Practical Approaches to Method Validation and Essential Instrument Qualification E-Book
Chung Chow Chan
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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
Practical approaches to ensure that analytical methods and instruments meet GMP standards and requirements
Complementing the authors' first book, Analytical Method Validation and Instrument Performance Verification, this new volume provides coverage of more advanced topics, focusing on additional and supplemental methods, instruments, and electronic systems that are used in pharmaceutical, biopharmaceutical, and clinical testing. Readers will gain new and valuable insights that enable them to avoid common pitfalls in order to seamlessly conduct analytical method validation as well as instrument operation qualification and performance verification.
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Part 1, Method Validation, begins with an overview of the book's risk-based approach to phase appropriate validation and instrument qualification; it then focuses on the strategies and requirements for early phase drug development, including validation of specific techniques and functions such as process analytical technology, cleaning validation, and validation of laboratory information management systems
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Part 2, Instrument Performance Verification, explores the underlying principles and techniques for verifying instrument performance—coverage includes analytical instruments that are increasingly important to the pharmaceutical industry, such as NIR spectrometers and particle size analyzers—and offers readers a variety of alternative approaches for the successful verification of instrument performance based on the needs of their labs
At the end of each chapter, the authors examine important practical problems and share their solutions. All the methods covered in this book follow Good Analytical Practices (GAP) to ensure that reliable data are generated in compliance with current Good Manufacturing Practices (cGMP).
Analysts, scientists, engineers, technologists, and technical managers should turn to this book to ensure that analytical methods and instruments are accurate and meet GMP standards and requirements.
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Veröffentlichungsjahr: 2011
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Table of Contents
Title Page
Copyright Page
Preface
Contributors
Chapter 1: Overview of Risk-Based Approach to Phase Appropriate Validation and Instrument Qualification
1 Risk-Based Approach to Pharmaceutical Development
2 Regulatory Requirements for Performance Verification of Instruments
3 General Approach to Instrument Performance Qualification
Chapter 2: Phase Appropriate Method Validation
1 Introduction
2 Parameters for Qualification and Validation
3 Qualification and Validation Practices
4 Common Problems and Solutions
Chapter 3: Analytical Method Verification, Method Revalidation, and Method Transfer
1 Introduction
2 Cycle of Analytical Methods
3 Method Verification Practices
4 Method Revalidation
5 Method Transfer
6 Common Problems and Solutions
Chapter 4: Validation of Process Analytical Technology Applications
1 Introduction
2 Parameters for Qualification and Validation
3 Qualification, Validation, and Verification Practices
4 Common Problems and Solutions
Chapter 5: Validation of Near-Infrared Systems for Raw Material Identification
1 Introduction
2 Validation of an NIR System
3 Validation Plan
Chapter 6: Cleaning Validation
1 Introduction
2 Scope of the Chapter
3 Strategies and Validation Parameters
4 Analytical Methods in Cleaning Validation
5 Sampling Techniques
6 Acceptance Criteria of Limits
7 Campaign Cleaning Validation
8 Common Problems and Solutions
Chapter 7: Risk-Based Validation of Laboratory Information Management Systems
1 Introduction
2 LIMS and the LIMS Environment
3 Understanding and Simplifying Laboratory Processes
4 GAMP Software Categories and System Life Cycle for a LIMS
5 Validation Roles and Responsibilities for a LIMS Project
6 System Life-Cycle Detail and Documented Evidence
7 Maintaining the Validated Status
8 Summary
Chapter 8: Performance Qualification and Verification of Balance
1 Introduction
2 Performance Qualification
3 Common Problems and Solutions
Chapter 9: Performance Verification of NIR Spectrophotometers
1 Introduction
2 Performance Attributes
3 Practical tips in NIR performance verification
Chapter 10: OPERATIONAL QUALIFICATION IN PRACTICE FOR GAS CHROMATOGRAPHY INSTRUMENTS
1 Introduction
2 Parameters for Qualification
3 Operational Qualification
4 Preventive Maintenance
5 Common Problems and Solutions
Chapter 11: Performance Verification on Refractive Index, Fluorescence, and Evaporative Light-Scattering Detection
1 Introduction
2 Qualification of Differential Refractive Index Detectors
3 Qualification of Fluorescence Detectors
4 Qualification of Evaporative Light-Scattering Detectors
Chapter 12: Instrument qualification and performance verification for particle size instruments
1 Introduction
2 Setting the scene
3 Particle counting techniques
4 Particle Size analysis and distribution
5 Instrument qualification for particle size
6 Qualification of instruments used in particle sizing
7 Method development
8 Verification: particle size distribution checklist
9 Common problems and solutions
10 Conclusions
Chapter 13: Method Validation, Qualification, and Performance Verification for Total Organic Carbon Analyzers
1 Introduction
2 TOC Methodologies
3 Parameters for Method Validation, Qualification, and Verification
4 Qualification, Validation, and Verification Practices
5 Common Problems and Solutions
Chapter 14: Instrument Performance Verification: MicroPipettes
1 Introduction
2 Scope of the Chapter
3 Verification Practices: Volume Settings, Number of Replicates, and Tips
4 Parameters: Accuracy, Precision, and Uncertainty
5 Summary
Chapter 15: Instrument Qualification and Performance Verification for Automated Liquid-Handling Systems
1 Introduction
2 Commonalities between volume verification methods for performance evaluation
3 Volume verification methods
4 Importance of standardization
5 Summary
Chapter 16: Performance Qualification and Verification in Powder X-Ray Diffraction
1 Introduction
2 Basics of X-ray diffraction
3 Performance Qualification
4 Performance Verification: Calibration Practice
Index
Copyright © 2010 by John Wiley & Sons, Inc. All rights reserved.
Published by John Wiley & Sons, Inc., Hoboken, New Jersey.
Published simultaneously in Canada.
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Library of Congress Cataloging-in-Publication Data:
Practical approaches to method validation and essential instrument qualification /
edited by Chung Chow Chan, Herman Lam, Xue Ming Zhang.
p. ; cm.
Complement to: Method validation and instrument performance verification / edited by Chung Chow Chan … [et al.]. c2004.
Includes bibliographical references and index.
ISBN 978-0-470-12194-8 (hardback)
1. Drugs—Analysis—Methodology—Evaluation. 2. Laboratories—Equipment and supplies— Evaluation. 3. Laboratories—Instruments—Evaluation. I. Chan, Chung Chow. II. Lam, Herman. III. Zhang, Xue Ming. IV. Method validation and instrument performance verification.
[DNLM: 1. Chemistry, Pharmaceutical—instrumentation. 2. Chemistry, Pharmaceutical— methods. 3. Clinical Laboratory Techniques—standards. 4. Technology, Pharmaceutical— methods. QV 744 M5915 2010]
RS189.M425 2010
615′.1901—dc22
2009054243
Printed in SingaporePreface
This book is a complement to our first book, Method Validation and Instrument Performance Verification. As stated there, for pharmaceutical manufacturers to achieve commercial production of safe and effective medications requires the generation of a vast amount of reliable data during the development of each product. To ensure that reliable data are generated in compliance with current good manufacturing practices (cGMPs), all analytical activities involved in the process need to follow good analytical practices (GAPs). GAPs can be considered as the culmination of a three-pronged approach to data generation and management: method validation, calibrated instrumentation, and training.
The chapters are written with a unique practical approach to method validation and instrument performance verification. Each chapter begins with general requirements and is followed by strategies and steps taken to perform these activities. The chapters end with the authors sharing important practical problems and their solutions with the reader. I encourage you to share your experience with us, too. If you have any observations or solutions to a problem, please do not hesitate to email it to me at [email protected].
The method validation section focus on the strategies and requirements for early-phase drug development, the validation of specific techniques and functions [e.g. process analytical technology (PAT)], cleaning, and laboratory information management systems (LIMSs). Chapter 1 is an overview of the regulatory requirements on quality by design in early pharmaceutical development and instrument performance verification. Instrument performance verification and performance qualification are used as synonyms in this book. Chapter 2 is an overview of the strategies of phase 1 and 2 development from the analytical perspective. Chapter 3 provides guidance on compendial method verification, analytical revalidation, and analytical method transfer. Discussed are strategies for an equivalent analytical method and how that can be achieved. Chapters 4 and 5 cover method validation of specific techniques in PAT and near-infrared identification. Chapters 6 and 7 give guidance on cleaning validation and LIMS validation.
The instrument performance verification section (Chapters 8 to 16) provides unbiased information on the principles involved in verifying the performance of instruments that are used for the generation of reliable data in compliance with cGXPs (all current good practices). Guidance is given on some common and specialized small instruments and on several approaches to the successful performance verification of instrument performance. The choice of which approach to implement is left to the reader, based on the needs of the laboratory. Chapter 9 provides background information on the most fundamental and common but most important analytical instrument used in any laboratory, the balance. A generic protocol template for the performance verification of the balance is also included to assist young scientists in developing a feel for writing GXP protocol. Performance verification requirements for near-infrared, gas chromatographic, and high-performance liquid chromatographic detectors are described in Chapters 10, 11, and 12. Chapter 13 gives guidance on performance verification of particle size, which is very challenging for its concept. Chapter 14 covers the requirements needed for the specialized technique of total organic content. Performance verification of small equipment used in pipettes and liquid-handling systems is discussed in Chapters 15 and 16. Chapter 17 provides an overview of x-ray diffraction technique and performance verification of this instrument.
The authors of this book come from a broad cultural and geographical base—pharmaceutical companies, vendor and contract research organizations—and offer a broad perspective to the topics. I want to thank all the authors, coeditors, and reviewers who contributed to the preparation of the book.
CHUNG CHOW CHAN
CCC Consulting
Mississauga, Ontario, Canada
Contributors
Keith J. Albert, Artel, Inc., Westbrook, Maine, USA
Richard W. Andrews, Waters Corporations, Milford, Massachusetts, USA
John Thomas Bradshaw, Artel, Inc., Westbrook, Maine, USA
Chung Chow Chan, CCC Consulting, Mississauga, Ontario, Canada
Ian Ciesniewski, Mettler Toledo Inc., Columbus, Ohio, USA
Richard Curtis, Artel, Inc., Westbrook, Maine, USA
Lenny Dass, GlaxoSmithKline Canada Inc., Mississauga, Ontario, Canada
Alison C. E. Harrington, ABB Ltd., Daresbury, United Kingdom
Stephan Jansen, Agilent Technologies Inc., Amstelveen, The Netherlands
Herman Lam, Wild Crane Horizon Inc., Scarborough, Ontario, Canada
Paul Larson, Agilent Technologies Inc., Wilmington, Delaware, USA
Charles T. Manfredi, Agilent Technologies Inc., Wilmington, Delaware, USA
José E. Martínez-Rosa, JEM Consulting Services Inc., Caguas, Puerto Rico
R. D. McDowall, McDowall Consulting, Bromley, Kent, United Kingdom
Anthony Qu, Patheon Inc., Cincinnati, Ohio, USA
Alan F. Rawle, Malvern Instruments Inc., Westborough, Massachusetts, USA
Arthur Reichmuth, Mettler Toledo GmbH, Greifensee, Switzerland
George Rodrigues, Artel, Inc., Westbrook, Maine, USA
Shauna Rotman, Wild Crane Horizon Inc., Scarborough, Ontario, Canada
Pramod Saraswat, Azopharma Product Development Group, Hollywood, Florida, USA
Aniceta Skowron, Activation Laboratories Ltd., Ancaster, Ontario, Canada
William H. Wilson, Agilent Technologies Inc., Wilmington, Delaware, USA
Wolfgang Winter, Matthias Hohner AG, Karlsruhe, Germany
Xue Ming Zhang, Apotex Inc., Richmond Hill, Ontario, Canada
1
Overview of Risk-Based Approach to Phase Appropriate Validation and Instrument Qualification
CHUNG CHOW CHAN
CCC Consulting
HERMAN LAM
Wild Crane Horizon Inc.
XUE MING ZHANG
Apotex, Inc.
STEPHAN JANSEN, PAUL LARSON, CHARLES T. MANFREDI, AND WILLIAM H. WILSON
Agilent Technologies Inc.
WOLFGANG WINTER
Matthias Hohner AG
1 Risk-Based Approach to Pharmaceutical Development
In the United States, the U.S. Food and Drug Administration (FDA) ensures the quality of drug products using a two-pronged approach involving review of information submitted in applications as well as inspection of manufacturing facilities for conformance to requirements for current good manufacturing practice (cGMP). In 2002, the FDA, together with the global community, implemented a new initiative, “Pharmaceutical Quality for the 21st Century: A Risk-Based Approach” to evaluate and update current programs based on the following goals:
The most up-to-date concepts of risk management and quality system approaches are incorporated while continuing to ensure product quality.The latest scientific advances in pharmaceutical manufacturing and technology are encouraged.The submission review program and the inspection program operate in a coordinated and synergistic manner.Regulatory and manufacturing standards are applied consistently.FDA resources are used most effectively and efficiently to address the most significant issues.In the area of analytical method validation and instrument performance qualification, principles and risk-based orientation, and science-based policies and standards, are the ultimate driving forces in a risk-based approach to these activities.
1.Risk-based orientation. To comply with the new guiding regulatory principle to provide the most effective public health protection, regulatory agencies and pharmaceutical companies must match their level of effort against the magnitude of risk. Resource limitations prevent uniform intensive coverage of all pharmaceutical products and production.
2.Science-based policies and standards. Significant advances in the pharmaceutical sciences and in manufacturing technologies have occurred over the last two decades. Although this knowledge has been incorporated in an ongoing manner, the fundamental nature of the changes dictates a thorough evaluation of the science base to ensure that product quality regulation not only incorporates up-to-date science but also encourages further advances in technology. Recent science can also contribute significantly to assessment of risk.
Related directly or indirectly to implementation of the risk-based approach to pharmaceutical quality, the following guidance affecting the analytical method and instrument qualification had been either initiated or implemented.
FDA 21 Code of Federal Regulations (CFR) Part 11: Electronic Records Requirements. The final guidance for industry Part 11, Electronic Records, Electronic Signatures: Scope and Application, clarifies the scope and application of the Part 11 regulation and provides for enforcement discretion in certain areas. The guidance explains the goals of this initiative, removes barriers to scientific and technological advances, and encourages the use of risk-based approaches.
ICH (International Conference on Harmonization) Q9: Risk Management. The goal of the guidance is to manage risk to patients, based on science, from information on the product, process, and facility. The level of oversight required is commensurate with the level of risk to patients and the depth of product and process understanding.
FDA Guidance for Industry PAT: A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance. This guidance is intended to encourage the voluntary development and implementation of innovative pharmaceutical manufacturing and quality assurance technologies. The scientific, risk-based framework outlined in this guidance, process analytical technology (PAT), helps pharmaceutical manufacturers design, develop, and implement new and efficient tools for use during product manufacture and quality assurance while maintaining or improving the current level of product quality assurance. It also alleviates any concerns that manufacturers may have regarding the introduction and implementation of new manufacturing technologies.
FDA Guidance for Industry: Quality Systems Approach to Pharmaceutical cGMP Regulations. One of the objectives of this guidance is to provide a framework for implementing quality by design, continual improvement, and risk management in the drug manufacturing process.
FDA Guidance for Industry INDs: cGMP for Phase 1 Investigational Drugs. This guidance recommended that sponsors and producers of phase 1 material consider carefully risks in the production environment that might adversely affect the resulting quality of an investigational drug product.
Implementation of a risk-based approach to analytical method validation and performance verification should be done simultaneously and not in isolation. It is only through a well-thought-out plan on the overall laboratory system of instrument performance verification that quality data for analytical method validation will be obtained. The laboratory will subsequently be able to support the manufacture of either clinical trial materials or pharmaceutical products for patients. Details of risk-based approaches to phase appropriate analytical method validation and performance verification are presented in subsequent chapters.
2 Regulatory Requirements for Performance Verification of Instruments
System validation requirements are specified in many different sources, including 21 CFR Part 58 [good laboratory practice (GLP)], 21 CFR Parts 210 and 211 (cGMP) [1], and more recently, in the GAMP 4 guide [2]. GLP, and GMP/cGMP are often summarized using the acronym GXP. Current GXP regulations require that analytical instruments be qualified to demonstrate suitability for the intended use. Despite the fact that instrument qualification is not a new concept and regulated firms invest a lot of effort, qualification-related deviations are frequently cited in inspectional observations and in warning letters by regulatory agencies such as the FDA and its equivalents in other countries. In common terms, the objective of qualification is to establish documented evidence that a system has been designed and installed according to specifications and operates in such a way that it fulfills its intended purpose.
GLP makes the following provisions in 21 CFR 58.63 about maintaining, calibrating, and testing equipment:
Equipment is to be adequately inspected, cleaned, maintained, calibrated, and tested.Written standard operating procedures (SOPs) are required for testing, calibration, and maintenance.Written records are to be maintained for all inspection, maintenance, calibration, and testing.cGMP makes the following provisions in 21 CFR 211.68(a):
Automatic equipment, including computers, that will perform a function satisfactorily may be used.Equipment is to be calibrated, inspected, or checked routinely according to a written program designed to assure proper performance.Written records of calibration checks and inspections are to be maintained.Many validation professionals in regulated firms are not sure what exactly to qualify or requalify, test, and document. How much testing is enough? Unlike analytical method validation, there were no clear standards for equipment qualification. The United States Pharmacopeia (USP) has addressed this issue by publishing General Chapter (1058} on analytical instrument qualification (AIQ) [3,4]. The USP establishes AIQ as the basis for data quality and defines the relationship to analytical method validation, system suitability testing, and quality control checks. Similar to analytical method validation, the intent of AIQ is to ensure the quality of an instrument before conducting any tests. In contrast, system suitability and quality control checks ensure the quality of analytical results right before or during sample analyses.
3 General Approach to Instrument Performance Qualification
Testing is one of the most important analytical measures for system developers and system users when verifying that a system fulfills the defined system requirements and is fit for the intended purpose. Generally, the fitness of systems for the intended purpose (i.e., their quality) needs to be ensured through constructive and analytical measures. Constructive measures are defined in terms of recognized professional engineering practices and include formal design methodologies that typically follow a life-cycle approach. System qualification follows a structured approach that uses test cases and test parameters based on a scientific and risk-based analysis. Defining and executing these tests typically require the use of metrology.
Other analytical measures include trending analysis of metrics such as error rates, formal methods of failure analysis, and formal reviews and inspections. Testing and the associated collection of documented evidence on the system test activities are key tasks of quality assurance. The documented evidence comprises test planning, test execution, test cases, and test results, all of which must be traceable to the requirements documented in various levels of specification documents (i.e., user requirements specification, functional specifications, design specifications, test specifications, etc.).
3.1 Definition of Terms
Many different definitions are used for the relevant terms in the area of equipment qualification. Not all of them are identical. For the sake of this chapter, we use the terms design qualification (DQ), installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ), in line with the definitions originally published by the Valid Analytical Measurement Instrument Working Group (see Figure 1). Similar system qualification approaches are discussed thoroughly in GAMP (Good Automated Manufacturing Practice) Forum publications and in USP General Chapter (1058). DQ, IQ, OQ, and PQ constitute important phases that result in key deliverables during the overall validation activities necessary over a system's life cycle (see Figure 2).
Figure 1 The four stages of instrument qualification and definition of terms according to the Valid Analytical Measurement Instrument Working Group. (From [5].)
Figure 2 Activities, phases, and key deliverables during a system's validation life cycle. For the sake of simplification, system retirement (decommissioning) is not shown.
Design Qualification
During DQ, the functional and operational specifications of an instrument need to be defined and documented. DQ is an important decision-making tool for selecting the best system and supplier. The right type of equipment is selected for specific tasks, and the supplier's ability to meet and reproduce these performance criteria consistently through appropriate quality processes in design, development, manufacturing, and support is crucial for efficacy and risk mitigation. DQ is primarily the user's responsibility, because this is the only logical place to define site requirements. The supplier, however, typically needs to provide materials such as technical specifications and other documents relevant to system validation. This includes evidence on processes that are critical to quality, including the life-cycle methodology. DQ focuses on specifications, design documentation, requirements traceability from design to test, corrective action procedures, impact analyses, test plans, and test evidence. DQ responds to a requirement originally defined in GLP (21 CFR Part 58.61) that mandates that appropriate design and adequate capacity for consistent functioning as intended are assured for equipment used in activities subject to this regulation.
Installation Qualification
IQ uses procedures that demonstrate, to a high degree of assurance, that an instrument or system has been installed according to accepted standards. IQ provides written evidence that the system has been installed according to the specifications defined by the manufacturer (supplier) and, if applicable, the user's organization. IQ checks the correctness of the installation and documents the intactness of the system, typically through system inventory lists, part numbers, firmware revisions, system drawings, and wiring and plumbing diagrams. Several organizations have provided specific guidance about the scope of an IQ and elaborated on the potential division of responsibilities between the system supplier and the user's organization. One important conclusion is that assembly checks performed at the supplier's factory cannot be substituted for an IQ performed at the user's site [6]. The supplier's documented test results (e.g., factory acceptance tests), however, can be used to reduce the extent of validation activities performed during an IQ. The key is that IQ demonstrates and documents that the system has been received and installed in the user's domain according to the relevant specifications.
The IQ is usually provided by the vendor at a cost. The typical deliverables include the following information:
System locationEquipment model/serial numbersDocumentation of basic function and safety featuresDocumentation about compliance with site requirementsOperational Qualification
In contrast to an IQ, which challenges the installation process, operational qualification focuses on the functionality of the system. An OQ challenges key operational parameters and, if required, security functions by running a well-defined suite of functional tests. The OQ uses procedures that demonstrate, to a high degree of assurance, that an instrument or system is operating according to accepted standards. In most cases, the OQ is delivered as a paid service from the provider. It typically includes a suite of component and system tests that are designed to challenge the functional aspects of the system. The OQ deliverable needs to provide documented and auditable evidence of control. The frequency of the OQ is determined by the user's organization. In most laboratories, the typical frequency is once or twice a year after the initial OQ.
Performance Qualification and Performance Verification
The terms performance qualification (PQ) and performance verification (PV) are used as synonyms. PQ verifies system performance under normal operating conditions across the anticipated operating range of the equipment. This makes PQ mostly an application-specific test with application-specific acceptance limits. For chromatography equipment, ongoing verification of system performance includes system suitability tests, as defined in General Chapter (621) on chromatography of the USP [7], which outlines the apparatus tests as well as the calculation formulas to be used for quantification and the evaluation of system suitability. The European and Japanese pharmacopeias use a similar approach, but there are regional differences in how certain system suitability parameters have to be calculated. In the following chapters we focus on the holistic and modular tests required for operational qualification but do not elaborate in detail on application-specific performance qualification.
Requalification After Repair (RQ)
In essence, RQ is similar to OQ. RQ's goal is to verify the correctness and success of a repair procedure performed on a system, and to put the system back into the original qualified state by running a series of appropriate tests. RQ typically is a subset of an OQ, but for complex repairs to components that are critical to the overall performance of the system, it may be necessary to perform the complete suite of OQ tests.
1.3.2 Analytical Instrument Qualification: USP (1058)
USP General Chapter (1058) is a step forward for the validation community [8]. It establishes the well-proven 4Q model as the standard for instrument qualification and provides useful definitions of roles, responsibilities, and terminology to steer the qualification-related activities of regulated firms and their suppliers. The 4 Qs in the model refer to DQ, IQ, OQ, and PQ (see Figure 3).
Figure 3 The 4Q model, consisting of DQ, IQ, OQ, and PQ, along with the key questions answered by each phase and its key deliverables.
The 4Q model helps answer the following critical questions:
How can an analytical laboratory prove that a given analysis result is based on trustworthy and reliable instrument data?How can the analytical laboratory ascertain the validity of the analysis result and show appropriate evidence that the analytical instrument was really doing what the analyst thought it would do and that the instrument was within the specifications required for the analysis?The AIQ chapter of the USP categorizes the rigor and extent of the qualification activities by instrument class. As an example, gas chromatographs are categorized as class C (complex instruments with highly method-specific conformance requirements). The acceptance limits (conformity bounds) are determined by the application. The deployment (installation and qualification) of such an instrument is complicated and typically requires assistance from specialists. In any case, USP (1058) class C instruments are required to undergo a full qualification process, which requires structured and extensive documentation about the system and the approach used for qualification.
1.3.3 Recommendations for Analytical Instrument Qualification
1. Develop an SOP for AIQ according to the 4Q qualification model.
2. If you already have an SOP for AIQ, determine how it can be mapped to the 4Q model.
3. If your SOP proposes a different methodology than that of 4Q, you need to come up with a scientifically sound rationale. Document your rationale and explain how your methodology ensures trustworthy, reliable, and consistent instrument data.
4. Use a single procedure for an instrument category, independent of the vendor and the location. Acceptance criteria may have to vary by make, model, and intended application.
5. Assess which instruments are used for regulated activities and whether the data generated by the instrument are subject to a predicate rule.
6. Assess the risk of instrument failure or nonconformance, using scientific knowledge.
7. Define qualification protocols for the various instrument classes in your lab. If necessary and appropriate, work with your instrument suppliers or partner with someone who has a proven track record in the field of instrument qualification services.
8. The USP guidance is general regarding the use and impact of data systems. Therefore, plan additional qualification and acceptance tests to obtain a high degree of assurance that control, communication, and data are accurate and reliable. Your integrated validation and qualification approach needs to consider the system as a whole, including the data system.
References
1. 21 Code of Federal Regulations, Parts 210 and 211. Part 210: Current Good Manufacturing Practice In Manufacturing, Processing, Packing, or Holding of Drugs; Part 211: Current Good Manufacturing Practice for Finished Pharmaceuticals. FDA, Washington, DC, 1996. Available at www.fda.gov/cder/dmpq/cgmpregs.htm#211.110. Accessed Aug. 17, 2007.
2. GAMP Guide for Validation of Automated Systems, 4th ed. International Society for Pharmaceutical Engineering, Tampa, FL, 2001.
3. S. K. Bansal, T. Layloff, E. D. Bush, M. Hamilton, E. A. Hankinson, J. S. Landy, S. Lowes, M. M. Nasr, P. A. St. Jean, and V. P. Shah. Qualification of analytical instruments for use in the pharmaceutical industry: a scientific approach. AAPS PharmSciTech, 5(1): article 22, 2004.
4. U.S. Pharmacopeia, General Chapter (1058), Analytical Instrument Qualification. USP, Rockville, MD.
5. P. Bedson. Guidance on Equipment Qualification of Analytical Instruments: High Performance Liquid Chromatography (HPLC). Published by LGC in collaboration with the Valid Analytical Measurement Instrumentation Working Group, June 1998.
6. Guidance Notes on Installation and Operational Qualification. GUIDE-MQA-006-005. Health Sciences Authority, Manufacturing and Quality Audit Division, Centre for Drug Administration, Singapore, Sept. 2004.
7. U.S. Pharmacopeia, General Chapter (621), Chromatography. USP, Rockville, MD.
8. W. Winter. Analytical instrument qualification: standardization on the 4Q model. BioProcess Int., 4(9): 46–50, 2006.
2
Phase Appropriate Method Validation
CHUNG CHOW CHAN
Pramod Saraswat
CCC Consulting
Azopharma Product Development Group
1 Introduction
The 2002 initiative “Pharmaceutical Quality for the 21st Century: A Risk-Based Approach” formally known as the “Pharmaceutical cGMP Initiative for the 21st Century,” was intended to modernize the U.S. Food and Drug Administration's (FDA's) regulation of pharmaceutical quality for veterinary and human drugs, select human biological products such as vaccines, and capture the larger issue of product quality, with current good manufacturing practices (cGMPs) being an important tool toward improving overall product quality. This regulation acknowledges the need, and provides for, assessment of the risk and benefits of drug development and forms a foundation to provide guidance for reasonable, minimally acceptable method validation practices.
1.1 Cycle of Analytical Methods
The analytical method validation activity is a dynamic process, as summarized in the life cycle of an analytical procedure shown in Figure 1. An analytical method will be developed and validated for use in analyzing samples during the early development of a drug substance or drug product. The extent and level of analytical method development and analytical method validation will change as the analytical method progresses from phase 1 to commercialization.
Figure 1 Life cycle of the analytical method.
In the United States, the FDA recognized that application of the cGMP regulations, as described in 21 Code of Federal Regulations (CFR) 211, is not always relevant for the manufacture of clinical investigational drug products. The FDA recognized the need to develop specific GMPs for investigational products and elected to address the progressive phase-appropriate nature of cGMPs in drug development for a wide variety of manufacturing situations and product types for compliance with cGMPs starting with phase 1 studies and progressing through phase 3 and beyond, referred to in this chapter as phase appropriate method development and method validation. The final method will be validated for its intended use, whether for a market image drug product or for clinical trial release.
1.2 Challenges of New Technologies
Regulatory agencies understand and encourage companies to apply new technologies to provide information on the physical, chemical (micro), and biological characteristics of materials to improve process understanding and to measure, control, and/or predict the quality and performance of products. New technologies [e.g., liquid chromatography–mass spectrometry (LCMS)] are being applied increasingly to support new products and new processes. Immunogenicity assay may be required for some biotechnology-derived products.
1.3 To Validate or Not to Validate?
Sometimes the question is asked: Should analytical method be validated as early as when going from preclinical to phase 1 studies? This question arose perhaps from a mis-interpretation of the guidance document “Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products,” which stated that validation data and established specifications ordinarily need not be submitted at the initial stage of drug development. The answer is, of course, that the analytical method should be validated. The validation data need not be submitted, but the validation must be completed so that the analytical methods used will assure the strength, identity, purity, safety, and quality (SISPQ) of the drug substance and the drug product.
In the cGMP guidance for phase 1 investigational drugs [1], it is stated explicitly that laboratory tests used in the manufacture (e.g., testing of materials, in-process material, packaging, drug product) of phase 1 investigational drugs should be scientifically sound (e.g., specific, sensitive, and accurate), suitable, and reliable for the specified purpose. The tests should be performed under controlled conditions and follow written procedures describing the testing methodology. Records of all test results, procedures, and changes in procedures should be maintained. Laboratory testing of a phase 1 investigational drug should evaluate quality attributes that define the SISPQ.
1.4 Quality by Design: A Risk-Based Approach
The focus of the concept of quality by design is to ensure that quality is built into a product, with a thorough understanding of the product and process by which it is developed and manufactured, along with a knowledge of the risks involved in manufacturing the product and how best to mitigate those risks. Regulatory bodies recognize that knowledge of a drug product and its analytical methods will evolve through the course of development. This is stated explicitly in ICH (International Conference on Harmonization) Q7A. Changes are expected during development, and every change in product, specifications, or test procedures should be recorded adequately. It is therefore reasonable to expect that changes in testing, processing, packaging, and so on, will occur as more is learned about the molecule. However, even with the changes, the need to ensure the safety of subjects in clinical testing should not be compromised.
The purpose in the early phase of drug development is to deliver a known dose that is bioavailable for clinical studies. As product development continues, increasing emphasis is placed on identifying a stable, robust formulation from which multiple bioequivalent lots can be manufactured and ultimately scaled up, transferred, and controlled for commercial manufacture. The method validation requirements of methods need to be adjusted through the life cycle of a method.
The development and validation of analytical methods should follow a similar progression. The purpose of analytical methods in early stages of development is to ensure potency, to understand the impurity and degradation product profile, and to help understand key drug characteristics. As development continues, the method should indicate stability and be capable of measuring the effect of key manufacturing parameters to ensure consistency of the drug substance and drug product.
Analytical methods used to determine purity and potency of an experimental drug substance that is very early in development will need a less rigorous method validation exercise than would be required for a quality control laboratory method at the manufacturing site. An early-phase project may have only a limited number of lots to be tested, and the testing may be performed in only one laboratory by a limited number of analysts. The ability of the laboratory to “control” the method and its use is relatively high, particularly if laboratory leadership is clear in its expectations for performance of the work.
The environment in which a method is used changes significantly when the method is transferred to a quality control laboratory at the manufacturing site. The method may be replicated in several laboratories, multiple analysts may use it, and the method may be one of many methods used daily in the laboratory. Late development and quality control methods need to be run accurately and consistently in a less controlled environment (e.g., in several laboratories with different brands of equipment). The developing laboratory must therefore be aware of the needs of the receiving laboratories (e.g., a quality control laboratory) and the regulatory expectations for successful validation of a method to be used in support of a commercial product.
Each company's phase appropriate method validation procedures, and processes will vary, but the overall philosophy is the same. The extent of and expectations from early-phase method validation are lower than the requirements in the later stages of development. The validation exercise becomes larger and more detailed, and it collects a larger body of data to ensure that the method is robust and appropriate for use at the commercial site.
2 Parameters for Qualification and Validation
Typical analytical performance characteristics that should be considered in the validation of the types of procedures described here are listed in Table 1.
Table 1 Validation Parameters
a−, Characteristic is not normally evaluated.
b+, Characteristic is normally evaluated.
cIn cases where reproducibility has been performed, intermediate precision is not needed.
dLack of specificity of one analytical procedure could be compensated by other, supporting analytical procedure(s).
eMay be needed in some cases.
3 Qualification and Validation Practices
3.1 Phase Appropriate Method Validation
Regulatory agencies recognize that some controls, and the extent of controls needed to achieve appropriate product quality, differ not only between investigational and commercial manufacture, but also among the various phases of clinical studies [2]. It is therefore expected that a company will implement controls that reflect product and production considerations, evolving process and product knowledge, and manufacturing experience. The term qualification is sometimes used loosely to represent method validation in the early stage of method development.
3.2 Preclinical Method Validation
As described in more detail below, there is even less guidance on the requirements for method development for preclinical method validation. The scientist should qualify and not validate the method to the extent that the data generated to make decisions and provide information should be scientifically sound. A minimum study of linearity, repeatability, detection limit (for quantitation of impurities), and specificity will be required.
3.3 Phase 1 to Phase 2 to Phase 3: Drug Substance and Drug Product Method Validation
The typical process that is followed in an analytical method validation is listed chronologically below, irrespective of the phases of method validation. However, the depth and detail of treatment for each of the following activities will vary with the phase [e.g., an abbreviated validation protocol (Table 2) versus detail validation protocol (Table 3)].
1. Planning and deciding on the method validation experiments
2. Writing and approval of method validation protocol
3. Execution of the method validation protocol
4. Analysis of the method validation data
5. Reporting on the analytical method validation
6. Finalizing the analytical method procedure
Table 2 Abbreviated Validation Protocol
MethodExperimentalProposed Acceptance CriteriaDissolution by high-performance liquid chromatography (HPLC)Linearity for x mg capsules according to method (0.05–0.15 mg/mL)
Accuracy and precision of six capsules of known release profile
Standard and sample stability (e.g., at 24 and 48 h)
Specificity
1. Meet system suitability.
2. Meet method requirement for linearity (R, slope, y-intercept, etc.).
3.Q = 65% at 60 min.
4. Report the % relative standard deviation (RSD) for precision.
5. Stability within 2% of initial.
6. There is no coeluting peak from the dissolution medium.
Linearity for x mg capsules according to method (0.05–0.15 mg/mL)
Accuracy and precision of six capsules
Standard and sample stability (e.g. at 24 and 48 h)
Specificity of degraded sample
1. Meet system suitability.
2. Meet method requirement for linearity (R, slope, y-intercept, etc.).
3. Accuracy recovery of 97–103%.
4. Report the % RSD for precision.
5. Stability within 2% of initial.
6. No coeluting peaks were detected. The peak of the drug substance is pure.
Table 3 Detailed Validation Protocol
A. IntroductionThis protocol outlines qualification activities to be performed for the HPLC identity, assay, and impurity tests in the compound X capsule.B. SpecificityProcedure: The following solutions are prepared and analyzed according to the identity and assay methods.Mobile phase AMobile phase BKnown impurity xxx, etc.Acceptance Criteria:1. No peaks in the dissolving solvent, and mobile-phase injections should coelute or otherwise interfere with compound X or its known impurities.
2. Known impurities should be resolved from compound X.
1. The correlation coefficient (r) should be NLT 0.99.
2. Record the slope, y-intercept, residuals, and % y-intercept of response vs. nominal concentration.
1. The correlation coefficient (r) should be NLT 0.98.
2. Record the slope, y-intercept, residuals and % y-intercept of response vs. nominal concentration.
1. Prepare triplicate sample preparations of compound X (total of nine sample preparations) according to the draft method procedure in x mL volumetric flasks that will yield 50%, 100%, and 150% nominal related substance sample solution.
2. Calculate the recovery of compound X, area% of compound X, individual impurities present at 0.05% (or greater) with respect to compound X peak, and total impurities at each concentration level.
1. The percent recovery values at each level should be between 98 and 102%.
2. The retention times of compound X should be greater than Y min.
3. Report the impurities ≥0.05% at each level.
1. Three additional replicate sample solutions are prepared at nominal concentration and analyzed according to the draft analytical method.
2. Combine the results from the triplicate samples of the 100% accuracy level. Calculate the relative standard deviation (% RSD) of the following: compound X recovery, individual impurity present at 0.05% (or greater) with respect to compound X, and total impurities in the six samples.
3. Record the retention times and % RSD of compound X from all the results.
1. The % RSD of the six assay values should not be greater than 2.0%.
2. The % RSD of the six % area values for compound X should not be greater than 2.0%.
3. Report results of the individual impurity (>0.05% or greater) and total impurity.
4. The % RSD of the retention times of compound X should not be greater than 2.0%.
1.Assay. To be considered stable, the recovery of compound X should be 98 to 102% compared to the initial time point.
2.Purity. The profile of the sample at each time point should be similar to that at the initial time point. The individual impurity > 0.05% and total % impurity should be NMT 0.1% (absolute) compared to the initial time point.
Method validation experiments should be well planned and laid out to ensure efficient use of time and resources during execution of the method validation. The best way to ensure a well-planned validation study is to write a method validation protocol that will be reviewed and signed by the appropriate person (e.g., laboratory management, quality assurance). However, there are differences in the terms of agreement for writing a validation protocol and in the details of the protocol in the early stages of method development.
A normal validation protocol should contain the following elements at a minimum:
1. The objective of the protocol
2. Validation parameters that will be evaluated
3. Acceptance criteria for all the validation parameters evaluated
4. Information regarding the experiments to be performed
5. A draft analytical procedure
Phase Appropriate Validation of a Drug Substance in Early Development
Linearity
For most early-phase methods, the assay and impurity methods are combined. One possibility is to determine two linearity curves: one for impurity from LOQ level to 2.0% and one for assay from approximately 50 to 150%. There are different strategies using three to five concentrations for each set of linearity. Sample linearity plots are shown in Figures 2 and 3.
Figure 2 Linearity plot of peak area response vs. concentration (assay).
Figure 3 Linearity plot of peak area response vs. concentration (impurity).
Accuracy
Accuracy can be inferred from the precision, linearity, and specificity. The overall mass balance of the drug substance peak and known impurities should be used to verify the accuracy of a method. An example of accuracy data for recovery of a drug substance and impurities are given in Table 4.
Table 4 Accuracy Recovery of Assay Validation
System Precision and Method Precision
System Precision
System precision will be derived from the system suitability requirements, which are tested at the time of method validation.
Method Precision
Method precision repeatabilityThe precision repeatability of assay and impurity methods may be assessed by testing at least three sample concentrations or six replicate sample preparations at the nominal concentration. The latter strategy is often used. These results give analytical scientists a high level of confidence regarding the precision of the assay and impurity methods. Example sets of repeatability data for the assay and impurities are given in Tables 5 and 6.
At early stages of drug substance development, the methods are typically carried out in one laboratory by a few analysts. It is therefore usually not necessary to determine the intermediate precision and reproducibility of an assay or impurity method at the early stage of development.
Table 5 Repeatability Data of Assay Validation
Sample NameAssay (%)Precision 1101.2Precision 2102.1Precision 3100.3Precision 4100.7Precision 5101.7Precision 6100.7 Average (%)101.1 % RSD0.7Table 6 Repeatability Data of Assay and Impurities Validation
1RRT, Relative retention time.
Stability of Sample and Standard Solutions
At the early phase of development, validation should demonstrate that the standard and sample solutions are adequately stable for the duration of their use in the laboratory. Sample sets of data for stability of sample and standard solutions are given in Tables 7 to 9. During method development and early stages of drug development, the analyst should develop an experience base. This information is useful for later-stage development of specific robustness experiments and helps establish appropriate system suitability requirements for later methods.
Table 7 Stability of Standard Solution (Assay)
Table 8 Stability of Sample Solution (Assay)
Table 9 Stability of Impurity in Sample Solution
Specificity
Assay and impurity method specificity should be evaluated during the early development stages. The specificity should be reviewed and reevaluated regularly as changes are made to the drug substance synthetic process. It is important that the method can demonstrate separation of the main component and impurities from the raw materials and intermediates. As the synthetic process continues to change with the progress of the development project, the scientist should constantly evaluate the potential for generating new impurities of side products and demonstrate the capability of the assay and impurity methods to separate new intermediates, side products, and raw materials. As appropriate, samples stored under relavant stress conditions (see drug product section) should be used to demonstrate specificity. A chromatogram of the specificity is shown in Figure 4.
Figure 4 Overlay chromatogram of a specificity sample solution.
Phase Appropriate Validation of Drug Product
At the beginning of drug development, it is anticipated that the formulation of the new drug will be the drug substance in a bottle, a simple immediate-release capsule or tablet formulation, and will be the assumption in the discussion below. The four principal methods of analysis of drug products are described in this section: assay, impurities, dissolution, and content uniformity. The general principles can be applied to other tests (e.g., the Karl Fischer test).
Linearity
Linearity is a very simple experiment and should be performed when possible. For most early-phase methods, assay and impurity are combined. This test is performed as described earlier. There are different strategies that use three to five concentrations for each set of linearity.
Accuracy
At an early stage of development, a minimum number of recovery studies are recommended. For the assay, recovery of the drug substance at 100% level at each strength is minimally required. ICH recommendations should be followed, as they require only preparing an additional two sets of spike solution (e.g., at 50 and 150%). For multiple strengths, a bracket at the lowest strength (e.g., 50% lowest strength) coupled with that at the highest strength (e.g., 150% highest strength) will cover the full range. For dissolution, recovery of the drug substance in the presence of excipients may cover 50, 100, and 120%. However, in certain cases a lower range may be required (e.g., 10% if a dissolution profile is required). For content uniformity, recovery of the drug substance from 70 to 130% is required, as this is the content uniformity range expected. For a multiple-strength product, bracketing may be used as for an assay. Degradation products may be scarce or not available at an early stage of development. Therefore, the accuracy of the impurity method is replaced by recovery of the drug substance in the presence of excipients from the reporting limit to specification or 150% of the specification level of the impurities.
System Precision and Method Precision
System Precision
System precision will be derived from the system suitability requirements that are tested at the time of method validation.
Method Precision
RepeatabilityThe repeatability of assay, impurity, content uniformity, and dissolution methods are generally carried out using triplicate sample preparations, and in combination with the triplicate preparations from the accuracy experiments, to give six replicates. For the impurity method, additional repeatability using the specification level of the impurity for the drug substance may be performed. For multiple strengths of similar formulation, the bracketing principle in the accuracy section may be applied.
Intermediate precision and reproducibilityAs for the drug substance, at the early stage of drug product development, the methods are typically carried out in one laboratory by a few analysts. It is therefore usually not necessary to determine the intermediate precision and reproducibility of an assay or impurity method.
Stability of Standard and Sample Solution
The standard and sample solutions should be adequately stable for the duration of their use in the laboratory.
Robustness
During method development and the early stages of drug development, the analyst should develop an experience base. This information is useful in later stages and helps establish appropriate system suitability requirements for later method revision.
Specificity
As for the drug substance, assay and impurity methods specificity should be evaluated during the early development stages. It is important that the assay method can demonstrate separation of the drug substance and impurities from the excipients and intermediates. For the impurity assay method, the drug product should be appropriately degraded to demonstrate that degradation peaks are resolved from the drug substance and synthetic impurities. Common degradation studies utilize 0.1 N HCl, 0.1 N NaOH, 3% hydrogen peroxide, or ultraviolet/visible light to give about 10 to 30% degradants. For the content uniformity and dissolution methods, the absence of interference from the extracting solvent, dissolution media, and excipients will need to be demonstrated.
LOD and LOQ
It is a regulatory requirement that the quantitation limit (LOQ) for the drug product impurity method be no greater than its reporting limit. The limit of detection (LOD) is not required at this stage (except for a limit test), but most companies determine it at the time of generating the LOQ by using an additional set of solution that is further diluted from the LOQ solution. For the assay, content uniformity, and dissolution methods, LOD and LOQ are not required.
3.4 Documentation for Phase Appropriate Method Validation
The fundamental concepts of cGMPs must be applied regardless of the details of the phase appropriate method validation strategy used [3]. Examples of these include:
1. Proper documentation
2. Change control
3. Deviations
4. Equipment and utilities qualification
5. Proper training
The raw laboratory data generated for the validation of analytical methods must be documented properly in a notebook or other GMP-compliant data storage device. Upon completion of all the experiments, all the data should be compiled into a detail validation report that will conclude the success or failure of the validation exercise. Depending on the company's strategy, only a summary of the validation data may be generated. Successful execution of the validation process will lead to a final analytical procedure that can be used by the laboratory to support future analytical work for a drug substance or drug product.
Information Required in an Analytical Procedure
To ensure compliance with traceability and GMP, the minimum information that should be included in a final analytical procedure is summarized below.
1. The rationale of the analytical procedure and description of the capability of the method. Revisions of the analytical procedure should include the advantages offered by the new revision.
2. The analytical procedure. This section should contain a complete description of the analytical procedure in sufficient detail to enable another analytical scientist to replicate it. The write-up should include all important operational parameters and specific instructions (e.g., preparation of reagents, system suitability tests, precautions, and explicit formulas for calculation of the test results).
3. The validation data. Either a detailed set or a summary set of validation data is included.
4. The revision history.
5. The signatures of authors, reviewers, management, and quality assurance.
4 Common Problems and Solutions
4.1 Three-Point vs. One-Point Calibration for Quantitation
It is common and advantageous to use one-point calibration for a method, as it will save analyst time and create less documentation. However, the behavior of the drug substance may not allow the method to do that. Under the latter circumstance, it will be necessary to prepare three standard solutions at the time of each assay experiment.
4.2 Sink Condition for Dissolution
For a dissolution test, it is important to ensure that dissolution conditions are able to satisfy sink conditions. Sink condition refers to the ratio (usually 3:1) of the recommended volume of solvent or medium for dissolution testing to the volume required to dissolve the drug in the unit (tablet or capsule) to saturate the solution. The reason for this requirement is to assure that a sufficient volume of dissolution medium is available to dissolve the drug from the product. The solution should not reach saturation or it will affect the dissolution rate negatively. Without sink conditions, the dissolution results may lead to variable results during routine dissolution analysis.
References
1. Guidance for Industry: cGMP for Phase 1 Investigational Drugs. FDA, Washington, DC, July 2008.
2. Guidance for Industry: Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products. FDA, Washington, DC, Nov. 1995.
3. Guidance for Industry: Quality Systems Approach to Pharmaceutical cGMP Regulations. FDA, Washington, DC, Sept. 2006.
3
Analytical Method Verification, Method Revalidation, and Method Transfer
CHUNG CHOW CHAN
Pramod Saraswat
CCC Consulting
Azopharma Product Development Group
1 Introduction
The applicable U.S. Pharmacopeia (USP) or National Formulary (NF) standard applies to any article marketed in the United States that (1) is recognized in the compendium and (2) is intended or labeled for use as a drug or as an ingredient in a drug. This applicable standard applies to such articles whether or not the added designation “USP” or “NF” is used. These standards of identity, strength, quality, and purity of the article are determined by official tests, procedures [1], and acceptance criteria, whether incorporated in the monograph itself, in the general notices, or in the applicable general chapters in the USP. Method verification refers to the experiments required to verify the suitability of the compendial procedure under actual conditions of use in the testing laboratory.
When manufacturers make changes to the manufacturing process of a drug substance (e.g., route of synthesis) or drug product (e.g., formulation), the changes will necessitate revalidation of the analytical procedures [2]. Revalidation should be carried out to ensure that the analytical procedure maintains its analytical characteristics (e.g., specificity) and to demonstrate that the analytical procedure continues to ensure the identity, strength, quality, purity, and potency of the drug substance and drug product. The degree of revalidation is dependent on the nature of the change. When a different regulatory analytical procedure is substituted for the current method [e.g., high-performance liquid chromatography (HPLC) is used to replace titration] the new analytical procedure should be validated.
Analytical method transfer is the transfer of analytical procedure from an originator laboratory to a receiving laboratory. The analytical parameters that need to be considered for method transfer are similar to those for analytical method revalidation and verification.
2 Cycle of Analytical Methods
Analytical method validation is not a one-time study. This was illustrated and summarized for the life cycle of an analytical procedure in Figure 1 of Chapter 2. An analytical method will be developed and validated for its intended use to analyze samples during the early development of an active pharmaceutical ingredient (API) or drug product. As drug development progresses from phase 1 to its commercialization, the analytical method will follow a similar progression. The final method will be validated for its intended use for the market image drug product and transferred to the quality control laboratory for the launch of the drug product. However, if there are any changes in the manufacturing process that have the potential to change the analytical profile of the drug substance and drug product, this validated method may need to be revalidated to ensure that it is still suitable for analyzing the drug substance or drug product for its intended purpose.
3 Method Verification Practices
3.1 Method Verification Versus Method Validation
U.S. Food and Drug Administration (FDA) regulation 21 CFR 211.194(a)(2) states specifically that users of analytical methods in the USP and NF are not required to validate the accuracy and reliability of these methods [2] but merely to verify their suitability under actual conditions of use. USP has issued a guidance for verification in General Chapter (1226) [3]. This general guidance provides general information to laboratories on the verification of compendial procedures that are being performed for the first time to yield acceptable results utilizing the laboratories' personnel, equipment, and reagents.
Verification consists of assessing selected analytical performance characteristics, such as those that are described in Chapter 2, to generate appropriate, relevant data rather than repeating the validation process. Although complete revalidation of a compendial method is not required to verify the suitability of the method under actual conditions of use, some of the analytical performance characteristics listed in USP General Chapter (1225) [4] or ICH (International Conference on Harmonization) Q2 (R1) [5] may be used for the verification process. Only those characteristics that are considered to be appropriate for the verification of the particular method need to be evaluated. The degree and extent of the verification process may depend on the level of training and experience of the user, on the type of procedure and its associated equipment or instrumentation, on the specific procedural steps, and on which article(s) are being tested.
Table 1 compares the validation requirements with the verification requirements of an example HPLC assay of a finished dosage form. ICH requires validation of the analytical properties of accuracy, precision, specificity, linearity, and range. However, verification will require only a minimum of precision and specificity validation. The accuracy requirements will depend on the specific situation of the final dosage form.
Table 1 Validation and Verification Requirements or HPLC Assay of Final Dosage Forms
Analytical Validation ParameterDrug Product ValidationDrug Product VerificationSystem suitabilityYesYesMethod precisionYesYesAccuracyYesYesLimit of detection (LOD)NoNoLimit of quantification (LOQ)NoNoSpecificityYesYesRangeYesNoLinearityYesNoRuggednessaNoaMay be required.
