mm03: molecular diagnostic methods for infectious diseases, … · 2017-06-14 · mm03, 3rd ed....
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3rd Edition
MM03Molecular Diagnostic Methods for Infectious Diseases
This report addresses topics relating to clinical applications,
amplified and nonamplified nucleic acid methods, selection
and qualification of nucleic acid sequences, establishment and
evaluation of test performance characteristics, inhibitors, and
interfering substances, controlling false-positive reactions,
reporting and interpretation of results, quality assurance,
regulatory issues, and recommendations for manufacturers and
clinical laboratories.
A CLSI report for global application.
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Clinical and Laboratory Standards Institute Setting the standard for quality in clinical laboratory testing around the world.
The Clinical and Laboratory Standards Institute (CLSI) is a not-for-profit membership organization that brings together the varied perspectives and expertise of the worldwide laboratory community for the advancement of a common cause: to foster excellence in laboratory medicine by developing and implementing clinical laboratory standards and guidelines that help laboratories fulfill their responsibilities with efficiency, effectiveness, and global applicability. Consensus Process
Consensus—the substantial agreement by materially affected, competent, and interested parties—is core to the development of all CLSI documents. It does not always connote unanimous agreement, but does mean that the participants in the development of a consensus document have considered and resolved all relevant objections and accept the resulting agreement. Commenting on Documents
CLSI documents undergo periodic evaluation and modification to keep pace with advancements in technologies, procedures, methods, and protocols affecting the laboratory or health care.
CLSI’s consensus process depends on experts who volunteer to serve as contributing authors and/or as participants in the reviewing and commenting process. At the end of each comment period, the committee that developed the document is obligated to review all comments, respond in writing to all substantive comments, and revise the draft document as appropriate.
Comments on published CLSI documents are equally essential, and may be submitted by anyone, at any time, on any document. All comments are addressed according to the consensus process by a committee of experts. Appeals Process
If it is believed that an objection has not been adequately addressed, the process for appeals is documented in the CLSI Standards Development Policies and Process document.
All comments and responses submitted on draft and published documents are retained on file at CLSI and are available upon request.
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MM03, 3rd ed.
February 2015
Replaces MM03-A2
Molecular Diagnostic Methods for Infectious Diseases
Stephen P. Day, PhD
Cynthia L. Jackson, PhD
Frederick S. Nolte, PhD, D(ABBM), F(AAM)
Zivana Tezak-Fragale, PhD
Abstract Nucleic acid methods for the detection and characterization of microorganisms in clinical specimens are now firmly established
in laboratory medicine. These methods offer opportunities for clinical laboratories to provide more rapid and accurate results, and
have changed the practice of clinical microbiology and infectious diseases. Clinical and Laboratory Standards Institute document
MM03—Molecular Diagnostic Methods for Infectious Diseases addresses topics relating to clinical applications, amplified and
nonamplified nucleic acid methods, selection and qualification of nucleic acid sequences, establishment and evaluation of test
performance characteristics, inhibitors, and interfering substances, controlling false-positive reactions, reporting and
interpretation of results, QA, regulatory issues, and recommendations for manufacturers and clinical laboratories.
Clinical and Laboratory Standards Institute (CLSI). Molecular Diagnostic Methods for Infectious Diseases. 3rd ed. CLSI report
MM03 (ISBN 1-56238-997-1 [Print]; ISBN 1-56238-998-X [Electronic]). Clinical and Laboratory Standards Institute, 950 West
Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA, 2015.
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 health care 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 documents. Current editions are listed in
the CLSI catalog and posted on our website at www.clsi.org. If you or 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.
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ii
Copyright ©2015 Clinical and Laboratory Standards Institute. Except as stated below, any reproduction of
content from a CLSI copyrighted standard, guideline, companion product, or other material requires
express written consent from CLSI. All rights reserved. Interested parties may send permission requests to
CLSI hereby grants permission to each individual member or purchaser to make a single reproduction of
this publication for use in its laboratory procedure manual at a single site. To request permission to use
this publication in any other manner, e-mail [email protected].
Suggested Citation
CLSI. Molecular Diagnostic Methods for Infectious Diseases. 3rd ed. CLSI report MM03. Wayne, PA:
Clinical and Laboratory Standards Institute; 2015.
Previous Editions:
March 1994, December 1995, April 2005, February 2006
ISBN 1-56238-997-1 (Print)
ISBN 1-56238-998-X (Electronic)
ISSN 1558-6502 (Print)
ISSN 2162-2914 (Electronic) Volume 35, Number 5
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v
Contents
Abstract .................................................................................................................................................... i
Committee Membership ........................................................................................................................ iii
Foreword .............................................................................................................................................. vii
Chapter 1: Introduction ........................................................................................................................... 1
1.1 Scope ............................................................................................................................. 1 1.2 Background ................................................................................................................... 2 1.3 Standard Precautions ..................................................................................................... 2 1.4 Terminology .................................................................................................................. 2
Chapter 2: Applications .......................................................................................................................... 9
2.1 Utility of Molecular Diagnostic Tests for Infectious Diseases ..................................... 9 2.2 Screening or Initial Testing ......................................................................................... 10 2.3 Confirmatory and Supplemental Testing .................................................................... 11
Chapter 3: Specimen Collection, Transport, and Processing ................................................................ 13
Chapter 4: Contributors to False-Negative Results and Controls ......................................................... 15
4.1 Detection of Inhibitors and Interfering Substances ..................................................... 16 4.2 Inhibitory Samples ...................................................................................................... 17
Chapter 5: Methods ............................................................................................................................... 19
5.1 Physical and Chemical Methods for Nucleic Acid Detection ..................................... 19 5.2 Detection Formats ....................................................................................................... 20 5.3 Nucleic Acid Amplification Technologies ................................................................. 23 5.4 Real-Time Polymerase Chain Reaction Instruments .................................................. 26
Chapter 6: Selection and Qualification of Nucleic Acid Sequences ..................................................... 29
6.1 Target Region ............................................................................................................. 29 6.2 Polymerase Chain Reaction Primer Sequence Selection ............................................ 29 6.3 Hybridization Probe Sequence Selection .................................................................... 30 6.4 Fluorescence Resonance Energy Transfer Probes ...................................................... 31 6.5 Probe and Primer Forms and Purity ............................................................................ 33
Chapter 7: Establishment and Evaluation of Performance Characteristics of Molecular Diagnostic
Tests ......................................................................................................................................... 35
7.1 Limit of Detection (Analytical Sensitivity) ................................................................ 35 7.2 Analytical Specificity ................................................................................................. 36 7.3 Precision...................................................................................................................... 36 7.4 Cutoff Values .............................................................................................................. 36 7.5 Diagnostic Sensitivity ................................................................................................. 37 7.6 Diagnostic Specificity ................................................................................................. 37 7.7 Predictive Values ........................................................................................................ 38 7.8 Diagnostic Accuracy ................................................................................................... 38 7.9 Diagnostic Value ......................................................................................................... 38 7.10 Test Limitations .......................................................................................................... 39 7.11 Implementation of US Food and Drug Administration–Cleared Tests ....................... 39
Chapter 8: Quality Assurance ............................................................................................................... 41
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Contents (Continued)
8.1 Laboratory Design and Practices ................................................................................ 41 8.2 Instruments.................................................................................................................. 43 8.3 Quality Assurance During Development of Molecular Diagnostic Tests ................... 43 8.4 Control Materials ........................................................................................................ 44 8.5 Selecting Organism Strains for Analytical Studies ..................................................... 46 8.6 Preparing Nucleic Acid Controls ................................................................................ 46 8.7 Types of Testing During Assay Development ............................................................ 47 8.8 Quality Assurance for Implementation of Molecular Diagnostic Tests ...................... 54 8.9 Trend Analysis ............................................................................................................ 55 8.10 Proficiency Testing ..................................................................................................... 55 8.11 Controlling False-Positive Nucleic Acid Target Amplification Reactions ................. 55
Chapter 9: Reporting of Results ............................................................................................................ 61
9.1 Organism and Nucleic Acid Target ............................................................................ 61 9.2 Equivocal Results ....................................................................................................... 61 9.3 Reference Range ......................................................................................................... 61 9.4 Critical Results ............................................................................................................ 61 9.5 Test Limitations .......................................................................................................... 61 9.6 Interpretation ............................................................................................................... 62 9.7 Clarifying Statements ................................................................................................. 62
Chapter 10: Recommendations for Manufacturers and Clinical Laboratories ...................................... 63
10.1 Regulatory Requirements ........................................................................................... 63 10.2 Recommendations to Assay Developers ..................................................................... 63 10.3 Recommendations for Clinical Laboratories .............................................................. 64 10.4 Selection of Referral Laboratories .............................................................................. 64
Chapter 11: Conclusion ......................................................................................................................... 66
Chapter 12: Supplemental Information ................................................................................................. 66
References ................................................................................................................................ 67
Additional References .............................................................................................................. 73
Appendix. Nucleic Acid Amplification Technologies ............................................................. 74
The Quality Management System Approach ........................................................................... 90
Related CLSI Reference Materials .......................................................................................... 92 SAMPLE
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Foreword
MM03 was originally published as an approved guideline in 1995. It was the first of what was to become
many CLSI molecular diagnostics guidelines, and the first molecular microbiology consensus guideline
published. Molecular microbiology is the application of nucleic acid methods to the diagnosis and
management of patients with infectious diseases. The field has advanced enormously since the publication
of the first approved edition of MM03 and is now an integral part of laboratory medicine.
Overview of Changes
With the change in format and category definitions for all CLSI documents, MM03 has been
recategorized as a report and replaces MM03-A2. Although MM03 has been revised for the purpose of
keeping information current, the revisions do not significantly affect the scope or purpose of the
document, nor do they change the methodology used. Revisions to the document include:
Formatting and template design have been updated to reflect current CLSI style.
References to most trademarked products have been deleted.
CLSI references have been updated to reflect current document numbers and editions.
International Organization for Standardization definitions and references have been updated to reflect
current editions.
New test descriptions and figures have been added to the text and the appendix in order to reflect
current technology.
Key Words
Development, implementation, infectious disease, molecular methods, molecular microbiology, nucleic
acid amplification, quality assurance, reporting, validation, verification
Note that the trade name TaqMan® is included as a reference to Figure 1 of this document. It is
Clinical and Laboratory Standards Institute’s policy to avoid using a trade name unless the
product identified is the only one available, or it serves solely as an illustrative example of the
procedure, practice, or material described. In this case, the working group and consensus
committee believe the illustration derived from the published reference is an important
descriptive adjunct to the document. In such cases, it is acceptable to use the product’s trade
name when the illustration is being reprinted from a referenced publication. It should be
understood that information on this product in this document also applies to any equivalent
products.
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©Clinical and Laboratory Standards Institute. All rights reserved. 1
Molecular Diagnostic Methods for Infectious Diseases
Chapter 1: Introduction
This chapter includes:
Document scope and applicable exclusions
Background information pertinent to the document content
Standard precautions information
“Note on Terminology” that highlights particular use and/or variation in use of terms and/or
definitions
Terms and definitions used in the document
Abbreviations and acronyms used in the document
1.1 Scope
This document describes general principles for the development, evaluation, and application of tests
designed for direct detection of microorganisms in clinical specimens and for identification of
microorganisms grown in culture. The document provides evidence-based recommendations, where
appropriate.
The following content areas are addressed:
Clinical applications
Amplified and nonamplified nucleic acid methods
Selection and qualification of nucleic acid sequences
Establishment and evaluation of test performance characteristics, inhibitors, and interfering
substances
Controlling false-positive reactions
Reporting and interpretation of results
QA
Regulatory issues
Recommendations for manufacturers and clinical laboratories
This document is intended for use by clinical laboratories, test developers and manufacturers, and
regulatory agencies. It is not intended to be a compilation of successful protocols for
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©Clinical and Laboratory Standards Institute. All rights reserved. 2
detection/characterization of microorganisms, but rather to describe general principles for the
development, evaluation, and application of these tests. Users are directed to the Manual of Clinical
Microbiology1 and Molecular Microbiology: Diagnostic Principles and Practice2 for more information on
specific applications.
This document should be used in conjunction with the following related CLSI documents: MM06,3
MM09,4 MM10,5 MM13,6 MM14,7 MM17,8 and MM19.9
1.2 Background
Nucleic acid–based methods for detection and identification of microorganisms are commonly used in
clinical laboratories. However, the inherent complexity and unparalleled analytical sensitivity require
special attention to the assay design, use of controls, and laboratory practice. The diagnostic industry has
not kept pace with the medical demand for these tests, and in many cases, laboratory-developed nucleic
acid tests (NATs) have become the standard of care. Due to the number of different laboratory-developed
tests (LDTs) used, molecular diagnostic methods for infectious diseases often lack standardization.
Although molecular diagnostic methods are becoming more pervasive in clinical laboratories, efforts
should continue to increase the understanding of the strengths and limitations of these new methods.
These methods often may enhance diagnostic capabilities. However, the results should be interpreted
within the clinical context in which they are used, and on the basis of individual laboratory performance.
This document presents consensus recommendations for method development, verification, and
validation. It is a guide to practical implementation of molecular tests in the clinical laboratory and to the
assessment of their clinical utility. It also provides recommendations to assay developers in clinical
laboratories and industry. This document is also intended to serve as a resource for the relevant regulatory
agencies.
1.3 Standard Precautions
Because it is often impossible to know what isolates or specimens might be infectious, all patient and
laboratory specimens are treated as infectious and handled according to “standard precautions.” Standard
precautions are guidelines that combine the major features of “universal precautions and body substance
isolation” practices. Standard precautions cover the transmission of all known infectious agents and thus
are more comprehensive than universal precautions, which are intended to apply only to transmission of
bloodborne pathogens. The Centers for Disease Control and Prevention address this topic in published
guidelines that address the daily operations of diagnostic medicine in human and animals while
encouraging a culture of safety in the laboratory.10 For specific precautions for preventing the laboratory
transmission of all infectious agents from laboratory instruments and materials and for recommendations
for the management of exposure to all infectious disease, refer to CLSI document M29.11
1.4 Terminology
1.4.1 Note on Terminology
CLSI, as a global leader in standardization, is firmly committed to achieving global harmonization
wherever possible. Harmonization is a process of recognizing, understanding, and explaining differences
while taking steps to achieve worldwide uniformity. CLSI recognizes that medical conventions in the
global metrological community have evolved differently in the United States, Europe, and elsewhere; that
these differences are reflected in CLSI, International Organization for Standardization (ISO), and
European Committee for Standardization (CEN) documents; and that legally required use of terms,
regional usage, and different consensus timelines are all important considerations in the harmonization
process. In light of this, CLSI’s consensus process for development and revision of standards and
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The Quality Management System Approach
Clinical and Laboratory Standards Institute (CLSI) subscribes to a quality management system (QMS) 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 QMS approach applies a core set of “quality
system essentials” (QSEs), basic to any organization, to all operations in any health care service’s path of workflow
(ie, 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 QSEs are as follows:
Organization Personnel Process Management Nonconforming Event Management
Quality Customer Focus Purchasing and Inventory Documents and Records Assessments
Facilities and Safety Equipment Information Management Continual Improvement
MM03 addresses the QSE indicated by an “X.” For a description of the other documents listed in the grid, please
refer to the Related CLSI Reference Materials section on page 92.
Org
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AUTO01
AUTO02 AUTO02
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AUTO04 AUTO04
AUTO05
C24
EP05
EP12
EP17
EP23
EP24
GP27 GP27 GP27
M29
MM06
MM09
MM10
MM13
MM14
MM17
MM19 MM19 MM19 MM19 MM19 MM19 MM19 MM19 MM19 MM19 MM19 MM19 QMS01 QMS01 QMS01 QMS01 QMS01 QMS01 QMS01 QMS01 QMS01 QMS01 QMS01 QMS01
QMS02
QMS05
QMS06
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Path of Workflow
A path of workflow is the description of the necessary processes to deliver the particular product or service that the
organization or entity provides. A laboratory path of workflow consists of the sequential processes: preexamination,
examination, and postexamination and their respective sequential subprocesses. All laboratories follow these
processes to deliver the laboratory’s services, namely quality laboratory information.
MM03 addresses the clinical laboratory path of workflow steps indicated by an “X.” For a description of the other
documents listed in the grid, please refer to the Related CLSI Reference Materials section on the following page.
Preexamination Examination Postexamination
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MM09
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MM06
MM09
MM13
MM19
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X
EP23
MM06
MM09
MM10
MM19
QMS01
X
EP23
MM06
MM09
MM10
MM19
QMS01
EP23
MM06
MM09
MM10
MM19
QMS01
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AUTO03
MM06
MM09
MM10
QMS01
MM09
MM13
QMS01
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Related CLSI Reference Materials* AUTO01 Laboratory Automation: Specimen Container/Specimen Carrier. 1st ed., 2000. This document provides
standards for the design and manufacture of specimen containers and carriers used for collecting and
processing liquid samples, such as blood and urine, for clinical testing in laboratory automation systems.
AUTO02 Laboratory Automation: Bar Codes for Specimen Container Identification. 2nd ed., 2005. This
document provides specifications for use of linear bar codes on specimen container tubes in the clinical
laboratory and for use on laboratory automation systems.
AUTO03 Laboratory Automation: Communications With Automated Clinical Laboratory Systems, Instruments,
Devices, and Information Systems. 2nd ed., 2009. This document provides standards to facilitate accurate
and timely electronic exchange of data and information between the automated laboratory elements.
AUTO04 Laboratory Automation: Systems Operational Requirements, Characteristics, and Information
Elements. 1st ed., 2001. This document describes operational requirements, characteristics, and required
information elements of clinical laboratory automation systems. This information is used to determine the
status of a clinical specimen within the clinical laboratory automation system, as well as the status of the
actual components of the clinical laboratory automation system.
AUTO05 Laboratory Automation: Electromechanical Interfaces. 1st ed., 2001. This document provides standards
for the development of an electromechanical interface between instruments and specimen processing and
handling devices used in automated laboratory testing procedures.
C24 Statistical Quality Control for Quantitative Measurement Procedures: Principles and Definitions. 3rd
ed., 2006. This guideline provides definitions of analytical intervals, planning of quality control procedures,
and guidance for quality control applications.
EP05 Evaluation of Precision of Quantitative Measurement Procedures. 3rd ed., 2014. This document provides
guidance for evaluating the precision performance of quantitative measurement procedures. It is intended for
manufacturers of quantitative measurement procedures for laboratories that develop or modify such
procedures.
EP12 User Protocol for Evaluation of Qualitative Test Performance. 2nd ed., 2008. This document provides a
consistent approach for protocol design and data analysis when evaluating qualitative diagnostic tests.
Guidance is provided for both precision and method-comparison studies.
EP17 Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures. 2nd ed., 2012. This document provides guidance for evaluation and documentation of the detection capability of clinical
laboratory measurement procedures (ie, limits of blank, detection, and quantitation), for verification of
manufacturers’ detection capability claims, and for the proper use and interpretation of different detection
capability estimates.
EP23TM Laboratory Quality Control Based on Risk Management. 1st ed., 2011. This document provides guidance
based on risk management for laboratories to develop quality control plans tailored to the particular
combination of measuring system, laboratory setting, and clinical application of the test.
EP24 Assessment of the Diagnostic Accuracy of Laboratory Tests Using Receiver Operating Characteristic
Curves. 2nd ed., 2011. This document provides a protocol for evaluating the accuracy of a test to discriminate
between two subclasses of subjects when there is some clinically relevant reason to separate them. In addition
to the use of receiver operating characteristic curves and the comparison of two curves, the document
emphasizes the importance of defining the question, selecting the sample group, and determining the “true”
clinical state.
GP27 Using Proficiency Testing to Improve the Clinical Laboratory. 2nd ed., 2007. This guideline provides
assistance to laboratories in using proficiency testing as a quality improvement tool.
* CLSI documents are continually reviewed and revised through the CLSI consensus process; therefore, readers should refer to
the most current editions.
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Related CLSI Reference Materials (Continued) M29 Protection of Laboratory Workers From Occupationally Acquired Infections. 4th ed., 2014. Based on
US regulations, this document provides guidance on the risk of transmission of infectious agents by aerosols,
droplets, blood, and body substances in a laboratory setting; specific precautions for preventing the laboratory
transmission of microbial infection from laboratory instruments and materials; and recommendations for the
management of exposure to infectious agents.
MM06 Quantitative Molecular Methods for Infectious Diseases. 2nd ed., 2006. This document provides guidance
for the development and use of quantitative molecular methods, such as nucleic acid probes and nucleic acid
amplification techniques of the target sequences specific to particular microorganisms. It also presents
recommendations for quality assurance, proficiency testing, and interpretation of results.
MM09 Nucleic Acid Sequencing Methods in Diagnostic Laboratory Medicine. 2nd ed., 2014. This document
addresses diagnostic sequencing using both automated capillary-based sequencers and massively parallel
sequencing instruments. Topics include specimen collection and handling; isolation and extraction of nucleic
acid; template preparation; sequence generation, alignment, and assembly; validation and verification;
ongoing quality assurance; and reporting results.
MM10 Genotyping for Infectious Diseases: Identification and Characterization. 1st ed., 2006. This guideline
describes currently used analytical approaches and methodologies applied to identify the clinically important
genetic characteristics responsible for disease manifestation, outcome, and response to therapy in the
infectious disease setting. It also provides guidance on the criteria to be considered for design, validation, and
determination of clinical utility of such testing.
MM13 Collection, Transport, Preparation, and Storage of Specimens for Molecular Methods. 1st ed., 2005. This document provides guidance related to proper and safe biological specimen collection and nucleic acid
isolation and purification. These topics include methods of collection, recommended storage and transport
conditions, and available nucleic acid purification technologies for each specimen/nucleic acid type.
MM14 Design of Molecular Proficiency Testing/External Quality Assessment. 2nd ed., 2013. This document
provides guidelines for a quality proficiency testing/external quality assessment program, including reliable
databases; design control in the choice of materials and measurands; good manufacturing processes;
documentation procedures; complaint handling; corrective and preventive action plans; and responsive timing
of reports.
MM17 Verification and Validation of Multiplex Nucleic Acid Assays. 1st ed., 2008. This guideline provides
recommendations for analytic verification and validation of multiplex assays, as well as a review of different
types of biologic and synthetic reference materials.
MM19 Establishing Molecular Testing in Clinical Laboratory Environments. 1st ed., 2011. This guideline
provides comprehensive guidance for planning and implementation of molecular diagnostic testing, including
strategic planning, regulatory requirements, implementation, quality management, and special considerations
for the subspecialties of molecular genetics, infectious diseases, oncology, and pharmacogenetics.
QMS01 Quality Management System: A Model for Laboratory Services. 4th ed., 2011. This document provides a
model for medical laboratories that will assist with implementation and maintenance of an effective quality
management system.
QMS02 Quality Management System: Development and Management of Laboratory Documents. 6th ed., 2013.
This document provides guidance on the processes needed for document management, including creating,
controlling, changing, and retiring a laboratory’s policy, process, procedure, and form documents in both
paper and electronic environments.
QMS05 Quality Management System: Qualifying, Selecting, and Evaluating a Referral Laboratory. 2nd ed.,
2012. This guideline provides recommended criteria and easily implemented processes for qualifying,
selecting, and evaluating a referral laboratory.
QMS06 Quality Management System: Continual Improvement. 3rd ed., 2011. This guideline considers continual
improvement as an ongoing, systematic effort that is an essential component of a quality management system.
A continual improvement program may consist of fundamental processes and common supporting elements
described in this guideline.
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