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(fǎngzhì)药与相关问题探讨上海复星普适医药(yīyào)科技有限公司何平第一页，共四十一页。编辑课件内容提要(nèirónɡtíyào)开发仿制药的重要性和机遇开发仿制药的挑战申报仿制药的分类仿制药研发团队仿制药的研发过程QbD在制剂开发中怎么体现研发(高难)仿制药的一些体会：案例(ànlì)研究第二页，共四十一页。编辑课件开发(kāifā)仿制药的重要性新药与仿制药-NDA

and

ANDA开发仿制药与我国药物研发的海外(hǎiwài)战略药物制剂目标(mùbiāo)主流市场第三页，共四十一页。编辑课件开发(kāifā)仿制药的挑战性开发(kāifā)仿制药更具挑战性药物制剂专利仿制药的竞争仿制药厂之间的竞争由品牌药转成仿制药第四页，共四十一页。编辑课件仿制药竞争(jìngzhēng)的方式

HOWTOCOMPETECost-IRProductRawMaterialsProcessFinishedProductTechnology-ModifiedReleaseProducts第五页，共四十一页。编辑课件申报(仿制(fǎngzhì))新药的分类规范市场(FDA)1。P-I2。P-II3。P-III4。P-IV(1sttofile)中国(zhōnɡɡuó)市场（sFDA）1类2类3类4类5类6类第六页，共四十一页。编辑课件仿制(fǎngzhì)药研发团队

CONCEPT-1BUILDUPATEAMINFORMATIONFORMULATIONPRODUCTREGULATORYANALYTICALBIO-PHARMACEUTICALPROJECTLEGEL第七页，共四十一页。编辑课件DRUGDELIVERYSYSTEMSFORORALSOLIDFORMULATIONS-MRMATRIXSYSTEMSRESERVIORSYSTEMSOSMOTICALPUMPSYSTEMSCOMBO-SYSTEMS缓控释给药的技术平台(píngtái)和给药系统

CONCEPT-2BUILDUPASYSTEM第八页，共四十一页。编辑课件ProductDevelopmentRoadmap仿制药的研发(yánfā)过程第九页，共四十一页。编辑课件•Quality–Acceptablylowriskoffailingtoachievethedesiredclinical

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

empiricallyderivedfromperformanceoftestbatches’WhatisQbD

(QualitybyDesign)?QbD在制剂(zhìjì)开发中怎么体现？第十页，共四十一页。编辑课件WhatisQbD?QbD在制剂(zhìjì)开发中怎么体现？PharmaceuticalQualitybyDesign(QbD)QbDmeansdesigninganddevelopingformulationsandmanufacturingprocessestoensurepredefinedproductqualityUnderstandingandcontrollingformulationandmanufacturingprocessvariablesaffectingthequalityofadrugproduct第十一页，共四十一页。编辑课件EssentialelementsofQbDDefinitionofthequalitytargetproductprofileHighlevelqualityaspectsoftheproduct:purity,drugrelease(dissolution/disintegrationtime),pharmacokineticprofile,etc.Criticalqualityattributes(CQAs)fordrugproduct•CharacteristicsofDPwhichhaveimpactondesiredprofile•ConsciousattempttostudyandcontrolCriticalProcessParameters(CPPs)•IdentificationofmaterialpropertiesandprocessparameterswhichhaveeffectonproductCQAsDesignSpace:ThemultidimensionalcombinationandinteractionofinputvariablesandprocessparametersthathavebeendemonstratedtoprovideassuranceofqualityIdentificationofacontrolstrategyforcriticalprocessparametersWhatisQbD?QbD在制剂开发中怎么(zěnme)体现？第十二页，共四十一页。编辑课件RawMaterialsEquipmentEnvironmentOperatorsVariable

Inputsx“Locked”Process=VariableQualityHowDidWeWorkinthePastWhatisQbD?QbD在制剂开发中怎么(zěnme)体现？第十三页，共四十一页。编辑课件RawMaterialsEquipmentEnvironmentOperatorsUnderstoodVariableInputsxUnderstoodandControlledProcess=PredefinedQualityFlexibleProcessDesignSpaceHowCanWeWorkintheFutureWhatisQbD?QbD在制剂开发(kāifā)中怎么体现？第十四页，共四十一页。编辑课件WhatisQbD?QbD在制剂(zhìjì)开发中怎么体现？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionProduct第十五页，共四十一页。编辑课件DrugSubstanceExcipientsSourceAssayImpurities……LODPS

……WhatisQbD?QbD在制剂开发(kāifā)中怎么体现？RawMaterialsWetGranulationFluidBedDryingBlendingCompression第十六页，共四十一页。编辑课件WaterBinderTempSprayRateSpeedTimeP.SWhatisQbD?QbD在制剂(zhìjì)开发中怎么体现？RawMaterialsWetGranulationFluidBedDryingBlendingCompression第十七页，共四十一页。编辑课件WhatisQbD?QbD在制剂(zhìjì)开发中怎么体现？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionAirFlowTempRHShockCycleP.S.第十八页，共四十一页。编辑课件WhatisQbD?QbD在制剂开发(kāifā)中怎么体现？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionFillVolumeRotationSpeedEndPoint(Time)BlendUniformityDensitiesAngleofRepose第十九页，共四十一页。编辑课件WhatisQbD?QbD在制剂(zhìjì)开发中怎么体现？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionFeedFrameToolingPunchPenetrationDepthCompression

ForcePressSpeedFeederSpeed……第二十页，共四十一页。编辑课件QualityAssessmentunderQbRQuestion-basedReview(QbR)isageneralframeworkforascienceandrisk-basedassessmentofproductqualityQbRcontainstheimportantscientificandregulatoryreviewquestionstoComprehensivelyassesscriticalformulationandmanufacturingprocessvariablesSetregulatoryspecificationsrelevanttoqualityDeterminethelevelofriskassociatedwiththemanufactureanddesignoftheproduct第二十一页，共四十一页。编辑课件ExamplesofQbDquestionsunderQbR•ControlofDrugSubstance–Whatisthedrugsubstancespecification?Doesitincludeallthecriticaldrugsubstanceattributesthataffectthemanufacturingandqualityofthedrugproduct?(2pages)•DrugProduct–Whatattributesshouldthedrugproductpossess?(1.5pages)–Howweretheexcipientsandtheirgradesselected?–Howwasthefinalformulationoptimized?•ManufacturingProcess–Howarethemanufacturingsteps(unitoperations)relatedtothedrugproductquality?–Howwerethecriticalprocessparametersidentified,monitored,and/orcontrolled?•PharmaceuticalDevelopment•Manufacture•ContainerClosureSystem第二十二页，共四十一页。编辑课件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(xiǎojié)-SUMMARY第二十三页，共四十一页。编辑课件研发(yánfā)(高难)仿制药的一些体会第二十四页，共四十一页。编辑课件案例(ànlì)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(fǎzhì)粒)第二十五页，共四十一页。编辑课件Dissolution

Profile-体外溶出曲线(qūxiàn)第二十六页，共四十一页。编辑课件生物(shēngwù)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第二十七页，共四十一页。编辑课件原因(yuányīn)调查第二十八页，共四十一页。编辑课件案例(ànlì)研究-2

CASESTUDY2-ERCAPSULESNoPatent

(无专利(zhuānlì))CoatedPellets

(包衣微丸)1stBioStudyFailedFast:CloseFed(ComparedwithFast):Brand:BAReducedTested:BAIncreased第二十九页，共四十一页。编辑课件TEAMWORKMoreInformationCollectedAnalyticalSupportIdentifytheProcessUsedProvidetheInfoforFunctionalCoatingOnemorePilotandOneFullBioPassed第三十页，共四十一页。编辑课件案例(ànlì)研究-3

CASESTUDY3-ERCAPSULESBrandProductMicro-TabletsinCapsules95%ofAPIexistedinFinishedProductSystemandProcessPatented第三十一页，共四十一页。编辑课件UNIQUESYSTEM-CREATIVEDESIGNCompressedGranulesinCapsulesRequirementSameDissolutionBehaviorUniformYieldAcceptable第三十二页，共四十一页。编辑课件SYSTEMCOMPARISON第三十三页，共四十一页。编辑课件PILOTBIO-STUDYPRODUCTPDATA(LogTransformedData,Fast,n-12)RatioofGeometricMeansx10090%CIofLogTransformedDataCV(%)TestAvsReferenceAUC10690.4;12322.0Cmax10480.1;13436.4TestBvsReferenceAUC133114;15522.0Cmax129100;16736.4第三十四页，共四十一页。编辑课件PILOTBIO-STUDYPRODUCTPDATA(LogTransformedData,FED,n-11)RatioofGeometricMeansx10090%CIofLogTransformedDataCV(%)TestAvsReferenceAUC96.175.4;12332.7Cmax10983.5;14135.3TestBvsReferenceAUC92.472.5;11832.7Cmax10983.7;14135.3第三十五页，共四十一页。编辑课件PIVOTALBIO-STUDYPRODUCTPDATA(LogTransformedData)RatioofGeometricMeansx10090%CIofLogTransformedDataCV(%)FA