蛋白质的生产工艺验证-PDA-TR4205-en

TechnicalReportNo.42ProcessValidationofProteinManufacturingPDAJournalofPharmaceuticalScienceandTechnologySeptember/October2005SupplementVolume59No.S-4PDATechnicalReportNo.42ProcessValidationofProteinManufacturingProcessValidationofProteinManufacturingTaskForceMembers/AuthorsChrisBussineau,Ph.D.,ChironCorporation,Co-ChairRobertSeely,Ph.D.,Amgen,Inc.,Co-ChairGenevieveLovitt,G.I.Lovitt&Associates,ProjectManager/TechnicalEditorJamesFernandez,FernandezandAssociates,PDALiaisonGregBlank,Ph.D.,Genentech,Inc.E.J.Brandreth,Favrille,Inc.ChrisBussineau,Ph.D.,ChironCorporationDorisConrad,Consultant,GlaxoSmithKlineBiologicalsRebeccaA.Devine,Ph.D.,IndependentRegulatoryConsultantRobertJ.Ferris,Ph.D.,ChironCorporationKoendeHeyder,GlaxoSmithKlineBiologicalsRobertW.Juffras,M.S.,WyethBioPharmaPeterLevy,MillenniumPharmaceuticals,Inc.WolfgangList,Ph.D.,AventisBehringMortenMunk,CMCBiopharmaceuticalsA/SBrianC.Neely,DonHillandAssociates,Inc.StephenNotarnicola,Ph.D.,BiogenIdecRhonaO’Leary,Ph.D.,Genentech,Inc.HaroldvanDeinse,BaxterHealthcareCorporationProcessValidationofProteinManufacturingTechnicalReportNo.42SupplementVol.59,No.S-4September/October2005©2005byPDAPDATECHNICALREPORTNO.42PROCESSVALIDATIONOFPROTEINMANUFACTURINGTableofContents1.INTRODUCTION...........................11.1Purpose................................11.2Scope..................................12.DEFINITIONS.............................23.PROCESSVALIDATIONPREREQUISITES...43.1Introduction............................43.2Planning...............................53.3ProcessDevelopment....................53.3.1SequenceofActivitiesLeadingtoFormalProcessValidation..................53.3.2RawMaterials.....................73.3.3ProcessDescription.................73.3.4AnalyticalMethods.................73.3.5RiskAssessment...................83.3.6ProcessCharacterization.............83.3.7CellLineandExpressionConstructChar-acterization.......................103.3.8ExtractablesfromProduct-contactSurfaces..........................113.3.9DevelopmentDocumentation........113.4EquipmentandFacilities................113.5Training..............................124.PROCESSVALIDATION4.1Introduction...........................124.2ProcessValidationOptions..............124.3ValidationApproaches..................124.3.1UnitOperationValidation..........124.3.2FamilyandMatrixValidation.......134.4ScaleofStudies........................134.5ProcessValidationStudies...............144.5.1ViralClearance...................144.5.2ImpurityClearance................154.5.3ProcessConsistency...............164.5.4ProcessIntermediateStability.......164.5.5ProcessSolutionStability..........174.5.6DrugSubstanceFill/Freeze/Thaw/Storage..........................174.5.7MixingStudies...................184.5.8ChromatographyResinandReusableMembraneLifetimeValidation......185.POST-VALIDATIONACTIVITIES...........195.1ChangeControl........................195.2OngoingProcessMonitoring.............205.3ProcessRe-validation...................206.DOCUMENTATION.......................206.1Introduction...........................206.2ValidationProtocols....................216.3ValidationReports......................226.4ComplianceProgram....................227.APPENDICES.............................227.1IdealizedProcessValidationWorkflow....227.2ProcessDescriptionExample.............227.2.1CellCultureProcessDescription....237.2.2DownstreamPurificationProcessFlow..241IntroductionSignificantadvancementinthedesignandimplementa-tionofeffectivevalidationprogramshasbeenmadesincethe1987FoodandDrugAdministration(FDA)GuidelineonGeneralPrinciplesofProcessValidation.(1)Open,candiddiscussionsatconferences,manyofwhichwerededicatedspecificallytoprocessvalidation,andatotheropenforumshaveresultedincommonpractices.Theguidelinespresentedhereareintendedtoassistinthedesignandexecutionofprocessvalidationstudiestoensurethereproducibilityandrobustnessoftheprocess.Pointstoconsiderareprovidedtofacilitatecollectionofdatatosupportaregulatoryfilingfortheapprovalofadrugsubstanceintendedtobeusedinapharmaceuticalproduct.Theinformationprovidedintheseguidelinesisonetechnicalapproachtoprocessvalidationactivitiesanddocumentationbasedontheexperiencesandprac-ticesofaPDATaskForcethatrepresentsacross-sectionofindustryprofessionals.Thefollowingguidelinesrepresentwhattheauthorsbelievetobebestpracticesthatarescience-basedandvalue-addedandarebelievedtomakegoodbusinesssenseaswellasmeetcurrentregulatoryexpectations.Thedocumentdoesnotcontainisolatedresponsestoindividualinspectionsorreviews.Suchresponsesareoftendrivenbycase-by-caserequirementsparticulartospecificorganizationalneeds.1.1PurposeThistechnicalreportprovidespracticalguidanceforcom-pliancewithcurrentGoodManufacturingPractices(cGMP)andInternationalConferenceonHarmonisationofTechni-calRequirementsforRegistrationofPharmaceuticalsforHumanUse(ICH)guidancesforthevalidationofbiophar-maceuticalprocessestothedrugsubstancestage.1.2ScopeThefocusofthistechnicalreportisvalidationofbio-pharmaceuticalprocessesusedtomanufactureth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