ANALYTICAL METHOD VALIDATIONAND INSTRUMENT PERFORMANCEVERIFICATION

Edited by

CHUNG CHOW CHANEli Lilly Canada, Inc.

HERMAN LAMGlaxoSmithKline Canada, Inc.

Y. C. LEEPatheon YM, Inc.

XUE-MING ZHANGNovex Pharma

A JOHN WILEY & SONS, INC., PUBLICATION

Innodata047146371X.jpg

ANALYTICAL METHOD VALIDATIONAND INSTRUMENT PERFORMANCEVERIFICATION

ANALYTICAL METHOD VALIDATIONAND INSTRUMENT PERFORMANCEVERIFICATION

Edited by

CHUNG CHOW CHANEli Lilly Canada, Inc.

HERMAN LAMGlaxoSmithKline Canada, Inc.

Y. C. LEEPatheon YM, Inc.

XUE-MING ZHANGNovex Pharma

A JOHN WILEY & SONS, INC., PUBLICATION

Copyright 2004 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:

Analytical method validation and instrument performance verification /Chung Chow Chan . . . [et al.].

p. ; cm.Includes bibliographical references and index.

ISBN 0-471-25953-5 (cloth : alk. paper)1. DrugsAnalysisMethodologyEvaluation. 2.

LaboratoriesEquipment and suppliesEvaluation. 3.LaboratoriesInstrumentsEvaluation.

[DNLM: 1. Chemistry, Pharmaceuticalinstrumentation. 2. Chemistry,Pharmaceuticalmethods. 3. Clinical Laboratory Techniquesstandards.4. Technology, Pharmaceuticalmethods. QV 744 A532 2004] I. Chan,Chung Chow.

RS189.A568 2004610.28dc21

2003014141

Printed in the United States of America.

10 9 8 7 6 5 4 3 2 1

http://www.copyright.com

CONTENTS

Contributors vii

Preface ix

1 Overview of Pharmaceutical Product Development and ItsAssociated Quality System 1Chung Chow Chan and Eric Jensen

2 Potency Method Validation 11Chung Chow Chan

3 Method Validation for HPLC Analysis of Related Substancesin Pharmaceutical Drug Products 27Y. C. Lee

4 Dissolution Method Validation 51Chung Chow Chan, Neil Pearson, Anna Rebelo-Cameirao, and Y. C. Lee

5 Development and Validation of Automated Methods 67Chantal Incledon and Herman Lam

6 Analysis of Pharmaceutical Inactive Ingredients 85Xue-Ming Zhang

7 Validation Study of JP Heavy Metal Limit Test 95Yoshiki Nishiyama

v

vi CONTENTS

8 Bioanalytical Method Validation 105Fabio Garofolo

9 Procurement, Qualification, and Calibration of LaboratoryInstruments: An Overview 139Herman Lam

10 Performance Verification of UVVis Spectrophotometers 153Herman Lam

11 Performance Verification of HPLC 173Herman Lam

12 Operational Qualification of a Capillary ElectrophoresisInstrument 187Nicole E. Baryla

13 LC-MS Instrument Calibration 197Fabio Garofolo

14 Karl Fisher Apparatus and Its Performance Verification 221Rick Jairam, Robert Metcalfe, and Yu-Hong Tse

15 The pH Meter and Its Performance Verification 229Yu-Hong Tse, Rick Jairam, and Robert Metcalfe

16 Qualification of Environmental Chambers 243Gilman Wong and Herman Lam

17 Equipment Qualification and Computer System Validation 255Ludwig Huber

18 Validation of Excel Spreadsheet 277Heiko Brunner

Index 299

CONTRIBUTORS

Nicole E. Baryla, Ph.D., Eli Lilly Canada, Inc., 3650 Danforth Avenue, Toronto,Ontario M1N 2E8, Canada

Heiko Brunner, Ph.D., Lilly Forschung GmbH, Essener Strasse 93, D-22419Hamburg, Germany

Chung Chow Chan, Ph.D., Eli Lilly Canada, Inc., 3650 Danforth Avenue,Toronto, Ontario M1N 2E8, Canada

Fabio Garofolo, Ph.D., Vicuron Pharmaceuticals, Inc., via R. Lepetit 34,I-21040 Gerenzano, Italy

Ludwig Huber, Ph.D., Agilent Technologies, Hewlett-Packard Strasse 8, 76337Waldbronn, Germany

Chantal Incledon, GlaxoSmithKline Canada, Inc., 7333 Mississauga Road North,Mississauga, Ontario L5N 6L4, Canada

Rick Jairam, GlaxoSmithKline Canada, Inc., 7333 Mississauga Road North,Mississauga, Ontario L5N 6L4, Canada

Eric Jensen, Ph.D., Eli Lilly & Company, Indianapolis, IN

Herman Lam, Ph.D., GlaxoSmithKline Canada, Inc., 7333 MississaugaRoad North, Mississauga, Ontario L5N 6L4, Canada

Y.C. Lee, Ph.D., Patheon YM, Inc., 865 York Mills Road, Toronto, OntarioM3B 1Y5, Canada

Robert Metcalfe, Ph.D., GlaxoSmithKline Canada, Inc., 7333 MississaugaRoad North, Mississauga, Ontario L5N 6L4, Canada

vii

viii CONTRIBUTORS

Yoshiki Nishiyama, Eli Lilly Japan KK, 4-3-3 Takatsukadai, Nishi-ku, Kobe651-2271, Japan

Neil Pearson, Eli Lilly Canada, Inc., 3650 Danforth Avenue, Toronto, OntarioM1N 2E8, Canada

Anna Rebelo-Cameirao, Eli Lilly Canada, Inc., 3650 Danforth Avenue,Toronto, Ontario M1N 2E8, Canada

Yu-Hong Tse, Ph.D., GlaxoSmithKline Canada, Inc., 7333 MississaugaRoad North, Mississauga, Ontario L5N 6L4, Canada

Gilman Wong, GlaxoSmithKline Canada, Inc., 7333 Mississauga Road North,Mississauga, Ontario L5N 6L4, Canada

Xue-Ming Zhang, Ph.D., Novex Pharma, 380 Elgin Mills Road East, RichmondHill, Ontario L4C 5H2, Canada

PREFACE

For pharmaceutical manufacturers to achieve commercial production of safe andeffective medications requires the generation of a vast amount of reliable dataduring the development of each product. To ensure that reliable data are generatedin compliance with current Good Manufacturing Practices (cGMPs), all analyt-ical activities involved in the process need to follow Good Analytical Practices(GAPs). GAPs can be considered as the culmination of a three-pronged approachto data generation and management: method validation, calibrated instrument, andtraining. The requirement for the generation of reliable data is very clearly repre-sented in the front cover design, where the three strong pillars represent methodvalidation, calibrated instrument, and training, respectively.

This book is designed to cover two of the three pillars of data generation. Thechapters are written with a unique practical approach to method validation andinstrument performance verification. Each chapter begins with general require-ments and is followed by the strategies and steps taken to perform these activities.The chapter ends with the author sharing important practical problems and theirsolutions with the reader. I encourage you to share your experience with us, too.If you have observations or problem solutions, please do not hesitate to emailthem to me at chung chow chan@cvg.ca. With the support of the Calibration &Validation Group (CVG) in Canada, I have set up a technical solution-sharingpage at the Web site www.cvg.ca. The third pillar, training, is best left to indi-vidual organizations, as it will be individualized according to each organizationsstrategy and culture.

The method validation section of this book discusses and provides guidance forthe validation of common and not-so-common analytical methods that are used tosupport development and for product release. Chapter 1 gives an overview of theactivities from the discovery of new molecules to the launch of new products in

ix

x PREFACE

the pharmaceutical industry. It also provides an insight into quality systems thatneed to be built into the fundamental activities of the discovery and developmentprocesses. Chapters 2 to 5 provide guidance and share practical information forvalidation of common analytical methods (e.g., potency, related substances, anddissolution testing). Method validation for pharmaceutical excipients, heavy met-als, and bioanalysis are discussed in Chapters 6 to 8.

The instrument performance verification section of the book provides unbiasedinformation on the principles involved in verifying the performance of instru-ments that are used for the generation of reliable data in compliance with cGMPs.The reader is given different approaches to the successful verification of instru-ment performance. The choice of which approach to implement is left to thereader based on the needs of the laboratory. Chapters 9 to 15 provide infor-mation on common analytical instruments used in the development laboratory(e.g., HPLC, UVVis spectrophotometers, and pH meters). Chapter 13 providesa detailed discussion of the LC-MS system, which is fast becoming a standardanalytical laboratory instrument. Since a great portion of analytical data from thedrug development process comes from stability studies, Chapter 16 is includedto provide guidance to ensure proper environmental chamber qualification.

Computers have become a central part of the analytical laboratory. Therefore,we have dedicated the last two chapters to an introduction to this field of computersystem and software validation. Chapter 17 guides quality assurance managers,lab managers, information technology personnel, and users of equipment, hard-ware, and software through the entire qualification and validation process, fromwriting specifications and vendor qualification to installation and to both initialand ongoing operations. Chapter 18 is an in-depth discussion of the approachesto validation of Excel spreadsheets, one of the most commonly used computerprograms for automatic or semiautomatic calculation and visualization of data.

The authors of this book come from a broad cultural and geographical base ofpharmaceutical companies, vendors and contract manufacturers and offer a broadperspective to the topics. I want to thank all the authors, co-editors, reviewers,and the management teams of Eli Lilly & Company, GlaxoSmithKline Canada,Inc., Patheon Canada, Inc., Novex Pharma, and Agilent Technologies who havecontributed to the preparation of this book. In addition, I want to acknowledgeHerman Lam for the design of the front cover, which clearly depicts the cGMPrequirements for data generation.

CHUNG CHOW CHAN, PH.D.

1OVERVIEW OF PHARMACEUTICALPRODUCT DEVELOPMENT AND ITSASSOCIATED QUALITY SYSTEM

CHUNG CHOW CHAN, PH.D.Eli Lilly Canada, Inc.

ERIC JENSEN, PH.D.Eli Lilly & Company, Indianapolis

1.1 INTRODUCTION

Pharmaceutical product development consists of a series of logical and system-atic processes. When successful, the final outcome is a commercially availabledosage form. However, this process can become a long and complicated pro-cess if any of the steps lose their focus. The industry has undergone manychanges over the years to increase focus on efficiency and efficacy of the devel-opment process. The overall cycle of pharmaceutical product development issummarized in Figure 1.1. The clinical study of drug development is the mostobvious and best known to laypersons and scientists. However, many associatedbehind-the-scene activities are also actively pursued in a parallel and timely man-ner to ensure the success of pharmaceutical product development. Clinical andcommercial success cannot be achieved without successful completion of theseother activities. It is important to note that the clinical phase boxes in Figure 1.1may not be aligned exactly chronologically with other development activities.

Analytical Method Validation and Instrument Performance Verification, Edited by Chung ChowChan, Herman Lam, Y. C. Lee, and Xue-Ming ZhangISBN 0-471-25953-5 Copyright 2004 John Wiley & Sons, Inc.

1

2 PHARMACEUTICAL PRODUCT DEVELOPMENT AND QUALITY SYSTEM

Productdecision Phase I Phase II Phase III

Defineformulation/syntheticroute

Definitivestabilitymanufac-ture

Manufactureprocessvalidation

Develop earlyanalyticalmethod

Support earlydevelopmentformulation/synthesis

Developfinalmethod

Finalanalyticalmethod

Optimizeformula-tion/synthesis

Qualitycontrollab

Manufac-turing

Market

Discoveryresearch

Figure 1.1. Overview of the drug development process.

Historically, the time period for pharmaceutical drug product development isusually on the order of 10 to 15 years. However, with the ever-increasing com-petition between pharmaceutical companies, it is of utmost important to reducethe time utilized to complete the development process.

1.1.1 Discovery Research

In the discovery research phase of drug development, new compounds are createdto meet targeted medical needs, hypotheses for model compounds are proposed,and various scientific leads are utilized to create and design new molecules.Thousands of molecules of similar structure are synthesized to develop a struc-tureactivity relationship (SAR) for the model. To reach this stage, large phar-maceutical companies rely on new technologies, such as combinatorial chemistryand high-throughput screening, which are cornerstones in drug discovery. Thenew technologies increase the choice of compounds that can be synthesized andscreened. Various in vivo and in vitro models are used to determine the value ofthese new candidate compounds.

The sequencing of the complete human genome was completed in 2000 throughthe Human Genome Project, which was begun in 1995. Knowledge of the completehuman genome will provide the basis for many possible targets for drug discoverythrough genomics, proteonomics, and bioinformatics.

1.1.2 Preclinical Phase

The most promising drug candidates would be worthless if they could not be devel-oped, marketed, or manufactured. New therapeutic drugs from drug discovery will

INTRODUCTION 3

undergo extensive testing to obtain initial safety and efficacy data in animal models.Upon completion of successful animal safety and efficacy evaluation, submissionto appropriate regulatory bodies is made to gain approval to administer the firsthuman dose in the clinical phase I trial.

1.1.3 Clinical Phases

The clinical phase I trial is used to assess the safety and, occasionally, the efficacyof a compound in a few healthy human volunteers. These studies are designedto determine the metabolism and pharmacological action of the drug in humans,the side effects associated with increasing doses, and if possible, to gain veryearly information on the drugs effectiveness. Safety data from these trials willhelp determine the dosage required for the next phase of drug development. Thetotal number of subjects in phase I studies is generally in the range 20 to 80.

Clinical phase II trials are conducted to evaluate the effectiveness of a drug fora particular indication or indications in patients with the targeted disease. Thesestudies also help to determine the common short-term side effects and risksassociated with the drug. Phase II studies are typically well controlled, closelymonitored, and conducted in a relatively small number of patients, usually nomore than several hundred.

Active Pharmaceutical Ingredient (API). In this early stage of drug devel-opment, only a small quantity of drug substance is needed. As developmentprogresses into later stages, greater quantities of drug substance are needed andwill trigger efforts to optimize the synthetic route.

Formulation Development. The formulation of the new drug product will bedesigned in conjunction with medical and marketing input. Excipients to be usedwill be tested for chemical and physical compatibility with the drug substance.The preliminary formulation design will be optimized at this stage.

Analytical Development of API and Drug Products. Early methods to sup-port synthetic and formulation developments are often developed in the form ofpotency assay, impurities/related substance assay, dissolution, Karl Fischer, iden-tity, chiral method, and content uniformity. These analytical methods are devel-oped and validated in a fast and timely manner to support all phase II studies.

Common Studies Performed on the API and Drug Product. At this stage of thedevelopment, it is important to gain preliminary information of the stability of theAPI and drug product. Therefore, open dish (i.e., nonprotected) stability studiesare carried out to understand the chemical and physical stability of both theAPI and the drug product. Preliminary packaging stability studies are conductedto obtain a preliminary assessment of packaging materials that can be used,and photostability and thermal studies are conducted to determine the light andthermal stability of the API and drug product.

ANALYTICAL METHOD VALIDATION AND INSTRUMENT PERFORMANCE VERIFICATIONCONTENTSContributorsPreface1 Overview of Pharmaceutical Product Development and Its Associated Quality System2 Potency Method Validation3 Method Validation for HPLC Analysis of Related Substances in Pharmaceutical Drug Products4 Dissolution Method Validation5 Development and Validation of Automated Methods6 Analysis of Pharmaceutical Inactive Ingredients7 Validation Study of JP Heavy Metal Limit Test8 Bioanalytical Method Validation9 Procurement, Qualification, and Calibration of Laboratory Instruments: An Overview10 Performance Verification of UVVis Spectrophotometers11 Performance Verification of HPLC12 Operational Qualification of a Capillary Electrophoresis Instrument13 LC-MS Instrument Calibration14 Karl Fisher Apparatus and Its Performance Verification15 The pH Meter and Its Performance Verification16 Qualification of Environmental Chambers17 Equipment Qualification and Computer System Validation18 Validation of Excel SpreadsheetIndex