Parenteral Quality Control: Sterility, Pyrogen, Particulate, and Package Integrity Testing

389 Pages·2002·12.243 MB·English

by  Michael K. Akers, Dan Larrimore, Dana Guazzo

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.
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ISBN: 0-8247-0885-7
The secondedition was authored byMichael J. Akers(Marcel Dek-
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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
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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
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Contents
Prefacev
1.SterilityTesting1
Introduction1
SterilityandSterilityTestRegulations3
SamplingforSterilityTesting8
CultureMedia14
TimeandTemperatureofIncubation20
SterilityTestMethods26
SterilityRetesting31
FDAGuidelinesonSterilityTesting32
SterilityTestingofDifferentSterileProducts40
SterilityTestingofAntibioticsandProteins51
ControlinSterilityTesting52
ValidationoftheSterilityTest57
LimitationsoftheUSP/NFRefereeSterility
Test58
vii
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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
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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
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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
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