Parenteral Quality Control: Sterility, Pyrogen, Particulate, and Package Integrity Testing PDF
Preview Parenteral Quality Control: Sterility, Pyrogen, Particulate, and Package Integrity Testing
Parenteral Quality Control Sterility, Pyrogen, Particulate, and Package Integrity Testing Third Edition, Revised and Expanded Michael J. Akers and Daniel S. Larrimore Baxter Pharmaceutical Solutions LLC Bloomington, Indiana, U.S.A Dana Morton Guazzo RxPax, LLC Bridgewater, New Jersey, U.S.A Marcel Dekker, Inc. New York Basel • Copyright ©2002 by Marcel Dekker,Inc. All Rights Reserved. Copyright © 2003 Marcel Dekker, Inc. Library of Congress Cataloging-in-Publication Data AcatalogrecordforthisbookisavailablefromtheLibraryofCongress. ISBN: 0-8247-0885-7 The secondedition was authored byMichael J. Akers(Marcel Dek- ker, 1993). This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016 tel: 212-696-9000; fax: 212-685-4540 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-260-6300; fax: 41-61-260-6333 World Wide Web http://www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Profes- sional Marketing at the headquarters address above. Copyright 2003 by Marcel Dekker, Inc. All Rights Re- served. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storageandretrievalsystem,withoutpermissioninwritingfromthe publisher. Current printing (last digit): 10 9 8 7 6 5 4 3 2 1 PRINTED IN THE UNITED STATES OF AMERICA Copyright © 2003 Marcel Dekker, Inc. Please purchase PDF Split-Merge on www.verypdf.com to remove this watermark. To my mother —D.L. Copyright © 2003 Marcel Dekker, Inc. Please purchase PDF Split-Merge on www.verypdf.com to remove this watermark. Preface Drug products administered byinjection arecharacterized by three qualities possessed by no other type of pharmaceutical dosageform:sterility,freedomfrompyrogenicity,andfreedom fromparticulatematter.Theachievementofsterile, nonpyro- genic,andparticulate-freeparenteralproductsprovidesasig- nificantchallengetotheingenuityandcreativityofparenteral scientists and technologists. Of equal challenge are the suc- cessful application and performance of analytical testing pro- cedures to verify the claims of parenteral products that they areindeed,sterile,pyrogen-free,andfreefromvisibleparticu- late contamination. Official compendial tests for sterility, pyrogens, and par- ticulates evoke widespread controversy regarding their reli- ability, sensitivity, and applicability. While impressive tech- nological advances have been made in the production of parenteral products, the testing for the quality of these prod- ucts involves relatively simple procedures. One of the objec- tives of this book is to critique the adequacy of current meth- ods for sterility, pyrogen, particulate, and leak testing and to review futuretrends and improvedtechnology inthese areas. v Copyright © 2003 Marcel Dekker, Inc. Please purchase PDF Split-Merge on www.verypdf.com to remove this watermark. vi Preface The focus of this third edition of Parenteral Quality Con- trol is to update the QC practitioner on the ever-changing re- quirements of various regulatory bodies and to educate the practitioneronnewtechnologiesassociatedwithtestingmeth- odsofthefinishedproductform.Methodologiesforperforming tests that meet U.S. and European requirements are empha- sized. The late 1990s brought many regulatory changes to the pharmaceutical industry. Not only are inspectors from FDA and Europeanregulatory bodies focusing onquality in manu- facturingareasbuttheseregulatorsarealsoexpectinghigher standards,especiallywithrespecttosterilityassurance,endo- toxin,andparticulatecontrolinthequalitycontrollaboratory. WhiletheMCA,USP,EP,andFDAallhavedifferentexpecta- tions,thelatterpartofthe1990sbroughtgreatharmonization where quality control is concerned with the previously men- tioned areas of testing. These updates and harmonization ef- fort are discussed in this book. New to this edition is an expanded discussion of barrier isolationtechnology,whichhasbecomethestandardinsteril- ity testing. While no regulations exist for the use of barrier isolationsystems,industryexpectationsexistforqualification ofthesesystemswhenusedforfinished-productsterilitytest- ing. Regulators are especially concerned with the generation ofafalse-negativeresultwhensurfacedecontaminationisem- ployed with the use of a barrier isolation system. Methods of validationofsuchasystemarediscussed.Finally,thechapter on package integrity testing has been updated to educate the reader as to developments in recent technology. Updated ref- erences have been added throughout the chapters to provide recent information. IwouldliketothankKarimAbdelkader,RyanAkers,and the marketing department at Baxter Pharmaceutical Solu- tions LLC for the cover photograph. Daniel S. Larrimore Copyright © 2003 Marcel Dekker, Inc. Please purchase PDF Split-Merge on www.verypdf.com to remove this watermark. Contents Prefacev 1.SterilityTesting1 Introduction1 SterilityandSterilityTestRegulations3 SamplingforSterilityTesting8 CultureMedia14 TimeandTemperatureofIncubation20 SterilityTestMethods26 SterilityRetesting31 FDAGuidelinesonSterilityTesting32 SterilityTestingofDifferentSterileProducts40 SterilityTestingofAntibioticsandProteins51 ControlinSterilityTesting52 ValidationoftheSterilityTest57 LimitationsoftheUSP/NFRefereeSterility Test58 vii Copyright © 2003 Marcel Dekker, Inc. Please purchase PDF Split-Merge on www.verypdf.com to remove this watermark. viii Contents IsolationChambersandRoboticSterilityTest Units67 SupportTechniquesandProceduresfor SterilityAssurance75 AlternativestotheCompendialSterilityTest102 References109 2.PyrogenTesting119 Introduction119 History122 SpecificRequirementsoftheUSPRabbit PyrogenTest124 The Limulus AmebocyteLysateTest140 ModificationsofRabbitandLALTestsfor Pyrogens182 References183 3.ParticulateMatterTesting197 Introduction197 BackgroundofParticulateMatterConcernsin ParenteralProducts198 NatureandSourceofParticulates202 TheRealityofParticulateMatter ContaminationinParenteralSolutions203 ParticulateMatterStandards206 VisualInspection:ManualMethods210 VisualInspection:AutomaticMethods221 CurrentIssueswithVisibleParticleDetection andInspectionProcedures233 USPTestforSubvisibleParticulateMatterin Large-VolumeInjectionsforSingle-Dose InfusionandSmall-VolumeInjections235 ElectronicParticleCounters239 LightObscurationParticleCountTest248 Copyright © 2003 Marcel Dekker, Inc. Please purchase PDF Split-Merge on www.verypdf.com to remove this watermark. Contents ix MicroscopicParticleCountTest252 AutomatedMicroscopicParticulateMatterTest257 ComparisonofMicroscopicandElectronic Particle-CountingMethods260 CurrentIssueswithElectronicParticle Counters266 FactorsAffectingAccurateParticleTesting269 InternationalCompendiaStandardsfor ParticulateMatterContentinParenteral Solutions271 References273 4.PackageIntegrityTesting281 Introduction281 RegulationsandGuidances283 Leakage287 EstablishingLeakRateSpecifications294 PackageIntegrityTestMethods307 TheChangingPharmaceuticalIndustry349 PackageIntegrityandtheProductLifeCycle354 Conclusion361 References363 AppendixI ExampleofStandardOperating ProcedureforSterilityTestingby DirectInoculation369 AppendixII ExampleofStandardOperating ProcedureforSterilityTestingby MembraneFiltration373 AppendixIII AsepticProceduresattheLaminar FlowWorkbench379 Copyright © 2003 Marcel Dekker, Inc. Please purchase PDF Split-Merge on www.verypdf.com to remove this watermark. 1 Sterility Testing INTRODUCTION Sterility, or freedom from the presence of viable microorgan- isms,isastrict,uncompromisingrequirementofaninjectable dosage form. Unlike interal administration, parenteral (Greek, para enteron (cid:1) beside the intestine) administration ofdrugsavoidsmanyof thenaturalprotectivedefensesofthe body. The injection of a product contaminated with living mi- croorganisms would invite a multitude of complications to a potentially immunocompromised patient. Whenthetermsterileappearsonthelabelofaparenteral product,itmeansthatthebatchorlotfromwhichthesample originatedpassedtherequirementsoftheU.S.Pharmacopela (USP)sterilitytest(cid:2)71(cid:3)(orothernationalcompendialsteril- ity test requirement). The USP sterility test provides an esti- mate of the probable, not actual, sterility of a lot of articles. The actual product administered to a patient has not been testedforsterility.Thesterilitytestisadestructivetest;thus, it is impossible to test every item for sterility. This presents a major limitation of the sterility test. Sterility is based on 1 Copyright © 2003 Marcel Dekker, Inc. Please purchase PDF Split-Merge on www.verypdf.com to remove this watermark.
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