHAPTER 23 1. FDA (2010) website. Guidance for Industry: incorporation of physical-chemical identifiers into solid oral dosage form drug products for anticounterfeiting. www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/ guidances/UCM171575.pdf (accessed 7 June 2010). 2. UK MHRA (2009) website: Class 2 Drug Alert (Action within 48 hours): Allen and Hanburys—Seretide 250 Evohaler (25 micrograms of salmeterol xinafoate and 250 micrograms of fluticasone propionate per actuation)—EL (09) A/12. 12 May 2009. www.mhra.gov.uk/Publications/Safetywarnings/ DrugAlerts/CON046565 (accessed 7 June 2010). 3. FDA (2010) website. FDA warns consumers about counterfeit Alli: the counterfeit products contain controlled substance sibutramine. 18 January 2010. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm197857.htm (accessed 7 June 2010). 4. Glaxo SmithKline was the victim of a large-scale theft in August 2009 when 25,000 Advair® inhalers were stolen from its facility in Richmond, VA. GSK website: GSK advisory: warehouse theft. 24 August (2009). http://us.gsk.com/html/media-news/pressreleases/2009/2009_us_pressrelease_ 10053.htm (accessed 7 June 2010). 5. LifeScan, Inc. (2010) website: Genuine OneTouch®. www.lifescan.com/ company/about/press/genuineonetouch (accessed 7 June 2010).

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6. UK MHRA (2010) website: Counterfeit medicines and devices. www.mhra. gov.uk/Safetyinformation/Generalsafetyinformationandadvice/Adviceandinfor mationforconsumers/Counterfeitmedicinesanddevices/index.htm (accessed 12 January 2010). 7. GS1 (2010) website: GS1 standards. www.gs1.org/healthcare/standards (accessed 1 July 2010). 8. Standards are also promoted by the Health Industry Communications Council. www.hibcc.org (accessed 30 August 2010) 9. FDA (2010) website: Unique device identification. www.fda.gov/Medical Devices/DeviceRegulationandGuidance/UniqueDeviceIdentifiers/default.htm (accessed 1 July 2010).

CHAPTER 24 1. NASPO (2010) website: Standards documents. www.naspo.info/pages/standards. html (accessed 1 July 2010). 2. CEN (2010) website: www.cen.eu/cen/pages/default.aspx (accessed 1 July 2010). 3. FDA (2010) website: Guidance for industry: warnings and precautions, contraindications, and boxed warning sections of labeling for human prescription drug and biological products—content and format. January 2006. www.fda.gov/ downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm 075096.pdf (accessed 7 June 2010). 4. Astrazeneca (2007) website: Important information regarding Losec iv., Nexium blister packs, Nexium iv. & Iressa local package. 31 October 2007. http://en.astrazeneca.com.cn/8875294/8875302/news1?itemId=8881963 (accessed 7 June 2010). 5. FDA (2010) website: FDA warns consumers about counterfeit Alli: the counterfeit products contain controlled substance sibutramine. 18 January 2010. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm197857.htm (accessed 7 June 2010).

CHAPTER 25 1. Shanley, A. (2009) Anticounterfeiting the Focus of USP Science Meeting. PharmaManufacturing.com www.pharmamanufacturing.com/articles/2009/140.html (accessed 17 June 2010). 2. Sherer, S. & Anderson, E. (2004) Topomicroscopy: producing 3D images. Adv. Mater. Proc. 162 (10), 27–28.

CHAPTER 26 1. FDA (2010) website: Combination product definition. www.fda.gov/Combination Products/AboutCombinationProducts/ucm118332.htm (accessed 2 February 2010).

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2. Baikait, R. (2003) Unsafe injections blamed for 1.3 million premature deaths annually. Pharmabiz.com, 21 May 2003. www.pharmabiz.com/article/detnews. asp?Arch=&articleid=15772§ionid=13 (accessed 7 June 2010). 3. Chauhan, P. (2006) Police gives clean chit in expired stent case. The Tribune (India) Online edition, 21 March 2006. www.tribuneindia.com/2006/20060322/ himachal.htm#4 (accessed 7 June 2010).

CHAPTER 27 1. FDA (2010) website: FDA urges industry to take additional steps to prevent cargo theft. FDA press release, 28 April 2010. www.fda.gov/NewsEvents/News room/PressAnnouncements/ucm209911.htm (accessed 7 June 2010). 2. See www.pcscpharma.com (accessed 30 August 2010) 3. Eban, K. and Graham, J.A. (2010) Are you buying illegal drugs? New York Times, 31 March 2010. www.nytimes.com/2010/04/01/opinion/01eban.html (accessed 7 June 2010).

CHAPTER 28 1. www.ispe.org. (accessed 30 August 2010)

CHAPTER 29 1. FDA (2010) website: National drug code directory. www.fda.gov/Drugs/Infor mationOnDrugs/ucm142438.htm (accessed 8 June 2010). 2. EFPIA (2006) Position paper: identification and coding of pharmaceutical products In Europe. November 2006. www.efpia.org/Objects/2/Files/codingRIFD 0906.pdf (accessed 1 July 2010). 3. ISO/IEC 16022:2006. Information technology: Automatic identification and data capture techniques: Data Matrix bar code symbology specification www.iso.org/iso/catalogue_detail.htm?csnumber=44230 (accessed 8 June 2010). 4. GS1 Healthcare (2010) website: www.gs1.org/healthcare (accessed 8 June 2010). 5. ISO/IEC 15418:2009. Information technology: automatic identification and data capture techniques: GS1 Application Identifiers and ASC MH10 Data Identifiers and maintenance www.iso.org/iso/catalogue_detail.htm?csnumber= 51504 (accessed 8 June 2010). 6. ISO/IEC 15434:2006. Information technology: Automatic identification and data capture techniques: Syntax for high-capacity ADC media www.iso.org/iso/ catalogue_detail.htm?csnumber=43692 (accessed 8 June 2010). 7. ISO/IEC 15415:2004. Information technology: Automatic identification and data capture techniques: Bar code print quality test specification: Twodimensional symbols www.iso.org/iso/catalogue_detail.htm?csnumber=27658 (accessed 8 June 2010).

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8. Denso Wave, Inc. (2010) website: QR code standardization. www.densowave.com/qrcode/qrstandard-e.html (accessed 1 July 2010). 9. BRIDGE Consortium (2009) BRIDGE: building radio frequency identification solutions for the global environment. Final Report, October 2009. www.bridgeproject.eu/data/File/BRIDGE_Final_report.pdf (accessed 8 June 2010). 10. Nokia (2010) website. Mobile codes. http://mobilecodes.nokia.com/index.htm (accessed 8 June 2010). 11. Glover, B. & Bhatt, H. (2006) RFID Essentials. O’Reilly, Sebastopol, CA. 12. FDA (2003) website. Counterfeit drug task force report. October 2003. www.fda.gov/Drugs/DrugSafety/ucm174388.htm (accessed 1 July 2010). 13. Seevers, R.H. (2005) Report to FDA of PQRI RFID Working Group. 1 December 2005. www.pqri.org/pdfs/RFID_Report_to_FDA_23Mar2006.pdf (accessed 9 June 2010). 14. Bennett, S. (2010) Mobile phones fight Africa’s drug wars. Bloomberg BusinessWeek , 13 May 2010. www.businessweek.com/magazine/content/10_21/ b4179037128534.htm (accessed 9 June 2010).

CHAPTER 30 1. GS1 (2010) website: Healthcare GTIN allocation rules. 3 October 2007. www.gs1.org/docs/gsmp/healthcare/GS1_Healthcare_GTIN_Allocation_Rules. pdf (accessed 9 June 2010). 2. GS1 (2010) website: Healthcare industry sunrise dates. www.gs1us.org/sectors/ healthcare/healthcare_sunrise_dates (accessed 9 June 2010). 3. FDA (2010) website: Guidance for industry: standards for securing the drug supply chain - standardized numerical identification for prescription drug packages. March 2010. www.fda.gov/RegulatoryInformation/Guidances/ucm125505 .htm#_Toc254967078 (accessed 9 June 2010). 4. EPCglobal, Inc. (2007) website: EPC Information Services (EPCIS) Version 1.0.1 Specification. 21 September 2007. www.epcglobalinc.org/standards/epcis/ epcis_1_0_1-standard-20070921.pdf (accessed 9 June 2010). 5. EPCglobal, Inc. (2010) website: EPC tag data standard (TDS) www.epc globalinc.org/standards/tds/ (accessed 2 September 2010). 6. Prooftag SAS (2010) website: The Bubble Tag™: the ultimate visible security solution. www.prooftag.net/en/technology/concept (accessed 29 June 2010). 7. Buchanan, J.D.R., Cowburn, R.P., Jausovec, A.-V., et al., (2005) ‘Fingerprinting’ documents and packaging. Nature 436–475.

CHAPTER 31 1. Framework Convention Alliance (2008) Technology and the fight against illicit tobacco trade. Media Briefing. www.fctc.org/dmdocuments/Media%20Briefing_ technology.pdf (accessed 9 June 2010).

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2. For excellent discussions of inference and related problems in drug tracking, see Dirk Rodgers’s blog at www.rxtrace.com (accessed 30 August 2010) 3. EFPIA, Apoteket AB (2010) EFPIA product verification project. Joint final report, April 2010. www.efpia.eu/Content/Default.asp?PageID=559&DocID= 8770 (accessed 9 June 2010). 4. AFSSAPS (2010) website: www.afssaps.fr/var/afssaps_site/storage/original/ application/b02d12c20a61ec4c6119974c92c0d15f.pdf (accessed 9 June 2010). 5. Taylor, P. (2010) GSK is ’serialisation-ready’ thanks to France’s CIP13 deadline. Securing Pharma, 4 June 2010. www.securingpharma.com/40/articles/496 .php (accessed 9 June 2010). 6. FDA (2003) website: Guidance for industry Part 11, electronic records: electronic signatures—scope and application. August 2003. www.fda.gov/ downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM 072322.pdf (accessed 6 July 2010). See also the Federal Information Processing Standards Publications produced by the Information Technology Laboratory (ITL) of the US National Institute of Standards and Technology. www.itl.nist.gov/fipspubs/ (accessed 6 July 2010). 7. GS1 Healthcare website: www.gs1.org/healthcare. (accessed 30 August 2010)

CHAPTER 32 1. State of Florida Statutes (2009) Chapter 499: drug, cosmetic, and household products: part I: drugs, devices, cosmetics, household products. www.leg.state. fl.us/statutes/index.cfm?App_mode=Display_Statute&URL=Ch0499/ch0499. htm (accessed 6 July 2010). 2. Rogers, D. (2009) The Florida pedigree law. RxTrace.com, 10 August 2009. www.rxtrace.com/2009/08/florida-pedigree-law.html (accessed 1 May 2010). 3. California State Board Of Pharmacy (2008) Response of the California State Board of Pharmacy [to FDA] docket No. FDA-2008-N-0120. 12 May 2008. www.pharmacy.ca.gov/laws_regs/docket_0120_comments.pdf (accessed 10 June 2010). 4. California State Board Of Pharmacy (2010) website: www.pharmacy.ca.gov/ about/gov_proposed_epedigree_amends.pdf (accessed 10 June 2010). 5. Rogers, D. (2010) California pedigree law: historic change to commerce. RxTrace.com, 14 June 2010. www.rxtrace.com/2010/06/california-pedigreelaw-historic-change-to-commerce.html (accessed 14 June 2010). 6. FDA (2010) website: Standards for securing the drug supply chain - standardized numerical identification for prescription drug packages. March 2010. www.fda.gov/RegulatoryInformation/Guidances/ucm125505.htm (accessed 10 June 2010). 7. Electronic Code of Federal Regulations (2010) website. Title 21 Part 207: registration of producers of drugs and listing of drugs in commercial distribution. http://ecfr.gpoaccess.gov/cgi/t/text/text-idx?c=ecfr&tpl=/ecfr browse/title21/21cfr207_main_02.tpl (accessed 10 June 2010).

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8. Barlas, S. (2010) With health care reform out of the way, Congress can now confront drug safety. Pharm. Therap. 35 (5) 246 www.ncbi.nlm.nih.gov/pmc/ articles/PMC2873706/ (accessed 6 July 2010). 9. U.S. Congress (2009) H.R. 759: Food and Drug Administration Globalization Act of 2009. www.govtrack.us/congress/bill.xpd?bill=h111-759 (accessed 6 July 2010). 10. European Commission (2008) website: Pharmaceutical package. 10 December 2008 http://ec.europa.eu/enterprise/sectors/pharmaceuticals/humanuse/package_en.htm (accessed 10 June 2010). 11. Council of Europe (2010) website: www.coe.int/t/dghl/standardsetting/ medicrime/CDPC%20_2009_15Fin%20E%20Draft%20Convention%2009% 2011%2009CM.pdf (accessed 24 July 2010). 12. EFPIA, Apoteket AB (2010) EFPIA product verification project. Joint final report, April 2010. www.efpia.eu/content/default.asp?PageID=559&DocID= 8770 (accessed 10 June 2010). 13. Alexander, J. (2010) Commerce Ministry plans to make barcodes compulsory for exports of pharma products. Pharmabiz.com 8 September 2010 http://www.pharmabiz.com/article/detnews.asp?articleid=57262§ionid= (accessed 15 September 2010). 14. UN Data (2010) website: Malaysia. http://data.un.org/CountryProfile.aspx? crName=Malaysia (accessed 2 May 2010). 15. Details correct at 17 July 2010. See website for updates: www.mediharta. com.my. 16. CIA (2010) The World Factbook: Turkey. www.cia.gov/library/publications/ the-world-factbook/geos/tu.html (accessed 11 June 2010). 17. Neylan, D. (2009) Barcode system to stamp out counterfeit drugs. Today’s Zaman, 18 August 2009 www.todayszaman.com/tz-web/news-184271-barcode -system-to-stamp-out-counterfeit-drugs.html (accessed 11 June 2010). 18. Turkish Ministry of Health (2010) website: The Turkish pharmaceuticals track & trace system (ITS). www.iegm.gov.tr/Default.aspx?sayfa=tracking&lang=en (accessed 11 June 2010). 19. Bate, R. (2009) Fighting a bitter prescription. The American, 30 July 2009. www.american.com/archive/2009/july/fighting-a-bitter-prescription (accessed 11 June 2010). 20. Taylor, P. (2010) Safety in numbers: Brazil’s medicine serialization initiative. Securing Pharma, 10 April 2010 . http://www.securingpharma.com/40/articles/ 440.php (accessed 21 July 2010).

CHAPTER 33 1. Delval, P. & Zilberstein, G. (2008) La Contrefacon: Un Crime Organis´e JeanClaude Gawsewitch, Paris. 2. Naim, M. (2005) Illicit. Doubleday, New York.

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3. Eke, S. (2006) Fake Russian alcohol ‘kills many’. BBC News, 23 June 2006 http://news.bbc.co.uk/1/hi/world/europe/5111762.stm (accessed 11 June 2010). 4. SICPA Product Security S.A. (2007) Republic of Turkey’s Ministry of Finance mandates SICPA-Assan to implement security tracking system for tobacco and alcohol products. PR Newswire, 24 April 2007. www.prnewswire.com/ news-releases/republic-of-turkeys-ministry-of-finance-mandates-sicpa-assanto-implement-security-tracking-system-for-tobacco-and-alcohol-products59207587.html (accessed 11 June 2010). 5. European Commission (2004) European Commission and Philip Morris International sign 12-year Agreement to combat contraband and counterfeit cigarettes. EC Press Release, 9 July 2004. http://ec.europa.eu/anti_fraud/ budget/pr_en.pdf (accessed 11 June 2010). 6. www.fctc.org. (accessed 30 July 2010) 7. www.producetraceability.org. (accessed 30 July 2010) 8. www.harvestmark.com. (accessed 30 July 2010) 9. www.foodsafetyworkinggroup.gov. (accessed 30 July 2010) 10. Associated Press (2007) Mattel issues new massive China recall. MSNBC.com, 14 August 2007. www.msnbc.msn.com/id/20254745/ (accessed 11 June 2010). 11. Toy Industries of Europe (2009) Traceability in the 2009 toy safety directive. Factsheet, October 2009. http://ec.europa.eu/enterprise/sectors/toys/documents/ pdf/tie_ec_factsheet_tr_october_2009_final_en.pdf (accessed 11 June 2010). 12. US Consumer Product Safety Commission (2010) website: Consumer product safety improvement act. www.cpsc.gov/about/cpsia/cpsia.html (accessed 11 June 2010).

CHAPTER 34 1. US Drug Enforcement Administration (2010) Two plead guilty in $40 million meth conspiracy. DEA Press Release, 21 January 2010. www.justice. gov/dea/pubs/states/newsrel/2010/stlouis012110.html (accessed February 2010). 2. HM Treasury (1997) Managing the risk of fraud—a guide for managers. HM Treasury (UK) website: http://archive.treasury.gov.uk/fraud/mriskf.pdf (accessed 11 June 2010). 3. Experian Ltd (2007) Resist and repel: the experian insider fraud dossier. Experian White Paper , November 2007. www.experian-da.com/Web/News/ Newsletters/0806/InsiderFraudWP(Resist%20and%20Repel).pdf (accessed 11 June 2010). 4. Dhar, A. (2010) Whistleblower scheme on spurious drugs evokes fake complaints. The Hindu, 27 May 2010. http://beta.thehindu.com/news/national/ article439233.ece (accessed 11 June 2010).

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CHAPTER 36 1. NobelPrize.org (2010) website: The Nobel Prize in Physics 1922: Niels Bohr. http://nobelprize.org/nobel_prizes/physics/laureates/1922/bohr-bio.html (accessed 16 July 2010). 2. WHO IMPACT (2009) An overview of the IMPACT Working Groups’ documents and activities. 2 April 2009. www.who.int/impact/activities/overviewof IMPACTworkingdocs.pdf (accessed 11 June 2010).

CHAPTER 37 1. Sabat´e, E. (ed.) (2003) Adherence to long term therapies: evidence for action. World Health Organization, Geneva. 2. Henderson, M. (2010) Francis Collins: the extended genome anniversary interview. The Times Online, 24 June 2010. http://timesonline.typepad.com/science/ 2010/06/francis-collins-the-extended-genome-anniversary-interview.html (accessed 12 July 2010). 3. Bailey, A. (2009) Banknotes in circulation—still rising. What does this mean for the future of cash? Address by the Executive Director for Banking Services and Chief Cashier of the Bank of England. Banknote 2009 Conference, Washington DC, 6 December 2009. www.bis.org/review/r091214e.pdf (accessed 11 June 2010).

CHAPTER 38 1. Buenos Aires Herald (2010) 400,000 counterfeit erectile dysfunction pills seized in port. www.buenosairesherald.com/BreakingNews/View/22181 (accessed 24 February 2010). 2. Ministry of Justice, Brazil (2009) Record Seizure of drugs serves as a warning to consumers. www.jurisway.org.br/en/article.asp?id_dh=2752 (accessed 16 July 2010). 3. Canada Border Services Agency (2009) RCMP and CBSA caution against purchasing drugs online. CBSA Press Release, 19 November 2009. http://cbsaasfc.gc.ca/media/release-communique/2009/2009-11-20-eng.html (accessed 16 July 2010). 4. Cockburn, R., Newton, P.N., Agyarko, E.K., Akunyili, D., & White, N.J. (2005) The global threat of counterfeit drugs: why industry and governments must communicate the dangers. PLoS Med . 2 (4) e100. doi:10.1371/ journal.pmed.0020100 (accessed 11 June 2010). 5. BBC News (2007) Death penalty for China official. BBC News online, 24 May 2007. http://news.bbc.co.uk/1/hi/6699441.stm (accessed 11 June 2010). 6. European Commission (2008) Customs: millions of illegal medicines stopped by ‘MEDI-FAKE’ action. EC Press Release, 16 December 2008.

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7.

8.

9.

10.

11.

12. 13. 14.

15.

16. 17.

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http://europa.eu/rapid/pressReleasesAction.do?reference=IP/08/1980&format= HTML&aged=0&language=en&guiLanguage=en (accessed 11 June 2010). Bate, R. (2009) India’s counterfeit claims on counterfeit drugs. The American, 1 October 2009. http://american.com/archive/2009/september/indias-counterfeitclaims-on-counterfeit-drugs (accessed February 2010). WHO (2006) Counterfeit medicines: an update on estimates. WHO IMPACT Press Release, 15 November 2006. www.who.int/medicines/services/counterfeit /impact/TheNewEstimatesCounterfeit.pdf (accessed 6 July 2010). Bate, R., Tren, R., & Mooney, L., et al. (2009) Pilot study of essential drug quality in two major cities in India. PLoS One 4 (6) e6003. doi:10.1371/journal.pone.0006003. White, N.J., Pongtavornpinyo, W., Maude, R.J., et al. (2009) Hyperparasitaemia and low dosing are an important source of antimalarial drug resistance. Malaria J . 8, 253. doi:10.1186/1475-2875-8-253. Newton, P.N., Fern´andez, F.M., Planc¸on, A., et al. (2008). A collaborative epidemiological investigation into the criminal fake artesunate trade in South East Asia. PLoS Med , 5 (2) e32. Nigeria intercepts fake drugs from China. Zeenews.com, 8 June 2010. www.zeenews.com/news632329.html (accessed 11 June 2010). Parfitt, T. (2006) Russia cracks down on counterfeit drugs. The Lancet 368 (9546), 1481–482. doi:10.1016/S0140-6736(06)69619-0. Interpol press release (26 August 2010) East Africa’s Operation Mamba III bolsters fight against counterfeit medicines with INTERPOL-IMPACT support. www.interpol.int/Public/ICPO/PressReleases/PR2010/PR065.asp (accessed 30 August 2010). UK MHRA (2007) Counterfeit medicines gang convicted in operation stormgrand. MHRA Press Release, 17 September 2007. www.mhra.gov. uk/NewsCentre/PressReleases/CON2032385 (accessed 16 July 2010). Eban, K. (2005) Dangerous Doses. Harcourt, Orlando. FDA (2010) website: Shire pharmaceuticals notification about stolen carbatrol appearing as expired returns http://www.fda.gov/ICECI/CriminalInvestigations/ ucm223749.htm (accessed 15 September 2010).

A PATIENT’S GUIDE TO AVOIDING COUNTERFEIT DRUGS 1. FDA (2010) website: Drugs@FDA—FDA approved drug products. www.accessdata.fda.gov/scripts/cder/drugsatfda/ (accessed 11 June 2010). 2. NABP (2010) website: Where can you find an online pharmacy you can trust? Look for the VIPPS Seal. www.nabp.net/consumers/vipps-online-pharmacies/ (accessed 11 June 2010).

Glossary

Some of the terminology used in pharmaceutical anti-counterfeiting is explained below. AAS Atomic absorption spectroscopy. ACTA Anti-Counterfeiting Trade Agreement. Adherence In the pharmaceutical context, adherence is the degree to which patients take their medication as prescribed (or “adhere” to their program). Patients commonly miss doses, take medication at the wrong time, or discontinue medication altogether. Adhesive A means of sticking two surfaces together. In the anticounterfeiting context, label adhesive should allow efficient application but prevent unauthorized removal. ADR Authorized Distributor of Record: a distributor who has an ongoing, written, and direct business relationship with the original manufacturer (and thus generally receives the product direct from the factory). Alphanumeric code Human-readable code format that may contain both letters (A–Z) and numbers (0–9). The increased number of permutations therefore allows data to be encoded with fewer characters than if only numbers are used.

Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

363

364

GLOSSARY

Ampoule/Ampule Most commonly a small glass container with a snapoff tip, containing a single-use injectable product. Antibody detection Authentication technology based on the affinity (binding) between a small molecule (marker) added to the product or its packaging during production, and a protein (the antibody) added during the test. Anti-counterfeiting technologies Technical measures designed to prevent or detect counterfeiting. Not synonymous with “track and trace technologies,” which may be for purely logistical purposes (codes on mail items, for example). API Active pharmaceutical ingredient. Authentication The process of proving that packaging, product, or other item is (or is not) genuine. Generally divided into digital authentication (codes, databases, transaction history, etc.) and sensory authentication (holograms, inks, taggants, etc.). Barcode (or bar code) A pattern of black bars and white spaces encoding data in a linear format capable of being read by a laser scanner or camera—therefore sometimes known as “1D barcodes.” Misleadingly, the so-called “2D barcodes” do not have bars but usually consists of a pattern of dots or squares in a matrix format. These require a camera reader and are not compatible with laser scanners. Bi-fluorescent An ink that fluoresces at two different wavelengths. Blister foil Aluminum foil used to seal pills or capsules into a blister pack. Blister pack In the pharmaceutical context, almost always a plastic or laminate tray with separate wells for each pill or capsule, sealed with blister foil. Blow-fill-seal An integrated process for forming plastic containers such as bottles and vials, filling them (often aseptically) and then sealing them without human intervention. Bookend system A term used to describe a pharmaceutical tracking approach with (usually) only two main points of control, at the beginning and end of the supply chain (like bookends holding up books on a shelf). Developed as a pragmatic solution to implementing tracking in a complex multi-stakeholder distribution environment. Braille text Text readable by touch, consisting of raised dots. Often used on cardboard outer packs and mandatory in some jurisdictions. CE Capillary electrophoresis.

GLOSSARY

365

Clich´e printing Transfer of ink by a pad or stamp directly onto the packaging. Closure seal A means of sealing a pack to prevent accidental opening. For anti-counterfeiting purposes, closure seals need to be tamperevident and secure, or they can easily be replaced. CMO Contract Manufacturing Organization. Coin-reactive ink An ink that changes color when scraped with a coin or similar metallic object. Cold chain The systems and processes that are used to maintain heat-sensitive products (such as vaccines, blood products, and other injectables) at the appropriate temperature during distribution from manufacturer to consumer. Cold chain security is the verification that products have been stored and handled appropriately at all times. During diversion, theft, or other criminal activity involving injectable products, cold chain is often breached—leading to degraded products that may be inactive or toxic. Colorimetry The analysis and measurement of color. Often used as a relatively cheap field-based technique. Colorshift ink An ink that reflects light at two different wavelengths depending on the angle of view, with a characteristic “flip-flop” effect when the substrate is tilted. Not to be confused with iridescent inks. Compliance An older term for Adherence. Compliance-prompting packaging Packaging design that encourages the patient to “comply” with their medication regime. Such packs often include prompts and design features, which make it easier for the patient to take their medication in the correct dosage or combination and at the correct time. Continuous inkjet A digital printing technique in which a continuous fine stream of electrically charged ink is formed and diverted onto the substrate, as needed, to form the printed image. Unused ink is collected and reused. Converter A packaging supplier who “converts” raw materials (paper, carton board, aluminum foil, etc.) into finished packaging components. The term is often used as a loose synonym for packaging printer, and the two functions are often combined in the same supplier. Counterfeit The definition of a counterfeit drug is controversial, encompassing intellectual property issues, substandard drugs, unauthorized generics, etc. In general, the functional definition of a counterfeit used in this book is a product made with the intent to deceive, by misrepresenting it as something which it is not.

366

GLOSSARY

Covert Hidden or concealed, not visible to the naked eye. A covert feature can only be seen with specific equipment. A distinction is sometimes made between “semi-covert” features, which can be viewed with low-cost devices such as filters or lamps and “covert” features, which require such a more sophisticated reader or laboratory instrument. CRO Contract Research Organization. Datamatrix Also known as a 2D barcode but in fact only one of the possible symbologies of 2D codes. Consists of a square matrix of small squares and spaces, the pattern of which can encode information. Debossing Creating an image (such as expiry and batch data), which is sunk below the level of the surrounding substrate, using a die, plate, or punch. Diagnostic products Products used in the detection or monitoring of disease or disease markers but not directly in treatment. Diffractive optically variable image device (DOVID) A feature that diffracts light, creating images that vary according to the viewing angle. These effects can be three-dimensional or appear to move. Holograms are DOVIDs but not all DOVIDs are holograms. DOVIDs have been widely used in pharmaceutical packaging, often in the form of a label or seal. Digital printing Any printing process where the electronic image file is converted to a printed image directly by the printer (usually inkjet) without an intermediate step of preparing print rollers or screens. Dissolution test The process of dissolving a solid dosage form in a solvent (usually water) and measuring the time taken. A common and cheap way of distinguishing between genuine drugs and unsophisticated copies. Diversion The sale of genuine goods outside the authorized supply chain. Diversion and parallel trade are sometimes used synonymously but they are different. Diversion is usually taken to refer to illegal trade or commercial activity that breaks the terms of a commercial arrangement or donation. Diversion often occurs in conjunction with counterfeiting. DNA markers Short, specific strands of DNA incorporated covertly into ink or onto a packaging substrate as taggants. The DNA can then be detected by portable kits.

GLOSSARY

367

Dosage form The physical shape and form of the therapeutic component itself with all packaging removed. A dosage form can be a tablet, capsule, injectable liquid or powder, inhaled substance, implantable drug depot, and so on. Down-converter An ink or substance, which absorbs incident light at a specific wavelength and emits it at a lower energy (longer wavelength). Usually, these substances absorb ultraviolet light and emit visible light. Drop-on-demand inkjet (DoD) A digital printing technology used on production lines, often to print variable data such as lot numbers and expiry dates. In contrast tocontinuous inkjet, DoD printers only create ink drops as needed to form the image. They tend to be faster than continuous inkjet printers. Drug-device kit A combination of a therapeutic drug and a means of administration. Most commonly used for injectable drugs. ECC200 A format for two-dimensional codes. The most commonly used, GS1-compliant, two-dimensional matrix code type in pharmaceuticals. EDX (or EDS) Energy-dispersive X-ray spectroscopy. Ejection system A method of removing non-compliant packs as they move down the production line. An ejection system is a necessary component of most product coding systems used on production lines, and is placed downstream of the printer and vision system. In serialization systems, any mis-coded or uncoded product must be removed before the units are packed for shipping since they will be subsequently untraceable. EMA (formerly EMEA) European Medicines Agency, formerly the European Medicines Evaluation Agency. The principal drug regulatory body for the 27 members of the European Union. Embossing Creating an image (such as Braille text) that is above the level of the surrounding substrate, using a die, plate, or punch. EPC Electronic Product Code. A data standard for the unique identification of any item around the world. EPCglobal The organization, which administers the Electronic Product Code systems and coordinates the development of the associated data standards. EPCIS Electronic Product Code Information Service. A data standard used to track the progress of coded objects as they move through the supply chain. EPCIS provides the standards necessary for the storage,

368

GLOSSARY

communication, and dissemination of serialization data between stakeholders using different software and hardware systems. E-pedigree An electronic history of all of the movements and transactions involving an individual pack, from manufacturer to patient. Differs from bookend systems in that all intermediate steps are recorded. Excipient Any component of the dosage form, which is not a pharmacologically active ingredient. FDA United States Food and Drug Administration. FDAAA The United States Food and Drug Administration Amendments Act of 2007. Fingerprinting In the pharmaceutical context, this is the analysis of randomly distributed physical features on a particular area of the product or its packaging to generate a unique data file for that pack or item. The random features may be either naturally present (surface roughness) or added (bubbles, etc.). By reference to the original database, the fingerprint of an item allows it to be checked and unambiguously identified. Flats The pre-printed packaging used for boxes and cartons. Flexography/Flexo Common packaging printing method using rubber or polymer cylinder plates with raised image-printing area. Fluorescence Absorption of light of one wavelength and emission at a different wavelength. Fluorescent inks Usually, this refers to inks that absorb UV light and emit visible light. The effect is instantaneous and stops when the light source is removed (c.f. photochromic inks). Foil Either aluminum foil (or foil/polymer laminate) used for sealing blister packs or the means of applying various effects or coatings such as holograms where it is also known as hot stamping foil or transfer foil . Forensic markers Substances present in the product or its packaging, which cannot be visualized by the eye or using simple tools or readers. The presence of a covert forensic marker is designed to provide litigation-grade proof of authenticity or conversely to demonstrate beyond doubt that a suspect sample is counterfeit. Generally, the term is reserved for those technologies that require complex, often laboratorybased, analysis. Form-fill-seal The process whereby the packaging is manufactured, filled with pharmaceutical product, and sealed in a single integrated process. The term is most commonly used for blister packs and related

GLOSSARY

369

forms. Blow-fill-seal is a related term more commonly used for bottles and vials. Frangible Brittle, easily broken, and difficult to remove in one piece. Mostly used in reference to security labels or other substrates, which split into fragments when removal is attempted. GAMP Good Automated Manufacturing Practice. A set of standards designed by the International Society of Pharmaceutical Engineers, which covers the design, installation, validation, and operation of automated and computerized equipment in the pharmaceutical production environment. The standards do not have the force of law but are very comprehensive and widely recognized. GC Gas chromatography. An analytical technique used to separate mixtures of molecules. GCP Good Clinical Practice. International standards for the conduct and recording of clinical trials. GLN Global Location Number. In the GS1 system, a 13-digit number that uniquely identifies a physical location involved in a transaction. GLP Good Laboratory Practice. Standards for the conduct and recording of laboratory experiments and procedures. GMP Good Manufacturing Practice. Legally enforceable process and quality requirements for the manufacture of drugs. GMP helps ensure consistency in manufacturing. Any process, which is added to the pharmaceutical production line (such as serialization, etc.), must therefore be compatible with GMP. Sometimes known as cGMP or current Good Manufacturing Practice. GPS Global Positioning System, used for satellite tracking of suitably equipped items. GRAS An abbreviation used by the US FDA meaning “Generally Regarded as Safe” and which refers to substances that have an accepted safety profile. Gravure printing A printing technique that uses a cylinder plate with the image (ink-bearing area) recessed below the plane of the cylinder. GS1 An international, not-for-profit organization dedicated to the development and worldwide adoption of supply chain data standards. GTIN Global Trade Item Number. A GS1 standard number unique to each stock-keeping unit (SKU) or specific product type but not unique to the individual pack itself (see SGTIN).

370

GLOSSARY

Hardness A measure of the ability of a solid dosage form to withstand compression. Used to compare the physical characteristics of suspect samples with the known profiles of genuine products. Can be measured by a simple, subjective method (crush between thumb and finger) or measured quantitatively and expressed in newtons (N). Hologram An optically variable image created through light interference. Commonly used in pharmaceutical packaging and for decorative and packaging applications in other industries. There is wide variation in the visual effect and security value of holograms, which are a type of DOVID. Induction seal An aluminum foil or paper seal bonded over the opening of (usually) bottles after they have been filled with pills or capsules. Provides tamper-evidence but can potentially be illegally replaced if plain foils with no security features are used on the original product. IIG Inactive Ingredients Guide. An FDA database of excipients and formulation components that are not known to have any significant positive or negative pharmacological effects in humans. Inference The process of associating multiple codes from individual unit packs inside a larger container with a separate code on the outside of the larger box. Potentially allows the pedigree information for each unit pack to be updated without unpacking the carton, by scanning the outer code and inferring the presence of the other codes within by reference to the database. Inference can be repeated in a hierarchy of several packaging layers. Management of inference is complex and can be problematic. Infrared (IR) Light with a longer wavelength than visible light, in the region of the electromagnetic spectrum between visible light and microwaves. Used for various types of detector. Most analytical IR instruments use near infrared radiation, the most energetic (high frequency) form. Inhaler Device for the delivery of drugs into the airways and the lungs. Inkjet printing Non-contact, digital printing method that forms an image from fine droplets sprayed at the substrate. May be continuous inkjet or drop-on-demand. Iridescent Materials that reflect visible light at multiple wavelengths simultaneously to give multi-colored or rainbow effects. Iridescent inks are sometimes used as low-grade security features. They are not the same as colorshift inks.

GLOSSARY

371

Isotopes Atoms with the same number of protons (atomic number) and therefore having the same chemical properties, but having different numbers of neutrons. This means that different isotopes of the same element have different mass and can be distinguished by mass spectroscopy. Isotopic analysis The measurement of the isotope composition of innate components of the product (or its packaging) or of substances added as markers. The comparison of suspect samples with reference material can provide evidence of counterfeiting. Isotopic tags A forensic marker technology that involves adding isotopic variants of one or more components of the formulation or packaging, to allow the identification of genuine products. Laser ablation A marking technique used to add small amounts of variable data to cartons or labels. The effect is usually achieved by using a laser to selectively burn off the ink from a pre-printed black area. The data therefore appears as white lettering on a black background. Laser engraving The direct etching of data onto or into a surface (usually glass) using a laser. Laser printing A print technique that uses dry toner particles rather than liquid ink. Security components can be incorporated into the toner. Since the technique does not need pre-prepared cylinders or screens, it is useful for printing variable data. Laser printing is often used to print security labels in-house at the pharmaceutical manufacturer. Layering The use of multiple security technologies (“layers”) on the same product, to increase the level of protection against counterfeiting. LC Liquid chromatography. Used to separate mixtures of molecules. Line of sight A straight and uninterrupted line of view between a code and a scanner. This is required for 2D data matrix codes used in many serialization systems, and for almost all other security features, which use UV, IR, or visible light. Line of sight is usually not required for RFID, which uses radio waves that can penetrate many (but not all) materials. MS Mass spectroscopy A technique used to analyze mixtures by measuring the different molecular masses of the components or their fragments. Meditag® A serialized hologram system used to authenticate drugs in Malaysia.

372

GLOSSARY

Metallic ink Ink, which, when printed, gives the appearance of a reflective, metallic surface. Often used for decorative effect but not a very secure technology. Microparticles Micron-scale (one millionth of a meter) security markers. They are not visible to the naked eye but can be seen with a low-powered microscope. Often incorporated into security inks or other applied features. Microprint Security printing features that require magnification in order to be visualized. They are generally too small to be reproduced by photocopying or scanning and therefore provide some protection from unsophisticated copies. Minilab® Self-contained kit used for field analysis of suspected counterfeit or substandard drugs, usually in developing countries. Nanoparticles Nanometer-scale (one billionth of meter) forensic markers. Cannot be seen with a low-powered microscope and require an electron microscope to be visualized. NDC National Drug Code. The legally required number format for all pharmaceuticals sold in the United States. The eventual serialization of drugs in the United States with unique pack numbers will use a numbering system based on a serialized NDC (sNDC). NGO Non-governmental organization. Often key stakeholders in the distribution of drugs in developing countries. NMR Nuclear magnetic resonance. A widely used and versatile analytical tool in pharmaceutical science and the analysis of suspected counterfeits. Offset lithography An indirect printing technique where the image area is recessed below the plane of the cylinder. The inked cylinder transfers ink via an intermediary surface to the substrate. Dry offset lithography is a less commonly used variant. Overt Visible to the naked eye without additional tools or readers. Overt security features on pharmaceutical products are generally aimed at the general public. The same feature, printed or applied in one step, may contain multiple overt and covert aspects. Palynology The study of organic (carbon-containing) microparticles and microfossils. In pharmaceutical product security, palynology is generally used to look at pollen types in a suspect sample. Since pollen from

GLOSSARY

373

different plants can be readily differentiated, and many plants have geographically defined ranges, the technique can be useful to identify the probable country of origin of counterfeit products. Parallel trade The resale of products outside their original intended sales channel or geographic market. This is not necessarily illegal provided that the product complies with the regulations of its final destination country. Parallel trade is sometimes used as a synonym for diversion but usually the former refers to legal activities and the latter to gray market or illegal commerce. Patient information leaflet (PIL) The folded paper leaflet (or sometimes an integral folding label) that details the possible side effects, recommended dosage, and other information relating to the product. PCIDs Physical–chemical identifiers. A term used by the US FDA to refer to substances added into or onto the dosage form that allow it to be verified as genuine. PDMA The United States Prescription Drug Marketing Act of 1987. Contains some provisions that have not yet been fully enforced, such as a requirement for traceability. Pedigree A history of all of the movements and transactions involving an individual pack, from manufacturer to patient. Pedigrees may be paper based or electronic (see e-pedigree). Required (or soon to be required) by law in some jurisdictions (notably California). Photochromic inks Inks which change color when exposed to UV light and only revert to the original appearance a few seconds or minutes after the UV source is removed. Compare with fluorescent inks that revert immediately. Polarizing inks Inks which reflect incident, randomly oriented (nonpolarized) light waves at a specific (polarized) angle or which change the angle of an incident beam of polarized light. These inks can be visualized with inexpensive filters and are an example of a semi-covert technology. The polarizing feature may be translucent or part of a second overt feature. Pouch An example of form-fill-seal packaging that can be used for single doses of liquids or powders. Primary packaging The first layer of packaging around the dosage form. This may be a bottle, blister pack, vial, inhaler, etc. Print-on-demand Technology that allows packaging (usually labels) to be printed as needed at the pharmaceutical production facility, rather than pre-ordered and stored before use.

374

GLOSSARY

Push-through pack (PTP) Packaging format where each pill or capsule is held in an individual well within a lidded tray and is extracted by the patient pushing it through the lidding foil as required. Randomization The use of randomly generated (rather than sequential) number elements in a serialization scheme to prevent prediction of the subsequent numbers in a sequence. RFID Radio frequency identification. A tracking technology that uses radio waves received and transmitted by small tags or labels containing a microchip and antenna. At the time of writing (2010), the technology is generally considered still too expensive for most unit pack applications but is commonly used for higher level packaging (pallets, cases, etc.). The technology has the major advantage that it does not require line of sight, so RFID tags can be read through packaging. Sachet A single dose, form-fill-seal packaging type used for liquids, solids, and powders. Scratch-off Some consumer-focused authentication systems use concealed one-time codes, protected with a scratch-off coating in the same way as a lottery scratch-card. The customer reveals the code and then calls or sends an SMS to a manufacturer helpline to have their product verified. Screen printing Print process using mesh screens. The negative of the required image is coated onto the screen with an impermeable substance and the ink is then scraped through the remaining mesh to form the image. Useful for thick or coarse-grained inks but not suited to very high-volume printing. Secondary packaging Additional packaging layer(s) used to protect the dosage form and the primary packaging from damage in transit, to aid in efficient packing into shipping cartons and to allow the incorporation of other items such as patient information leaflets. Security cuts Small incisions made in labels to prevent their removal in one piece after application onto the product. SEM Scanning electron microscopy. Used to assess small differences in packaging and to identify natural inclusions such as pollen or added features such as nanoparticles. Semi-covert Security features that are not visible to the naked eye but that can be visualized with commonly available devices such as magnifying lenses and polarizing filters and do not require sophisticated machinery or laboratory analysis.

GLOSSARY

375

Serialization Commonly used to mean the process of identifying and tracking items at the unit level, using a number specific to each unit pack and unique worldwide. Various number formats exist, although most of the proposed or implemented systems use variants of the GS1 system. In the United States, the format for a standardized numerical identifier has been stipulated by FDA and is based on the existing NDC system. The number used for serialization may be printed as an alphanumeric code or a data matrix or encoded on an RFID chip. SGTIN Serialized Global Trade Item Number. Addition of a serial number to the GTIN format enables unique identification of individual packs anywhere in the world. Shrink sleeve A length of polymer tube, which is typically placed over a closure (e.g., bottle cap) and heated, causing it to shrink and form a tight, tamper-evident secondary closure. The sleeve may be printed with additional security features (to deter removal and replacement with another sleeve) and is usually perforated to allow the patient to remove it more easily. Shrink labels These are an extension of the shrink sleeve concept and cover most of the bottle. They incorporate the marketing and other functions of the label, and are perforated to allow the area around the primary closure to be removed when the pack is opened, leaving the rest of the wrapping intact. Shrink wrap A transparent polymer film that is wrapped around and shrunk onto the product using heat. Commonly applied as a tamperevident overwrap to cartons in many industries, such as tobacco, but perhaps less commonly in pharmaceuticals. The removal of shrink wrap may be facilitated with tear tape. A thicker grade of shrink wrap is also used to cover larger consignments such as pallets. Simulation The approximation rather than exact copying of brand attributes or security features. This may involve trade names that sound like the original, or color schemes that look very similar. Genuine security technologies may be crudely simulated with alternative features. Simulation is easier if consumers are not well informed about the lack of equivalence between similar looking medicines, or exactly what to look for to verify authenticity. SKU Stock-keeping unit. Each unique inventory item type (e.g., “Ingesta 20 mg, 30 capsules”) will have an identifying SKU number (or alphanumeric code), which is often also printed as a linear bar code. SKU data gives no information about batch number or individual pack identity.

376

GLOSSARY

SMS Short Message Service. The data standard used to send text rather than voice data via mobile phone networks—known as “text messaging” or “texting.” SMS systems have been used in some consumer verification systems for pharmaceuticals, notably in Africa. sNDC Serialized National Drug Code. An extension of the existing NDC system to enable the unique identification of individual unit packs. The sNDC is a GS1-compatible system and was adopted as a standardized numerical identifier (SNI) for all drugs in the United States by the FDA in 2010. SNI Standardized Numerical Identifier. The data structure chosen by FDA, as part of the implementation of the FDA Amendments Act (FDAAA), to allow all pharmaceuticals to be tracked at item level. SODF Solid oral dosage form (e.g., tablet, capsule). Spectroscopy Analysis of the interaction between light and a sample of interest. The output is usually a spectrum of the intensity of the light detected versus wavelength. Comparison with known reference spectra allows this technique to be used for the detection of counterfeits. Steganography The concealment of an image or data within a second image or file, so that the presence of the information is not suspected by an unauthorized person. Distinct from cryptography, where the information is unreadable or undecipherable to an unauthorized person but they may be aware of its presence. Strip pack A form-fill-seal pack with each dose (pill, powder, liquid) in an individually sealed compartment in a flexible strip. Substrate The underlying packaging material (e.g., paper, foil, plastic) to which a security feature is applied. Symbology Strictly speaking, the study of symbols. In a security context, the symbology is the “language” of a coding system, specifying the rules for converting alphanumeric information into another visual form or symbol, such as a linear bar code or a data matrix code. Syringe A container with an integral plunger and an integral or separate needle, used to hold liquid for injection. Tack The immediate “stickiness” of an adhesive—not necessarily related to its long-term adhesion to the substrate. Taggant Often used synonymously with forensic markers, this term describes a covert feature which is difficult to find without prior knowledge and appropriate equipment. Taggants come in many forms and are detected, either with specialist readers or laboratory equipment, on the basis of specific and unique chemical and/or physical properties.

GLOSSARY

377

Tamper-evident Closure devices or sealing features that can be opened easily without special tools but that are designed for one-time use. Breakage of the seal thus demonstrates that the packaging has been opened and the product may have been tampered with, refilled, or replaced. Tamper-resistant A packaging feature that discourages casual opening or tampering but is not designed to resist a determined attempt to open it. Tamper-proof A packaging design or closure that cannot be opened without force or the use of special equipment and tools. Tear tape Strong, thin tape used in conjunction with shrink wrap to aid removal of the wrap. It can incorporate additional overt and covert security features and provides tamper-evidence. Tear tape can also carry printed consumer messages including security-related information. Third-party logistics (3PL) Those transport and logistics operations that are not conducted by the original manufacturer. Many pharmaceutical corporations now subcontract their drug storage, transport, and supply chain operations to specialist 3PL providers, who can often provide a fully outsourced service. Thermochromic ink Ink that changes color (reversibly or irreversibly) when heat is applied. The heat may be in the form of thumb pressure, for example, allowing the ink to be used as an authentication feature. Alternatively, the ink may change color irreversibly above a certain temperature to act as an alert when cold chain conditions have been breached. TLC Thin layer chromatography: a simple, portable, and often very effective tool for the analysis of suspected counterfeit medicines. Track and trace The process of recording data as an item moves through the supply chain. The level and frequency of data recording varies between systems. Tracking is the routine following of a product or consignment as it moves from producer to customer. Tracing is used to find an item or batch in the event of a recall or to identify a product’s history in the event of a counterfeiting incident. Up-converter Material which appears to add energy to light by absorbing photons at lower energies and emitting at higher energies (usually as visible light). The actual mechanism involves the conversion of energy from more than one incoming photon into that of a single outgoing photon. The quantum efficiency of this process is rather low and hence these materials usually require specialized light sources and detectors.

378

GLOSSARY

These technologies are much less common than down converters and are therefore considered to be more secure. Uplabeling The illegal practise of changing the label on a genuine product to indicate a higher dose. Since higher dose usually means higher price, this is a very profitable activity and is very dangerous for the patient. UV Ultraviolet light. UV drying A process used for the rapid drying of (usually watersoluble) inks after application onto packaging. Solvent-based inks are usually dried by evaporation, sometimes with the assistance of mild heat. Vial A glass or plastic container used to hold solids or liquids. Most commonly used for sterile materials for injection. Vision system In serialization systems, this is an automated camera placed downstream of the product coding printer (or label applicator) on the production line. Its role is to detect mis-coded or uncoded product so that it can be removed by the ejection system. Voiding The process whereby the removal of an adhesive label leaves behind a colored or detectable residue, usually spelling out a word. This is a useful tamper-evident feature. Wallet A packaging type that combines a blister pack and secondary carton into one integrated pack. Wallets and their derivatives are very useful in raising the level of adherence to medication and are also useful in keeping important patient information associated with the medication. From an anti-counterfeiting perspective, wallet packs are more complex to reproduce and thus raise the barrier for counterfeiters. X-ray fluorescence spectroscopy A technique which probes the atomic structure of a sample. Energy-dispersive X-ray spectroscopy (EDX or EDS) is one of the commonly used variants, and uses a beam of charged particles to stimulate the emission of X-rays by the sample. The emission spectrum is a distinctive fingerprint for a given molecule. In the laboratory, the technique is frequently coupled with scanning electron microscopy.

Index

2D codes, see Two-dimensional codes 3D topomicroscopy, 206 3PL, see Logistics, third party Abrasion resistance, 177–178 Acetaminophen, 50 Active pharmaceutical ingredient (API), 11, 34, 39, 42–45, 97–102, 103, 105, 113, 115, 117, 126, 205, 212, 227, 276–285, 299 ACTs, see Artesunate Adherence, 94, 180, 321 Adhesion of ink to substrate, 177–178 Adhesive, 90, 146–147, 164, 201 Adulteration, 29, 97, 293 Adverse events, 69–70, 98, 322, 341 Africa, 23, 40, 56, 98, 242–244 Age, 56 Air Force One, 232 Aircraft, pre-flight checks of, 56 Alcoholic beverages, 291–293

Alignment of labels or features, 149–150, 179, 25 Allergic reactions to counterfeits, 98, 209 Alphanumeric, see Codes Aluminum foil, 131, 175 Ampoules, 184–187 Analytical techniques, 113–126, 191–192, 205–207 Animal research facility, 89 Annealing of foil, 177 Antibiotics, 116, 205 resistance, 22–23 Antibody systems, 168 Anticoagulant, 98 Anti-Counterfeiting Trade Agreement (ACTA), 77 Anti-freeze, as unauthorized ingredient, 11, 23, 101 Antimalarials, 8, 17, 21, 156. See also Artesunate resistance, 19

Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs, First Edition. Mark Davison. © 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

391

392

INDEX

API, see Active Pharmaceutical Ingredient Arbitrage, 46–47. See also Drug prices, geographical variations of Argentina, 329 Armed guards, 219 Artemisinin, see Artesunate Artemisinin-based combination therapies (ACTs), see Artesunate Artesunate, 19, 156 Asymptomatic conditions, 94 Atomic absorption spectroscopy (AAS), 118–119 Audit security, 60, 198 supplier, 60, 100, 198, 216–217, 306 supply chain, 60 Australia, 77 Authentication bulk material, 97–102 digital methods, 83, 87–88, 109, 231–245 personal, 93–95. See also Medical cards physical or sensory methods, 83, 87–88, 153, 256, 265 Autopsy, 18 Baby milk, 23, 101 Balanced scorecard, 59 Banknotes, 87, 128, 153, 156, 160–161, 207, 299, 324 Baseline data, establishment of, 59–60 Batch number, 130, 138, 232 traceability, 266 variation, 23 Baxter Healthcare, 98, 120 Beer-Lambert law, 117 Belgium, 24, 234 Bi-fluorescent inks, 162 Biometric devices, 322 Black box warning, 199 Blackmail, 300 Blister foil, 145. See also Aluminum foil

Blister pack, 39, 103, 125, 174–179, 184, 194 Blister packing machines, 177 Blogging, see Social media Blood products, 163 Bohr, Niels, 313 Bollino system, 275 Bookend systems, 262–267, 285–286 Bottle, 103, 130, 181, 203 Box, see Carton Braille text, 195 Brand erosion, 27–29, 50 parasites, 27, 127–128 Brazil, 34, 41, 65, 102, 163, 290, 292, 330 BRIDGE project, 141, 241–242 Broadband internet access, 252, 287 Budget, 141 Bulk bags, 100 Bulk packaging, 131, 215–222 Burundi, 332 Bush, President George W., 272 California, 252, 259–261, 270–271, 292 Board of Pharmacy, 252, 271 Cambodia, 331 Canada, 77, 198, 330 Capillary electrophoresis, 98, 120–121 Carousel tax fraud, 190 Carton, 103, 131, 138, 184, 193–196 Cement mixer, 23 Certificate of Analysis, 101, 212 Certificate of Suitability to Monographs of the European Pharmacopoeia (CEP), 99 Chain of custody, 100, 191–192 Chalk, as unauthorized ingredient, 11, 23 Chemical fingerprint, 107 Chief Financial Officer, 89 Child-proof packaging, 38 Chile, 34 China, 34, 40, 98, 101, 330, 332 Chondroitin sulphate, 98, 120

INDEX

CIP 13 system, 266 Civil prosecution, 79 Claims, unsupported, 7 Clich´e printing, 138 Clinical trials, 7, 9 Closure seals, 90, 195 Cloud computing, 321 Coatings, 105, 111 Coca-Cola, 75 Code of Federal Regulations, 110, 272 Codes, 82–83, 87–89, 155, 186–187, 190, 199, 231–245, 257–267, 285–290 Coin reactive inks, 163 Cold chain logistics, 184 Cold-form film, 176 Colombia, 40 Color photocopying, 162 Color-shift inks, 88, 155, 190, 231, 317 Comit´e Europ´een de Normalisation (CEN), 198 Communication, between departments, 59 during a crisis, 53 with customers, 59 Compliance legal, 58, 267 with medication regime, see Adherence Compressive strength, 116 Consumer, 4, 21 behavior, 14, 49–50 confusion, 54, 171, 317 developing countries, 49 education, 49, 156, 204, 289 goods, 3, 4 role in authentication, 49, 54, 155, 169, 193, 206, 236–237, 242 ubiquity of, 54, 90 use of mobile phones, 51 Consumer Product Safety Improvement Act, 294 Contract research and manufacturing organisations, 99, 196, 309–310 Converters, packaging, 140 Co-payment, 214

393

Corporate issues liability, 30, 89, 111, 281 local operating companies, role of, 187 reputation, 215 sales departments, 26, 64 security function, 207 strategy, integration with product security, 58, 63–64 Corruption, 17–18, 33, 44, 69, 216, 300–302 Cost of Goods Sold (COGS), 26, 58 Costa Rica, 34 Cough syrup, 23, 101 Council of Europe, 275–285 Counterfeit Pharmaceutical Interagency Committee, 73 Counterfeiting definitions, controversy surrounding, 36–37 industrialization and globalization of, 38 prevalence of, 15, 25, 27–28 Country of origin, false, 40 Covert features, 54, 88, 105, 128–129, 139, 155, 165–168 Creams, 112 Credit cards, 70, 153, 156 Criminal penalties, for drug counterfeiting, 12, 282–285 prosecution, 79 Cultural factors, 55 Curved surfaces, 141–144, 187–188 Customs, 70, 76–78, 114, 161, 324 Customs and Border Protection, U.S., 76 Data mining, 69–70 security and privacy concerns, 240, 256 segregation, 249–250, 286 Death certificates, 70 De-blistering, 179 Debossing, 105, 138

394

INDEX

Decontamination, lack of, 23 Decryption, 236 Demand reduction, 289 Design complexity, use of, 129, 132, 188, 324 features, 90 Designer goods, see Consumer goods Developing countries, 17, 34, 115, 237, 252, 323 Diagnostic products, 189 Dies cutting of security slits, 132 tabletting, 112 Diethylene glycol, see Anti-freeze Diffractive optically variable devices (DOVIDs), 144–145, 153–157, 161. See also Holograms Digital methods authentication, 81, 88, 231–245 health records, 70 image subtraction, 206 printing, 11, 37 scanning, 11 signatures, 266 Dilution, unauthorized, 42 Direct-to-consumer (DTC) advertising, 52, 55, 129, 236–237 Disclosure, of hidden features, 110 Discoloration, 177 Dissolution, 115–116 Distortion, 177 Distribution, 24, 45, 68, 145, 225–229, 238–245, 247–256, 261–267, 274–275, 287 direct to patient, 322 direct to pharmacy, 296 Diversion, 45, 47, 228–229 DNA markers, 167–168 Doctors, 24, 213 potential mistrust of, 24 Documents, counterfeit, 43, 279 Domain names, 79 Domestic security, as analogy for product security, 36, 62–62

Donated pharmaceuticals, 43, 45, 47, 323 Double bagging, 125 DRASTIC planning process, 58–59, 64 Drop shipment logistics, 18 Drucker, Peter, 60 Drugs controlled, 299 cost of raw materials, 140 development cost to counterfeiters, 10 cost to innovator companies, 9 process, 9 device combinations, 187–188, 209 ineffectiveness of, 8, 21–22 interactions, 112, 199 inventory management of, 41 medical claims for, 9 price, 9, 194 geographical variations of, 46–47 safety, see Pharmacovigilance Drums, 125 Dumpster diving, see Packaging, re-use of Dyes, 90, 106, 108 ECC200 code, 235–245, 274 Ejection mechanism, 179 Electronic Product Code Information Service (EPCIS), 249–256, 258–267 Embarrassment, role of, 13, 337 Embezzlement, 298 Embossing, 105, 138 Encryption, 236 EPCglobal, 249 ePedigree, see Pedigree Error rates (coding), 237 Ethnicity, 56 Ethylene glycol, see Anti-freeze European Alliance for Access to Safe Medicines (EAASM), 13 European Directorate of Quality Management and Healthcare (EDQM), 99, 285

INDEX

European Federation of Pharmaceutical Industry Associations (EFPIA), 262–265, 285–287 European Medicines Agency (EMA), 53, 101 European Observatory on Counterfeiting and Piracy, 66 European Pharmacopoeia, 99 European Union, 40, 65, 75, 77, 102, 141, 233, 250, 262–263, 273–285, 316, 331 Excipients, 34, 39, 97, 103, 105, 108, 117, 212, 227, 276–285 Excise duty, 292 Expired stock, disposal of, 40 Expiry date, 40–41, 130, 138, 195 Facebook, 52–53 Falsified Medicines Directive, 274 Fast Red TR test, 115 Federal Trade Commission, 100 Financial services industry, 299–300 Fingerprinting technologies, 131, 254–255 First-in-first-out (FIFO) principle, 41 Flexography, 136, 145, 160–164, 177 Florida, 269 Fluorescent inks, 162 Fold-out labels, 132, 181, 212 Fonts, variations of, 206 Food and Drug Administration (FDA), 34, 53, 99, 106–112, 174, 190, 210, 216, 233–245, 249, 270–273 FDA Amendments Act (FDAAA), 272 FDA Globalization Act, 273 Food industry, 200, 292 Food Drug and Cosmetic Act, 37 Food Safety Working Group, 293 Forensic features, 62, 111, 121–122, 166–168 Form-fill-seal, 176–177 Fourier transform infrared spectroscopy (FTIR), 124 Framework Convention on Tobacco Control, 292

395

France, 266 Frangibility, 147–148 Fraud false paperwork, 212–214, 252, 289 insider, 217–219, 256, 296, 298–301 Free trade zones, 11 Freight, 39 Friability, 202 Gas chromatography, 120–121 Gender, 56 General Certificate of Conformity (consumer goods), 294 General Sales Tax, 291 Generally recognised as safe (GRAS), 107–109 Generic drugs, 8, 26 Gentamicin, 97 Global Location Number (GLN), 247–256 Global Pharma Health Fund (GPHF), 115 Global positioning system (GPS), 101, 219–222, 319 Global Trade Item Number (GTIN), 233–245, 247, 256, 273–274 Globalization, 38–39, 212 Glycerol, 101 Good Automated Manufacturing Practise (GAMP), 228 Good Manufacturing Practice (GMP), 10, 99, 110, 289 Government issues, 65 Gravure printing, 136–137, 178 Gray market, 216 Greece, 24 Groupthink, avoidance of, 59 GS1, 66, 190, 248, 258, 267, 274, 290 Hardness, 115–116 Health Insurance Portability and Accountability Act (HIPAA), 147, 233 Health insurers, 25 Heparin, 98, 101, 120, 314

396

INDEX

Hijacking, 217–219 Hologram Industries S.A., 288 Holograms, 26, 61, 88, 107, 132, 144, 153–157, 176, 179, 190, 231, 317 reconciliation and waste management, 301 Impermeability, 176 Implantable devices, 189 Importation importers, 24 licenses, 212 points, restriction of, 326 IMS Health, 15 Inactive ingredients guide (IIG), 107–108 Incentivization of employees, relevance to anti-counterfeiting strategy, 26 India, 34, 40, 210, 287–288, 301, 331 In-dose marking, 106–109 Induction seals, 203 Inference, 257–262 Inflation of healthcare costs due to counterfeiting, 32 Information management, 218 Infrared absorbing inks, 165–166 Infrared spectroscopy, 123–125 Ingestible inks, 105 Inhalers, 112, 175, 187–188 In-house application (of security features), 198 Injectables, 105, 112, 184 Ink reconciliation and waste management, 301 security, 61, 90, 159–164, 176 Inkjet printing, 105, 130, 133, 138, 145, 179, 181, 198 Insurance as a pricing model, 310 Intaglio printing, 137, 160–161 Intellectual property (IP), 8, 11, 34, 37, 66, 73, 78, 111, 205–206, 315 enforcement of, 73–79, 275–285 Enforcement Coordinator, 73

International Authentication Association, 168 International cooperation, 284 International Federation of Pharmaceutical Manufacturer Associations (IFPMA), 67 International Medicinal Products Anti-Counterfeiting Taskforce (IMPACT), 12–13, 315, 332 International Organisation for Standardization (ISO), 66, 91 International Organisation for Standardization (ISO), standardization of anti-counterfeiting tools, 91–92, 170 International Organisation for Standardization (ISO), TC246 committee, 91 International Society for Pharmaceutical Engineering, 228 Internet pharmacy, 55, 71 role of, 8, 13, 31, 51, 78, 132, 321, 338, 340 service providers, 71 Interoperability of systems, 67, 233–245, 247–256, 267, 287 Interpol, 69 Ireland, 94 Iridescent inks, 161–162 ISO, see International Organisation for Standardization Isotopes ratio analysis, 120 tags, 167 ISPs, see Internet service providers Italy, 275 Japan, 77, 102 Jars, 181 Johnson and Johnson, 29 Jordan, 34 Judiciary, 77 Just-in-time inventory, 217

INDEX

Kenya, 332 Labels, 110, 132, 138, 144–157, 182 Laminate film, 175–178, 180 Language importance of, 55 use of local, 55 Laos, 331 Laser ablation, 138 Laser etching, 131, 181, 186 Laser printing, 137, 145, 198 Laser-viewable features, 154 Latin America, 23 Law enforcement, 69, 77–78, 114, 126, 192, 196, 261, 302, 324 Layering of countermeasures, 62, 90, 161, 169, 222 Lean manufacturing, 63, 196, 296 Legal issues, 66, 69 Liability, insurance, 30, 89 Life expectancy, 14, 68 Lifestyle drugs, 8 Linear bar codes, 234 Line-of-sight requirement, 237–245 Liquid chromatography, 115, 121 Literacy, 56 Litigation, 30, 79, 167–168 Logistics, 12, 215–222, 257–267, 296 reverse, 297–298 third party (3PL), 12, 216, 296–298 Lot number, see Batch number Louis Vuitton, 50 Loyalty cards, 94 Machine readable, 166. See also Covert features Madrid Protocol, 76 Mafia, 16 Malaria, 18, 331 consequences of counterfeiting, 21 Malaysia, 155, 288, 292 Manufacturing, 11, 26 manufacturing equipment traceability of, 61 used, 61, 324 Marketing, 11

397

authorization, 43 theory, 16 Markets, informal, purchase of drugs from, 18 Masking agents, 115, 299 Mass spectrometry, 120 Massachusetts, 292 Medical cards, 94 Medical devices, reuse of, 210 Medical Products Counterfeiting and Pharmaceutical Crime unit, 69, 332 Medical samples, sale of, 43 Medication errors, 130, 187, 228 Medicinal plants, 127 Medicines and Healthcare products Regulatory Agency (MHRA), 16, 129 Medicrime Convention, 275–285 MEDI-FAKE, Operation, 331 Mediharta Sdn Bhd, 288 Meditag, 155, 161, 288 Melamine, 23, 101 Metallic inks, 162 Metals, detection of, 118–119 Methyl ethyl ketone (MEK), 136 Mexico, 34, 77 Microfeatures, 132, 163–164 Microfractures, 186 Microparticles, 90, 204 Mictotext, 154, 204 Milling effects, 131, 176 Mimicking, 157 Minilab, see Global Pharma Health Fund Mobile phones, 51, 220, 236, 242–244, 318 Money, global transfer of, 18, 39, 70, 156 Morocco, 77 Myanmar, 331 Mystery shopper investigations, 25, 64, 70, 171, 207 NAFDAC, see Nigeria Nanoparticles, 90

398

INDEX

Narcotics, supply of, 12 National Association of Boards of Pharmacy (NABP), 13, 339 National Drug Code, 233–245, 272–273 Near infrared, 101, 125 Needles, 40, 187–188, 205, 209 Need-to-know principle, 5, 62–63, 133, 167–168, 199 New Zealand, 77 NGOs, see Non-governmental organisations Nigeria, 34, 40, 125, 326, 331 Non-destructive methods, 113, 119, 123–126 Non-governmental organisations, 6, 19, 37, 69 Non-printed surface features, 105 Non-repudiation, principle of, 266 Non-standard components, use of, 132 North American Security Products Association (NASPO), 198 Nuclear magnetic resonance (NMR), 98, 119–120 Nurses, 55, 322 Obama, President Barack, 293 Obesity, 22 Off-label use, 46 Offset lithography, 135, 145 Ointments, 112 Optically-variable devices, 90 Optimisation of security feature application process, 142, 307 Organisation for Economic Cooperation and Development (OECD), 24–25 Organized crime, 4, 14, 16, 33, 170, 205, 216, 219, 225, 264, 291, 326 Orientation of product on production line, 142, 181 Outsourcing, 99, 188, 196, 205, 293 Over-packaging, 47. See also Repackaging Overt features, 54, 128–129, 140, 155 Over-the-counter drugs, 216, 289

Packaging control of waste, 61 deliberate flaws in, 61 differentiation between related products, 42 general considerations, 11, 42, 61, 173–214, 196 hierarchy, management of, 257–267 non-standard, 128 removal of before sale, 40 re-use of, 40, 184–188 Pad printing, 138 Painkillers, 4, 17, 22 Paint, as unauthorized ingredient, 11, 23, 112 Pallets, 238–245, 257–267 Palynology, 121–122 Panama, 101 Paper-based tracking and pedigree systems, 228, 251, 269–272 Paracetamol, see Acetaminophen Parallel trade, 45–47, 274–275 Parallel universe issue, 243–244, 326 Parent-child relationship, see Packaging, hierarchy, management of Patents, 9, 36, 66 Patent Cooperation Treaty, 74 Paternalism, 51 Patient information leaflet (PIL), 45, 193–196, 211 Patient safety, 49, 267 Pattern recognition, 90 Payors, 25, 212 Pearlescent inks, 105 Pedigree, 58, 81, 229, 231–245, 251–252, 269–272 Peeling, 177 Penicillin, 23 Perforation, 148 Persistence (in taking medication), see Adherence Pfizer, 27 Pharmaceutical Cargo Security Consortium, 216 Pharmaceutical crime, concept of, 12

INDEX

Pharmaceutical industry economics of, 9 revenues of, 15 Pharmaceutical Research and Manufacturers Association (PhRMA), 384 Pharmaceutical Security Institute, 16–17, 91 Pharmacist, role of, 6, 24, 33, 41, 55, 90, 94, 155, 161, 181–182, 193, 213, 225, 240, 261–267, 285–286, 290, 339 Pharmacovigilance, 69–70, 98. See also Adverse events Pharmacy hospital, 129 retail, see Pharmacist, role of Photochromic inks, 163 Photolithography, 107 Physical-chemical identifiers (PCIDs), 107–110, 126, 174–175 Plastic film, 131, 164 resin, 164 Point-of-sale, 234 Polarizing inks, 161 Polypharmacy, 342 Portable authentication devices, 114, 318 Posters, 55 Pouches, 180 Prescription Drug Marketing Act (PDMA), 271 Prescriptions and prescription fraud, 33, 213 Printer ink, as unauthorized colorant, 11, 112 Printing, 135–142 onto pills and capsules, 111 printing speed for codes, 237 print-on-demand (POD), 137, 145, 179 Procurement, 26, 197 Produce Traceability Initiative, 293 Product recalls, 29, 228, 267, 286, 293–294, 297–298

399

Product security teams, 26, 88 Production volumes, control of, 60–61 PSI, see Pharmaceutical Security Institute, 16 Public relations, 28 Public role of, 50 trust, loss of, 30–31 Push-through packaging (PTP), 174 QR codes, 235 Quality drugs, 34 quality assurance (QA), 114 quality by design (QbD), 109 quality control (QC), 150, 179 Quantitative analysis, 42 Quenching of signal, 236 Radio Frequency Identification (RFID), 88–89, 181, 219–220, 238–245, 319 Radio, 56 Raman spectroscopy, 125 Randomization, 250–251 Raw materials cost of, 11 substitution of, see Active Pharmaceutical Ingredient unorthodox or toxic, 11, 43 Real estate (available white space on pack), 129, 139, 195, 234 Reality check, 58–59 Re-boxing, see Repackaging Recordation by customs, 76 Redundancy of data in codes, 235 Regulatory system, 10, 22, 31–32, 54, 109–112, 234, 250, 264 Reimbursement, 33, 68, 94, 212, 275, 287, 290. See also Social healthcare Re-importation, 45–46 Relabeling, 41–42, 47, 146 Religion, 56 Removal of packaging before sale, 104

400

INDEX

Repackaging, 24, 40, 47, 130, 217, 227, 233, 274, 298 Request-for-Information, 305 Request-for-Proposal, 305 Return on investment (ROI), 22, 292, 304 Revenue erosion, 24–25 Risk and costs to business, 24, 58 Rolex, 50 Roll Back Malaria, 18 Russia, 332 Rwanda, 332 Rx-360, 44, 100 Sachets, 180 Safeguarding America’s Pharmaceuticals Act, 273 Sales departments, 26, 64 Sampling bias, 64 Scanning electron microscopy (SEM), 119 Scratch-off codes, 243–244 Screen printing, 137, 160 Secondary packaging, 39, 193–204 Security checks on employees, 218 facilities and fixed assets, 216 slits and cuts, 148 substrates, 90 vendors and security printers, 140, 200 Self-medication, 24 Senses, human, 88 Serial Shipping Container Code (SSSC), 249 Serialization, 26, 81, 88, 90, 141, 154, 189, 200, 229, 231–245, 247–256, 318 Shamanism, 7 Shape, as differentiator, 104, 111 Shareholders, 57, 65 Shrink sleeves, 182 Shrink wrap, 155, 203 SICPA-Assan, 292 Silk screen, see Screen printing

Simple approaches, usefulness of, in anti-counterfeiting, 36 Singapore, 77, 332 Single-use products, 187 security features, 182, 191 Situational crime prevention, 36 Snake oil, 7 Social healthcare, 25, 32–34, 68, 212, 289. See also Reimbursement Social media, 51 Solid oral dosage forms (SODFs), 42, 101, 105–112, 174 Solution providers, 36 South Korea, 77 Southeast Asia, 22, 101, 156 Standard numerical identifier (SNI), 272–273 Steganography, 235 Stents, 211 Stockholders, see Shareholders Stock-keeping unit (SKU), 232 Stoppers, 184–187 Storage conditions, 147, 150, 178, 201 Strategy, 58–59, 64, 198 Strip packaging, 104, 180 Sub-potency, role in resistance, 23, 115 Sub-standard drugs, 36–37 Suicide, 50 Supply chain, 55, 60, 90, 212, 216, 231–245, 247–256, 261–267 security, 60, 102, 133, 159, 215–222, 295–302 Surface features innate, 182 marking, 105 Surveillance, 17, 64, 79, 171 Suspensions, 112 Sustained or modified release formulations, 108 Sutures, 190–191 Sweden, 285–286 Switzerland, 77, 274 Symbology, 234–245 Synthetic imaging, 156

INDEX

Syringes, 187–188 Syrups, 112 Tabletting, 116 Tack, 146 Taggants and tracers, 42, 90, 103, 105, 107, 112, 136, 139, 154, 161, 163–168, 190, 231 Tamper-evident seals and closures, 100, 155, 182, 200–204, 274 Tampering, prevention of, 37, 47 Tanzania, 332 Tear tape, 203 Technology, implementation of, 58 Television, 54 Terahertz imaging, 126 Terrorism, 17, 217, 337 Testudo, Roman tactic of, 64 Text messaging (SMS), 56, 243–244 Text, obscuring of, 141 Theft cargo, 216, 290 fixed facilities, 188, 216 transit, 216, 228, 232 Thermochromic inks, 163 Thin layer chromatography (TLC), 116–117 Tobacco, 258, 291, 325 Toner, 137 Tooling, 104 Toothpaste, 23 Tote assembly, 242, 261 Toxicology, 18, 70, 174 Toys, 39, 293–294 Toy Safety Directive, 294 Traceability, 81, 83, 102, 227–229, 231–245, 291–294 Track and trace, 81–83, 88, 131, 155, 231–245, 253 Tracking systems, 33, 231–245, 291–294 Trade Related Aspects of Intellectual Property (TRIPS), 66 Trademarks, 75–76, 79 Tragedy of the Commons, 65, 316

401

Training manual, for customs and law enforcement, 76 Transport security, 215–222 Triage, in identification of counterfeits, 114–115 Trojan Horse tactics, for concealment of product origin, 45 Tubes, 183–184 Turkey, 289–292 Twitter, 53 Two-dimensional codes, 141, 234–245 Tylenol, 29 Uganda, 332 Ultraviolet/visible spectroscopy, 117–118 Unique Device Identifier (UDI), 190 Unit dose packs, 38, 174, 316 Unit-based pricing of security features, 301, 308 United Kingdom, 16, 54, 129, 333 United States, 45, 56, 65, 77, 98, 102, 129, 147, 175, 181, 198, 216, 232, 249–256, 258–267, 269–273, 314, 333 Upconverters, see Infrared absorbing inks Upgrading of anti-counterfeiting features, 171 Uplabeling, 42, 146, 181, 185, 293 Use-by date, see Expiry date UV drying, 136 UV inks, see Fluorescent inks Vaccines, 4, 40, 42, 163 Validation, process, 150, 180 Value documents, 212 Value-Added Tax (VAT), 291 Varnish, 136, 140, 164 Verified Internet Pharmacy Practice Sites (VIPPS), 13, 339 Viagra, 27 Vials, 103, 132, 183–187 Vietnam, 331 Vigilance, 296 Vision systems, 179, 182, 237

402

INDEX

Visual inspection, of counterfeits, 113, 206 Voiding, 148–149, 202 Wallet packs, 132, 179, 212 Wallpaper pattern of security feature, 180 Warhol, Andy, 137 Waste management 179, 299 Web sites, 53, 243–244 Wireless access to databases, 88 World Customs Organisation, 18

World Health Assembly, 75 World Health Organization (WHO), 12–13, 19, 37, 67, 315, 331–332 World Intellectual Property Organisation (WIPO), 74, 76, 315 World Malaria Report World Trade Organisation, 66, 77 WTO, see World Trade Organization X-ray techniques, 119, 123, 168 YouTube, 53