ISPE-China-Annual-Conference-2012-Jun-Ouyang-final

16th–17thApril2012,BeijingAssessingChangesDuringDevelopmentofNewBiologicProductsJunOuyang,Ph.D.Genentech,AMemberoftheRocheGroupSouthSanFrancisco,California,USA•BiopharmaceuticalDevelopmentPhasesandExpectedChanges•KeyConceptsofComparability•ComparabilityAssessmentduringClinicalDevelopment•CaseStudy:comparabilityforahostcellchangeatPhaseII•ConsiderationsforStabilityComparability•QbDApproach:ExpandedComparabilityProtocols(eCP)•Summary•AcknowledgementsOutlineBiopharmaceuticalDevelopmentPhasesandExpectedChangesPhIVLOPre-clinicalPhIPhIIPhIIILIMarketPilotscaleproductionSmallscaleproductionUpscaleofproductionCommercialisedlargescaleproductionPotentialmajorchangessupportedbyappropriatecomparabilityand/orbridgingdataDualsourcing20-5020-300300-3000patientsPhysicaldesignProcessoptimization200L1000L~10,000LProcessimprovementsProcesscharacteriza-tionandvalidationUpto25,000LPlatformProcess“Fit”ofprocessintoplatformPost-marketprocessimprovementCommercialscaleproductionProcessoptimizationSmallscaleproductionProcessLockedUpscaleofproductionProductcomparabilitydataforchangesinthemanufacturingprocessandsiteslinkthematerialsusedthroughoutclinicaldevelopmentandcommercialproductionEarlypreclinicalstudiesEarlynon-clinicalstudiesPhaseI/IIPhaseIIIPivotaltrialsPhaseIVManufacturingsiteAManufacturingsiteBManufacturingsiteC,DManufacturingsite(s)Theprocess&sitesofmanufacturechangeduringdevelopmentandpost-approvalBiopharmaceuticalDevelopmentPhasesandExpectedChangesSitechangeisthemostcommonCMCchangeinaproductlifecyclePhaseIIIManufacturingsiteAManufacturingsiteBManufacturingsiteCManufacturingsite(s)PhaseI/IILaunchPostapproval•SitechangescanhappenafterpivotalPhIIItrialsandpost-approval•Thesamecomparabilityprinciples(ICHQ5E)canbeappliedtothesesitechangesInmanycases,thecommerciallotsarelaunchedatadifferentsitefromPhIIIproduction•BiopharmaceuticalDevelopmentPhasesandExpectedChanges•KeyConceptsofComparability•ComparabilityAssessmentduringClinicalDevelopment•CaseStudy:comparabilityforahostcellchangeatPhaseII•ConsiderationsforStabilityComparability•QbDApproach:ExpandedComparabilityProtocols(eCP)•Summary•AcknowledgementsOutlineComparability:Whatisit?Ascientificapproachthatbridgestheclinical/commercialmaterialsfrompre-topost-changesThegoalistodemonstrateahighdegreeofsimilaritybetweenproductsproducedbydifferentmanufacturingprocesses,equipmentsand/orsites,suchthatnoadverseimpactonquality,safetyorefficacyoccursAdata-driven,risk-basedcomprehensiveassessmentComparability:Why?Changesareoftennecessaryandcriticalforbiologicsdevelopment–Sitechange/additiontomeetincreased(oftenglobal)demandandmitigaterisks(e.g.naturaldisaster)–Processchangestoimproveproductivity,robustness,productqualityandmarketcompetitiveness–Newregulationrequirements(e.g.avoidanimalsourcedmaterial)Comparabilityisanessentialactivityrequiredtosupportproductlifecyclemanagementandcontinualimprovement,tofacilitateregulatoryapprovalandensureconsistentdeliveryofproducttopatientsGlobalGuidanceonComparability•ICHQ5Eguidanceon“ComparabilityofBiotechnological/BiologicalProductsSubjecttoChangesinTheirManufacturingProcess”•ComparabilityisawellestablishedglobalregulatorymechanismthatisadoptedintheUSandEUregulationsbasedontheICHQ5E.–US:GuidanceforIndustry,ComparabilityProtocols—ProteinDrugProductsandBiologicalProducts,Chemistry,Manufacturing,andControlsInformation,DraftGuidance,September2003–EU:GuidelineonComparabilityofBiotechnology-DerivedMedicinalProductsafteraChangeintheManufacturingProcess:Non-clinicalandClinicalIssues.EffectivesinceNov.1,2007.2012ISPECHINAANNUALCONFERENCEEvolutionofComparabilityConcept….Establishmentof“Well-CharacterizedBiological”conceptandconferenceTIMELINE:15YEARSDevelopmentofregulatoryguidance(ICH)andstudydesigndevelopmentof“ComparabilityExtensiveuseofComparabilityforsinglesite,productchangeswithregulatoryreliefExpansionofcomparabilityapplicationstomultiplesimplechanges(componentsimplification,bioreactorfamily…)LeverageQbDinitiativetoadvocatefor“expandedComparability/ChangeProtocols”2011:FirstApprovalof2eCPacrossmultiplefacilitiesandproductsImpactofinfluence:Significantregulatoryrelief(submissioncategorydowngradeandreductioninnumberofsubmissionsrequired)achievedthroughadvocacyinScientificConferencesandIndustryAssociationsComparabilityAssessment:How?Keytosuccess•ProductKnowledge–Criticalattributes:whatmattersandwhy?–Structure-functionunderstanding:BiologicalCharacterization–Productstabilityprofile:real-timeandaccelerated–Historicalranges:comparabilityacceptancecriteria•ProcessUnderstanding–Criticalprocessparameters–Linkbetweenprocessparametersandproductqualityattributes–Sourcesofvariability(e.g.rawmaterials)•SiteTransfer:astructured,documentedanddisciplinedapproach•BiopharmaceuticalDevelopmentPhasesandExpectedChanges•KeyConceptsofComparability•ComparabilityAssessmentduringClinicalDevelopment•CaseStudy:comparabilityforahostcellchangeatPhaseII•ConsiderationsforStabilityComparability•QbDApproach:ExpandedComparabilityProtocols(eCP)•Summary•AcknowledgementsOutline•Duringclinical