2022年医学专题-报批美国FDA仿制药研发与相关问题探讨-Final

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。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(ɡāonán))仿制药的一些体会：案例研究第二页，共四十一页。开发(kāifā)仿制药的重要性

新药与仿制(fǎngzhì)药-NDA

and

ANDA开发仿制药与我国药物研发的海外战略药物制剂目标(mùbiāo)主流市场第三页，共四十一页。开发(kāifā)仿制药的挑战性

开发仿制药更具挑战性药物制剂专利

仿制药的竞争(jìngzhēng)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。仿制(fǎngzhì)药竞争的方式

HOWTOCOMPETECost-IRProductRawMaterialsProcessFinishedProductTechnology-ModifiedReleaseProducts第五页，共四十一页。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。仿制(fǎngzhì)药研发团队

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

CONCEPT-2BUILDUPASYSTEM第八页，共四十一页。ProductDevelopmentRoadmap仿制(fǎngzhì)药的研发过程第九页，共四十一页。•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。WhatisQbD?QbD在制剂开发(kāifā)中怎么体现？PharmaceuticalQualitybyDesign(QbD)QbDmeansdesigninganddevelopingformulationsandmanufacturingprocessestoensurepredefinedproductqualityUnderstandingandcontrollingformulationandmanufacturingprocessvariablesaffectingthequalityofadrugproduct第十一页，共四十一页。EssentialelementsofQbDDefinitionofthequalitytargetproductprofileHighlevelqualityaspectsoftheproduct:purity,drugrelease(dissolution/disintegrationtime),pharmacokineticprofile,etc.Criticalqualityattributes(CQAs)fordrugproduct•CharacteristicsofDPwhichhaveimpactondesiredprofile•ConsciousattempttostudyandcontrolCriticalProcessParameters(CPPs)•IdentificationofmaterialpropertiesandprocessparameterswhichhaveeffectonproductCQAsDesignSpace:ThemultidimensionalcombinationandinteractionofinputvariablesandprocessparametersthathavebeendemonstratedtoprovideassuranceofqualityIdentificationofacontrolstrategyforcriticalprocessparametersWhatisQbD?QbD在制剂开发中怎么(zěnme)体现？第十二页，共四十一页。RawMaterialsEquipmentEnvironmentOperatorsVariable

Inputsx“Locked”Process=VariableQualityHowDidWeWorkinthePastWhatisQbD?QbD在制剂(zhìjì)开发中怎么体现？第十三页，共四十一页。RawMaterialsEquipmentEnvironmentOperatorsUnderstoodVariableInputsxUnderstoodandControlledProcess=PredefinedQualityFlexibleProcessDesignSpaceHowCanWeWorkintheFutureWhatisQbD?QbD在制剂开发(kāifā)中怎么体现？第十四页，共四十一页。WhatisQbD?QbD在制剂开发中怎么(zěnme)体现？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionProduct第十五页，共四十一页。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。WaterBinderTempSprayRateSpeedTimeP.SWhatisQbD?QbD在制剂开发(kāifā)中怎么体现？RawMaterialsWetGranulationFluidBedDryingBlendingCompression第十七页，共四十一页。WhatisQbD?QbD在制剂(zhìjì)开发中怎么体现？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionAirFlowTempRHShockCycleP.S.第十八页，共四十一页。WhatisQbD?QbD在制剂开发中怎么(zěnme)体现？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionFillVolumeRotationSpeedEndPoint(Time)BlendUniformityDensitiesAngleofRepose第十九页，共四十一页。WhatisQbD?QbD在制剂开发中怎么(zěnme)体现？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionFeedFrameToolingPunchPenetrationDepthCompression

ForcePressSpeedFeederSpeed……第二十页，共四十一页。QualityAssessmentunderQbRQuestion-basedReview(QbR)isageneralframeworkforascienceandrisk-basedassessmentofproductqualityQbRcontainstheimportantscientificandregulatoryreviewquestionstoComprehensivelyassesscriticalformulationandmanufacturingprocessvariablesSetregulatoryspecificationsrelevanttoqualityDeterminethelevelofriskassociatedwiththemanufactureanddesignoftheproduct第二十一页，共四十一页。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。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。研发(高难(ɡāonán))仿制药的一些体会第二十四页，共四十一页。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。Dissolution

Profile-体外溶出曲线(qūxiàn)第二十六页，共四十一页。生物等效(děnɡxiào)(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。原因(yuányīn)调查第二十八页，共四十一页。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。TEAMWORKMoreInformationCollectedAnalyticalSupportIdentifytheProcessUsedProvidetheInfoforFunctionalCoatingOnemorePilotandOneFullBioPassed第三十页，共四十一页。案例(ànlì)研究-3

CASESTUDY3-ERCAPSULESBrandProductMicro-TabletsinCapsules95%ofAPIexistedinFinishedProductSystemandProcessPatented第三十一页，共四十一页。UNIQUESYSTEM-CREATIVEDESIGNCompressedGranulesinCapsulesRequirementSameDissolutionBehaviorUniformYieldAcceptable第三十二页，共四十一页。SYSTEMCOMPARISON第三十三页，共四十一页。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。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。PIVOTALBIO-STUDYPRODUCTPDATA(LogTransformedData)RatioofGeometricMeansx10090%CIofLogTransform