中美仿制药研发申报流程课件.ppt

中美仿制药研发和申报流程,涂家生，Ph.D.中国药科大学药剂学教授Telmail:jiashengtu2011.11郑州,我国仿制药申报、审评和研发对策,主要内容,中美关于原研药和仿制药的背景,美国仿制药：申报、基于问题的审评和研发对策,展望,1,2,3,4,CompanyLogo,3,药物经济学催生美国仿制药制度,美国社会安全制度导致政府赤字严重SSA已经破产：如何破局？降低医疗费用成为必然Hatch-Waxman法案出台美国FDA药品注册申请：新药（两类）、仿制药和非处方药申请,1984年后,NewDrugApplications(NDAs),AbbreviatedNewDrugApplications(ANDAs),“FullReports”ofSafetyandEfficacyInvestigationsApplicanthasrightofreferencetoessentialinvestigations?,DuplicateofanalreadyapprovedproductNosafety/efficacydatapermitted(onlybioequivalence),505(b)(1),505(b)(2),505(j),NDA的研发和申报,505(b)(1)新药申报资料内容,IndexSummaryChemistry,ManufacturingandControlSamples,MethodsValidationPackageandLabelingNonclinicalPharmacologyandToxicology,6.HumanPharmacokineticsandBioavailability7.Microbiology(foranti-microbialdrugsonly)8.ClinicalData9.SafetyUpdatereport(typicallysubmitted120daysaftertheNDAssubmission),10.Statistical11.CaseReportTabulations12.CaseReportForms13.PatentInformation14.PatentCertification,505(b)(2):历史过程,HatchWaxman法案：1984ParkmanLetterPhantomANDAFDADraftGuidanceforIndustry(1999)FDAResponsetoCitizensPetition(2003)可以降低研发的费用和审评力量的浪费,505(b)(2)的关键:可靠性,Whatis“Reliance”Bywhom?Onwhat?RelianceandExclusivityMarketvs.DataExclusivitySafety/EfficacyDatavs.CMQualitybyDesignModule4:NonclinicalModule5:Clinical(Bioequivalence),新药申报（NDA）和仿制药申报（ANDA）的比较,NDArequirements,ANDArequirements,美国仿制药申报,FDA仿制药部（OGD）鼓励申请人根据ICH对于人用药物的注册技术要求，即通用技术文件（CTD）的格式，提交ADNA。包括以下模块：,OGDQBRThequestionbasedreview(QBR)servesasageneralframeworkfortheCMCassessmentofANDAsthatfocusesoncriticalpharmaceuticalattributesofproductquality.Withjustification,deviationsoralternateapproachestothisframeworkcanbeutilize,asnecessary,toensuretheadequacyoftheassessmentofproductqualityForeaseofdiscussion,asimpledosageformisdefinedasasolutionoranimmediaterelease(IR)solidoraldosageform.,QBR:DrugSubstance,DescriptionandCharacterizationWhatarethenomenclature,molecularstructure,molecularformula,andmolecularweight?WhatarethepKa,aqueoussolubility(asfunctionofpH),partitioncoefficient,polymorphism,hygroscopicity,andmeltingpoints?ControlofDrugSubstanceAppearanceandIdentificationArethespecificationsforappearanceandidentificationappropriate?AssayIstheproposeddrugsubstanceassaylimitacceptable?Istheanalyticalmethodvalidatedandstability-indicating?ImpuritiesandResidualSolventsAreallthepossibleimpuritiesaccountedfor?Whatisthejustificationfortheimpurityacceptancelimits?Aretheanalyticalmethodsvalidatedandsuitablefortheirintendedfunction?AdditionalSpecificationsBasedonthereviewofthedrugproductandmanufacturingprocessarespecification(s)requiredonparticlesize,solidstateform,moisturecontent,orotherpropertiesofthedrugsubstanceandwhy?Foreachadditionalspecification:Whatisthejustificationfortheacceptancelimit?Isitsuitableforitsintendedfunction?,QBR:DrugProduct,DescriptionandCompositionWhatarethecomponentsandcompositionofthefinalproduct?Whatisthefunctionofeachexcipient?DoanyexcipientsexceedIIGlimitsinthecontextofmaximumdailydoseandrouteofadministration?IfproductisanNTIdrugoranon-simpledosageformAretheresignificantdifferencesbetweenthisformulationandtheRLDthatpresentpotentialconcernswithrespecttoproductperformance?ControlofExcipientsWhatarethespecificationsfortheinactiveingredientsandaretheyappropriatepertheirintendedfunction?,SimpleDosageForm:EitherasolutionoranIRsolidoraldosageform,QBR:DrugProduct(Continued),ManufactureForallproductsDoesthebatchformulaaccuratelyreflectthedrugproductcomposition?Ifnot,whatarethedifferencesandthejustifications(e.g.potencyadjustment,overage,excesscoatingsolution,etc.)?IfproductisnotasolutionWhatarethekeyunitoperationsinthedrugproductmanufacturingprocess?Arein-processtestsidentifiedbythesponsorappropriate?Whatisthedifferenceinsizebetweencommercialscaleandbiobatchanddotheyusethesameunitoperations?IfproductisanNTIdrugoranon-simpledosageformWhatarethecriticalstepsinthemanufacturingprocess?Whatarethein-processtests/controlsthatensureeachcriticalstepissuccessful?Intheproposedscaleupprocesswhatoperatingconditionswillbeadjustedtoensuretheproductmeetsallin-processandfinalproductspecifications?Whydoyoubelievethesponsorhasdemonstratedareasonableplantoscaleuptheprocess?,QBR:DrugProduct(Continued),ControlofDrugProductIdentityIsthespecificationfortheidentityofthedrugproductappropriate?AssayandUniformityAretheproposeddrugassaylimitsacceptable?Istheassaymethodvalidatedandstability-indicating?Howisthecontentuniformityevaluated?Isitacceptable?Impurities/DegradationProductsArethedegradationproductsandtheiroriginsadequatelydescribed?Whatisthejustificationfortheacceptancelimitsondegradationproducts?Aretheanalyticalmethodsvalidatedandsuitablefortheirintendedfunction?DissolutionWhatarethedissolutionmethodsandacceptancecriteriaandhowweretheyselected?Whatisthesignificantroleofdissolutiontestingforthisproduct?AdditionalSpecificationsArethereadditionalspecificationsthatarerequiredtoensuretheproductwillperformaslabeledandwhy?Foreachadditionalspecification:Whatisthejustificationfortheacceptancelimit?Aretheanalyticalmethodsvalidatedandsuitablefortheirintendedfunction?,QBR:DrugProduct(Continued),ReferenceStandardArethereaqualificationreportandCOAprovidedforthereferencestandardoristhismaterialpurchasedfromanappropriatesource?Container/ClosureSystemHasthecontainer/closuresystembeenusedinapreviouslyapprovedproductorotherwisequalifiedforthisdosageform?Whatspecificcontainer/closureattributesarenecessarytoensureproductperformance?DrugProductStabilityDataWhatstabilitydatahasbeensubmitted?Hasthesponsorprovidedstabilitydataforthedrugproductpackagedintheproposedcontainer/closure?AcceptancelimitsAreallattributesthatcouldchangeovertimeevaluatedinthestabilitytests?Whataretheacceptablelimitsontheseattributes?Shelf-liferecommendationWhatisthejustificationofshelflife?Isthepost-approvalstabilityprotocolacceptable?,QBR:ProductDevelopmentReportforComplexDosageFormsandNTIDrugs,DrugSubstanceWhichpropertiesorphysicalchemicalcharacteristicsofthedrugsubstanceaffectdrugproductperformance?ExcipientsIsthereanyevidenceofincompatibilitybetweentheexcipientsanddrugsubstance?FormulationWhatistheformulationintendedtodo?Whatmechanismdoesitusetoaccomplishthis?Wereanyotherformulationalternativesinvestigatedandhowdidtheseperform?Wereanyformulationoptimizationorsensitivitystudiescarriedoutforvariationsincompositionaroundthefinalformulation?Werethesestudiessufficienttoestablishadesignspaceforformulationcomposition?Istheformulationdesignconsistentwiththedosageformclassificationinthelabel?DrugProductWhatarethecriticalqualityattributesthatensuretheproductwillperformaslabeled?,QBR:ProcessDevelopmentReport,ProcessDescriptionWhywasthismanufacturingprocessselectedforthisdrugproduct?Werealternativeunitoperationsinvestigatedbyprocessdevelopmentstudies?CriticalStepsandScaleUpHowwerethecriticalstepsintheprocessidentified?Whatarethecriticalprocessparametersforeachcriticalstepandhowweretheyidentified,monitoredand/orcontrolled?Wereprocessdevelopmentstudiesthatvariedstartingmaterialsoroperatingparametersconducted?Werethesestudiessufficienttoestablishadesignspaceforprocess?InprocesstestsWhyiseachinprocesstestrequired?Howweretheacceptancelimitschosen?Whywerethein-processtestsidentifiedascriticaltoproductquality?Whatscale-upexperiencedoesthesponsorhavewiththeunitoperationsinthisprocess?,QBR:RiskSummary,NTIdrugClassifiedasanon-NTIdrug,riskscore=+0ClassifiedasanNTIdrug,riskscore=+1DosageFormSimpleDosageForm,riskscore=+0OtherDosageFormsandNTIdrugs,riskscore=+1DevelopmentReportIfthesponsorsubmitsadevelopmentreportthataddressestheFDAsquestions:Riskscore=+0SolutionandIRProducts:ProductDevelopmentReportOtherDosageForms:ProductandProcessDevelopmentReportsInsufficientormissingdevelopmentreport,riskscore=+1IftheapplicationisofhighoverallqualityLessthanorequalto2cycles,riskscore=+0.Greaterthan2cycles,riskscore=+1,QBR:Risk-BasedConclusion,Shouldtheapplicationbeapproved?Whatpost-approvalwaivers/commitmentsareappropriateforthisproduct?Ifthetotalriskscoreislessthanorequalto1CBE0andCBE30changesmaybeinannualreportsManyPAStoCBE30Ifthetotalriskscoreisgreaterthan1Allsupplementsshouldbesubmittedasusual,生物等效性豁免,生物等效性豁免是指基于体外数据审批的管理程序。固体制剂往往采用溶出度、释放度作为证据。,I、基于药物剂型的生物等效性豁免,只有供试品和参比制剂的原料及其含量一致，辅料一致、用量相当，且符合如下规定时，可生物等效性豁免：1、注射液；2、口服溶液，含量一致，且不含已知会影响胃肠道功能和主药稀释的辅料；3、气体；4、溶液散剂；5、耳用或眼用溶液；、6、外用溶液；7、采用同样装置使用的吸入剂或鼻喷剂。,II、基于剂型剂量比例的生物等效性豁免,当最高剂量的BE数据具备时，下列情况可生物等效性豁免：1、同样的剂型；2、主药和辅料的比例相当；3、对于缓释制剂，同样的释放机制；4、