ANALYTICAL METHOD VALIDATION
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ANALYTICAL METHOD VALIDATIONAND INSTRUMENT PERFORMANCEVERIFICATIONEdited byCHUNG CHOW CHANEli Lilly Canada, Inc.HERMAN LAMGlaxoSmithKline Canada, Inc.Y. C. LEEPatheon YM, Inc.XUE-MING ZHANGNovex PharmaA JOHN WILEY & SONS, INC., PUBLICATION
ANALYTICAL METHOD VALIDATIONAND INSTRUMENT PERFORMANCEVERIFICATION
ANALYTICAL METHOD VALIDATIONAND INSTRUMENT PERFORMANCEVERIFICATIONEdited byCHUNG CHOW CHANEli Lilly Canada, Inc.HERMAN LAMGlaxoSmithKline Canada, Inc.Y. C. LEEPatheon YM, Inc.XUE-MING ZHANGNovex PharmaA 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.No part of this publication may be reproduced, stored in a retrieval system, or transmitted in anyform or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise,except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, withouteither the prior written permission of the Publisher, or authorization through payment of theappropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers,MA 01923, 978-750-8400, fax 978-646-8600, or on the web at www.copyright.com. Requests tothe Publisher for permission should be addressed to the Permissions Department, John Wiley &Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008.Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their bestefforts in preparing this book, they make no representations or warranties with respect to theaccuracy or completeness of the contents of this book and specifically disclaim any impliedwarranties of merchantability or fitness for a particular purpose. No warranty may be created orextended by sales representatives or written sales materials. The advice and strategies containedherein may not be suitable for your situation. You should consult with a professional whereappropriate. Neither the publisher nor author shall be liable for any loss of profit or any othercommercial damages, including but not limited to special, incidental, consequential, or otherdamages.For general information on our other products and services please contact our Customer CareDepartment within the U.S. at 877-762-2974, outside the U.S. at 317-572-3993 orfax 317-572-4002.Wiley also publishes its books in a variety of electronic formats. Some content that appears inprint, however, may not be available in electronic format.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. Drugs—Analysis—Methodology—Evaluation. 2.Laboratories—Equipment and supplies—Evaluation. 3.Laboratories—Instruments—Evaluation.[DNLM: 1. Chemistry, Pharmaceutical—instrumentation. 2. Chemistry,Pharmaceutical—methods. 3. Clinical Laboratory Techniques—standards.4. Technology, Pharmaceutical—methods. QV 744 A532 2004] I. Chan,Chung Chow.RS189.A568 2004610 .28—dc212003014141Printed in the United States of America.10 9 8 7 6 5 4 3 2 1
CONTENTSContributorsviiPrefaceix1Overview of Pharmaceutical Product Development and ItsAssociated Quality System1Chung Chow Chan and Eric Jensen2Potency Method Validation11Chung Chow Chan3Method Validation for HPLC Analysis of Related Substancesin Pharmaceutical Drug Products27Y. C. Lee4Dissolution Method Validation51Chung Chow Chan, Neil Pearson, Anna Rebelo-Cameirao, and Y. C. Lee5Development and Validation of Automated Methods67Chantal Incledon and Herman Lam6Analysis of Pharmaceutical Inactive Ingredients85Xue-Ming Zhang7Validation Study of JP Heavy Metal Limit Test95Yoshiki Nishiyamav
vi8CONTENTSBioanalytical Method Validation105Fabio Garofolo9Procurement, Qualification, and Calibration of LaboratoryInstruments: An Overview139Herman Lam10Performance Verification of UV–Vis Spectrophotometers153Herman Lam11Performance Verification of HPLC173Herman Lam12Operational Qualification of a Capillary ElectrophoresisInstrument187Nicole E. Baryla13LC-MS Instrument Calibration197Fabio Garofolo14Karl Fisher Apparatus and Its Performance Verification221Rick Jairam, Robert Metcalfe, and Yu-Hong Tse15The pH Meter and Its Performance Verification229Yu-Hong Tse, Rick Jairam, and Robert Metcalfe16Qualification of Environmental Chambers243Gilman Wong and Herman Lam17Equipment Qualification and Computer System Validation255Ludwig Huber18Validation of Excel Spreadsheet277Heiko BrunnerIndex299
CONTRIBUTORSNicole E. Baryla, Ph.D., Eli Lilly Canada, Inc., 3650 Danforth Avenue, Toronto,Ontario M1N 2E8, CanadaHeiko Brunner, Ph.D., Lilly Forschung GmbH, Essener Strasse 93, D-22419Hamburg, GermanyChung Chow Chan, Ph.D., Eli Lilly Canada, Inc., 3650 Danforth Avenue,Toronto, Ontario M1N 2E8, CanadaFabio Garofolo, Ph.D., Vicuron Pharmaceuticals, Inc., via R. Lepetit 34,I-21040 Gerenzano, ItalyLudwig Huber, Ph.D., Agilent Technologies, Hewlett-Packard Strasse 8, 76337Waldbronn, GermanyChantal Incledon, GlaxoSmithKline Canada, Inc., 7333 Mississauga Road North,Mississauga, Ontario L5N 6L4, CanadaRick Jairam, GlaxoSmithKline Canada, Inc., 7333 Mississauga Road North,Mississauga, Ontario L5N 6L4, CanadaEric Jensen, Ph.D., Eli Lilly & Company, Indianapolis, INHerman Lam, Ph.D., GlaxoSmithKline Canada, Inc., 7333 MississaugaRoad North, Mississauga, Ontario L5N 6L4, CanadaY.C. Lee, Ph.D., Patheon YM, Inc., 865 York Mills Road, Toronto, OntarioM3B 1Y5, CanadaRobert Metcalfe, Ph.D., GlaxoSmithKline Canada, Inc., 7333 MississaugaRoad North, Mississauga, Ontario L5N 6L4, Canadavii
viiiCONTRIBUTORSYoshiki Nishiyama, Eli Lilly Japan KK, 4-3-3 Takatsukadai, Nishi-ku, Kobe651-2271, JapanNeil Pearson, Eli Lilly Canada, Inc., 3650 Danforth Avenue, Toronto, OntarioM1N 2E8, CanadaAnna Rebelo-Cameirao, Eli Lilly Canada, Inc., 3650 Danforth Avenue,Toronto, Ontario M1N 2E8, CanadaYu-Hong Tse, Ph.D., GlaxoSmithKline Canada, Inc., 7333 MississaugaRoad North, Mississauga, Ontario L5N 6L4, CanadaGilman Wong, GlaxoSmithKline Canada, Inc., 7333 Mississauga Road North,Mississauga, Ontario L5N 6L4, CanadaXue-Ming Zhang, Ph.D., Novex Pharma, 380 Elgin Mills Road East, RichmondHill, Ontario L4C 5H2, Canada
PREFACEFor 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 analytical 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 represented 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 requirements 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 individual organizations, as it will be individualized according to each organization’sstrategy 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 inix
xPREFACEthe 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 metals, 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 instruments that are used for the generation of reliable data in compliance with cGMPs.The reader is given different approaches to the successful verification of instrument performance. The choice of which approach to implement is left to thereader based on the needs of the laboratory. Chapters 9 to 15 provide information on common analytical instruments used in the development laboratory(e.g., HPLC, UV–Vis 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, hardware, 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 SYSTEMCHUNG CHOW CHAN, PH.D.Eli Lilly Canada, Inc.ERIC JENSEN, PH.D.Eli Lilly & Company, Indianapolis1.1 INTRODUCTIONPharmaceutical product development consists of a series of logical and systematic processes. When successful, the final outcome is a commercially availabledosage form. However, this process can become a long and complicated process 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 development 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 manner 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
2PHARMACEUTICAL PRODUCT DEVELOPMENT AND QUALITY SYSTEMDiscoveryresearchProductdecisionPhase on/synthesisDevelop earlyanalyticalmethodSupport earlydevelopmentformulation/synthesisPhase Phase odMarketManufacturingQualitycontrollabFigure 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 competition between pharmaceutical companies, it is of utmost important to reducethe time utilized to complete the development process.1.1.1 Discovery ResearchIn 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 structure–activity relationship (SAR) for the model. To reach this stage, large pharmaceutical 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 PhaseThe most promising drug candidates would be worthless if they could not be developed, marketed, or manufactured. New therapeutic drugs from drug discovery will
INTRODUCTION3undergo 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 PhasesThe 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 drug’s 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 development, 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 support synthetic and formulation developments are often developed in the form ofpotency assay, impurities/related substance assay, dissolution, Karl Fischer, identity, chiral method, and content uniformity. These analytical methods are developed 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.
4PHARMACEUTICAL PRODUCT DEVELOPMENT AND QUALITY SYSTEMSuccessful efficacy and safety data will guide the decision to proceed to clinicalphase III in product development. In this stage, the new drug is administered toa larger population of patients using blinded clinical studies. These studies maydemonstrate the potential advantages of the new compound compared with similarcompounds already marketed. The data collected from this stage are intendedto evaluate the overall benefit–risk relationship of the drug and to provide anadequate basis for labeling. Phase III studies usually include from several hundredto several thousand subjects and often include single- or double-blind studiesdesigned to eliminate possible bias on the part of both physicians and patients.Positive data from this stage will trigger implementation of a global registrationand commercialization of the drug product.Impurities Level in New Drug Product. As the new drug product formulationprogresses to this late stage of development, impurity profiles may differ fromthose of earlier formulations. The rationale for reporting and control of impuritiesin the new drug product is often decided at this stage as are recommended storageconditions for the product. Degradation products and those arising from excipientinteraction and/or container closure systems will be isolated and identified. Theimpurity profile of the representative commercial process will be compared withthe drug product used in development, and an investigation will be triggered ifany difference is observed. Identification of degradation products is required forthose that are unusually potent and produce toxic effects at low levels.Primary and developmental stability studies help development scientists understand the degradation pathways. These studies are developed to get informationon the stability of the drug product, expected expiry date, and recommendedstorage conditions. All specified degradation products, unspecified degradationproducts, and total degradation products are monitored in these studies.Impurities in API. Treatment of the impurities in the API is similar to that forthe new drug product. Impurities in the API include organic impurities (processand drug related), inorganic impurities, and residual solvents. Quality controlanalytical procedures are developed and validated to ensure appropriate detectionand quantitation of the impurities. Specification limits for impurities are set basedon data from stability studies and chemical development studies. A rationale forthe inclusion or ex
validation of common analytical methods (e.g., potency, related substances, and dissolution testing). Method validation for pharmaceutical excipients, heavy met-als, and bioanalysis are discussed in Chapters 6 to 8. The instrument perf
Analytical Method Development and Validation of Bendamustine in Bulk Using RP-HPLC J Pharm Res Analytical Method Development and Validation of Bendamustine in Bulk Using RP-HPLC . Table 3: Variables in HPLC.-Hplc Method Validation is a key process for effective quality assurance. "Validation" is established documented .
Validation guidelines 1. ICH Q2A Text on validation of analytical procedures: Definitions and terminology (March 1995) 2. ICH Q2B Validation of analytical procedures: Methodology (June 1997) 3. FDA (Draft) Guidance for Industry: Analytical procedures and methods validation 4. Pharmacopoeias USP and European Pharmacopoeia Guidelines
Keywords: analytical validation, pharmaceutical analysis, analytical method INTRODUCTION Analytical methods play an essential role in the adequate fulfillment of product quality attributes. However, the proper quality can only be reached if the analytical method undergoes an appropriate validation pr
The protocol on the validation study should include the follow-ing points in the validation study: 1) the purpose and scope of the analytical method, 2) the type of analytical method and validation characteristics, 3) acceptance criteria for each validation character-istics. Consideration on the following points will be useful to pre-
Non-pharmacopoeial methods 141 5. Method validation 142 6. Method verification 143 7. Method transfer 8.144 Revalidation 145 9. Characteristics of analytical procedures 146 147 1. PRINCIPLE 148 149 1.1 This appendix presents some information on the characteristics that should be considered 150 during validation of analytical methods. Approaches .
Cleaning validation Process validation Analytical method validation Computer system validation Similarly, the activity of qualifying systems and . Keywords: Process validation, validation protocol, pharmaceutical process control. Nitish Maini*, Saroj Jain, Satish ABSTRACTABSTRACT Sardana Hindu College of Pharmacy, J. Adv. Pharm. Edu. & Res.
All of the analytical validation parameters for this proposed method were determined according to ICH guidelines. Obtained validation parameters are presented in Table 1. Table 1. Analytical validation parameters (system suitability and linearity). Parameter Azelnidipine Telmisartan Linearity (μg/ml) 10-60 μg/ml 12.25-7.5 µg/ml
EPA Test Method 1: EPA Test Method 2 EPA Test Method 3A. EPA Test Method 4 . Method 3A Oxygen & Carbon Dioxide . EPA Test Method 3A. Method 6C SO. 2. EPA Test Method 6C . Method 7E NOx . EPA Test Method 7E. Method 10 CO . EPA Test Method 10 . Method 25A Hydrocarbons (THC) EPA Test Method 25A. Method 30B Mercury (sorbent trap) EPA Test Method .
