Preparation and Testing of Reagent Water in the Clinical Laboratory; Approved Guideline- Fourth Edition C3-A4 Vol 26 #22 (26)

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Clinical and Laboratory Standards Institute Advancing Quality in Healthcare Testing The Clinical and Laboratory Standards Institute (CLSI, formerly NCCLS) is an international, interdisciplinary, nonprofit, standards-developing, and educational organization that promotes the development and use of voluntary consensus standards and guidelines within the healthcare community. It is recognized worldwide for the application of its unique consensus process in the development of standards and guidelines for patient testing and related healthcare issues. Our process is based on the principle that consensus is an effective and cost-effective way to improve patient testing and healthcare services. In addition to developing and promoting the use of voluntary consensus standards and guidelines, we provide an open and unbiased forum to address critical issues affecting the quality of patient testing and health care. PUBLICATIONS A document is published as a standard, guideline, or committee report. Standard A document developed through the consensus process that clearly identifies specific, essential requirements for materials, methods, or practices for use in an unmodified form. A standard may, in addition, contain discretionary elements, which are clearly identified. Guideline A document developed through the consensus process describing criteria for a general operating practice, procedure, or material for voluntary use. A guideline may be used as written or modified by the user to fit specific needs.

Most documents are subject to two levels of consensus— “proposed” and “approved.” Depending on the need for field evaluation or data collection, documents may also be made available for review at an intermediate consensus level. Proposed A consensus document undergoes the first stage of review by the healthcare community as a proposed standard or guideline. The document should receive a wide and thorough technical review, including an overall review of its scope, approach, and utility, and a line-by-line review of its technical and editorial content. Approved An approved standard or guideline has achieved consensus within the healthcare community. It should be reviewed to assess the utility of the final document, to ensure attainment of consensus (i.e., that comments on earlier versions have been satisfactorily addressed), and to identify the need for additional consensus documents. Our standards and guidelines represent a consensus opinion on good practices and reflect the substantial agreement by materially affected, competent, and interested parties obtained by following CLSI’s established consensus procedures. Provisions in CLSI standards and guidelines may be more or less stringent than applicable regulations. Consequently, conformance to this voluntary consensus document does not relieve the user of responsibility for compliance with applicable regulations. COMMENTS

The CLSI voluntary consensus process is a protocol establishing formal criteria for:

The comments of users are essential to the consensus process. Anyone may submit a comment, and all comments are addressed, according to the consensus process, by the committee that wrote the document. All comments, including those that result in a change to the document when published at the next consensus level and those that do not result in a change, are responded to by the committee in an appendix to the document. Readers are strongly encouraged to comment in any form and at any time on any document. Address comments to Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, PA 19087, USA.

•

the authorization of a project

VOLUNTEER PARTICIPATION

•

the development and open review of documents

•

the revision of documents in response to comments by users

•

the acceptance of a document as a consensus standard or guideline.

Healthcare professionals in all specialties are urged to volunteer for participation in CLSI projects. Please contact us at [email protected] or +610.688.0100 for additional information on committee participation.

Report A document that has not been subjected to consensus review and is released by the Board of Directors. CONSENSUS PROCESS

Volume 26 Number 22

C3-A4 ISBN 1-56238-610-7 ISSN 0273-3099

Preparation and Testing of Reagent Water in the Clinical Laboratory; Approved Guideline—Fourth Edition W. Gregory Miller, PhD, DABCC, FACB Erich L. Gibbs, PhD Dennis W. Jay, PhD, DABCC, FACB Kenneth W. Pratt, PhD Bruno Rossi, MS Christine M. Vojt, MT(ASCP), MS Paul Whitehead, PhD, CChem, FRSC

Abstract CLSI document C3-A4—Preparation and Testing of Reagent Water in the Clinical Laboratory; Approved Guideline—Fourth Edition provides information on water purity requirements for clinical laboratory testing, validation of specifications, technology available for water purification, and test procedures to monitor and trend water purity parameters. Clinical and Laboratory Standards Institute (CLSI). Preparation and Testing of Reagent Water in the Clinical Laboratory; Approved Guideline—Fourth Edition. CLSI document C3-A4 (ISBN 1-56238-610-7). Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2006.

The Clinical and Laboratory Standards Institute consensus process, which is the mechanism for moving a document through two or more levels of review by the healthcare community, is an ongoing process. Users should expect revised editions of any given document. Because rapid changes in technology may affect the procedures, methods, and protocols in a standard or guideline, users should replace outdated editions with the current editions of CLSI/NCCLS documents. Current editions are listed in the CLSI catalog, which is distributed to member organizations, and to nonmembers on request. If your organization is not a member and would like to become one, and to request a copy of the catalog, contact us at: Telephone: 610.688.0100; Fax: 610.688.0700; E-Mail: [email protected]; Website: www.clsi.org

(Formerly NCCLS)

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This publication is protected by copyright. No part of it may be reproduced, stored in a retrieval system, transmitted, or made available in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise) without prior written permission from Clinical and Laboratory Standards Institute, except as stated below. Clinical and Laboratory Standards Institute hereby grants permission to reproduce limited portions of this publication for use in laboratory procedure manuals at a single site, for interlibrary loan, or for use in educational programs provided that multiple copies of such reproduction shall include the following notice, be distributed without charge, and, in no event, contain more than 20% of the document’s text. Reproduced with permission, from CLSI publication C3-A4—Preparation and Testing of Reagent Water in the Clinical Laboratory; Approved Guideline—Fourth Edition (ISBN 1-56238-610-7). Copies of the current edition may be obtained from Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898, USA. Permission to reproduce or otherwise use the text of this document to an extent that exceeds the exemptions granted here or under the Copyright Law must be obtained from Clinical and Laboratory Standards Institute by written request. To request such permission, address inquiries to the Executive Vice President, Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898, USA. Copyright ©2006. Clinical and Laboratory Standards Institute.

Suggested Citation (Clinical and Laboratory Standards Institute. Preparation and Testing of Reagent Water in the Clinical Laboratory; Approved Guideline—Fourth Edition. CLSI document C3-A4 [ISBN 1-56238-610-7]. Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2006.)

Proposed Standard—First Edition

Approved Guideline—Second Edition

January 1976

August 1991

Tentative Standard—First Edition

Approved Guideline—Third Edition

January 1978

October 1997

Approved Standard—First Edition

Proposed Guideline—Fourth Edition

February 1980

June 2005

Proposed Guideline—Second Edition

Approved Guideline—Fourth Edition

June 1985

June 2006

Tentative Guideline—Second Edition December 1988 ISBN 1-56238-610-7 ISSN 0273-3099 ii

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Committee Membership Area Committee on Clinical Chemistry and Toxicology David A. Armbruster, PhD, DABCC, FACB Chairholder Abbott Laboratories Abbott Park, Illinois W. Gregory Miller, PhD Vice-Chairholder Virginia Commonwealth University Richmond, Virginia John Rex Astles, PhD, FACB Centers for Disease Control and Prevention Atlanta, Georgia David M. Bunk, PhD National Institute of Standards and Technology Gaithersburg, Maryland Neil Greenberg, PhD Ortho-Clinical Diagnostics, Inc. Rochester, New York Christopher M. Lehman, MD Univ. of Utah Health Sciences Center Salt Lake City, Utah

Richard R. Miller, Jr. Dade Behring Inc. Newark, Delaware

Harvey W. Kaufman, MD Quest Diagnostics, Incorporated Lyndhurst, New Jersey

Linda Thienpont, PhD University of Ghent Gent, Belgium

Gary L. Myers, PhD Centers for Disease Control and Prevention Atlanta, Georgia

Hubert Vesper, PhD Centers for Disease Control and Prevention Atlanta, Georgia

David Sacks, MD Brigham and Women’s Hospital and Harvard Medical School Boston, Massachusetts

Advisors Mary F. Burritt, PhD Mayo Clinic Rochester, Minnesota Paul D’Orazio, PhD Instrumentation Laboratory Lexington, Massachusetts Carl C. Garber, PhD, FACB Quest Diagnostics, Incorporated Teterboro, New Jersey Uttam Garg, PhD, DABCC Children’s Mercy Hospital Kansas City, Missouri

Bette Seamonds, PhD Mercy Health Laboratory Swarthmore, Pennsylvania Dietmar Stöckl, PhD University of Ghent Gent, Belgium Thomas L. Williams, MD Nebraska Methodist Hospital Omaha, Nebraska Jack Zakowski, PhD, FACB Beckman Coulter, Inc. Brea, California

Working Group on Reagent Water W. Gregory Miller, PhD, Chairholder Virginia Commonwealth University Richmond, Virginia Erich L. Gibbs, PhD High-Q, Inc. Wilmette, Illinois Dennis W. Jay, PhD, DABCC, FACB St. Jude Children’s Research Hospital Memphis, Tennessee Kenneth W. Pratt, PhD National Institute of Standards and Technology Gaithersburg, Maryland Bruno Rossi, MS Millipore SAS Guyancourt, France

Christine M. Vojt, MT(ASCP), MS Ortho-Clinical Diagnostics, Inc. Rochester, New York

Stephane Mabic Millipore SAS Guyancourt, France

Paul Whitehead, PhD, CChem, FRSC ELGA LabWater, Lane End, Bucks, United Kingdom

Alan Mortimer, CChem, FRSC ELGA LabWater, Lane End, Bucks, United Kingdom

Advisors

Keith W. Richardson Associates of Cape Cod, Inc. Woods Hole, Massachusetts

Kelli Buckingham-Meyer Montana State University Bozeman, Montana

Staff

Darla M. Goeres, MS Montana State University Bozeman, Montana Marilyn J. Gould, PhD Falmouth, Massachusetts Zenaida Maicas, PharmD Cape Neddick, Maine

Clinical and Laboratory Standards Institute Wayne, Pennsylvania John J. Zlockie, MBA Vice President, Standards Tracy A. Dooley, BS, MLT(ASCP) Staff Liaison

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Staff (Continued) Donna M. Wilhelm Editor Melissa A. Lewis Assistant Editor

Acknowledgement CLSI acknowledges the experts and their institutions listed below for their “special review,” advice, and help in preparing the approved-level, fourth edition of this guideline: Ellen Jo Baron, PhD, Stanford University Hospital and Medical School Anita Highsmith, Highsmith Environmental Consultants, Inc. Gary A. O'Neill, PhD, Selective Micro Technologies Bette Seamonds, PhD, DABCC, Mercy Health Laboratories

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Contents Abstract ....................................................................................................................................................i Committee Membership........................................................................................................................ iii Foreword .............................................................................................................................................. vii 1

Scope..........................................................................................................................................1

2

Introduction................................................................................................................................1

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Definitions .................................................................................................................................2

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Specifications.............................................................................................................................5 4.1 4.2 4.3 4.4 4.5 4.6 4.7

5

Validation and Trend Monitoring ............................................................................................10 5.1 5.2 5.3

6

Validation of Purified Water as Fit for Its Intended Purpose in Laboratory Procedures...................................................................................................................10 Trend Monitoring of Water Purity Specifications ......................................................11 Water Purification System Validation ........................................................................12

Design Considerations .............................................................................................................13 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8

7

Organization of Water Purity Specifications ................................................................6 Clinical Laboratory Reagent Water (CLRW) ...............................................................7 Special Reagent Water (SRW)......................................................................................8 Instrument Feed Water..................................................................................................9 Water Supplied by a Method Manufacturer for Use as a Diluent or Reagent ..............9 Commercially Bottled, Purified Water .........................................................................9 Autoclave and Wash Water Applications ...................................................................10

Filters ..........................................................................................................................14 Reverse Osmosis (RO) Membranes............................................................................14 Contactor Membranes.................................................................................................16 Ion-Exchange Resins ..................................................................................................16 Activated Carbon ........................................................................................................18 Distillation ..................................................................................................................19 Ultraviolet Light .........................................................................................................21 Storage and Distribution .............................................................................................21

Testing .....................................................................................................................................24 7.1 7.2 7.3 7.4 7.5

Resistivity ...................................................................................................................24 Microbial Content by Colony Count...........................................................................29 Microbial Content by Epifluorescence Microscopy ...................................................31 Endotoxins ..................................................................................................................34 Determination of Oxidizable Organic Substances, Expressed as Total Organic Carbon (TOC) .............................................................................................................36

References.............................................................................................................................................41 Additional References...........................................................................................................................43 Appendix A. Resistivity Measurement in a Sparged Water Sample....................................................44 v

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Contents (Continued) Appendix B. Methods for Correction or Compensation of Resistivity Measurements .......................46 Summary of Consensus and Delegate Comments and Working Group Responses .............................48 The Quality System Approach..............................................................................................................62 Related CLSI/NCCLS Publications ......................................................................................................63

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Foreword This edition of the guideline includes updated information regarding the preparation and testing of reagent water in clinical laboratories. Specifications are based on measuring parameters that serve as indicators for the total ionic, organic, and microbial contamination. Emphasis is placed on the value of trending these parameters as an effective way to control the quality and consistency of purified laboratory water, as well as the importance of validating that a given type of laboratory water is fit for its intended purpose. A new section provides guidelines for water purification system validation, ongoing maintenance, and revalidation on a recurring schedule. The Type I, II, III designations for types of purified laboratory water, used in the previous edition, have been replaced with purity types that provide more meaningful specifications for clinical laboratory testing. Clinical laboratory reagent water (CLRW) can be used in place of Type I and Type II water for most applications. Autoclave and wash water will generally be a satisfactory replacement for Type III water. The definitions of the new types of water include parameters that were not used in previous editions and some of the parameters that were used in previous editions. Resistivity measurement has been retained to monitor inorganic impurities. The previous edition recommended that water purification systems include a stage to reduce organic contamination, but required no control. This edition recognizes that organic contamination can be difficult to remove from feed water, can be introduced by components of water purification systems or biofilms, and must be controlled. Therefore, a total organic carbon (TOC) parameter has been added. Note that on-line or inhouse measurements of TOC are not required. It is acceptable to send CLRW samples to a referral laboratory for TOC measurement. (See Section 7.5 for additional information on contamination risks when TOC is at low levels.) Plate counting of colonies is a widely used method for monitoring the level of microorganisms in purified laboratory water, and this edition continues to specify this approach. However, epifluorescence and endotoxin testing have been added as optional tests, because they provide additional information and results can be determined quickly. Specifications and methods for measuring pH and silicates, as SiO2, have not been carried forward from the previous edition. Resistivity is more sensitive than pH to H+ and OH- contamination. Resistivity is not a sensitive indicator of weakly ionized contaminants, which may elute as concentrated pulses from ionexchange beds when they approach depletion. However, the release of weakly ionized contaminants (silica being but one example) can be avoided by appropriate design and regular maintenance of ionexchange components. A parameter for sterility of general-purpose purified laboratory water has not been included in this edition of the guideline, because most clinical laboratory applications do not require sterile water. Water can be sterilized as necessary for some applications; however, the method of sterilization may degrade the purity of the water. Key Words Autoclave and wash water, bottled water, clinical laboratory reagent water, high-purity water, instrument feed water, purified water, reagent water, special reagent water, water purification

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Preparation and Testing of Reagent Water in the Clinical Laboratory; Approved Guideline—Fourth Edition 1

Scope

A number of types of purified water for use in clinical laboratory testing procedures are specified: • • • • • •

clinical laboratory reagent water (CLRW); special reagent water (SRW); instrument feed water; water supplied by a method manufacturer; autoclave and wash water; and commercially bottled, purified water.

Procedures are provided for measuring parameters that monitor ionic, organic, and microbial contamination in purified laboratory water. These parameters should be monitored over time to identify trends in performance so corrective action can be taken before a parameter exceeds specified limits. Recommendations are provided to control particulate and colloidal contamination. The guideline includes validation by the laboratory that a selected type of water is fit for its intended purpose. Suggested approaches for validation of water purification systems are included. It is beyond the scope of this guideline to recommend specific types of water purification systems. Instead, the guideline provides information about discrete purification technologies and monitoring strategies that can be applied in various combinations to achieve and maintain the required water purity.

2

Introduction

The goal of every clinical laboratory is to produce accurate results. Purified water constitutes the major component of many reagents, buffers, and diluents used in clinical laboratory testing. It can also become an indirect component of tests when it is used for washing and sanitizing instruments and laboratory ware, generating autoclave steam, etc. Inadequate control of contamination in purified water is an important potential cause of laboratory error. This guideline recommends measuring certain parameters of purified water used in clinical laboratory applications as a means of quality control for purification systems. The parameters are: resistivity, an indicator of ionic contamination; total organic carbon, an indicator of organic contamination; and viable plate counts, an indicator of microorganism contamination. Epifluorescence and endotoxin testing are included as optional approaches for measuring contamination from microbial sources. Particulate contamination is controlled by including appropriate filtration, or distillation, in the purification system. The guideline is not intended to assure the adequacy of purified water for a given laboratory application; rather, water of a specified purity must be validated as fit for use in a particular laboratory application. Any parameters used to specify a type of purified water, or to monitor the performance of a purification system, must be measured frequently enough to detect potential changes in the system, and the measurement results should be monitored for trends to anticipate maintenance before the water quality degrades to a point that will cause problems with laboratory testing. Other organizations have published guidelines and specifications for purified water intended for various applications. Water conforming to the guidelines and specifications of these organizations may or may not be equivalent to the types of purified water described in this CLSI guideline. Any type of purified water should be validated as fit for purpose before being used in clinical laboratory testing. ©

Clinical and Laboratory Standards Institute. All rights reserved.

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Definitions

absorption – a process by which a substance is taken up chemically or physically in bulk by a material (absorbent) and held in pores or interstices in the interior; NOTE: See also adsorption, sorption. accuracy – closeness of agreement between a test result and the accepted reference value (ISO 3534-1)1; NOTE: Accuracy of a measurement is defined as the closeness of the agreement between the result of a measurement and a true value of the measurand (VIM93).2 activated carbon – porous carbon material used for removal of impurities; NOTE: See Section 6.5 for details. adsorption – adherence of molecules, atoms, and ionized species of gas or liquid to the surface of another substance (solid or liquid) as the result of a variety of weak attractions that involve ionic, Van der Waals, and surface-active (hydrophobic/hydrophilic) forces; NOTE: See also absorption, sorption. anion exchange resin – an ion-exchange resin with immobilized positively charged exchange sites, which can bind negatively charged ionized species. azeotrope – a blend of two or more components with equilibrium vapor phase and liquid phase compositions that are the same at a given temperature and pressure. bactericide – a chemical or physical agent that kills bacteria. biocide – a chemical or physical agent that kills microorganisms (as used in this document). biofilm – microorganisms, enclosed in a glycoprotein/polysaccharide matrix, that adhere to each other and/or to surfaces and may form macroscopic layers.3 CA membrane – a reverse osmosis membrane constructed of cellulose diacetate/triacetate. calibration – the set of operations that establish, under specified conditions, the relationship between values of quantities indicated by a measuring instrument or measuring system, or values represented by a material measure or a reference material, and the corresponding values realized by standards (VIM93).2 catalyst – a substance that increases the kinetics of a chemical reaction without being consumed in the reaction. cation exchange resin – an ion-exchange resin with immobilized negatively charged exchange sites, which can bind positively charged ionized species. colloid – small, solid particles that will not settle out of a solution. concentrate – the liquid containing dissolved and suspended matter that concentrates on one side of a membrane. condenser – the stage of a distillation system that removes sufficient heat from a vaporized liquid to cause the vapor to change to a liquid phase. conductivity – conductivity is the reciprocal of resistivity; NOTE: For water purification systems, conductivity is usually reported in microsiemens per centimeter (µS/cm). contactor membrane – a hydrophobic membrane used in removing dissolved gases from water. 2

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copolymer – a polymer formed from two or more different monomers. deadleg//dead volume – a region or volume of stagnation in an apparatus or distribution system. distillation – a purification process that utilizes changing the phase of a substance from liquid to vapor and back to liquid, usually at the boiling temperature of the substance, in order to separate it from other substances with higher or lower boiling points. electrodeionization (EDI) – technology combining ion-exchange resins and ion-selective membranes with direct current to remove ionic impurities from water and maintain the resin in regenerated condition. endotoxin – a thermostable lipopolysaccharide component from the cell wall of viable or nonviable gram-negative microorganisms. epifluorescence – method of fluorescence microscopy in which the excitation light is transmitted through the objective lens onto the specimen, and the fluorescence light is transmitted back through the objective lens to the eyepiece; NOTE: Fluorescence is the immediate emission of electromagnetic radiation, typically visible light, from molecules following absorption of light with a shorter wavelength. feed water – the water that is introduced into a purification process. filtration – a purification process in which the passage of fluid through a porous material results in the removal of impurities based on the physical interaction of the impurities with that porous material. fines – see particulates. gram-negative – refers to bacteria that do not retain the primary violet stain in the decolorization step in the procedure originally described by Gram. gram-positive – refers to bacteria that absorb and retain the primary violet stain in the decolorization step in the procedure originally described by Gram. ion exchange – a reversible chemical reaction between a solid containing immobilized ionic sites (ion exchanger) and a fluid (often water) by means of which ionized species may be exchanged from one substance to another. measurand – particular quantity subject to measurement (VIM93).2 microorganism – any organism that is too small to be viewed by the unaided eye, such as bacteria, viruses, molds, yeast, protozoa, and some fungi and algae. nonpurgeable organic carbon (NPOC) – the concentration of organic carbon remaining after sparging a sample to remove inorganic carbon. off-line – in water monitoring systems, referring to measurement devices that are not directly coupled to the water stream. on-line – in water monitoring systems, referring to measurement devices directly coupled to the water stream. particulates – discrete quantities of solid matter dispersed in water. permeate – substances passing through a semipermeable membrane. ©


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planktonic – a term used to describe aquatic microorganisms that float. plasticizer – a chemical component of plastics to make them softer and more flexible. polishing – in water purification systems, the final treatment stage(s) of the purification system. potable water – water that meets regulations as suitable for ingestion by humans. precision – closeness of agreement between independent test results obtained under stipulated conditions (ISO 3534-11); NOTE: Precision depends only on the distribution of random errors and does not relate to the true value or the specified value (ISO 3534-11). purgeable organic carbon (POC) – the concentration of carbon that escapes the sample in the gas phase during the process of sparging the sample to remove inorganic carbon prior to measuring the organic carbon. qualification – the act of establishing with documented evidence that the process, equipment, and/or materials are designed, installed, operated, and perform according to the predetermined specifications. reservoir – in water purification systems, a container holding quantities of purified water. resistivity – the electrical resistance between opposite faces of a one-centimeter cube of a given material at a specified temperature; NOTE 1: Resistivity is the reciprocal of conductivity; NOTE 2: For water analysis, resistivity is usually reported in megohm-centimeters (MΩ·cm). reverse osmosis (RO) – a process in which water is forced under pressure through a semipermeable membrane, leaving behind dissolved organic, dissolved ionic, and suspended impurities. risk – combination of the probability of occurrence of harm and the severity of that harm (ISO 151904); NOTE 1: risk assessment – scientific evaluation of known or potential adverse effects resulting from hazards. The process consists of the following steps: hazard, or potential hazard, identification; evaluation of the impact of the hazard; and assessment of the practicality of measures to mitigate the risk from the hazard. sanitization – chemical and/or physical processes used to kill microorganisms and reduce contamination from microorganisms. softening – a water treatment process whereby cations, notably divalent cations such as Ca++ and Mg++, are exchanged for sodium using cation-exchange resins in the sodium form. sorption – either or both of the processes of absorption and adsorption. sparging – injection of gas below the water surface to remove other dissolved gases and volatile organic compounds. stagnation – state of a liquid without current or circulation. sterilization – validated process used to render a product free from microorganisms (ISO 151904). TF membrane – a reverse osmosis membrane constructed of a thin film (TF) of polyamide materials. total carbon (TC) – total concentration of carbon (organic and inorganic) in a sample. 4

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total inorganic carbon (TIC) – total concentration of carbon as carbonates, bicarbonates, or dissolved carbon dioxide. total organic carbon (TOC) – total concentration of carbon in the form of organic compounds. validation – confirmation, through the provision of objective evidence, that requirements for a specific intended use or application have been fulfilled; NOTE 1: The term “validated” is used to designate the corresponding status (ISO 90005); NOTE 2: The use conditions for validation can be real or simulated (ISO 90005); NOTE 3: A term used by the FDA for a study used to determine whether a test system meets user needs (12 CFR Parts 808, 812, and 820)6; NOTE 4: WHO defines validation as “the action of proving that a procedure, process, system, equipment, or method used works as expected and achieves the intended result” (WHO-BS/95.1793). verification – confirmation, through the provision of objective evidence, that specified requirements have been fulfilled; NOTE 1: The term “verified” is used to designate the corresponding status (ISO 90005); NOTE 2: Confirmation can comprise activities such as: performing alternative calculations; comparing a new design specification with similar proven design specifications; undertaking tests and demonstrations; and reviewing the document prior to issue (ISO 90005); NOTE 3: ISO 8402 defines verification as “confirmation, by examination and provision of objective evidence, that specified requirements have been fulfilled”); NOTE 4: The FDA defines verification as “a study used to determine whether a test system meets specifications” (21 CFR Parts 808, 812, and 820).6

4

Specifications

Specifications or recommendations are provided for six types of purified water intended for different needs in clinical laboratory testing. At some stage in the preparation of every type of purified water, the water must meet or exceed regulations for potable drinking water comparable to those of the European Union, Japan, or the United States. All of the parameters associated with a water specification must be measured while water purification systems are operating routinely. Insofar as it is reasonable to do so, samples must be obtained for measurement, or on-line measurements made, after the last purification component and as close to the purification system output as possible. Where any purification or storage components exist after an online measurement, the user should validate that the water remains fit for purpose. When systems include a recirculating loop to distribute water to remote points of use, samples must be obtained for measurement, or on-line measurements made, at or after the last port of the loop to ensure that contamination is not introduced by the loop or as the result of backflow at one or more ports on the loop. Using water that meets the specified limits for all of the parameters will reduce the probability of contaminants existing at levels that could interfere with clinical laboratory tests. However, the purpose of water specifications based on the parameters used by this guideline is to monitor for continued control of water purification systems, not to ensure that the water they produce is necessarily fit for specific applications. Purified water must be validated separately as fit for a particular laboratory application (see Section 5.1). To ensure the stability of a purification system, any parameters used to specify a type of purified water, or to monitor the performance of the system, should be measured frequently enough and the results monitored for trends to detect changes and initiate maintenance (see Section 5.2). Each laboratory must determine how often to measure the parameters of its purified water and purification system and how often to revalidate the water as fit for purpose, based on a balance of risk and practicality. Measurements made at intervals have the risk that an out-of-specification condition could have existed and adversely affected clinical testing during the interval between measurements. Risk will increase as the ©


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time between measurements, and between revalidations, increases with respect to the stability of the purification system. Setting an alert threshold for a measured parameter at a more stringent level than the validated water purity can reduce the risk from gradual drift; however, this strategy does not protect against abrupt changes. A risk assessment should be carried out to establish an appropriate monitoring program.

4.1

Organization of Water Purity Specifications

This subsection is provided only as an organizational outline to facilitate the use of this guideline; it is not intended as a summary nor is it intended to have any significance outside the context of the complete guideline. 4.1.1

General Concepts Applicable to All Types of Water

The product water meeting a set specification must be validated as fit for purpose for each laboratory procedure in which it is to be used (see Section 5.1). The system producing purified water must be validated to meet the user requirements specification (see Section 5.3). Regular monitoring and trending of appropriate measured parameters must be carried out and documented to verify that water purification technologies and systems are working effectively (see Sections 5.2, 6, and 7). Procedures must be established for system maintenance to keep the system in conformance with water purity specifications (see Sections 5.2 and 6). 4.1.2 4.1.2.1

Clinical Laboratory Reagent Water (CLRW) Ionic Impurities

Resistivity ≥10 MΩ·cm referenced to 25 °C (see Sections 4.2.1 and 7.1) NOTE: Pretreatment to remove CO2 may be needed prior to measuring resistivity for purified water that contains dissolved CO2 (see Sections 4.2.1 and 7.1.2.3). 4.1.2.2

Microbiological Impurities

Total heterotrophic plate count 10 mΩ·cm or it does not. Further “processing” of a sample water to confirm that a specification is met only introduces error in the measurement. How does a user confirm that significant ionic contaminants were not added to the water in the process of removing CO2? I understand the objective of trying to differentiate dissolved CO2 (actually HCO3– is dropping the resistivity) from other ionic contaminants. I just don't think that the method described in this document is feasible in a real laboratory setting. •

As explained in the text, dissolved CO2 (as HCO3– plus H+) will lower the resistivity of otherwise pure water but has no effect on most clinical laboratory procedures. Consequently, removing CO2 prior to resistivity measurement allows a laboratory to verify the specification when the water may contain dissolved CO2, and it has been verified that the dissolved CO2 does not affect the laboratory procedures using that water. If dissolved CO2 did affect a procedure, then a special reagent water with suitable specification may be more appropriate. The method has been tested in one working group member’s laboratory. It is not anticipated this will be a common procedure, but it is provided for the laboratory that may find it useful to verify a resistivity specification. The text includes precautions to avoid contamination of the water sample to be tested. If ionic contamination were introduced in the procedure, the result would fail the specification, and the user would be expected to review the procedure to ensure there was no contamination introduced in the water sampling or measuring process.

Section 4.1.2.4, Particulate Content 20. There is a typographical error – [0.22 should read < 0.22] •

The text is correct as written; particles ≥ 0.22 µm are blocked by the filtration stage.

Section 4.1.3, Other Grades of Purified Water for Use in the Clinical Laboratory 21. “Grades” of purified water are defined by specifications. Only special reagent water, instrument feed water, and probably water supplied by a method manufacturer actually have specifications. As later defined, prepackaged bottled water could range from sterile water for injection to Poland Springs water. This variability does not define a “grade” of water. Likewise, tap water (if it had low levels of inorganic, organic, and particulate impurities) could meet the autoclave and wash water application “grade” of water. Who decides what level of impurities is a low level? •

“Grades” has been replaced with “types” to avoid confusion. The text has been edited to clarify that water in prepackaged bottles is not expected to meet the specifications for clinical laboratory reagent water at the time of opening the container. Such water may have met those specifications at the time of bottling, but at the time of use would be considered a special reagent water. The laboratory would need to establish acceptance criteria and validate the water as fit for purpose similarly to validation of other reagents used by the laboratory.

Section 4.2.1, Ionic Impurities 22. I think it would be good to mention the theoretical maximum achievable resistivity in this section in case a reader of the document does not read the later sections covering resistivity. •

The information has been added as suggested.

Section 4.2.1, Ionic Impurities and Section 7.1.2.4, Temperature Compensation 23. Is it the solution of 0.34 µmol/L (4.2.1) or the solution of 0.34 ng/g (Table 1, Section 7.1.2.4) that gives a resistivity of 10 megaohm-centimeters? •

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Section 4.2.3, Organic Impurities 24. As stated before in Comment 15, I believe TOC should be defined as total oxidizable carbon. •

See response to Comment 15.

Section 4.2.4, Particulate and Colloid Content 25. I think a brief explanation of the difference between a depth filter and surface, or screen, filter should be included here. Not all laboratorians will read later sections of the document where these differences are detailed. A very brief mention that there ARE different types of filters with the same micron rating is important to include in this section. •

The text has been clarified.

Section 4.6, Prepackaged Water 26. Comments about this section are already included above in Comment 21 on Section 4.1.3. •


27. I interpret CLRW as the replacement for type I water. Such water cannot be bottled or prepackaged. The water simply cannot meet the requirements for resistivity. In the previous water documents, a reference was included that demonstrated the observed degradation of bottled water in both glass and plastic [Gabler R et al. Degradation of high purity water on storage. J Liquid Chrom. 6:2565-2570 (1983)]. Certainly the TOC will change over time in plastic stored water; resistivity will continue to decrease; and the microbial content is likely to increase. Such statements as, “If a bottle is opened and reused over a period of time, the laboratory must validate the water remains fit for purpose throughout the entire period of use.” Do members of the subcommittee honestly believe that busy laboratorians in those small institutions are going to do all the required testing? •


Section 4.6.1, Proper Labeling 28. The phrase “for the lot of water as it exists in the container” should be replaced with “for the lot of water as it existed at the time of packaging.” There is no way to know the values of these parameters, short of measuring them, as they exist in a container. •

The suggested change has been made.

29. Define expiration date. Who sets this date? •

Section 4.6.2 states, “The laboratory must establish an expiration date for an opened container, based on storage conditions and validation of fitness for purpose, to prevent accumulation of microbial or other contaminants.” An expiration date is commonly understood to be the date after which the water is not to be used.

Section 4.6.2, Validation in the Clinical Laboratory 30. Generally, high-purity water degrades very quickly. Mention is not made as to how the bottled water is maintained/stored. •

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It would be difficult to anticipate all likely laboratory scenarios. The text emphasizes the laboratory is responsible to verify that the water in an opened bottle remains fit for purpose.


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Section 5.1, Validation of Purified Water as Fit for Its Intended Purpose in Laboratory Procedures 31. Under the third bullet, the statement “authenticated sources of purified water may include: 1) a different lot that was previously validated.” Since water cannot be stored for long periods, how is this practical? Likewise “2) a sample of validated water that was saved prior to a purification system sanitization, and was stored under conditions that would prevent contamination.” Isn’t this the same as statement 1? The document seems to contain many such repetitions. •

Depending on context, the two statements could be interpreted as very similar. Each statement, however, can apply to different situations. For example, (1) might apply to purchased, packaged water, while (2) might apply to a central purification system that requires periodic sanitization and verification that the wash was adequate. Both are included to suggest different approaches that could apply in different situations. Storage of water is challenging; thus the caution regarding conditions that would prevent contamination. Section 6.8.2 provides more information on storage considerations so the user can make appropriate judgments regarding suitability of a storage condition for a specific application.

32. Last sentence: “Validation is confirmed, through the provision of objective evidence...” is misleading. This needs to be more specific. For example, a technician may consider objective evidence as turbidity, taste, or odor. •

Examples of objective evidence are provided in the next paragraphs of Section 5.1. The text has been edited to clarify this point.

33. Last paragraph—Statement is misleading. Delete or rewrite. Omit “confirmation that the patient results from the procedures meet the clinical requirements of the healthcare system.” •

The phrase has been rewritten for clarity.

Section 5.1, Validation of Purified Water as Fit for Its Intended Purpose in Laboratory Procedures and Section 5.2, Trend Monitoring of Water Purity Specifications 34. The more stringent requirements for “Validation and Trend Monitoring” (Sections 5.1 and 5.2) may certainly be a challenge for small and medium sized laboratories. •

The several approaches to meeting the requirements for validation are provided to allow laboratories to understand different approaches for obtaining the necessary objective evidence of water performance in laboratory procedures. They should not be burdensome to a small laboratory because, in most cases, the quality control procedures already in place will be sufficient, when extended to consider water as a potential source of error. The trend monitoring requirements are analogous to those already in place to monitor quality control results, instrument function checks, maintenance, etc. Including water quality monitoring in the normal review process will help to avoid problems that may be caused by changes in water purity.

Section 5.2, Trend Monitoring of Water Purity Specifications 35. The document recommends testing at “established regular intervals.” The user needs guidance regarding testing frequency. No doubt, there will be sites that select quarterly or semiannual testing for microbial content. •

The term “established regular intervals” has been removed. The text has been edited to clarify that a laboratory needs to make judgments regarding the risk of water quality deterioration adversely affecting results, and establish the frequency of monitoring the quality parameters to provide adequate data for trend monitoring appropriate to mitigate that risk.

36. Words such as “trend monitoring and excursions” need to be defined. •

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Section 5.3.1, Validation of New and Major Upgrades to Water Purification Systems: A Master Validation Plan 37. I could not find a definition for URS in the document. This term may be very common in US laboratories, but I don't know what it is, and laboratorians in other countries might not, either. •

The words “user requirements specification” have been added in the text to define the initialism URS.

38. First bullet – Where is the definition of URS? •

The words “user requirements specification” have been added in the text to define the initialism URS.

39. Section 5.3.1.3 suggests simulation of adverse conditions. Seasonal changes are likely difficult to simulate and I seriously doubt that the vendors of purification systems will be in a position to complete such a task without incurring enormous cost to already fiscally challenged clinical laboratories (again remember the average bed capacity of hospitals in the US). In addition, in many cases, the laboratory has little or no input into system design when a new system is selected. This is especially true in smaller institutions. Architects and engineers sell administrations the least expensive solution and the laboratory often lives with the consequences. •

This section has been revised to remove simulation and clarify how to identify potential adverse conditions.

Section 5.3.2, Retrospective Qualification of Existing Water Purification Systems 40. The document recommends collecting data over two years to set up validation parameters. While this may be ideal, I suggest that it is impractical. •

A retrospective qualification assumes the purification system has been in service for a period of time and that trend monitoring data is available. The text has been revised to state “over a significant time period (e.g., one to two years)”; thus, one to two years is a suggestion for a significant time period.

Section 6, Design Considerations 41. Replace the word “expendable” with “consumable,” i.e., “consumable component” instead of “expendable component.” •

The suggested edit has been made.

42. Last paragraph—Add “alkaline phosphatase” to “microorganism growth and metabolism endotoxins),” i.e., “microorganism growth and metabolism (e.g., endotoxins, alkaline phosphatase).” •

(e.g.,


43. The recommendation that “a contamination profile over a year or two can be helpful in the selection of a water purification system” is, at best, impractical. What vendor has the information for the local area? None. This is an unrealistic recommendation. •

See the response to Comment 40.

Section 6.1.1, Microporous Filters 44. I think “surface filter” is a more accurate description than “screen filter.” •

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The alternate term “absolute” has been added to the text. “Surface” was considered uncommon usage and potentially confusing because a surface is difficult to define.


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Section 6.1.3, Vent Filters 45. High purity water is made on demand. Reference is made here to water storage containers. Elaborate on this point. •

A reference to Section 6.8, Storage and Distribution, has been added.

Section 6.2, Reverse Osmosis (RO) Membranes 46. It would be helpful if the formulas at the bottom of page 14 said “conductivity” and “resistivity” in front of the appropriate formula. •

The suggested edits have been made.

47. Paragraph 2: Water softening to minimize scale potential is VERY common pretreatment to RO systems. It should be added. •

Water softening has been included as a potential pretreatment at the end of the second paragraph.

48. Last paragraph: TF membranes provide twice the throughput of CA membranes “at equivalent operating pressures.” •


49. Last paragraph: Chlorine passage through RO membranes is pH dependent. Above about pH 7.8, very little chlorine will pass through an RO membrane. •

The text has been modified to state that chlorine can pass through a RO membrane under certain conditions, not that it always passes through.

50. Paragraph 1: RO are generally reliable, not “may be imperfect.” RO is a final stage in the purification system, not an early stage. •

Edits have been made to emphasize the general reliability of RO membranes. The sentence regarding placement of RO in a purification system has been deleted.

51. Last paragraph: RO membranes are available in three types. •

The two types of RO membranes mentioned in the document are the most common types used. There may be variants or modifications of these types that have been given different names.

Section 6.4, Ion-Exchange Resins 52. The second paragraph states “use of virgin resins avoids this potential problem” (of unexpected contamination). Vendors will not and cannot guarantee virgin resins. There is also a statement that “the manufacturer’s instructions for the rinse procedure should be followed when beds are exchanged.” Does the committee believe that laboratories will perform such procedures when such a process is not part of a service agreement? •

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Virgin resins are commonly provided by manufacturers of ion-exchange systems. It is a reasonable expectation that laboratories will use equipment according to the manufacturer’s instructions; it is expected that laboratories will follow recommendations for rinsing resins when putting them into service.

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Section 6.5, Activated Carbon 53. The pore size range given for activated carbon is VERY wrong. In addition to very large pores (10 000 A), high surface activated carbon will have a huge number of pores in the 10 A to 20 A range. In fact, most of the 1000 m2/gram of surface area is contained in these small pores. I assume that the “insoluble biocides” mentioned in the next-to-last paragraph includes silver impregnated into activated carbon. Silver impregnated in carbon is NOT insoluble. Its solubility is low (ppb range), but not zero. •

Specific pore sizes of activated carbon have been removed from the text. The word “insoluble” has been removed to avoid confusion.

Section 6.6, Distillation 54. The introduction to Section 6 states, “The section is not intended to be an in-depth review of water purification technologies; detailed information is available in texts and review articles.” Consistent with this statement, Sections 6.6.3 and 6.6.4 should be deleted. •

The sections have been retained because they contain useful information for users of distillation.

55. It seems that an inordinate amount of space is dedicated to this section. This process for water purification is not common in clinical laboratories nowadays, and will likely become less so with energy costs climbing. Stills are high maintenance equipment that cannot produce water with a resistivity of 18 megohm-centimeters due to high CO2 content. I do not believe any laboratorian will entertain sparging as an option. This is impractical. (I suggest deletion of Section 7.1.2.3 which describes, in detail, the sparging procedure). •

Distillation is a suitable technology in appropriate laboratory settings. The usefulness of the sparging technique was addressed in the response to Comment 19.

56. Define how distillation is used to prepare high purity water and/or other types of laboratory grade water. •

The document includes explanation of distillation technology in Section 6.6.

Section 6.6.2, Laboratory (Small-Scale) Stills 57. I am unaware of any clinical laboratories using stills for production of high purity water. Can you provide estimate of usage? •

It is estimated that 10% of clinical laboratories are using distillation technology.

Section 7.1.1, Summary of the Theory and Practice of Resistivity Measurement 58. I think the discussion of cell constant in resistivity measurements at the end of the section is well beyond the intended scope of this document. These paragraphs should be removed. •

The cell constant is the basis for traceability to the SI. The information is provided to ensure the accuracy of the measurement.

Section 7.1.2.2, Effects of CO2 Contamination 59. In light of the inaccuracies contained in Appendix A, the second paragraph of this section should either be rewritten or removed. •

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The original Appendix A has been deleted due to technical complexity; see response to Comment 71 for details.


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Section 7.1.2.3, Verifying the Resistivity Specification When Purified Water Contains Dissolved CO2 60. This entire section describes a technique that is almost never practiced and is completely impractical for implement in a real clinical laboratory. Its removal should be considered. •


Section 7.2, Microbial Content by Colony Count 61. Section 7.2.1.1 states, “water samples should be collected from points of use in the same manner as water is collected for normal laboratory use.” Why is there no guideline provided to the user on what is acceptable laboratory practice, e.g., opening the spigot and allowing the water to flow freely for at least one minute before collection? This document seems to leave every decision up to the user and does not give adequate working procedures or guidance. •

It is important that the water sampled for parameter testing is collected in the same manner as the water used for laboratory testing procedures. See response to Comment 66.

62. I take issue with the fact that the Filtration Kit Method has been removed. This is an extremely reliable approach for detecting heterotrophic bacteria and in my experience has been more reliable than filtration methods in some cases. The committee should keep in mind those small laboratories that have very limited microbiology capability and limited resources. •

Membrane filtration is included in the document. The previous edition referenced a pre-packaged kit that included the components needed. Specific reference to a kit has not been included in this edition, but a user can order the components in this manner if desired.

63. Overall, I do not think this document will be helpful to users seeking guidance on how to test and with what frequency. My concern is that, as has happened in the past, CAP will adopt the new guidelines and create even more confusion than already exists. •

This guideline is expected to provide a sound basis for decisions regarding preparation and use of purified water in clinical laboratory procedures. It is expected that each laboratory director will use this information to make appropriate judgments regarding fitness for purpose of water used in the laboratory, and to establish appropriate monitoring and trending procedures to ensure the appropriate water quality is maintained.

64. Delete first and second sentences, nonscientific. Microorganisms recovered from contaminated high purity water do not “become smaller and grow more slowly.” •

The text does not refer to changes in size of microorganisms after they are recovered from purified water; it refers to “microorganisms growing in purified water.” The text has been edited to make this clearer and to distinguish the growth rate in purified water from the growth rate in culture.

Section 7.2.1, Total Heterotrophic Plate Count 65. Is the pour plate technique still recommended for the determination of heterotrophic plate count? •

The limitations of the pour plate make it a less desirable option because subsurface organisms may not grow, or may grow very slowly due to oxygen requirements. They may also be more difficult to count and to subculture.

Section 7.2.1.1, Sample Collection 66. First bullet: The sampling point should be disinfected (usually with isopropyl alcohol) prior to sampling and water flushed from the port for one to two minutes before the sample is drawn. The objective of the sampling is to determine the microbiological content of the water in the water system, not to identify contaminated sample ports.

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The committee disagrees. It is important to identify two situations: 1) contaminated points of use where water is put into a secondary container or used for a laboratory procedure, and 2) microbial contamination in the water itself. The text has been edited to clarify that if water is sampled from a port intended only for the purpose of testing for microorganisms in the water produced by a purification system, then that port should be disinfected (usually with isopropyl alcohol) prior to sampling, and flushed thoroughly to remove the disinfectant before the water sample is drawn. In the first situation, it is important not to disinfect to enable the microbial testing to identify ports on the system that may be contaminated and need to be sanitized.

67. Samples must not be brought to ambient temperature before testing. This will increase counts. •

At the typical low level of microbial content in purified water, the count will not substantially increase in the 15 minutes it takes to warm to room temperature. Failure to warm the water sample increases the risk of shocking the organism and having viable organisms that do not grow in culture.

Section 7.2.1.2, Media and Incubation Conditions 68. Temp is recommended at 25 to 37 ºC. •

The most representative counts will be seen when the cultures are incubated at a similar temperature at which the water system is operating, usually ambient; higher temperatures can result in lower counts.

Section 7.2.1.4, Spread-Plate Technique (Direct) 69. Temp is recommended at 25 to 37 ºC. •


Section 7.4, Endotoxins 70. First sentence: Biofilms can occur in connective lines within a water treatment system; however, only at a minimum when proper sanitation is conducted. The majority of microorganisms are isolated from final product water. Endotoxin testing is important to include in the test parameters. Make reference that endotoxin indicates presence of gram-negative bacteria but not the presence of a gram-positive organism or fungi. •

Biofilms occur on all surfaces of a water purification system, including the connecting lines between the purification system components and the piping of a distribution system. Bacteria also grow in the purification components. The frequency of exchange of components and the frequency of system sanitization are established to control microbial contamination of the output water. See Section 6 for more details on microbial growth in components and Section 6.8.4 on system sanitization recommendations. The text has been edited to remind the reader that endotoxin is produced primarily by gram-negative microorganisms.

Appendix A, Permeability of Plastic Piping to Atmospheric CO2 71. This section contains significant errors and needs to either be rewritten or removed. Error 1: I have no idea where a value of 12400 cm3·mm·m-2·(24 h)-1·bar-1 for the permeability of CO2 in polypropylene was obtained. It's very hard to know, since no reference is cited. A value that I found from a reputable source is: 26+2 cm3·cm·m-2·day-1·atm-1 Converting this to the same units used in the appendix, one obtains 257 cm3·mm·m-2·(24 h)-1·bar-1 (Source: Department of Macromolecular Science, Center for Applied Polymer Research, Case Western Reserve University. Obtained from www.elsevier.com/locate/polymer) ©


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The permeability used in this analysis is incorrect by a factor of greater than 48. This will obviously lead to inaccurate results and conclusions. The permeability used may, possibly, be for porous, polypropylene membranes; however, it is not correct for dense polypropylene used for tubing and bottles. Error 2: The inside surface area of the tubing will be the limiting area for transfer of CO2, not the outside surface area. The inside surface area is: A = pi x D x L A = 3.14159 x 0.4 cm x 100 cm = 125.7 cm2 Thus, the surface area used in the calculation is 50% higher than the appropriate value (188.5 vs. 127.5) Errors 1 and 2 will both cause an overestimation of CO2 diffusion through polypropylene tubing. Combining these two errors shows that the diffusion rate is overestimated by a factor of 72.4 Error factor = (12400/257) x (188.5/127.5) = 72.4 Thus, the degradation of resistivity from 18.2 MΩ·cm to 3.5 mΩ·cm will take 72.4 times longer than calculated in the appendix. Degradation time = 10 minutes x 72.4 = 724 minutes = 12 hours and 4 minutes Even this corrected analysis overstates how quickly degradation will occur. The diffusion rate of CO2 out of the tubing into the water will slow as the concentration of CO2 in the water increases over time, thus reducing the driving force. •

The permeability 12 400 cm3·mm·m-2·(24 h)-1·bar-1 was obtained from http://www.nalgenelabware.com/techdata/Resin/index2.asp?m=&p=Permeability+CO2+%28metric%29 &txtMError (accessed 29 May 2005). The actual permeability of different plastics varies over a wide range, and the suggested value of 26 ± 2 cm3·cm·m-2·day-1·atm-1 is also representative. The commenter’s recalculation appears to be in error by a factor of 100. In converting from cm3·cm·m·day-1·atm-1 to cm3·mm·m-2·day-1·atm-1, the former is the rate of permeation through a centimeter of plastic, the latter is through 1 millimeter of plastic. Consequently, the latter should be higher by a factor of 10, but the commenter has divided by 10. Therefore, the suggested permeability value converts to 26 000 rather than 260 (257), which is approximately twice the original permeability value used.

2

The commenter’s second point is correct that the inner surface area is the limiting factor and this will give a value 127.5/188.5 smaller. Therefore, the overall effect of these changes is (26 000/12 400) x (127.5/188.5) = an increase of 1.42 x in permeability (not a decrease of 72.4 x as stated by the commenter). Additional simplifying assumptions regarding cumulative diffusion effects and non-linear diffusion over time would be necessary for a correct quantitative estimate of permeability of a gas through plastic. The original Appendix A has been deleted, because it was complex and required a number of assumptions about technical details to provide an example of plastic permeability to CO2. The important qualitative conclusions regarding the effect of plastic permeability on the resistivity of water have been included in the text.

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The Quality System Approach Clinical and Laboratory Standards Institute (CLSI) subscribes to a quality system approach in the development of standards and guidelines, which facilitates project management; defines a document structure via a template; and provides a process to identify needed documents. The approach is based on the model presented in the most current edition of CLSI/NCCLS document HS1—A Quality Management System Model for Health Care. The quality system approach applies a core set of “quality system essentials” (QSEs), basic to any organization, to all operations in any healthcare service’s path of workflow (i.e., operational aspects that define how a particular product or service is provided). The QSEs provide the framework for delivery of any type of product or service, serving as a manager’s guide. The quality system essentials (QSEs) are: Documents & Records Organization Personnel

Equipment Purchasing & Inventory Process Control

Information Management Occurrence Management Assessment

Process Improvement Service & Satisfaction Facilities & Safety

Facilities & Safety

Service & Satisfaction

Process Improvement

Assessment

X

Occurrence Management

Process Control

X

Information Management

Purchasing & Inventory

Equipment

Personnel

Organization

Documents & Records

C3-A4 addresses the quality system essentials (QSEs) indicated by an “X.” For a description of the other documents listed in the grid, please refer to the Related CLSI/NCCLS Publications section on the following page.

Adapted from CLSI/NCCLS document HS1—A Quality Management System Model for Health Care.

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Related CLSI/NCCLS Publications* C24-A2

Statistical Quality Control for Quantitative Measurements: Principles and Definitions; Approved Guideline—Second Edition (1999). This guideline provides definitions of analytical intervals, planning of quality control procedures, and guidance for quality control applications.

EP7-A2

Interference Testing in Clinical Chemistry; Approved Guideline—Second Edition (2005). This document provides background information, guidance, and experimental procedures for investigating, identifying, and characterizing the effects of interfering substances on clinical chemistry test results.

GP2-A5

Laboratory Documents: Development and Control; Approved Guideline—Fifth Edition (2006). This document provides guidance on development, review, approval, management, and use of policy, process, and procedure documents in the medical laboratory community.

*

Proposed-level documents are being advanced through the Clinical and Laboratory Standards Institute consensus process; therefore, readers should refer to the most current editions.

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Centers for Medicare & Medicaid Services/CLIA Program Chinese Committee for Clinical Laboratory Standards Department of Veterans Affairs Deutsches Institut für Normung (DIN) FDA Center for Biologics Evaluation and Research FDA Center for Devices and Radiological Health FDA Center for Veterinary Medicine Iowa State Hygienic Laboratory Massachusetts Department of Public Health Laboratories National Center of Infectious and Parasitic Diseases (Bulgaria) National Health Laboratory Service (South Africa) National Institute of Standards and Technology National Pathology Accreditation Advisory Council (Australia) New York State Department of Health Ontario Ministry of Health Pennsylvania Dept. of Health Saskatchewan Health-Provincial Laboratory Scientific Institute of Public Health; Belgium Ministry of Social Affairs, Public Health and the Environment Industry Members AB Biodisk Abbott Diabetes Care Abbott Laboratories Access Genetics Acrometrix Corporation AdvaMed Advancis Pharmaceutical Corporation Affymetrix, Inc. Agilent Technologies, Inc. Ammirati Regulatory Consulting Anna Longwell, PC Arpida Ltd A/S ROSCO AstraZeneca Pharmaceuticals Axis-Shield Diagnostics Axis-Shield POC AS Bayer Corporation – Tarrytown, NY Bayer Corporation - West Haven, CT Bayer HealthCare, LLC, Diagnostics Div. - Elkhart, IN BD BD Diabetes Care BD Diagnostic Systems BD VACUTAINER Systems Beckman Coulter, Inc. Beckman Coulter K.K. (Japan) Beth Goldstein Consultant (PA) Bio-Development S.r.l. Bio-Inova Life Sciences International Biomedia Laboratories SDN BHD bioMérieux (NC) bioMérieux, Inc. (IL) bioMérieux, Inc. (MO) Bio-Rad Laboratories, Inc. Bio-Rad Laboratories, Inc. – France Bio-Rad Laboratories, Inc. – Irvine, CA Bio-Rad Laboratories, Inc. – Plano, TX Black Coast Corporation – Health Care Systems Consulting Blaine Healthcare Associates, Inc. Cepheid Chen & Chen, LLC Chi Solutions, Inc. Chiron Corporation The Clinical Microbiology Institute Comprehensive Cytometric Consulting Control Lab Copan Diagnostics Inc. Cosmetic Ingredient Review Cubist Pharmaceuticals Cumbre Inc. Dade Behring Inc. - Cupertino, CA Dade Behring Inc. - Deerfield, IL Dade Behring Inc. - Glasgow, DE Dade Behring Inc. - Marburg, Germany Dade Behring Inc. - Sacramento, CA David G. Rhoads Associates, Inc. Diagnostic Products Corporation Digene Corporation

Eiken Chemical Company, Ltd. Elanco Animal Health Electa Lab s.r.l. Enterprise Analysis Corporation F. Hoffman-La Roche AG Focus Bio-Inova, Inc. Future Diagnostics B.V. Gavron Group, Inc. Gen-Probe Genaco Biomedical Products, Inc. Genomic Health, Inc. Gentris Corporation Genzyme Diagnostics GlaxoSmithKline Greiner Bio-One Inc. Immunicon Corporation Instrumentation Laboratory International Technidyne Corporation I-STAT Corporation Japan Assn. of Clinical Reagents Industries Johnson and Johnson Pharmaceutical Research and Development, L.L.C. K.C.J. Enterprises LabNow, Inc. LifeScan, Inc. (a Johnson & Johnson Company) Medical Device Consultants, Inc. Merck & Company, Inc. Micromyx, LLC MultiPhase Solutions, Inc. Nanogen, Point-of-Care Diagnostics Div. Nippon Becton Dickinson Co., Ltd. Nissui Pharmaceutical Co., Ltd. NovaBiotics (Aberdeen, UK) Novartis Institutes for Biomedical Research Olympus America, Inc. Optimer Pharmaceuticals, Inc. Ortho-Clinical Diagnostics, Inc. (Rochester, NY) Ortho-McNeil Pharmaceutical (Raritan, NJ) Oxoid Inc. Oxonica (UK) Paratek Pharmaceuticals Pathology Services Inc. PathWork Informatics Pfizer Animal Health Pfizer Inc Pfizer Italia Srl Phadia AB Powers Consulting Services PPD, Inc. Predicant Biosciences Procter & Gamble Pharmaceuticals, Inc. QSE Consulting Radiometer America, Inc. Radiometer Medical A/S Rapid Laboratories Microsystems Reliance Life Sciences Replidyne Roche Diagnostics GmbH Roche Diagnostics, Inc. Roche Diagnostics Shanghai Ltd. Roche Laboratories (Div. HoffmannLa Roche Inc.) Roche Molecular Systems Sanofi Pasteur Sarstedt, Inc. Schering Corporation Schleicher & Schuell, Inc. Seneca Medical Lab, Inc. SFBC Anapharm Sphere Medical Holding Streck Laboratories, Inc. Sysmex America, Inc. (Long Grove, IL) Sysmex Corporation (Japan) TheraDoc Theravance Inc. Third Wave Technologies, Inc. Thrombodyne, Inc. THYMED GmbH Transasia Engineers Trek Diagnostic Systems, Inc. TrimGen Corporation Watin-Biolife Diagnostics and Medicals Wyeth Research XDX, Inc. YD Consultant YD Diagnostics (Seoul, Korea) Trade Associations AdvaMed Japan Association of Clinical Reagents Industries (Tokyo, Japan)

Associate Active Members 35 MDSS/SGSAL (APO) 59th MDW/859 MDT/MTL (TX) 78th Medical Group (GA) Academisch Ziekenhuis -VUB (Belgium) ACL Laboratories (IL) ACL Laboratories (WI) Alexandria Hospital (IL) All Children’s Hospital (FL) Allina Health System (MN) Allina Labs Alton Memorial Hospital (MN) American University of Beirut Medical Center (NY) Anaheim Memorial Hospital (CA) Antwerp University Hospital (Belgium) Arnett Clinic, LLC (IN) Aspirus Wausau Hospital (WI) Associated Regional & University Pathologists (UT) Atlantic Health System (NJ) Avista Adventist Hospital Laboratory (CO) AZ Sint-Jan (Belgium) Azienda Ospedale Di Lecco (Italy) Barnes-Jewish Hospital (MO) Barnes-Jewish St. Peters (MO) Barnes-Jewish West County Hospital (MO) BayCare Health System (FL) Baystate Medical Center (MA) BC Biomedical Laboratories (Surrey, BC, Canada) Bedford Memorial Hospital (VA) Boone Hospital Center (MO) British Columbia Cancer Agency – Vancouver Cancer Center (BC, Canada) Broward General Medical Center (FL) Calgary Laboratory Services (Calgary, AB, Canada) California Pacific Medical Center Canterbury Health Laboratories (New Zealand) Capital Health System Fuld Campus (NJ) Capital Health System Mercer Campus (NJ) Carilion Consolidated Laboratory (VA) Carolinas Medical Center (NC) Central Baptist Hospital (KY) Central Ohio Primary Care Physicians Central Texas Veterans Health Care System Centura Laboratory (CO) Chang Gung Memorial Hospital (Taiwan) Children’s Healthcare of Atlanta (GA) Children’s Hospital Medical Center (Akron, OH) Children’s Hospital of Pittsburgh (PA) Childrens Hospital of Wisconsin Christian Hospital/Northeast/ Northwest (MO) Christus St. John Hospital (TX) City of Hope National Medical Center (CA) Clarian Health - Methodist Hospital (IN) Clendo Lab (PR) Clovis Community Hospital (CA) CLSI Laboratories (PA) Commonwealth of Kentucky Community Care 5 (OH) Community College of Rhode Island Covance Central Laboratory Services (IN) Creighton University Medical Center (NE) Danish Institute for Food and Veterinary Research (Denmark) Dekalb Memorial Hospital (IN) Detroit Health Department (MI) DFS/CLIA Certification (NC) Diagnofirm Med Labs Diagnósticos da América S/A (Sao Paulo) Dianon Systems (OK) Dr. Everett Chalmers Hospital (New Brunswick, Canada) East Kootenay Regional Hospital Laboratory (BC) Evangelical Community Hospital (PA) Faith Regional Health Services (NE)

FasTraQ Inc. (NV) Firelands Regional Medical Center (OH) Fisher-Titus Memorial Hospital (OH) Fleury S.A. (Brazil) Florida Hospital East Orlando Fresno Community Hospital and Medical Center Gamma Dynacare Medical Laboratories (Ontario, Canada) Gamma-Dynacare Laboratories (Brampton, Ontario) Geisinger Medical Center (Danville, PA) Geisinger Wyoming Valley Medical Center (Wilkes-Barre, PA) General Health System (LA) Hamad Medical Corporation (Qatar) Harris Methodist Fort Worth (TX) Hartford Hospital (CT) Health Network Lab (PA) Health Partners Laboratories (VA) High Desert Health System (CA) Hoag Memorial Hospital Presbyterian (CA) Holy Cross Hospital (MD) Hôpital Maisonneuve - Rosemont (Montreal, Canada) Hôpital Sainte - Justine (Quebec) Hospital Albert Einstein (Brazil) Hospital Consolidated Laboratories (MI) Hospital for Sick Children (Toronto, ON, Canada) Hôtel Dieu Grace Hospital (Windsor, ON, Canada) Hunter Area Pathology Service (DE) Hunterdon Medical Center (NJ) Indiana University Interior Health Authority Island Hospital (WA) Jackson Health System (FL) Jackson South Community Hospital (FL) Jacobi Medical Center (NY) John C. Lincoln Hospital (AZ) John H. Stroger, Jr. Hospital of Cook County (IL) Johns Hopkins at Bayview (MD) Johns Hopkins Howard County General Hospital (MD) Johns Hopkins Medical Institutions (MD) Kadlec Medical Center (WA) Kaiser Permanente (CA) Kaiser Permanente (MD) Kantonsspital Aarau AG (Aarau, AG) Karolinska University Hospital Kelowna General Hospital Laboratory (BC) King Abdulaziz Medical City – Jeddah (Jeddah, WR, Saudi Arabia) King Fahad National Guard Hospital (Saudi Arabia) King Faisal Specialist Hospital (Saudi Arabia) Kootenay Boundary Regional Hospital Laboratory (BC) Kosciusko Laboratory (IN) LabCorp (NC) Laboratoire de Santé Publique du Quebec (Canada) Laboratory Alliance of Central New York (NY) Laboratory Corporation of America (NJ)

Lewis-Gale Medical Center (VA) L’Hotel-Dieu de Quebec (Quebec, PQ) LifeCare Hospital Lab (PA) Littleton Adventist Hospital Laboratory (CO) Long Beach Memorial Medical Center (CA) Long Island Jewish Medical Center (NY) Magee Womens Hospital of UPMCHS (PA) Magruder Memorial Hospital (OH) Malmo University Hospital (Sweden) Manipal Acunova Pvt., Ltd. (India) Martin Luther King/Drew Medical Center (CA) Massachusetts General Hospital (Microbiology Laboratory) MDS Metro Laboratory Services (Burnaby, BC, Canada) Mease Countryside Hospital (FL) Mease Dunedin Hospital (FL) Medical Centre Ljubljana (Slovinia) Medical College of Virginia Hospital Medical University of South Carolina (SC) Memorial Hospital (OH) Memorial Medical Center (Napoleon Avenue, New Orleans, LA) Memorial Regional Hospital (FL) Methodist Hospital (TX) Missouri Baptist Medical Center (MO) Montreal General Hospital (Canada) Mount Sinai Hospital (NY) Mountainside Hospital (NJ) MRL Europe (Zaventem) National Healthcare Group (Singapore) National University Hospital (Singapore) NB Department of Health & Wellness (New Brunswick, Canada) NC State Lab of Public Health (NC) The Nebraska Medical Center New England Fertility Institute (CT) New York University Medical Center New Zealand Diagnostic Group NHG Diagnostics (Singapore) Nichols Institute Diagnostics (CA) NorDx (ME) North Bay Hospital North Coast Clinical Laboratory (OH) North Shore Hospital Laboratory (Auckland, New Zealand) North Shore - Long Island Jewish Health System Laboratories (NY) Northern Plains Laboratory (ND) Northwestern Memorial Hospital (IL) Ochsner Clinic Foundation (LA) Orange Coast Memorial Medical Center (CA) Orlando Regional Healthcare System (FL) Overlook Hospital (NJ) Parker Adventist Hospital Laboratory (CO) Parkland Health Center (MO) Pathology Associates Medical Laboratories (WA) Pathology Associates of Boone (NC)

Pediatrix Screening Inc. (PA) Penn State Hershey Medical Center (PA) Penticton Regional Hospital Laboratory (BC) The Permanente Medical Group (CA) Piedmont Hospital (GA) Pitt County Memorial Hospital (NC) Porter Adventist Hospital Laboratory (CO) PPD (KY) Presbyterian Hospital of Dallas (TX) Prince George Medical Lab (Prince George, BC) Provincial Health Services Authority (Vancouver, BC, Canada) Provincial Laboratory for Public Health (Edmonton, AB, Canada) Quest Diagnostics, Inc (San Juan Capistrano, CA) Quintiles Laboratories, Ltd. (GA) Regions Hospital Research Medical Center (MO) Rhode Island Department of Health Laboratories Riverview Hospital (BC, Canada) Riyadh Armed Forces Hospital (Riyadh) Royal Inland Hospital Laboratory (BC) Rural Health Ventures (NE) SAAD Specialist Hospital (Saudi Arabia) SAE – Laboratorio Medico (Brazil) St. Agnes Healthcare (MD) St. Anthony Hospital Central Laboratory (CO) St. Anthony Hospital North Laboratory (CO) St. Anthony’s Hospital (FL) St. Barnabas Medical Center (NJ) St. Christopher’s Hospital for Children (PA) St-Eustache Hospital (Quebec, Canada) St. John Hospital and Medical Center (MI) St. John Regional Hospital (St. John, NB, Canada) St. Joseph’s Hospital (FL) St. Joseph’s Hospital and Medical Center (AZ) St. Joseph’s Hospital-Marshfield Clinic (WI) St. Jude Children’s Research Hospital (TN) St. Louis Children’s Hospital (MO) St. Margaret Memorial Hospital (PA) St. Mary Corwin Regional Medical Center Laboratory (CO) St. Michael’s Hospital (Toronto, ON, Canada) San Antonio Community Hospital (TX) San Francisco General Hospital (CA) Santa Clara Valley Medical Center (CA) Shands at the University of Florida SJRMC Plymouth Laboratory (IN) Sonora Quest JV (AZ) South Bend Medical Foundation (IN) South Florida Baptist Hospital (FL) South Texas Laboratory (TX) South Western Area Pathology Service (Australia) Specialty Laboratories, Inc. (CA)

OFFICERS Robert L. Habig, PhD, President Abbott Laboratories Gerald A. Hoeltge, MD, President-Elect The Cleveland Clinic Foundation Wayne Brinster, Secretary BD W. Gregory Miller, PhD, Treasurer Virginia Commonwealth University Thomas L. Hearn, PhD, Immediate Past President Centers for Disease Control and Prevention Glen Fine, MS, MBA, Executive Vice President

Starke Memorial Hospital Laboratory (IN) State of Washington Department of Health Stormont-Vail Regional Medical Center (KS) Sunnybrook & Women’s College Health Sciences Centre (Toronto, Ontario) Sunnybrook Health Science Center (ON, Canada) Taiwan Society of Laboratory Medicine Tan Tock Seng Hospital (Tan Tock Seng) Temple Univ. Hospital - Parkinson Pav. (PA) Texas Department of State Health Services (TX) Timmins and District Hospital (Canada) The Children’s University Hospital (Ireland) Tri-Cities Laboratory (WA) Tripler Army Medical Center (HI) Tuen Mun Hospital (Hong Kong) Tuttle Army Health Clinic (GA) UCSD Medical Center (CA) UCSF Medical Center China Basin (CA) UNC Hospitals (NC) Union Clinical Laboratory (Taiwan) Universita Campus Bio-Medico (Italy) University Medical Center (CA) University of Chicago Hospitals (IL) University of Colorado Hospital University of Debrecen Medical Health and Science Center (Hungary) University of Illinois Medical Center (IL) University of Maryland Medical System University of MN Medical Center Fairview University of the Ryukyus (Japan) University of Virginia Medical Center University of Washington UPMC Horizon Hospital (PA) U.S. Army Health Clinic – Vicenza (APO) US LABS, Inc. (CA) USA MEDDAC-AK UZ-KUL Medical Center (Belgium) VA (Asheville) Medical Center (NC) Valley Health (VA) Vejle Hospital (VA) Vernon Jubilee Hospital Laboratory Virginia Beach General Hospital (VA) Warren Hospital (NJ) Washington Hospital Center (DC) Waterford Regional Hospital (Ireland) Wellstar Health Systems (GA) West China Second University Hospital, Sichuan University (P.R. China) William Beaumont Army Medical Center (TX) William Beaumont Hospital (MI) Winn Army Community Hospital (GA) Women’s Health Laboratory (TX) Woodlawn Hospital (IN) York Hospital (PA)

BOARD OF DIRECTORS Susan Blonshine, RRT, RPFT, FAARC TechEd

Gary L. Myers, PhD Centers for Disease Control and Prevention

Maria Carballo Health Canada

Valerie Ng, PhD, MD Alameda County Medical Center/ Highland General Hospital

Russel K. Enns, PhD Cepheid Mary Lou Gantzer, PhD Dade Behring Inc. Lillian J. Gill, DPA FDA Center for Devices and Radiological Health Jeannie Miller, RN, MPH Centers for Medicare & Medicaid Services

Klaus E. Stinshoff, Dr.rer.nat. Digene (Switzerland) Sàrl James A. Thomas ASTM International Kiyoaki Watanabe, MD Keio University School of Medicine

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