優(yōu)秀精品課件文檔資料優(yōu)秀精品課件文檔資料開發(fā)報批美國FDA的仿制藥與相關問題探討上海復星普適醫(yī)藥科技有限公司何平開發(fā)報批美國FDA的仿制藥與相關問題探討上海復星普適醫(yī)藥科技內容提要開發(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(xiàn)研發(fā)(高難)仿制藥的一些體會：案例研究內容提要開發(fā)仿制藥的重要性和機遇開發(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開發(fā)仿制藥的重要性新藥與仿制藥-NDAandANDA藥開發(fā)仿制藥的挑戰(zhàn)性開發(fā)仿制藥更具挑戰(zhàn)性藥物制劑專利仿制藥的競爭仿制藥廠之間的競爭由品牌藥轉成仿制藥開發(fā)仿制藥的挑戰(zhàn)性開發(fā)仿制藥更具挑戰(zhàn)性仿制藥競爭的方式

HOWTOCOMPETECost-IRProductRawMaterialsProcessFinishedProductTechnology-ModifiedReleaseProducts仿制藥競爭的方式

HOWTOCOMPETECost-I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類申報(仿制)新藥的分類規(guī)范市場(FDA)中國市場（sFDA）仿制藥研發(fā)團隊

CONCEPT-1BUILDUPATEAMINFORMATIONFORMULATIONPRODUCTREGULATORYANALYTICALBIO-PHARMACEUTICALPROJECTLEGEL仿制藥研發(fā)團隊

CONCEPT-1BUILDUPADRUGDELIVERYSYSTEMSFORORALSOLIDFORMULATIONS-MRMATRIXSYSTEMSRESERVIORSYSTEMSOSMOTICALPUMPSYSTEMSCOMBO-SYSTEMS緩控釋給藥的技術平臺和給藥系統(tǒng)

CONCEPT-2BUILDUPASYSTEMDRUGDELIVERYSYSTEMSFORORALProductDevelopmentRoadmap仿制藥的研發(fā)過程ProductDevelopmentRoadmap?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(xiàn)？?QualityWhatisQbD(QualityWhatisQbD?QbD在制劑開發(fā)中怎么體現(xiàn)？PharmaceuticalQualitybyDesign(QbD)QbDmeansdesigninganddevelopingformulationsandmanufacturingprocessestoensurepredefinedproductqualityUnderstandingandcontrollingformulationandmanufacturingprocessvariablesaffectingthequalityofadrugproductWhatisQbD?PharmaceuticalQuaEssentialelementsofQbDDefinitionofthequalitytargetproductprofileHighlevelqualityaspectsoftheproduct:purity,drugrelease(dissolution/disintegrationtime),pharmacokineticprofile,etc.Criticalqualityattributes(CQAs)fordrugproduct?CharacteristicsofDPwhichhaveimpactondesiredprofile?ConsciousattempttostudyandcontrolCriticalProcessParameters(CPPs)?IdentificationofmaterialpropertiesandprocessparameterswhichhaveeffectonproductCQAsDesignSpace:ThemultidimensionalcombinationandinteractionofinputvariablesandprocessparametersthathavebeendemonstratedtoprovideassuranceofqualityIdentificationofacontrolstrategyforcriticalprocessparametersWhatisQbD?QbD在制劑開發(fā)中怎么體現(xiàn)？EssentialelementsofQbDWhatRawMaterialsEquipmentEnvironmentOperatorsVariable

Inputsx“Locked”Process=VariableQualityHowDidWeWorkinthePastWhatisQbD?QbD在制劑開發(fā)中怎么體現(xiàn)？RawMaterialsEquipmentEnvironmRawMaterialsEquipmentEnvironmentOperatorsUnderstoodVariableInputsxUnderstoodandControlledProcess=PredefinedQualityFlexibleProcessDesignSpaceHowCanWeWorkintheFutureWhatisQbD?QbD在制劑開發(fā)中怎么體現(xiàn)？RawMaterialsEquipmentEnvironmWhatisQbD?QbD在制劑開發(fā)中怎么體現(xiàn)？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionProductWhatisQbD?RawMaterialsWetGDrugSubstanceExcipientsSourceAssayImpurities……LODPS

……WhatisQbD?QbD在制劑開發(fā)中怎么體現(xiàn)？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionSourceWhatisQbD?RawMaterialWaterBinderTempSprayRateSpeedTimeP.SWhatisQbD?QbD在制劑開發(fā)中怎么體現(xiàn)？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionWaterWhatisQbD?RawMaterialsWhatisQbD?QbD在制劑開發(fā)中怎么體現(xiàn)？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionAirFlowTempRHShockCycleP.S.WhatisQbD?RawMaterialsWetGWhatisQbD?QbD在制劑開發(fā)中怎么體現(xiàn)？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionFillVolumeRotationSpeedEndPoint(Time)BlendUniformityDensitiesAngleofReposeWhatisQbD?RawMaterialsWetGWhatisQbD?QbD在制劑開發(fā)中怎么體現(xiàn)？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionFeedFrameToolingPunchPenetrationDepthCompression

ForcePressSpeedFeederSpeed……WhatisQbD?RawMaterialsWetGQualityAssessmentunderQbRQuestion-basedReview(QbR)isageneralframeworkforascienceandrisk-basedassessmentofproductqualityQbRcontainstheimportantscientificandregulatoryreviewquestionstoComprehensivelyassesscriticalformulationandmanufacturingprocessvariablesSetregulatoryspecificationsrelevanttoqualityDeterminethelevelofriskassociatedwiththemanufactureanddesignoftheproductQualityAssessmentunderQbRQuExamplesofQbDquestionsunderQbR?ControlofDrugSubstance–Whatisthedrugsubstancespecification?Doesitincludeallthecriticaldrugsubstanceattributesthataffectthemanufacturingandqualityofthedrugproduct?(2pages)?DrugProduct–Whatattributesshouldthedrugproductpossess?(1.5pages)–Howweretheexcipientsandtheirgradesselected?–Howwasthefinalformulationoptimized??ManufacturingProcess–Howarethemanufacturingsteps(unitoperations)relatedtothedrugproductquality?–Howwerethecriticalprocessparametersidentified,monitored,and/orcontrolled??PharmaceuticalDevelopment?Manufacture?ContainerClosureSystemExamplesofQbDquestionsundeAspectsTraditionalQbDPharmaceuticaldevelopmentEmpirical;univariateexperimentsSystematic;multivariateexperimentsManufacturingprocessFixed;validationon3initialfull-scalebatches;focusonreproducibilityAdjustablewithindesignspace;continuousverification;focusoncontrolstrategyProcesscontrolIn-processtestingforgo/nogo;offlineanalysisw/slowresponsePATutilizedforfeedback&feedforward,realtimeProductspecificationPrimarymeansofqualitycontrol;basedonbatchdataPartoftheoverallqualitycontrolstrategy;basedondesiredproductperformanceControlstrategyMainlybyintermediateandendproducttestingRisk-based;controlsshiftedupstream;real-timereleaseLifecyclemanagementReactivetoproblems&OOS;post-approvalContinuousimprovementenabledwithindesignspaceQbD小結-SUMMARYAspectsTraditionalQbDPharmaceu研發(fā)(高難)仿制藥的一些體會研發(fā)(高難)仿制藥的一些體會案例研究-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)案例研究-1

CASESTUDY1-IRTabletsDissolution

Profile-體外溶出曲線DissolutionProfile-體外溶出曲線生物等效(BE)結果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生物等效(BE)結果AUC0-tAUC0-infCmaxFa原因調查原因調查案例研究-2

CASESTUDY2-ERCAPSULESNoPatent

(無專利)CoatedPellets

(包衣微丸)1stBioStudyFailedFast:CloseFed(ComparedwithFast):Brand:BAReducedTested:BAIncreased案例研究-2

CASESTUDY2-ERCAPSULETEAMWORKMoreInformationCollectedAnalyticalSupportIdentifytheProcessUsedProvidetheInfoforFunctionalCoatingOnemorePilotandOneFullBioPassedTEAMWORKMoreInformationColl案例研究-3

CASESTUDY3-ERCAPSULESBrandProductMicro-TabletsinCapsules95%ofAPIexistedinFinishedProductSystemandProcessPatented案例研究-3

CASESTUDY3-ERCAPSUUNIQUESYSTEM-CREATIVEDESIGNCompressedGranulesinCapsulesRequirementSameDissolutionBehaviorUniformYieldAcceptableUNIQUESYSTEM-CREATIVEDESIGNCSYSTEMCOMPARISONSYSTEMCOMPARISONPILOTBIO-STUDYPRODUCTPDATA(LogTransformedData,Fast,n-12)RatioofGeometricMeansx10090%CIofLogTransformedDataCV(%)TestAvsReferenceAUC10690.4;12322.0Cmax10480.1;13436.4TestBvsReferenceAUC133114;15522.0Cmax129100;16736.4PILOTBIO-STUDYPRODUCTPDATAPILOTBIO-STUDYPRODUCTPDATA(LogTransformedData,FED,n-11)RatioofGeometricMeansx10090%CIofLogTransformedDataCV(%)TestAvsReferenceAUC96.175.4;12332.7Cmax10983.5;14135.3TestBvsReferenceAUC92.472.5;11832.7Cmax10983.7;14135.3PILOTBIO-STUDYPRODUCTPDATAPIVOTALBIO-STUDYPRODUCTPDATA(LogTransformedData)RatioofGeometricMeansx10090%CIofLogTransformedDataCV(%)FASTAUC10293;11133,9Cmax10594.5;11638.8FEDAUC98.891.6;10726.4Cmax99.689.2;11138.4PIVOTALBIO-STUDYPRODUCTPDAT案例研究-4CASESTUDY4-ERCAPSULESAPIisWaterSoluble.Prototypeformulationwasproposedbasedoninvitrodissolution(OGDmethod).案例研究-4APIisWaterSoluble.PPILOTBIO-STUDYPRODUCTDATA(LogTransformedData)AUC0-tAUC0-infCmaxT-1Ratio111.21%112.48%140%90%GeometricC.I.104.40%to118.47%105.78%to119.60%133.7%to147.0%T-2Ratio117.5%117.2%135.9%90%GeometricC.I.113.2%to122.2%112.4%to122.1%129.5%to142.4%PILOTBIO-STUDYPRODUCTDATA(LFurtherInvestigationFurtherInvestigation謝謝!139-1866-7400paxhp@謝謝!139-1866-7400優(yōu)秀精品課件文檔資料優(yōu)秀精品課件文檔資料開發(fā)報批美國FDA的仿制藥與相關問題探討上海復星普適醫(yī)藥科技有限公司何平開發(fā)報批美國FDA的仿制藥與相關問題探討上海復星普適醫(yī)藥科技內容提要開發(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(xiàn)研發(fā)(高難)仿制藥的一些體會：案例研究內容提要開發(fā)仿制藥的重要性和機遇開發(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開發(fā)仿制藥的重要性新藥與仿制藥-NDAandANDA藥開發(fā)仿制藥的挑戰(zhàn)性開發(fā)仿制藥更具挑戰(zhàn)性藥物制劑專利仿制藥的競爭仿制藥廠之間的競爭由品牌藥轉成仿制藥開發(fā)仿制藥的挑戰(zhàn)性開發(fā)仿制藥更具挑戰(zhàn)性仿制藥競爭的方式

HOWTOCOMPETECost-IRProductRawMaterialsProcessFinishedProductTechnology-ModifiedReleaseProducts仿制藥競爭的方式

HOWTOCOMPETECost-I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類申報(仿制)新藥的分類規(guī)范市場(FDA)中國市場（sFDA）仿制藥研發(fā)團隊

CONCEPT-1BUILDUPATEAMINFORMATIONFORMULATIONPRODUCTREGULATORYANALYTICALBIO-PHARMACEUTICALPROJECTLEGEL仿制藥研發(fā)團隊

CONCEPT-1BUILDUPADRUGDELIVERYSYSTEMSFORORALSOLIDFORMULATIONS-MRMATRIXSYSTEMSRESERVIORSYSTEMSOSMOTICALPUMPSYSTEMSCOMBO-SYSTEMS緩控釋給藥的技術平臺和給藥系統(tǒng)

CONCEPT-2BUILDUPASYSTEMDRUGDELIVERYSYSTEMSFORORALProductDevelopmentRoadmap仿制藥的研發(fā)過程ProductDevelopmentRoadmap?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(xiàn)？?QualityWhatisQbD(QualityWhatisQbD?QbD在制劑開發(fā)中怎么體現(xiàn)？PharmaceuticalQualitybyDesign(QbD)QbDmeansdesigninganddevelopingformulationsandmanufacturingprocessestoensurepredefinedproductqualityUnderstandingandcontrollingformulationandmanufacturingprocessvariablesaffectingthequalityofadrugproductWhatisQbD?PharmaceuticalQuaEssentialelementsofQbDDefinitionofthequalitytargetproductprofileHighlevelqualityaspectsoftheproduct:purity,drugrelease(dissolution/disintegrationtime),pharmacokineticprofile,etc.Criticalqualityattributes(CQAs)fordrugproduct?CharacteristicsofDPwhichhaveimpactondesiredprofile?ConsciousattempttostudyandcontrolCriticalProcessParameters(CPPs)?IdentificationofmaterialpropertiesandprocessparameterswhichhaveeffectonproductCQAsDesignSpace:ThemultidimensionalcombinationandinteractionofinputvariablesandprocessparametersthathavebeendemonstratedtoprovideassuranceofqualityIdentificationofacontrolstrategyforcriticalprocessparametersWhatisQbD?QbD在制劑開發(fā)中怎么體現(xiàn)？EssentialelementsofQbDWhatRawMaterialsEquipmentEnvironmentOperatorsVariable

Inputsx“Locked”Process=VariableQualityHowDidWeWorkinthePastWhatisQbD?QbD在制劑開發(fā)中怎么體現(xiàn)？RawMaterialsEquipmentEnvironmRawMaterialsEquipmentEnvironmentOperatorsUnderstoodVariableInputsxUnderstoodandControlledProcess=PredefinedQualityFlexibleProcessDesignSpaceHowCanWeWorkintheFutureWhatisQbD?QbD在制劑開發(fā)中怎么體現(xiàn)？RawMaterialsEquipmentEnvironmWhatisQbD?QbD在制劑開發(fā)中怎么體現(xiàn)？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionProductWhatisQbD?RawMaterialsWetGDrugSubstanceExcipientsSourceAssayImpurities……LODPS

……WhatisQbD?QbD在制劑開發(fā)中怎么體現(xiàn)？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionSourceWhatisQbD?RawMaterialWaterBinderTempSprayRateSpeedTimeP.SWhatisQbD?QbD在制劑開發(fā)中怎么體現(xiàn)？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionWaterWhatisQbD?RawMaterialsWhatisQbD?QbD在制劑開發(fā)中怎么體現(xiàn)？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionAirFlowTempRHShockCycleP.S.WhatisQbD?RawMaterialsWetGWhatisQbD?QbD在制劑開發(fā)中怎么體現(xiàn)？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionFillVolumeRotationSpeedEndPoint(Time)BlendUniformityDensitiesAngleofReposeWhatisQbD?RawMaterialsWetGWhatisQbD?QbD在制劑開發(fā)中怎么體現(xiàn)？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionFeedFrameToolingPunchPenetrationDepthCompression

ForcePressSpeedFeederSpeed……WhatisQbD?RawMaterialsWetGQualityAssessmentunderQbRQuestion-basedReview(QbR)isageneralframeworkforascienceandrisk-basedassessmentofproductqualityQbRcontainstheimportantscientificandregulatoryreviewquestionstoComprehensivelyassesscriticalformulationandmanufacturingprocessvariablesSetregulatoryspecificationsrelevanttoqualityDeterminethelevelofriskassociatedwiththemanufactureanddesignoftheproductQualityAssessmentunderQbRQuExamplesofQbDquestionsunderQbR?ControlofDrugSubstance–Whatisthedrugsubstancespecification?Doesitincludeallthecriticaldrugsubstanceattributesthataffectthemanufacturingandqualityofthedrugproduct?(2pages)?DrugProduct–Whatattributesshouldthedrugproductpossess?(1.5pages)–Howweretheexcipientsandtheirgradesselected?–Howwasthefinalformulationoptimized??ManufacturingProcess–Howarethemanufacturingsteps(unitoperations)relatedtothedrugproductquality?–Howwerethecriticalprocessparametersidentified,monitored,and/orcontrolled??PharmaceuticalDevelopment?Manufacture?ContainerClosureSystemExamplesofQbDquestionsundeAspectsTraditionalQbDPharmaceuticaldevelopmentEmpirical;univariateexperimentsSystematic;multivariateexperimentsManufacturingprocessFixed;validationon3initialfull-scalebatches;focusonreproducibilityAdjustablewithindesignspace;continuousverification;focusoncontrolstrategyProcesscontrolIn-processtestingforgo/nogo;offlineanalysisw/slowresponsePATutilizedforfeedback&feedforward,realtimeProductspecificationPrimarymeansofqualitycontrol;basedonbatchdataPartoftheoverallqualitycontrolstrategy;basedondesiredproductperformanceControlstrategyMainlybyintermediateandendproducttestingRisk-based;controlsshiftedupstream;real-timereleaseLifecyclemanagementReactivetoproblems&OOS;post-approvalContinuousimprovementenabledwithindesignspaceQbD小結-SUMMARYAspectsTraditionalQbDPharmaceu研發(fā)(高難)仿制藥的一些體會研發(fā)(高難)仿制藥的一些體會案例研究-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)案例研究-1

CASESTUDY1-IRTabletsDissolution

Profile-體外溶出曲線DissolutionProfile-體外溶出曲線生物等效(BE)結果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生物等效(BE)結果AUC0-tAUC0-infCmaxFa原因調查原因調查案例研究-2

CASESTUDY2-ERCAPSULESNoPatent

(無專利)CoatedPellets

(包衣微丸)1stBioStudyFailedFast:CloseFed(ComparedwithFast):Brand:BAReducedTested:BAIncreased案例研究-2

CASESTUDY2-ERCAPSULETEAMWORKMoreInformationCollectedAnalyticalSupportIdentifytheProcessUsedProvidetheInfoforFunctionalCoatingOnemorePilotandOneFullBioPassedTEAMWO