齐鲁医学开发报批美国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上海复星普适医药科技有限公司何平开发报批美国FDA的仿制药与相关问题探讨共40页，您现在浏览的是第1页!内容提要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：案例研究开发报批美国FDA的仿制药与相关问题探讨共40页，您现在浏览的是第2页!开发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战略药物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共40页，您现在浏览的是第3页!仿制药竞争的方式

HOWTOCOMPETECost-IRProductRawMaterialsProcessFinishedProductTechnology-ModifiedReleaseProducts开发报批美国FDA的仿制药与相关问题探讨共40页，您现在浏览的是第4页!仿制药研发团队

CONCEPT-1BUILDUPATEAMINFORMATIONFORMULATIONPRODUCTREGULATORYANALYTICALBIO-PHARMACEUTICALPROJECTLEGEL开发报批美国FDA的仿制药与相关问题探讨共40页，您现在浏览的是第5页!ProductDevelopmentRoadmap仿制药的研发过程开发报批美国FDA的仿制药与相关问题探讨共40页，您现在浏览的是第6页!WhatisQbD?QbD在制剂开发中怎么体现？PharmaceuticalQualitybyDesign(QbD)QbDmeansdesigninganddevelopingformulationsandmanufacturingprocessestoensurepredefinedproductqualityUnderstandingandcontrollingformulationandmanufacturingprocessvariablesaffectingthequalityofadrugproduct开发报批美国FDA的仿制药与相关问题探讨共40页，您现在浏览的是第7页!RawMaterialsEquipmentEnvironmentOperatorsVariable

Inputsx“Locked”Process=VariableQualityHowDidWeWorkinthePastWhatisQbD?QbD在制剂开发中怎么体现？开发报批美国FDA的仿制药与相关问题探讨共40页，您现在浏览的是第8页!WhatisQbD?QbD在制剂开发中怎么体现？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionProduct开发报批美国FDA的仿制药与相关问题探讨共40页，您现在浏览的是第9页!WaterBinderTempSprayRateSpeedTimeP.SWhatisQbD?QbD在制剂开发中怎么体现？RawMaterialsWetGranulationFluidBedDryingBlendingCompression开发报批美国FDA的仿制药与相关问题探讨共40页，您现在浏览的是第10页!WhatisQbD?QbD在制剂开发中怎么体现？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionFillVolumeRotationSpeedEndPoint(Time)BlendUniformityDensitiesAngleofRepose开发报批美国FDA的仿制药与相关问题探讨共40页，您现在浏览的是第11页!QualityAssessmentunderQbRQuestion-basedReview(QbR)isageneralframeworkforascienceandrisk-basedassessmentofproductqualityQbRcontainstheimportantscientificandregulatoryreviewquestionstoComprehensivelyassesscriticalformulationandmanufacturingprocessvariablesSetregulatoryspecificationsrelevanttoqualityDeterminethelevelofriskassociatedwiththemanufactureanddesignoftheproduct开发报批美国FDA的仿制药与相关问题探讨共40页，您现在浏览的是第12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共40页，您现在浏览的是第13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共40页，您现在浏览的是第14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共40页，您现在浏览的是第15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共40页，您现在浏览的是第16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共40页，您现在浏览的是第17页!SYSTEMCOMPARISON开发报批美国FDA的仿制药与相关问题探讨共40页，您现在浏览的是第18页!PILOTBIO-STUDYPRODUCTPDATA(LogTransformedData,FED,n-11)RatioofGeometricMeansx10090%CIofLogTransformedDataCV(%)TestAvsReferenceAUC96.175.4;12332.7Cmax10983.5;14135.3TestBvsReferenceAUC92.472.5;11832.7Cmax10983.7;14135.3开发报批美国FDA的仿制药与相关问题探讨共40页，您现在浏览的是第19页!案例研究-4CASESTUDY4-ERCAPSULESAPIisWaterSoluble.Prototypeformulationwasproposedbasedoninvitrodissolution(OGDmethod).开发报批美国FDA的仿制药与相关问题探讨共40页，您现在浏览的是第20页!FurtherInvestigation开发报批美国FDA的仿制药与相关问题探讨共40页，您现在浏览的是第21页!开发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仿制药厂之间的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共40页，您现在浏览的是第22页!申报(仿制)新药的分类规范市场(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共40页，您现在浏览的是第23页!DRUGDELIVERYSYSTEMSFORORALSOLIDFORMULATIONS-MRMATRIXSYSTEMSRESERVIORSYSTEMSOSMOTICALPUMPSYSTEMSCOMBO-SYSTEMS缓控释给药的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共40页，您现在浏览的是第24页!•Quality–Acceptablylowriskoffailingtoachievethedesiredclinical

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

empiricallyderivedfromperformanceoftestbatches’WhatisQbD

(QualitybyDesign)?QbD在制剂开发中怎么体现？开发报批美国FDA的仿制药与相关问题探讨共40页，您现在浏览的是第25页!EssentialelementsofQbDDefinitionofthequalitytargetproductprofileHighlevelqualityaspectsoftheproduct:purity,drugrelease(dissolution/disintegrationtime),pharmacokineticprofile,etc.Criticalqualityattributes(CQAs)fordrugproduct•CharacteristicsofDPwhichhaveimpactondesiredprofile•ConsciousattempttostudyandcontrolCriticalProcessParameters(CPPs)•IdentificationofmaterialpropertiesandprocessparameterswhichhaveeffectonproductCQAsDesignSpace:ThemultidimensionalbinationandinteractionofinputvariablesandprocessparametersthathavebeendemonstratedtoprovideassuranceofqualityIdentificationofacontrolstrategyforcriticalprocessparametersWhatisQbD?QbD在制剂开发中怎么体现？开发报批美国FDA的仿制药与相关问题探讨共40页，您现在浏览的是第26页!RawMaterialsEquipmentEnvironmentOperatorsUnderstoodVariableInputsxUnderstoodandControlledProcess=PredefinedQualityFlexibleProcessDesignSpaceHowCanWeWorkintheFutureWhatisQbD?QbD在制剂开发中怎么体现？开发报批美国FDA的仿制药与相关问题探讨共40页，您现在浏览的是第27页!DrugSubstanceExcipientsSourceAssayImpurities……LODPS

……WhatisQbD?QbD在制剂开发中怎么体现？RawMaterialsWetGranulationFluidBedDryingBlendingCompression开发报批美国FDA的仿制药与相关问题探讨共40页，您现在浏览的是第28页!WhatisQbD?QbD在制剂开发中怎么体现？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionAirFlowTempRHShockCycleP.S.开发报批美国FDA的仿制药与相关问题探讨共40页，您现在浏览的是第29页!WhatisQbD?QbD在制剂开发中怎么体现？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionFeedFrameToolingPunchPenetrationDepthCompression

ForcePressSpeedFeederSpeed……开发报批美国FDA的仿制药与相关问题探讨共40页，您现在浏览的是第30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共40页，您现在浏览的是第31页!研发(高难)仿制药的一些体会开发报批美国FDA的仿制药与相关问题探讨共40页，您现在浏览的是第32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共40页，您现在浏览的是第33页!原因调查开发报批美国FDA的仿制药与相关问题探讨共40页，您现在浏览的是第34页!TEAMWORKMoreInformationCollectedAnalyticalSupportIdentifytheProcessUsedProvidetheInfoforFunctionalCoatingOnemorePilotandOneFullBioPassed开发报批美国FDA的仿制药与相关问题探讨共40页，您现在浏览的是第35页!UNIQUESYSTEM-CREATIVEDESIGNCompressedGranulesinCapsulesRequirementSameDissolutionBehaviorUniformYieldAcceptable开发报批美国FDA的仿制药与相关问题探讨共40页，您现在浏览的是第36页!PILOTBIO-