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30June2012EMA/CHMP/CVMP/QWP/199250/2009corrCommitteeforMedicinalProductsforHumanUse(CHMP)/CommitteeforMedicinalProductsforVeterinaryUse(CVMP)Guidelineonsettingspecificationsforrelatedimpuritiesinantibiotics抗生素中相关杂质质量标准制定的指导原则Final定稿DraftAgreedbyQualityWorkingParty2010年5月质量工作中批准草案May2010AdoptionbyCHMPforreleaseforconsultation2010年6月24日被人用药委员会采纳，公布征求意见稿24June2010AdoptionbyCVMPforreleaseforconsultation2010年7月15日被兽用药委员会采纳，公布征求意见稿15July2010Endofconsultation(deadlineforcomments)2011年1月31日结束征求意见31Jan2011AgreedbyQualityWorkingParty2012年5月质量工作组批准May2012AdoptionbyCHMP2012年5月14日被人用药委员会采纳14May2012AdoptionbyCVMP2012年6月14日被兽用药委员会采纳14June2012Dateforcomingintoeffect2013年6月30日生效30June2013学习之名（译注）Tableofcontents目录Executivesummary1.Introduction(background)2.Scope3.Legalbasis4.Generalrequirements5.Impurityprofilingandreporting,identificationandqualificationthresholds6.Newapplicationsandvariations7.Specificationsformedicinalproducts8.AnalyticalproceduresDefinitionsAnnex1:Explanatorynoteregardingthresholds.Annex2:ThresholdsAnnex3:Exampleof“fingerprintchromatogram”approachtocontrolverycompleximpurityprofiles概要1、背景介绍2、范围3、法规依据4、一般要求5、杂质分布以及报告、鉴别和界定阈值6、新申请和变更7、制剂产品质量标准8、分析方法定义附件1：关于阈值的注释附件2：阈值附件3：利用基于“指纹图谱”的方法对非常复杂的杂质分布进行控制举例Executivesummary概要Antibioticsactivesubstancescurrentlyonthemarketareproducedbyfermentation,byfermentationfollowedbyoneormoresyntheticsteps(semi-syntheticsubstances)orbychemicalsynthesis.Fermentationprocessesare,incomparisontosyntheticprocesses,morevariableandlesscontrollable,sotheimpurityprofileofanactivesubstancewhosemanufacturingprocessinvolvesfermentationmaybemorecomplexandlesspredictablethanthatofapurelysyntheticproduct.Forthisreasonfermentationproductsandsemi-syntheticsubstancesarenotincludedinthescopeoftheICHQ3andtheVICHGL10/GL11guidelines,whichsetthresholdsfortheidentification,reportingandqualificationofrelatedimpuritiesinactivesubstancesmanufacturedbychemicalsynthesis.目前上市的抗生素类活性物质是由发酵、发酵加一步或几步合成步骤（半合成）、化学合成制得。与合成工艺相比，发酵工艺更具多变性，不易控制，因此与单纯使用化学合成生产的产品相比，生产工艺含有发酵步骤的活性物质的杂质分布一般比较复杂和难以预测。基于此原因，发酵产品和半合成产品并不适用于ICHQ3和VICHGL10/GL11指南。因为这两个指南适用于由化学合成生产的活性物质。Thisguidelinehasbeendevelopedinordertoprovideguidanceonhowspecificationsforrelatedimpuritiesinantibioticsthatarefermentationproductsorsemi-syntheticsubstancesderivedfromfermentationproducts,andarethereforenotincludedinthescopeofthe(V)ICHguidelinesmentionedabove,shouldbeset.本指南旨在为不适用于ICHQ3指南的发酵产品或源于发酵产品的半合成物质中杂质质量标准的设定提供指导。Thresholdsaregivenintheguidelineforreporting,identificationandqualificationofrelatedimpuritiesforantibioticsmedicinalproductswhoseactivesubstanceisproducedbyfermentationorsemi-synthesis.Incaseswheretheactivesubstanceconsistsofamixtureofcloselyrelatedcompounds,whereitmaybedifficulttoapplygeneralthresholds,generalguidanceisgivenonhowtosetspecificthresholdsandspecificationsandonhowtoqualifyimpurityprofiles.TherelationshipsbetweentherequirementsintheguidelineandtheapplicablePh.Eur.chaptersandmonographsarealsoaddressed.对于活性成分为发酵或半合成来源的抗生素制剂产品的相关杂质，本指南给出了报告、鉴定和界定阈值。在活性物质由多个密切相关的化合物混合组成情况下，对其应用一般的阈值存在困难。针对此，本指南就如何设定阈值和如何论证杂质分布给出了指导。对于本指南与欧洲药典要求的关系，本指南也做了阐述。注：界定限（界定阈值）：指超过该限度的杂质需进行论证，包括安全性、设定的限度合理性等。1.Introduction(background)背景介绍Mostoftheantibioticscurrentlyonthemarketareproducedbyfermentationorchemicalsynthesis.Incertaincasesthechemicalstructureoftheantibioticsobtainedbyfermentationisfurthermodifiedbysomesyntheticsteps,beforethesubstanceisusedasanactivesubstanceinthemanufactureofmedicinalproducts(semi-syntheticsubstances).目前市售的大多数抗生素是由发酵或化学合成生产的。一些情况下，由发酵生产的抗生素在可用作生产制剂的活性成分前，其结构会经过一些合成步骤进行修改（半合成物质）Fermentationprocessesinvolvebiologicalsystemswhicharelesspredictable,lesscontrollableandmorecomplexthanstraightforwardchemicalreactions.Becauseofthis,thevariabilityinproductsderivedbyfermentationisoftengreaterthaninproductsderivedbychemicalsynthesis.Thus,theimpurityprofileofafermentationproductmaybemorecomplexandlesspredictablethanthatofasyntheticproduct.与直接化学方应相比，发酵工艺包含不易预测、控制和复杂的生物系统，发酵产品比化学合成产品更具多变性。因此，发酵产品的杂质分布会比化学合成产品的更复杂和不易预测。Forthisreason,fermentationproductsandsemi-syntheticsubstancesderivedfromthemarenotincludedinthescopeoftheICHQ3andtheVICHGL10/GL11guidelinesthatsetthresholdsfortheidentification,reportingandqualificationofrelatedimpuritiesinactivesubstancesmanufacturedbychemicalsynthesis.Thesethresholdsaredefinedintheguidelinesaslimitsabovewhichanimpurityhastobeeitheridentified,reportedorqualified,andthesamelimitsareappliedinthePh.Eur.generalmonograph‘SubstancesforPharmaceuticalUse’.Fermentationproductsandtheirsemisyntheticderivativesarealsoexcludedfromthescopeofthisgeneralmonograph.基于此，发酵产品和源于发酵产品的半合成物质并不适用于ICHQ3和VICHGL10/GL11。这两个指南旨在为化学合成物质的鉴别、报告和界定阈值提供指导。依据这两个指南设定的阈值也适用于欧洲药典总论“药用物质”。发酵产品和基于发酵产品的半合成物质并不适用于总论。Intheabsenceofotherguidance,relatedimpuritiesintheseproductshavebeenassessedonacase-by-casebasis,whichhasresultedintheacceptanceofdifferentimpuritythresholdsforthesameantibioticandfordifferentcompoundswithinthesameclass(e.g.cephalosporins).Thereisalsoaneedtoensurethattheauthorisationofnewantibioticsisenabledbyconsistentapproachesinsettingli