开发报批美国fda的仿制药与相关问题探讨

开发报批美国fda的仿制药与相关问题探讨开发报批美国fda的仿制药与相关问题探讨第1页开发报批美国FDA仿制药与相关问题探讨上海复星普适医药科技有限企业何平开发报批美国fda的仿制药与相关问题探讨第2页内容提要开发仿制药主要性和机遇开发仿制药挑战申报仿制药分类仿制药研发团体仿制药研发过程QbD在制剂开发中怎么表达研发(高难)仿制药一些体会：案例研究开发报批美国fda的仿制药与相关问题探讨第3页开发仿制药主要性新药与仿制药-NDA

and

ANDA开发仿制药与我国药品研发海外战略药品制剂目标主流市场开发报批美国fda的仿制药与相关问题探讨第4页开发仿制药挑战性开发仿制药更具挑战性药品制剂专利仿制药竞争仿制药厂之间竞争由品牌药转成仿制药开发报批美国fda的仿制药与相关问题探讨第5页仿制药竞争方式

HOWTOCOMPETECost-IRProductRawMaterialsProcessFinishedProductTechnology-ModifiedReleaseProducts开发报批美国fda的仿制药与相关问题探讨第6页申报(仿制)新药分类规范市场(FDA)1。P-I2。P-II3。P-III4。P-IV(1sttofile)中国市场（sFDA）1类2类3类4类5类6类开发报批美国fda的仿制药与相关问题探讨第7页仿制药研发团体

CONCEPT-1BUILDUPATEAMINFORMATIONFORMULATIONPRODUCTREGULATORYANALYTICALBIO-PHARMACEUTICALPROJECTLEGEL开发报批美国fda的仿制药与相关问题探讨第8页DRUGDELIVERYSYSTEMSFORORALSOLIDFORMULATIONS-MRMATRIXSYSTEMSRESERVIORSYSTEMSOSMOTICALPUMPSYSTEMSCOMBO-SYSTEMS缓控释给药技术平台和给药系统

CONCEPT-2BUILDUPASYSTEM开发报批美国fda的仿制药与相关问题探讨第9页ProductDevelopmentRoadmap仿制药研发过程开发报批美国fda的仿制药与相关问题探讨第10页•Quality–Acceptablylowriskoffailingtoachievethedesiredclinical

attributes•PharmaceuticalQuality=f{drugsubstance,excipients,manufacturing..}•QbD–‘Productandprocessperformancecharacteristicsscientificallydesignedtomeetspecificobjectives,notmerely

empiricallyderivedfromperformanceoftestbatches’WhatisQbD

(QualitybyDesign)?QbD在制剂开发中怎么表达？开发报批美国fda的仿制药与相关问题探讨第11页WhatisQbD?QbD在制剂开发中怎么表达？PharmaceuticalQualitybyDesign(QbD)QbDmeansdesigninganddevelopingformulationsandmanufacturingprocessestoensurepredefinedproductqualityUnderstandingandcontrollingformulationandmanufacturingprocessvariablesaffectingthequalityofadrugproduct开发报批美国fda的仿制药与相关问题探讨第12页EssentialelementsofQbDDefinitionofthequalitytargetproductprofileHighlevelqualityaspectsoftheproduct:purity,drugrelease(dissolution/disintegrationtime),pharmacokineticprofile,etc.Criticalqualityattributes(CQAs)fordrugproduct•CharacteristicsofDPwhichhaveimpactondesiredprofile•ConsciousattempttostudyandcontrolCriticalProcessParameters(CPPs)•IdentificationofmaterialpropertiesandprocessparameterswhichhaveeffectonproductCQAsDesignSpace:ThemultidimensionalcombinationandinteractionofinputvariablesandprocessparametersthathavebeendemonstratedtoprovideassuranceofqualityIdentificationofacontrolstrategyforcriticalprocessparametersWhatisQbD?QbD在制剂开发中怎么表达？开发报批美国fda的仿制药与相关问题探讨第13页RawMaterialsEquipmentEnvironmentOperatorsVariable

Inputsx“Locked”Process=VariableQualityHowDidWeWorkinthePastWhatisQbD?QbD在制剂开发中怎么表达？开发报批美国fda的仿制药与相关问题探讨第14页RawMaterialsEquipmentEnvironmentOperatorsUnderstoodVariableInputsxUnderstoodandControlledProcess=PredefinedQualityFlexibleProcessDesignSpaceHowCanWeWorkintheFutureWhatisQbD?QbD在制剂开发中怎么表达？开发报批美国fda的仿制药与相关问题探讨第15页WhatisQbD?QbD在制剂开发中怎么表达？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionProduct开发报批美国fda的仿制药与相关问题探讨第16页DrugSubstanceExcipientsSourceAssayImpurities……LODPS

……WhatisQbD?QbD在制剂开发中怎么表达？RawMaterialsWetGranulationFluidBedDryingBlendingCompression开发报批美国fda的仿制药与相关问题探讨第17页WaterBinderTempSprayRateSpeedTimeP.SWhatisQbD?QbD在制剂开发中怎么表达？RawMaterialsWetGranulationFluidBedDryingBlendingCompression开发报批美国fda的仿制药与相关问题探讨第18页WhatisQbD?QbD在制剂开发中怎么表达？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionAirFlowTempRHShockCycleP.S.开发报批美国fda的仿制药与相关问题探讨第19页WhatisQbD?QbD在制剂开发中怎么表达？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionFillVolumeRotationSpeedEndPoint(Time)BlendUniformityDensitiesAngleofRepose开发报批美国fda的仿制药与相关问题探讨第20页WhatisQbD?QbD在制剂开发中怎么表达？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionFeedFrameToolingPunchPenetrationDepthCompression

ForcePressSpeedFeederSpeed……开发报批美国fda的仿制药与相关问题探讨第21页QualityAssessmentunderQbRQuestion-basedReview(QbR)isageneralframeworkforascienceandrisk-basedassessmentofproductqualityQbRcontainstheimportantscientificandregulatoryreviewquestionstoComprehensivelyassesscriticalformulationandmanufacturingprocessvariablesSetregulatoryspecificationsrelevanttoqualityDeterminethelevelofriskassociatedwiththemanufactureanddesignoftheproduct开发报批美国fda的仿制药与相关问题探讨第22页ExamplesofQbDquestionsunderQbR•ControlofDrugSubstance–Whatisthedrugsubstancespecification?Doesitincludeallthecriticaldrugsubstanceattributesthataffectthemanufacturingandqualityofthedrugproduct?(2pages)•DrugProduct–Whatattributesshouldthedrugproductpossess?(1.5pages)–Howweretheexcipientsandtheirgradesselected?–Howwasthefinalformulationoptimized?•ManufacturingProcess–Howarethemanufacturingsteps(unitoperations)relatedtothedrugproductquality?–Howwerethecriticalprocessparametersidentified,monitored,and/orcontrolled?•PharmaceuticalDevelopment•Manufacture•ContainerClosureSystem开发报批美国fda的仿制药与相关问题探讨第23页AspectsTraditionalQbDPharmaceuticaldevelopmentEmpirical;univariateexperimentsSystematic;multivariateexperimentsManufacturingprocessFixed;validationon3initialfull-scalebatches;focusonreproducibilityAdjustablewithindesign

space;continuousverification;focusoncontrolstrategyProcesscontrolIn-processtestingforgo/nogo;offlineanalysisw/slowresponsePATutilizedforfeedback&feedforward,realtimeProductspecificationPrimarymeansofqualitycontrol;basedonbatchdataPartoftheoverallqualitycontrolstrategy;basedondesiredproductperformanceControlstrategyMainlybyintermediateandendproducttestingRisk-based;controlsshiftedupstream;real-timereleaseLifecyclemanagementReactivetoproblems&OOS;post-approvalContinuousimprovementenabledwithindesignspaceQbD小结-SUMMARY开发报批美国fda的仿制药与相关问题探讨第24页研发(高难)仿制药一些体会开发报批美国fda的仿制药与相关问题探讨第25页案例研究-1

CASESTUDY

1-IRTablets

VeryLowWaterSolubility(低水溶性)VeryLowPotency

(低剂量)MicronizedAPIused

(微粉化原料药)WetGranulationProcess

(湿法制粒)开发报批美国fda的仿制药与相关问题探讨第26页Dissolution

Profile-体外溶出曲线开发报批美国fda的仿制药与相关问题探讨第27页生物等效(BE)结果AUC0-tAUC0-infCmaxFastRatio108.01%108.12%86.26%90%GeometricC.I.103.49%to112.73%103.64%to112.79%75.28%to98.84%FedRatio111.21%112.48%85.24%90%GeometricC.I.104.40%to118.47%105.78%to119.60%73.47%to98.90%SummaryofinvivostudyresultsofTestFormulationvs.RLD开发报批美国fda的仿制药与相关问题探讨第28页原因调查开发报批美国fda的仿制药与相关问题探讨第29页案例研究-2

CASESTUDY2-ERCAPSULESNoPatent

(无专利)CoatedPellets

(包衣微丸)1stBioStudyFailedFast:CloseFed(ComparedwithFast):Brand:BAReducedTested:BAIncreased开发报批美国fda的仿制药与相关问题探讨第30页TEAMWORKMoreInformationCollectedAnalyticalSupportIdentifytheProcessUsedProvidetheInfoforFunctionalCoatingOnemorePilotandOneFullBioPassed开发报批美国fda的仿制药与相关问题探讨第31页案例研究-3

CASESTUDY3-ERCAPSULESBrandProductMicro-TabletsinCapsules95%ofAPIexistedinFinishedProductSystemandProcessPatented开发报批美国fda的仿制药与相关问题探讨第32页UNIQUESYSTEM-CREATIVEDESIGNCompressedGranulesinCapsulesRequirementSameDissolutionBehaviorUniformYieldAcceptable开发报批美国fda的仿制药与相关问题探讨第33页SYSTEMCOMPARISON开发报批美国fda的仿制药与相关问题探讨第34页PILOTBIO-STUDYPRODUCTPDATA(LogTransformedData,Fast,n-12)RatioofGeometricMeansx10090%CIofLogTransformedDataCV(%)TestAvsReferenceAUC10690.4;12322.0Cmax10480.1;13436.4TestBvsReferenceAUC133114;15522.0Cmax129100;16736.4开发报批美国fda的仿制药与相关问题探讨第35页PILOTBIO-STUDYPRODUCTPDATA(LogTransformedData,FED,n-11)RatioofGeometricMeansx10090%CIofLogTransformedDataCV(%)TestAvsReferenceAUC96.175.4;12332.7Cmax10983.5;14135.3TestBvsReferenceAU