2022年醫(yī)學專題-報批美國FDA仿制藥研發(fā)與相關問題探討-Final

開發(fā)報批美國FDA的仿制(fǎngzhì)藥與相關問題探討上海復星普適醫(yī)藥(yīyào)科技有限公司何平第一頁，共四十一頁。內容提要(nèirónɡtíyào)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(ɡāonán))仿制藥的一些體會：案例研究第二頁，共四十一頁。開發(fā)(kāifā)仿制藥的重要性

新藥與仿制(fǎngzhì)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(mùbiāo)主流市場第三頁，共四十一頁。開發(fā)(kāifā)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(jìngzhēng)仿制藥廠之間的競爭由品牌藥轉成仿制藥第四頁，共四十一頁。仿制(fǎngzhì)藥競爭的方式

HOWTOCOMPETECost-IRProductRawMaterialsProcessFinishedProductTechnology-ModifiedReleaseProducts第五頁，共四十一頁。申報(仿制(fǎngzhì))新藥的分類規(guī)范市場(FDA)1。P-I2。P-II3。P-III4。P-IV(1sttofile)中國(zhōnɡɡuó)市場（sFDA）1類2類3類4類5類6類第六頁，共四十一頁。仿制(fǎngzhì)藥研發(fā)團隊

CONCEPT-1BUILDUPATEAMINFORMATIONFORMULATIONPRODUCTREGULATORYANALYTICALBIO-PHARMACEUTICALPROJECTLEGEL第七頁，共四十一頁。DRUGDELIVERYSYSTEMSFORORALSOLIDFORMULATIONS-MRMATRIXSYSTEMSRESERVIORSYSTEMSOSMOTICALPUMPSYSTEMSCOMBO-SYSTEMS緩控釋給藥的技術(jìshù)平臺和給藥系統(tǒng)

CONCEPT-2BUILDUPASYSTEM第八頁，共四十一頁。ProductDevelopmentRoadmap仿制(fǎngzhì)藥的研發(fā)過程第九頁，共四十一頁。?Quality–Acceptablylowriskoffailingtoachievethedesiredclinical

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

empiricallyderivedfromperformanceoftestbatches’WhatisQbD

(QualitybyDesign)?QbD在制劑(zhìjì)開發(fā)中怎么體現(xiàn)？第十頁，共四十一頁。WhatisQbD?QbD在制劑開發(fā)(kāifā)中怎么體現(xiàn)？PharmaceuticalQualitybyDesign(QbD)QbDmeansdesigninganddevelopingformulationsandmanufacturingprocessestoensurepredefinedproductqualityUnderstandingandcontrollingformulationandmanufacturingprocessvariablesaffectingthequalityofadrugproduct第十一頁，共四十一頁。EssentialelementsofQbDDefinitionofthequalitytargetproductprofileHighlevelqualityaspectsoftheproduct:purity,drugrelease(dissolution/disintegrationtime),pharmacokineticprofile,etc.Criticalqualityattributes(CQAs)fordrugproduct?CharacteristicsofDPwhichhaveimpactondesiredprofile?ConsciousattempttostudyandcontrolCriticalProcessParameters(CPPs)?IdentificationofmaterialpropertiesandprocessparameterswhichhaveeffectonproductCQAsDesignSpace:ThemultidimensionalcombinationandinteractionofinputvariablesandprocessparametersthathavebeendemonstratedtoprovideassuranceofqualityIdentificationofacontrolstrategyforcriticalprocessparametersWhatisQbD?QbD在制劑開發(fā)中怎么(zěnme)體現(xiàn)？第十二頁，共四十一頁。RawMaterialsEquipmentEnvironmentOperatorsVariable

Inputsx“Locked”Process=VariableQualityHowDidWeWorkinthePastWhatisQbD?QbD在制劑(zhìjì)開發(fā)中怎么體現(xiàn)？第十三頁，共四十一頁。RawMaterialsEquipmentEnvironmentOperatorsUnderstoodVariableInputsxUnderstoodandControlledProcess=PredefinedQualityFlexibleProcessDesignSpaceHowCanWeWorkintheFutureWhatisQbD?QbD在制劑開發(fā)(kāifā)中怎么體現(xiàn)？第十四頁，共四十一頁。WhatisQbD?QbD在制劑開發(fā)中怎么(zěnme)體現(xiàn)？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionProduct第十五頁，共四十一頁。DrugSubstanceExcipientsSourceAssayImpurities……LODPS

……WhatisQbD?QbD在制劑開發(fā)(kāifā)中怎么體現(xiàn)？RawMaterialsWetGranulationFluidBedDryingBlendingCompression第十六頁，共四十一頁。WaterBinderTempSprayRateSpeedTimeP.SWhatisQbD?QbD在制劑開發(fā)(kāifā)中怎么體現(xiàn)？RawMaterialsWetGranulationFluidBedDryingBlendingCompression第十七頁，共四十一頁。WhatisQbD?QbD在制劑(zhìjì)開發(fā)中怎么體現(xiàn)？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionAirFlowTempRHShockCycleP.S.第十八頁，共四十一頁。WhatisQbD?QbD在制劑開發(fā)中怎么(zěnme)體現(xiàn)？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionFillVolumeRotationSpeedEndPoint(Time)BlendUniformityDensitiesAngleofRepose第十九頁，共四十一頁。WhatisQbD?QbD在制劑開發(fā)中怎么(zěnme)體現(xiàn)？RawMaterialsWetGranulationFluidBedDryingBlendingCompressionFeedFrameToolingPunchPenetrationDepthCompression

ForcePressSpeedFeederSpeed……第二十頁，共四十一頁。QualityAssessmentunderQbRQuestion-basedReview(QbR)isageneralframeworkforascienceandrisk-basedassessmentofproductqualityQbRcontainstheimportantscientificandregulatoryreviewquestionstoComprehensivelyassesscriticalformulationandmanufacturingprocessvariablesSetregulatoryspecificationsrelevanttoqualityDeterminethelevelofriskassociatedwiththemanufactureanddesignoftheproduct第二十一頁，共四十一頁。ExamplesofQbDquestionsunderQbR?ControlofDrugSubstance–Whatisthedrugsubstancespecification?Doesitincludeallthecriticaldrugsubstanceattributesthataffectthemanufacturingandqualityofthedrugproduct?(2pages)?DrugProduct–Whatattributesshouldthedrugproductpossess?(1.5pages)–Howweretheexcipientsandtheirgradesselected?–Howwasthefinalformulationoptimized??ManufacturingProcess–Howarethemanufacturingsteps(unitoperations)relatedtothedrugproductquality?–Howwerethecriticalprocessparametersidentified,monitored,and/orcontrolled??PharmaceuticalDevelopment?Manufacture?ContainerClosureSystem第二十二頁，共四十一頁。AspectsTraditionalQbDPharmaceuticaldevelopmentEmpirical;univariateexperimentsSystematic;multivariateexperimentsManufacturingprocessFixed;validationon3initialfull-scalebatches;focusonreproducibilityAdjustablewithindesign

space;continuousverification;focusoncontrolstrategyProcesscontrolIn-processtestingforgo/nogo;offlineanalysisw/slowresponsePATutilizedforfeedback&feedforward,realtimeProductspecificationPrimarymeansofqualitycontrol;basedonbatchdataPartoftheoverallqualitycontrolstrategy;basedondesiredproductperformanceControlstrategyMainlybyintermediateandendproducttestingRisk-based;controlsshiftedupstream;real-timereleaseLifecyclemanagementReactivetoproblems&OOS;post-approvalContinuousimprovementenabledwithindesignspaceQbD小結(xiǎojié)-SUMMARY第二十三頁，共四十一頁。研發(fā)(高難(ɡāonán))仿制藥的一些體會第二十四頁，共四十一頁。案例(ànlì)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(fǎzhì)粒)第二十五頁，共四十一頁。Dissolution

Profile-體外溶出曲線(qūxiàn)第二十六頁，共四十一頁。生物等效(děnɡxiào)(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第二十七頁，共四十一頁。原因(yuányīn)調查第二十八頁，共四十一頁。案例(ànlì)研究-2

CASESTUDY2-ERCAPSULESNoPatent

(無專利(zhuānlì))CoatedPellets

(包衣微丸)1stBioStudyFailedFast:CloseFed(ComparedwithFast):Brand:BAReducedTested:BAIncreased第二十九頁，共四十一頁。TEAMWORKMoreInformationCollectedAnalyticalSupportIdentifytheProcessUsedProvidetheInfoforFunctionalCoatingOnemorePilotandOneFullBioPassed第三十頁，共四十一頁。案例(ànlì)研究-3

CASESTUDY3-ERCAPSULESBrandProductMicro-TabletsinCapsules95%ofAPIexistedinFinishedProductSystemandProcessPatented第三十一頁，共四十一頁。UNIQUESYSTEM-CREATIVEDESIGNCompressedGranulesinCapsulesRequirementSameDissolutionBehaviorUniformYieldAcceptable第三十二頁，共四十一頁。SYSTEMCOMPARISON第三十三頁，共四十一頁。PILOTBIO-STUDYPRODUCTPDATA(LogTransformedData,Fast,n-12)RatioofGeometricMeansx10090%CIofLogTransformedDataCV(%)TestAvsReferenceAUC10690.4;12322.0Cmax10480.1;13436.4TestBvsReferenceAUC133114;15522.0Cmax129100;16736.4第三十四頁，共四十一頁。PILOTBIO-STUDYPRODUCTPDATA(LogTransformedData,FED,n-11)RatioofGeometricMeansx10090%CIofLogTransformedDataCV(%)TestAvsReferenceAUC96.175.4;12332.7Cmax10983.5;14135.3TestBvsReferenceAUC92.472.5;11832.7Cmax10983.7;14135.3第三十五頁，共四十一頁。PIVOTALBIO-STUDYPRODUCTPDATA(LogTransformedData)RatioofGeometricMeansx10090%CIofLogTransform