美欧原料药注册文件与GMP规范要求

1美欧原料药注册文件与GMP规范要求上海加中生物技术ShanghaiNovoScience加拿大新科咨询NovoScienceConsulting执行总裁程毓渡博士ExecutiveManagerDr.FrankCheng程毓渡博士（程毓渡博士（Dr.FrankChengDr.FrankCheng）在北美制药领域拥有十几年）在北美制药领域拥有十几年学习、研究与工作经历，先后在美国学习、研究与工作经历，先后在美国JOHNSHOPKINSJOHNSHOPKINS大学、加大学、加拿大国家科学院生物技术研究所、加拿大新科药业、加拿大拿大国家科学院生物技术研究所、加拿大新科药业、加拿大生化制药、日本第一制药等著名大学、研究所、制药企业工生化制药、日本第一制药等著名大学、研究所、制药企业工作合作与交流在原料药仿制药创新药开发生产与作合作与交流在原料药仿制药创新药开发生产与程毓渡博士程毓渡博士美欧美欧GMPGMP审计审计//培训培训//咨询高级专家咨询高级专家加拿大新科咨询加拿大新科咨询//上海新科咨询上海新科咨询作、合作与交流，在原料药、仿制药、创新药开发、生产与作、合作与交流，在原料药、仿制药、创新药开发、生产与市场准入规范方面具有广泛的专业知识，建立了作为现代市场准入规范方面具有广泛的专业知识，建立了作为现代GMPGMP规范基础的科学思维和验证技能。作为一个在中国工作的加规范基础的科学思维和验证技能。作为一个在中国工作的加籍华人专家，程毓渡博士自籍华人专家，程毓渡博士自20042004年以来在中国成功策划和主年以来在中国成功策划和主持了包括美欧持了包括美欧GMPGMP实施到文件注册在内的十几次美欧实施到文件注册在内的十几次美欧GMPGMP高级高级培训，同时受美欧厂商委托对数十家中国药厂进行了现场培训，同时受美欧厂商委托对数十家中国药厂进行了现场GMPGMP审计，零距离考察国内药厂在审计，零距离考察国内药厂在GMPGMP方面的现状。他主讲的美欧方面的现状。他主讲的美欧GMPGMP规范规范系统培训课程，系统培训课程，受到包括浙江海正药业等受到包括浙江海正药业等国内国内著名外著名外向型向型药企高度评价和热烈欢迎药企高度评价和热烈欢迎!!培训内容提要培训内容提要11--美欧化学原料药注册申请的相关法规要美欧化学原料药注册申请的相关法规要求（求（CTDCTD文件格式）文件格式）求（求（CTDCTD文件格式）文件格式）22、美欧原料药、美欧原料药DMFDMF文件的编写及审评制文件的编写及审评制度（度（CEPCEP证书申请评审）证书申请评审）33、美欧、美欧GMPGMP解读与实施（解读与实施（ICHQ7ICHQ7导读）导读）第一部分美欧化学原料药注册申请的相美欧化学原料药注册申请的相关法规要求（CTD文件格式）•EDMFcompilationinCTDformat:•a)Module3.2.S.DrugSubstance•b)Module2.3QualityOverallSummaryTechnicalRequirements•CEPProcedureversustheDMFProcedure•FilingstrategiesinEUcountries•CertificationofsuitabilitytothemonographsoftheEuropeanPharmacopoeia•Procedure,SubmissionoftheDossier,ContentoftheDossier/ExpertReport,Assessment,Timetable,Follow-upModule3.2.SDrugSubstance•3.2.S.1General•3.2.S.2Manufacture•3.2.S.3Characterisation•3.2.S.4ControlofDrugSubstance•3.2.S.5ReferenceStandards•3.2.S.6ContainerClosure•3.2.S.7Stability23.2.S.1GeneralInformation•3.2.S1.1Nomenclature•RecommendedInternationalProprietaryName(rINN)•Compendial(e.g.EuropeanPharmacopoeia)ifp(gpp)relevant•OtherNationalapprovednames(e.g.USAN,JAN)•SystematicChemicalName(IUPACnomenclature)•CompanyorlaboratoryCode•Chemicalabstractservice(CAS)registrynumber(RN)3.2.S.2Manufacture•3.2.S2.1Manufacturer•Nameandaddress•Responsibilityofeachmanufacturer•Eachproposedsiteoranysubcontractorinvolvedinmanufacturingandtesting3.2.S.2Manufacture•3.2.S2.2DescriptionoftheManufacturingProcessandProcessControls•ScaleofManufacture,Range,Yield:•Processdescriptionshouldindicatescaleofmanufactureandrangeforwhichtheconsideredprocessmaybeused•Alternativeprocesses:•Explanationandjustificationprovidingsufficientevidencethatfinalproductqualityremainsunchanged•Reprocessing:•Identificationandjustificationofcaseswhenreprocessingiscarriedout.3.2.S.2Manufacture•3.2.S2.3Controlofmaterials:•ActiveSubstance(AS)startingmaterial(SM)shouldbejustifiede.g.significantstructuralfragment(AS)•NameaddressofSMsupplierorsyntheticprocesspriortotheNameaddressofSMsupplierorsyntheticprocesspriortotheintroductionoftheSM•SMfullycharacterizedtoacertainsuitability•SpecificationandacceptancecriteriaofimpuritiesintheSMwithsuitablyvalidatedmethods•Relevantviralsafetyand/orTSEdataprovidedincaseofanimalderivedmaterial(e.g.fermentation,enzymes,aminoacidsetc.)•SolventsandprocessingaidsusedinthefinalstepspecificationsSchematicdescriptionSM1SM2catalystSolventAS3.2.S.2Manufacture•3.2.S2.5ProcessValidation:•Criticalstepsshouldbevalidated•32S26Manufacturingprocessdevelopment•3.2.S2.6Manufacturingprocessdevelopment•Descriptionanddiscussion33.2.S.3Characterisation•3.2.S3.1ElucidicationofStructureandotherCharacteristics:•Evidenceofchemicalstructure:•Elementalanalysis,IRspectra,NMR,MS,UVspectray,p,,,p•Evidenceofstructureofkeyintermediates,X-Raychristallography,opticalrotation•Physico-chemicalCharacteristics:•Polymorphism,Meltingpoint,DSC•Solubility•pKaandpHvalues3.2.S.3Characterisation•3.2.S3.2Impurities:•Informationonimpurities•Relatedsubstancesconsideredaspotentialimpuritiesarisingfromthesynthesisshouldbediscussed,indicatingorigin•Discussionofpossibleroutesofdegradation•Analyticalmethods(LODandLOQ)3.2.S.4ControloftheActivesubstance•3.2.S4.1Specification:•Description•Identification•Impurities•Assay•Additionaltests•Reference:•ICHQ3（R2）(ImpuritiesControl)•ICHQ6（Specification)3.2.S.4ControloftheActivesubstance•3.2.S4.2AnalyticalProecedures•Detailsoftheanalyticalprocedures•3.2.S4.3ValidationofAnalyticalProceduresRftlidtifltilthd(ICH381/95•Referencetovalidationofanalyticalmethods(ICH381/95andICH281/95);resultsandexempl.chromatograms•3.2.S4.4BatchAnalysis•Descriptionofbatchesandresultsofbatches•Analyticalresultsfrom3representativebatches(NLT10%ofmaximumcommercialbatchsize)•Resultsshouldinclude:Dateofmanufacture,batchsizeandbatchnumber,placeofmanufacture,resultsofanalyticaltest,useofbatches3.2.S.4ControloftheActivesubstance•3.2.S4.5JustificationofSpecification•SeeNoteforGuidanceonSpecification,impuritytestingguideline,residualsolvents•3.2.S5ReferenceStandardsorMaterials•Specifications,fullanalyticalandphysico-chemicalcharcterisation,impuritiesetc.•Referencesubstances(primaryandsecondary)incl.fullanalytical•3.2.S6ContainerClosureSystem•Descriptionofbulkstoragecontainerclosure•Specificationofprim