開發(fā)報批美國FDA的仿制藥與相關問題探討內容提要開發(fā)仿制藥的重要性和機遇

開發(fā)仿制藥的挑戰(zhàn)申報仿制藥的分類仿制藥研發(fā)團隊仿制藥的研發(fā)過程QbD在制劑開發(fā)中怎么體現研發(fā)(高難)仿制藥的一些體會：案例研究開發(fā)仿制藥的重要性

新藥與仿制藥-NDA

and

ANDA開發(fā)仿制藥與我國藥物研發(fā)的海外戰(zhàn)略藥物制劑目標主流市場仿制藥競爭的方式

HOWTOCOMPETECost-IRProductRawMaterialsProcessFinishedProductTechnology-ModifiedReleaseProducts申報(仿制)新藥的分類規(guī)范市場(FDA)1。P-I2。P-II3。P-III4。P-IV(1sttofile)中國市場（sFDA）1類2類3類4類5類6類仿制藥研發(fā)團隊

CONCEPT-1BUILDUPATEAMINFORMATIONFORMULATIONPRODUCTREGULATORYANALYTICALBIO-PHARMACEUTICALPROJECTLEGELProductDevelopmentRoadmap仿制藥的研發(fā)過程?Quality–Acceptablylowriskoffailingtoachievethedesiredclinical

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

empiricallyderivedfromperformanceoftestbatches’WhatisQbD

(QualitybyDesign)?QbD在制劑開發(fā)中怎么體現？WhatisQbD?QbD在制劑開發(fā)中怎么體現？PharmaceuticalQualitybyDesign(QbD)QbDmeansdesigninganddevelopingformulationsandmanufacturingprocessestoensurepredefinedproductqualityUnderstandingandcontrollingformulationandmanufacturingprocessvariablesaffectingthequalityofadrugproductRawMaterialsEquipmentEnvironmentOperatorsVariable

Inputsx“Locked”Process=VariableQualityHowDidWeWorkinthePastWhatisQbD?QbD在制劑開發(fā)中怎么體現？RawMaterialsEquipmentEnvironmentOperatorsUnderstoodVariableInputsxUnderstoodandControlledProcess=PredefinedQualityFlexibleProcessDesignSpaceHowCanWeWorkintheFutureWhatisQbD?QbD在制劑開發(fā)中怎么體現？WhatisQbD?QbD在制劑開發(fā)中怎么體現？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionProductWaterBinderTempSprayRateSpeedTimeP.SWhatisQbD?QbD在制劑開發(fā)中怎么體現？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionWhatisQbD?QbD在制劑開發(fā)中怎么體現？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionAirFlowTempRHShockCycleP.S.WhatisQbD?QbD在制劑開發(fā)中怎么體現？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionFillVolumeRotationSpeedEndPoint(Time)BlendUniformityDensitiesAngleofReposeQualityAssessmentunderQbRQuestion-basedReview(QbR)isageneralframeworkforascienceandrisk-basedassessmentofproductqualityQbRcontainstheimportantscientificandregulatoryreviewquestionstoComprehensivelyassesscriticalformulationandmanufacturingprocessvariablesSetregulatoryspecificationsrelevanttoqualityDeterminethelevelofriskassociatedwiththemanufactureanddesignoftheproductExamplesofQbDquestionsunderQbR?ControlofDrugSubstance–Whatisthedrugsubstancespecification?Doesitincludeallthecriticaldrugsubstanceattributesthataffectthemanufacturingandqualityofthedrugproduct?(2pages)?DrugProduct–Whatattributesshouldthedrugproductpossess?(1.5pages)–Howweretheexcipientsandtheirgradesselected?–Howwasthefinalformulationoptimized??ManufacturingProcess–Howarethemanufacturingsteps(unitoperations)relatedtothedrugproductquality?–Howwerethecriticalprocessparametersidentified,monitored,and/orcontrolled??PharmaceuticalDevelopment?Manufacture?ContainerClosureSystemAspectsTraditionalQbDPharmaceuticaldevelopmentEmpirical;univariateexperimentsSystematic;multivariateexperimentsManufacturingprocessFixed;validationon3initialfull-scalebatches;focusonreproducibilityAdjustablewithindesign

space;continuousverification;focusoncontrolstrategyProcesscontrolIn-processtestingforgo/nogo;offlineanalysisw/slowresponsePATutilizedforfeedback&feedforward,realtimeProductspecificationPrimarymeansofqualitycontrol;basedonbatchdataPartoftheoverallqualitycontrolstrategy;basedondesiredproductperformanceControlstrategyMainlybyintermediateandendproducttestingRisk-based;controlsshiftedupstream;real-timereleaseLifecyclemanagementReactivetoproblems&OOS;post-approvalContinuousimprovementenabledwithindesignspaceQbD小結-SUMMARY案例研究-1

CASESTUDY

1-IRTablets

VeryLowWaterSolubility(低水溶性)VeryLowPotency

(低劑量)MicronizedAPIused

(微粉化原料藥)WetGranulationProcess

(濕法制粒)Dissolution

Profile-體外溶出曲線案例研究-2

CASESTUDY2-ERCAPSULESNoPatent

(無專利)CoatedPellets

(包衣微丸)1stBioStudyFailedFast:CloseFed(ComparedwithFast):Brand:BAReducedTested:BAIncreasedTEAMWORKMoreInformationCollectedAnalyticalSupportIdentifytheProcessUsedProvidetheInfoforFunctionalCoatingOnemorePilotandOneFullBioPassed案例研究-3

CASESTUDY3-ERCAPSULESBrandProductMicro-TabletsinCapsules95%ofAPIexistedinFinishedProductSystemandProcessPatentedUNIQUESYSTEM-CREATIVEDESIGNCompressedGranulesinCapsulesRequirementSameDissolutionBehaviorUniformYieldAcceptableSYSTEMCOMPARISONPILOTBIO-STUDYPRODUCTPDATA(LogTransformedData,Fast,n-12)RatioofGeometricMeansx10090%CIofLogTransformedDataCV(%)TestAvsReferenceAUC10690.4;12322.0Cmax10480.1;13436.4TestBvsReferenceAUC133114;15522.0Cmax129100;16736.4PILOTBIO-STUDYPRODUCTPDATA(LogTransformedData,FED,n-11)RatioofGeometricMeansx10090%CIofLogTransformedDataCV(%)TestAvsReferenceAUC96.175.4;12332.7Cmax10983.5;14135.3TestBvsReferenceAUC92.472.5;11832.7Cmax10983.7;14135.3PIVOTALBIO-STUDYPRODUCTPDATA(LogTransformedData)Rat