原料药国际注册专题培训

努力每一天原料药国际注册专题培训201703中国杭州2017.03中国杭州目录第01章：DMF分类概述第02章：DMF工艺部分撰写第03章DMF设备部分撰第03章：DMF设备部分撰写第04章：DMF物料部分撰写第05章：FDA关于原料药的审评法规第05章：FDA关于原料药的审评法规第06章：国内外原料药注册制度区别分析第07章：EDQM原料药变更指南要点介绍第章原料药变更指南要点介绍第08章：国内原料药工艺变更要点介绍第09章：工艺验证要点解析原料药国际注册专题第01章：DMF分类概述1.1-美国DMF制度概述1.2-EUDMF制度概述1.3-WHODMF制度概述原料药国际注册专题1.1-美国DMF制度概述根据FDA官方培训资料，DMF是一份文件，其包含申报者的技术信息，允许FDA审核以支持第三方的申报，而不向第三方透漏相关信息。因此说，美国DMF整体都是保密文件。DMFsusuallycovertheChemistry,ManufacturingandCtl(CMC)ftfddtControls(CMC)ofacomponentofadrugproducte.g.drugsubstance,excipient,packagingmaterial.原料药国际注册专题美国DMF共包括5类DMF，目前主要类型如下：IIDrugsubstance,drugproduct,intermediatesandmaterialusedintheirmanufactureIIIPackagingIVExcipientsVOther-杂类原料药国际注册专题关于V类DMF，要求如下---Mustfirstsubmitaletterofintentfor“pre-clearance”byFDAtofile当申报如下信息时，必须预先向FDAD递交一封信以获得许可Cliil临床-Clinical临床-Toxicology毒理---Maybefiledwithoutsubmissionofletterofintent直接递交先说可以直接递交而不预先说明-Sterileprocessingfacilities无菌工艺厂房信息-Biotechmanufacturingfacilities生物制造厂房信息---Informationaboutthesefacilitiescan,likeanyothertypeofinformation,besubmitteddirectlyinanNDAorANDA在NDA/ANDA申报中，关于厂房信息，也可能是其他类型信息，可以直接递交交。DMF相关的角色分配DMF相关法规DMF申报数量分布原料药国际注册专题问题-是否必须申报DMF。答案：不是。---ThereisnolegalorregulatoryrequirementtofileaDMF.InformationcanbeinanApplicationORaDMF.---ADMFmaybefiledtoprovideCMCinformationthattheFDAreviews.Examples:drugsubstance,noveliitexcipient---Conversely,thereisnoneedtofileaDMFforinformationthatFDAdoesnotreviewinformationthatFDAdoesnotreview原料药国际注册专题问题：什么情况下，没有必要递交DMF？答案：NllthCMCfdiliit(litd---NormallytheCMCforacompendialexcipient(qualitycoveredbyUSPorNFmonograph)isnotreviewed---CMCformanypackagingmaterials(SeeMaPP5015.5CMCypgg(ReviewsofTypeIIIDMFsforPackagingMaterials)因为可以包含在药品申报资料中CMCfdbtdiOthCt(OTC)---CMCfordrugsubstancesusedinsomeOver-theCounter(OTC)drugproductsisnotreviewed原料药国际注册专题1.2-EUDMF制度概述欧盟DMF制度晚于美国FDA的DMF制度。以前称为EDMF，现在都称为ASMF；从名称上看，ASMF主要适用于API。ASMF分为公开部分和保密部分；公开部分递交给制剂客户。保密部分和公开部分一起递交给负责审评的官方。原料药国际注册专题原料药国际注册专题1.3-WHODMF制度概述在WHO的PQ中，APIMF文件申报流程有3种：---FullAssessment‒APIMFNotPreviouslyAssessed---AbbreviatedAssessmentofanAPIMFPreviouslySubmittedtoWHOUsingAPIMFProcedure---AbridgedAssessmentofanAPIMFPreviouslyApprovedbyanAuthorityapplyingstringentstandards原料药国际注册专题申报文件要求thecoveringletter(paperformat)lblldCDDVDtiialabelledCDorDVDcontaining•thecoveringletter(inWordortext-selectablePDF(portabledocument)format)•acompletedAPIprequalificationapplicationform(inbothWordandPDFft)format)•theAPImasterfile(APIMF)correctlyformatted(seebelow,HowtoorganizetheAPIMFforafullassessment)asitemasterfile(SMF)foreachmanufacturingsite(WordortextselectablePDF)•asitemasterfile(SMF)foreachmanufacturingsite(Wordortext-selectablePDF)•evidenceofcompliancewithWHOGoodManufacturingPractices(GMP),orarequestforinspectionbyWHOforeachmanufacturingsite(Wordortext-selectablePDF)selectablePDF).原料药国际注册专题根据WHOTRS948的Annex4《Guidelinesonactivepharmaceuticalingredientmasterfileprocedure》。APIMF分为公开部分和保密部分。分为公开部分和保密部分。公开部分一般包括如下内容：GeneralinformationMftManufactureCharacterizationControlofAPIReferencestandardsormaterialsContainerclosuresystemStabilityStability原料药国际注册专题保密部分（Restrictedpart）一般包括如下内容：ManufactureCharacterizationControlofAPI原料药国际注册专题第02章：DMF工艺部分撰写本部分以EDQMCTD要求为依据讲述。《Contentofthedossierforchemicalpurityandmicrobiologicalquality》201508版，文件编号是PA/PH/CEP(04)15R(04)1,5R。原料药国际注册专题Manufacture(3.2.S.2)Manufacturer(s)(3.2.S.2.1):Namesandaddressesofeachmanufacturerinvolvedinthemanufacturingprocessfromtheintroductionofttitil()tthfilbthldblitdstartingmaterial(s)tothefinalsubstanceshouldbelistedintheapplicationandtheirroleexplained.原料药国际注册专题DescriptionofmanufacturingprocessandProcessControls(3.2.S.2.2):ApplicantsareremindedthattherequirementsofthegeneralApplicantsareremindedthattherequirementsofthegeneralmonographsGM1468andGM1483shouldberespectedwhenapplicable.原料药国际注册专题Thefollowinginformationshouldbesupplied:—Anoutlineorflowdiagram,includingthestructuralformulaforthestartingmaterialsandallintermediatesaccompaniedbyallthestartingmaterialsandallintermediates,accompaniedbyallsolvents,reagentsandcatalystsusedintheprocess,—Thedescriptionofthemanufacturingmethodshouldincludeallthestepsoftheprocess,proceedingfromthestartingmaterials(s)toanyisolatedintermediates,andultimatelytothefinalsubstance.原料药国际注册专题—DetaileddescriptionofeachstageofthemanufactureincludingDetaileddescriptionofeachstageofthemanufacture,includinginformationonsolventsandreagents,catalysts,conditionsofreactions,informationonintermediates,whichareisolatedandpurified,quantitiesofallmaterialsusedintheprocesstoproduceabatchofthetypicalilidildfiltditdithldbiditdcommercialsizeandyieldsforisolatedintermediatesshouldbeindicatedforeachprocessstep.Specialemphasisshouldbegiventothefinalstepsincludingpurificationprocedures.—Themaximumbatchsize(orrange)forwhichthemanufacturerhas(g)acquiredexperiencewiththedefinedmethod,andwhichshouldcorrespondtobatchesreferredtointhedossier,shouldbestated.Wherethesubstancehasyettobeproducedincommercialquantities(onlypilotscalebatchesmanufactured)thecertificatecanbegrantedprovidedscalebatchesmanufactur