摘要药品生产的供应链全球化正在变得越来越复杂，药品质量和安全性风险相应的也在急剧增加。越来越多的关注和资源都在不断的集中于确保物料的安全性、真实性和完整性。原料药作为药品中的主要活性组分，正在受到越来越严格的控制。然而，在原料药当中，发酵来源的原料药因其复杂的发酵源杂质组成一直是生产企业质量控制和药政机构文件审评的难点。欧洲药品管理局近期发布的指南《抗生素中相关杂质的质量标准设定》[1]正式版为这类原料药的质量控制提供了法规依据，填补了现行法规的空白。人用药品注册技术要求国际协调委员会发布的指南《Q11原料药的研发与生产》[2]为企业从质量源于设计角度理解原料药的研发、生产和注册文件编写提供了指导。深入的研读这类指南以及现有的药品主文件将会对今后此类原料药的文件编写提供具有实际操作意义的帮助。和合成工艺相比，发酵工艺更加易变和不受控。因此，工艺中存在发酵步骤的原料药其杂质属性也更加复杂和难以预测。ICHQ3A[3]、Q3C[4]、VICHGL10[5]和GL11[6]等指南对原料药中杂质的含量和界定的申报提供了指导，但是这些指南明确指出其不涵盖发酵和半合成产品。欧洲药典通则《2034》[7]章节也针对原料药中杂质的含量和界定的申报提供了类似的依据，但是同样声明其不适用于上述类型的产品。本文从近期欧洲药品管理局发布的指南《抗生素中相关杂质的质量标准设定》入手，结合近两年国际主流药政机构发布的其他指南以及近期通过官方审评的药品主文件及其审评意见，从质量源于设计的角度对官方审评特点进行探究,为国内企业的药品主文件编写提供较为科学的、切合实际的指导。关键词：药物主文件；原料药；质量源于设计；风险QbD-BasedDMFReviewingAspectsofEUandUSAgenciesforFermentation-DerivedDrugSubstancesThesupplychainofdrugproductiongrowsincreasinglycomplex,andtheriskstodrugqualityandsafetycorrespondinglyproliferate,moreattentionandresourcesarebeingfocusedonsecuringthematerialsandassuringtheirauthenticityandintegrityastheymaketheirwaythroughthesupplychain.Asthemajoractivesubstanceofdrugproduct,APIsaremonitoredmoreandmorestrictly.However,thereisonetypeoffermentation-derivedactivesubstanceswhichhavecompleximpuritiescomponentsandarealwaystheblackspotsforbothqualitycontrollingofmanufacturerandDMFreviewingofagencies.ThefinalGuidelineonSettingSpecificationsforRelatedImpurities,recentlyissuedbyEMAprovidebasisfortheirqualitycontrolandfilledtheguides’bank.ICHreleasedQ11DevelopmentandManufactureofDrugSubstances,whichhelpthemanufacturertounderstandthedevelopment,manufacturingandregulatorysubmissionofAPIfromQbDaspects.ItisnecessarytodeeplyunderstandtheseassociatedguidesandsubmittedDMF/ASMF,whichwouldgiveuspracticalhelptocompiledocumentationinfuture.Comparedtosynthesisprocess,fermentationprocessesaremorevariableandlesscontrollable,sotheimpurityprofileofanactivesubstancewhosemanufacturingprocessinvolvesfermentationmaybemorecomplexandlesspredictable.ICHQ3andtheVICHGL10/GL11guidelinessetthresholdsfortheidentification,reportingandqualificationofrelatedimpuritiesinactivesubstances,however,theseguidelinesclearlyindicatethatfermentationproductsandtheirsemisyntheticderivativesareexcludedfromtheguidescope.ThesimilardefinitionsforexcludedsubstancesaredescribedinthePh.Eur.generalmonograph2034‘SubstancesforPharmaceuticalUse’.Thispaperfocusedontheguidelinesissuedrecentlybymainregulatoryorganizations,basedonthesubmittedDMF/ASMFandassessmentopinionsofagenciestothem.Itattemptstoexplorethereviewcharacteristicsofagencies,furtherprovidescientificandpracticalguidancetodomesticmanufacturerforDMFcompiling.Keywords:DrugMasterFiles,DMF,API,QbD，RiskAssessment目录第1章综述....................
