抗生素中相关杂质质量标准制定的指导原则

1、EUROPEANMEDICINESAGENCYSCIENCEMEDICINESHEALTH30June2012EMA心HMP心VMP/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DraftAgreedbyQualityWorki

2、ngParty2010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May2012Adoptio

3、nbyCHMP2012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目录概要背景介绍范围法规依据一般要求杂质分布以及报告、鉴别和界定阈值新申请和变更制剂产品质量标准分析方法定义附件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ExecutivesummaryIntroduction(background)ScopeLegal

4、basisGeneralrequirementsImpurityprofilingandreporting,identificationandqualificationthresholdsNewapplicationsandvariationsSpecificationsformedicinalproductsAnalyticalproceduresDefinitionsExplanatorynoteregardingthresholds.ThresholdsExampleof“fingerprintchromatogram”approachtocontrolverycompleximpuri

5、typrofilesExecutivesummary概要Antibioticsactivesubstancescurrentlyonthemarketareproducedbyfermentation,byfermentationfollowedbyoneormoresyntheticsteps(semi-syntheticsubstances)orbychemicalsynthesis.Fermentationprocessesare,incomparisontosyntheticprocesses,morevariableandlesscontrollable,sotheimpurityp

6、rofileofanactivesubstancewhosemanufacturingprocessinvolvesfermentationmaybemorecomplexandlesspredictablethanthatofapurelysyntheticproduct.Forthisreasonfermentationproductsandsemi-syntheticsubstancesarenotincludedinthescopeoftheICHQ3andtheVICHGL10/GL11guidelines,whichsetthresholdsfortheidentification

7、,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。Thisguidelinehasbeende

8、velopedinordertoprovideguidanceonhowspecificationsforrelatedimpuritiesinantibioticsthatarefermentationproductsorsemi-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

9、导。Thresholdsaregivenintheguidelineforreporting,identificationandqualificationofrelatedimpuritiesforantibioticsmedicinalproductswhoseactivesubstanceisproducedbyfermentationorsemisynthesis.Incaseswheretheactivesubstanceconsistsofamixtureofcloselyrelatedcompounds,whereitmaybedifficulttoapplygeneralthre

10、sholds,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

11、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。Introduction(background)背景介绍Mostoftheantibioticscurrentlyonthemarketareproducedbyfermentationorchemicalsynthesis.Incertaincasesthechemicalstructureoftheantibioticsobtainedbyfermentationisfurthermodi

12、fiedbysomesyntheticsteps,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,lesscontrollableandmorec

13、omplexthanstraightforwardchemicalreactions.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

14、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,reportingandqualificationofrelatedimpuritiesinactivesubstancesmanufacturedbychem

15、icalsynthesis.Thesethresholdsaredefinedintheguidelinesaslimitsabovewhichanimpurityhastobeeitheridentified,reportedorqualified,andthesamelimitsareappliedinthePh.Eur.generalmonographSubstancesforPharmaceuticalUse.Fermentationproductsandtheirsemisyntheticderivativesarealsoexcludedfromthescopeofthisgene

16、ralmonograph.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,whichhasresultedintheacceptanceofdifferentimpuritythresholds

17、forthesameantibioticandfordifferentcompoundswithinthesameclass(e.g.cephalosporins).Thereisalsoaneedtoensurethattheauthorisationofnewantibioticsisenabledbyconsistentapproachesinsettinglimitsfortheirimpurities.在以前没有其他指南的条件下，这些产品中的杂质是基于个案进行评估的，这就导致同一抗生素或同类下不能化合物有不同的杂质阈值。在批准新抗生素时也需要采用一致的方法来设定杂质限度。Itisth

18、ereforenecessarytoprovideguidance,basedoncurrentpracticeandexperience,toformulategeneralrecommendationsforimpuritythresholdsinantibioticsproducedbyfermentationorsemisynthesis.Thesearepresentedinthisguideline.因此，有必要基于目前的实践和经验，为发酵或源于发酵的半合成产品中杂质阈值设定提供指南。Evenso,itisacknowledgedthatinsomecaseshigherthres

19、holdsmaybeacceptableifnecessaryandjustifiedtakingaccountofuseandexposureofthedrugsubstance/product.Thiswouldalsoincludeanalyticalproblems(seeAnnex1:Explanatorynoteregardingthresholds).尽管如此，若考虑到药品的使用和用量，如果需要，采用较高的阈值也是可以接受的。见附件1：关于阈值的注释Scope范围Thisdocumentprovidesguidanceformarketingauthorisationapplic

20、ationsonsettingspecificationsforrelatedimpuritiesinantibiotics(i.e.antibacterialsubstances)thatarefermentationproductsorsemisyntheticsubstancesderivedfromfermentationproducts.Itisforeseentowidenthescopetootherantibiotics(e.g.antifungalsubstances)atalaterstage.本指南为源于发酵产品或源于发酵产品的半合成抗生素(例如抗菌物质)申请销售许可时，

21、提供相关杂质质量标准的设定指导。可以预见，后续本指南适用范围会进一步扩展(例如抗真菌物质)。Itprovidesguidanceforthecontentandqualificationofrelatedimpuritiesinbothactivesubstancesandmedicinalproducts.Theguidelineisnotintendedtoapplytonewactivesubstancesusedininvestigationalmedicinalproductsusedinclinicaltrials.可为活性物质和制剂中相关杂质的含量和界定提供指导。本指南不适用于处

22、在临床试验阶段的研究用活性物质。Inthisguidelinethresholdsaregivenforreporting,identificationandqualificationofrelatedimpurities.Forantibioticswheretheactivesubstanceconsistsofamixtureofcloselyrelatedcompoundswhereitmaybedifficulttoapplythesegeneralthresholds,generalguidanceisgivenonhowtosetthresholdsandspecificatio

23、nsandhowtoqualifyimpurityprofiles.Thethresholdsgiveninthisguidelinewouldrepresentageneralsetofrequirements,andthiscouldbesubject,forspecificsubstancesorproducts,toadaptationtothespecificsituation.Furtherrequirementsmightbeintroducedwhenconsiderednecessary,e.g.forsafetyreasons.本指南中给出了相关杂质的报告、鉴定和界定阈值。

24、对于活性物质为相近的化合物混合组成的抗生素，由于采用一般的阈值存在困难，指南给出了如何设定阈值和质量标准以及如何确定杂质分布的通用指导。本指南中给出的阈值代表一般的设定要求，对于特定的物质，需要根据特定情况进行调整。若需要，可将其他要求考虑在内，如安全因素。Thisguidelinedoesnotcoverresiduesfromthefermentationprocess,i.e.residuesfromtheproducermicro-organism,culturemedia,substratesandprecursors;thisiscoveredbythePh.Eur.general

25、monographProductsoffermentation.(Thismonographappliestosubstancesmanufacturedbyfermentationonly,andnottosubstancesmanufacturedbysemi-synthesis).本指南不包括发酵过程的残留，如生产菌株、培养基、基质和前体。这些残留依据欧洲药典总论“发酵产品”进行控制。此总论仅适用于发酵生产的产品，不包括半合成生产的产品。Thisguidelineappliestonewactivesubstancesandfornewsourcesofexistingactivesub

26、stances.ItistheApplicantsresponsibilitytodemonstratethattheactivesubstancehasalreadybeenmarketedintheEUwhenrelevant.本指南适用于新活性物质或新来源的已存在活性物质。需要时，申请者需说明该物质是否已在欧洲上市。Theguidelineshouldnotbeappliedretrospectively,butitisintendedthatthisguidelinewillactasastimulustoestablishbestpracticeandtoinitiatetherev

27、isionofrelevantPh.Eur.monographs(i.e.forregisteredproductsrevisedrequirementsaccordingtothemonographwillapplywhenthemonographisintroduced/revised).FornewsourcesofexistingactivesubstancesthisguidelineshouldbereadinconjunctionwithanyexistingPh.Eur.monographfortheactivesubstance.Itshouldbenotedthatcomp

28、arisonwithimpuritylevels/profilesofactivesubstancesourcesorproductsapprovedintheEUisoneoftheoptionsforqualifyingimpurities.本指南不可回顾性使用注：不适用于已完成注册上市销售的产品，但可作为建立最佳实践或推动欧洲药典专论修订的刺激因素(例如，对已注册的产品，当增加了某专论或修订了某专论，需依据情况进行修订)。对于新来源的已存在的活性物质，本指南阅读时需要结合相应的药典准了。需要指出的是，与已在欧洲批准上市的活性物质或制剂进行杂质分布对比，是一个确定杂质分布的方法。Itisf

29、oreseentore-evaluatetheScopewhenmoreexperiencehasbeenobtained.Legalbasis法规依据Thisguidelinehastobereadinconjunctionwiththeintroductionandgeneralprinciples(4)andpart1oftheAnnexIstoDirectives2001/82/ECand2001/83/ECasamended.Generalrequirements一般要求Theimpurityprofiledependsverymuchonthemanufacturingproces

30、s;evenforthesamestrainofamicro-organism,impurityprofilesmaybedifferent.Ingeneral,purificationstepsincludingcolumnchromatographyandultra-filtrationstepsmaybecrucialtoachieveasufficientlypureactivesubstance.杂质分布与生产工艺密切相关；甚至同一微生物生产产品的杂质分布也有不同。一般来说，纯化步骤包括柱层析和超滤，对获得一个纯品至关重要。Semi-syntheticsubstancesarenot

31、withinthescopeofthePh.Eur.generalmonographProductsoffermentation.However,thespecificationofthefermentedstartingmaterialshouldbejustifiedwithreferencetocurrentguidance,includinggeneralconceptsdescribedinthisgeneralmonograph,ifnecessary.(Thethresholdsinthisguidelinearenotintendedtoapplyforfermentedsta

32、rtingmaterials).半合成物质不在欧洲药典总论“发酵产品”要求范围内。然而，如果需要，半合成产品的源于发酵的起始物料质量标准应当满足总论“发酵产品”要求。(本指南中的阈值不适用于源于发酵的起始物质注：指半合成产品的起始物料)Theshorterthesyntheticrouteafterthefermentationandthemorecomplexthefermentedstartingmaterial,themorerelevancethegeneralmonographhas.Therefore,adetaileddescriptionofthefermentationste

33、psaswellasotheraspectsaddressedinthegeneralmonograph,inparticularpurificationsteps,shouldbepresentedforsemi-syntheticantibiotics,unlessjustifiedbythenoncomplexityofthefermentedstartingmaterialandthenumberand/ornatureofthesyntheticstepsfollowingfermentation.发酵后合成工艺越短、源于发酵的起始物料越复杂，越适用于药典总论“发酵产品”要求。因此，

34、对于半合成抗生素，应详细描述发酵工艺和总论中要求的其他方面，尤其是纯化步骤，除非有源于发酵的起始物料不复杂和发酵后的合成工艺的证明。Thesesyntheticstepsshouldcontributetoarelevantdepletionandinactivationoffermentationbyproductsinthefinalactivesubstance,soforexample,esterification,etherificationandsalificationoffermentationproducts(e.g.,erythromycinderivativeslikeer

35、ythromycinethylsuccinateorerythromycinlactobionate)arenotconsideredassignificantsyntheticstepswhichwouldjustifyanomissionofadetaileddescriptionofthefermentationprocess,inparticularofthepurification.合成步骤应当可以在一定程度上消耗或使发酵副产物失活。例如，发酵产品的酯化、醚化和成盐步骤，这类操作不认为是重要的合成步骤，此情况下不可省略发酵工艺的详细描述，尤其是纯化步骤。Incaseswherethe

36、fermentedstartingmaterialisnotcomplexandtakingintoconsiderationthenumberandnatureofthesyntheticstepsafterfermentation,itmaybesufficienttohaveasuitablespecificationforthefermentedstartingmaterialincludingassay,componentdistribution(ifrelevant)andrelatedimpurities(specified,unspecified,andtotal).Thiss

37、houldbeinanycasejustified.Foractivesubstancesmanufacturedbysemi-synthesis,theimpurityprofileofthefermentedstartingmaterialshouldbecriticallyevaluatedforitscontributiontotheimpurityprofileofthefinalactivesubstance.在源于发酵的起始物料不复杂的情况下，将发酵后合成工艺的步数和原理考虑在内，为源于发酵的起始物料建立包括含量、成分组成和相关杂质(特定杂质、非特定杂质、总杂)在内的质量标准足够

38、了，这在任何情况下都是合理的。对于半合成生产的活性物质，应当对源于发酵的起始物料引入的杂质进行充分地评估。Relatedimpuritiesobservedafterfermentationincludeby-products,intermediatesanddegradationproducts.Forsemi-synthesistheimpuritiesalsoincludethefermentedstartingmaterialandrelatedsubstancesinthisstartingmaterial,synthesisby-products(includingthoseder

39、ivedfromimpuritiesinthestartingmaterial),synthesisintermediatesanddegradationproducts.发酵后的相关杂质包括副产物、中间体和降解产物。对于半合成后的杂质，也包括起始物料、起始物料中的相关杂质、合成副产物(包括来自起始物料的副产物)、合成中间体和降解产物。Specificationsshouldbegivenforanycriticalintermediates(thisalsoincludesintermediatesbetweendifferentpurificationsteps).Thesespecifi

40、cationsshouldincludelimitsforspecifiedandsingleunspecifiedimpurities.Impuritiesthatcontributetotheimpurityprofileoftheactivesubstanceshouldbespecified.Theapplicantshouldprovideadiscussiononpotentialimpurities,howtheyareremovedandwhichimpuritiesappearintheactivesubstance.应当为关键中间体建立质量标准(包括不同纯化步骤间的中间体)

41、。标准应当包括特定杂质和非特定单一杂质的限度。进入最终活性物质的杂质应当详细说明。申请人应当提供针对潜在杂质的讨论，论述它们是如何除去和哪些杂质会在成品中出现。Evenifmanufacturedbyfermentationorsemi-synthesis,anantibioticmaybestructurallywelldefinedasamonocomponentsubstance,andthusitmaybeefficientlypurified.Foreachclassofantibiotic,itisconsideredpreferabletooptimisepurification

42、stepsasfaraspossible,inordertodecreasethelevelofimpuritytobelowthequalificationthreshold,thantoprovide(additional)safetydata.虽然一个抗生素是由发酵或半合成生产的，但它仍然可以是一个结构明确的单一组分物质，因它可经过有效地纯化。对于每类抗生素，充分利用纯化步骤尽可能地使杂质含量低于界定阈值比提供(额外的)安全数据更可取。Forantibioticsmanufacturedbyfermentation,theactivesubstancemayconsistofamixtu

43、reofcloselyrelatedcompoundsthatshowtherelevantbiologicalactivity.Insuchcasesitmaybedifficulttodecidewhetheracompoundispartoftheactivesubstanceorshouldberegardedasanimpuritywhensettingspecifications(e.g.gentamicin).Thedefinitionofwhichsubstancesarecomponentsoftheactivesubstanceshouldbebasedonpre-clin

44、icalandclinicalstudiesunlesstheactivesubstanceisdescribedinaPh.Eur.monographwheretheactivesubstancecomponentsaredefined.Relatedcompoundsthatarenotdefinedtobecomponentsoftheactivesubstanceareregardedasrelatedimpurities.对于由发酵生产的抗生素，活性物质可能由一组密切相关的化合物混合而成，从而表现出相应的生物活性。这种情况下，在设定质量标准时很难确定某个化合物是有效成分还是作为杂质(

45、例如庆大霉素)。有效成分的界定应当基于预临床和临床研究数据，除非药典专论中有相应说明。ThethresholdsgivenintheICHQ3andVICHGL10/GL11guidelinesandintheguidelineChemistryofNewActiveSubstances(CPMP/QWP/130/96Rev1,EMEA/CVMP/541/03)donotapplytofermentationproductsandsemi-syntheticsubstancesderivedfromfermentationproducts.Forotheraspects,wherespecif

46、icguidanceisnotgiveninthepresentguideline,referenceismadetotheprinciplesdescribedintheseguidelines.ICHQ3和VICHGL10/GL11指南以及新活性成分化学指南中的阈值不适用于发酵产品和源于发酵的半合成物质。对于本指南未提及的方面，可以参考这些指南。Inqualifyinganimpurityoragivenimpurityprofileatthelevelspecified,severalpossibilitiesexist:appropriatebatteryofnon-clinicalt

47、ests,literaturebaseddata;comparisonwithimpuritylevels/profilesofactivesubstancesources/productsapprovedintheEU;orprovingthattherelevantimpurityisasignificantmetaboliteoftheactivesubstance.在界定指定的杂质或杂质分布时，存在几种方案：一套合适的非临床试验、文献数据、与已被批准的活性物质/制剂的杂质水平进行对比、或证明相应杂质是活性物质的重要代谢物。Impurityprofilingandreporting,id

48、entificationandqualificationthresholds杂质分布以及杂质的报告、鉴定、界定阈值Forantibioticdrugsubstances,theimpurityprofileshouldbecharacterisedaccordingtotheguidancedescribedinICHQ3A(VICHGL10).对于抗生素原料药，其杂质分布应当依据ICHQ3A进行描述。Inaccordancewiththatguidance,withrespecttorelatedsubstances,limitsshouldbesetfor:应当为以下相关物质设定限度：?E

49、achspecifiedidentifiedimpurity;每个特定的已鉴别杂质?Eachspecifiedunidentifiedimpurity;每个特定的未鉴别杂质?Anyunspecifiedimpurity,withanacceptancecriterionofnotmorethantheidentificationthreshold;任意非特定杂质，标准为不高于鉴定阈值?Totalimpurities.总杂Exceptionally,ifitisshownthatitisnotpracticallypossibletoidentifyanindividualimpurity,su

50、fficientevidenceofitsstructureshouldbeprovided(e.g.byHPLC/massspectrometrytoshowthatitmaybesatisfactorilyclassifiedasarelatedsubstanceoftheparentcompound.Inthiscase,itshouldbespecifiedusinganappropriateanalyticalmarkere.g.HPLCRelativeRetentionTime(RRT),asaspecifiedunidentifiedimpurity.Asageneralprin

51、ciple,forimpuritieswhicharenotstructurallycloselyrelated(seesection5.3below)totheparentcompound,thresholdsasgivenbyICHQ3A(VICHGL10)shouldbeappliedunlessstateddifferentlyinthefollowingsections.尤其，如果难以鉴定某个单一杂质，应提供其充足的结构证据（例如，通过HPLC/质谱）证明其可以分类为母体化合物的有关杂质。此情况下，应当采用适当的分析标记对其进行说明，例如HPLC相对保留时间，作为一个特定的未鉴别杂质

52、。参照一般原则，对于在结构上与母体化合物非密切相关的杂质（见5.3部分），应依据ICHQ3A对其设定阈值，除非后续部分有特殊阐述。Forthereasonsdiscussedinsection4above,andtakingintoaccountthatthedurationoftreatmentwithantibioticsisinmostcaseslimited,forantibioticrelatedsubstancesthethresholdstobeappliedmaybehigherthanthosestatedinICHQ3A/VICHGL10,andalsodifferentf

53、oreachofthedifferentclassesofantibiotic.Thesethresholdsaregivenbelow.考虑到抗生素的作用时间有限，综合第4部分阐述的原因，抗生素相关物质的限度可能比ICHQ3A中设定的稍高，并可能不同的抗生素限度不同。这些限度如下：Activesubstancesmanufacturedbysemi-synthesis半合成工艺生产的活性物质Semi-syntheticsubstancesareobtainedfromafermentedstartingmaterialbyaprocessinvolvingatleastcleavageand

54、formationofcovalentbondsandincludingextraction/purificationsteps.Acceptancecriteriaforrelatedimpuritiesshouldbesetinaccordancewiththethresholdsgivenbelow.半合成物质源于发酵，至少应包含共价键的断裂和形成以及提取纯化工艺。杂质的限度设定应符合以下规定：TheICHQ3Athresholdsforreporting,identificationandqualificationapply.适用ICHQ3A中的报告、鉴定和界定阈值Reportingt

55、hreshold报告限:0.05%/0.03%Identificationthreshold鉴定限:0.10%/0.05%Qualificationthreshold界定限:0.15%/0.05%Ifthesemi-syntheticactivesubstanceconsistsofafamilyofcloselyrelatedcompoundsitmaybenecessarytoapplyrequirementsuptothethresholdsdescribedforsubstancesmanufacturedbyfermentation,familyofcompounds（see5.3）

56、.Ajustificationshouldbegiven.如果半合成活性物质由密切相关的化合物家族组成，有必要将其阈值提高至为发酵产品（家族化合物）标准（见5.3部分），并进行合理性说明。Activesubstancesmanufacturedbyfermentation,singlecompound发酵生产的活性物质（单一化合物）Acceptancecriteriaforrelatedimpuritiesshouldbesetinaccordancewiththethresholdsgivenbelow.Reportingthreshold报告限:0.10%Identificationand

57、qualificationthresholds鉴定限和界定限:0.15%Activesubstancesmanufacturedbyfermentation,familyofcompounds发酵生产的活性物质（家族化合物）Acceptancecriteriaforrelatedimpuritiesshouldbesetinaccordancewiththethresholdsgivenbelow.Reportingthreshold报告限:0.10%Identificationthreshold鉴定限:0.15%Qualificationthreshold界定限:0.50%/0.2%Theq

58、ualificationthresholdof0.50%forstructurallycloselyrelatedimpurities（seedefinition）iscombinedwithaqualificationthresholdof0.2%forotherrelatedimpurities.Justificationforclaimingthatarelatedimpurity(compoundnotdefinedtobeincludedintheactivesubstance)isstructurallycloselyrelatedtotheparentcompoundsshoul

59、datleastbebasedonevidencesuchasHPLC/massspectrometryortheuseofreferencematerials.Theproposed0.50%/0.2%limitsaresuggestedtoapplyevenfordailydosesof2g,whichmayberelevantforsomeoftheseantibiotics.结构密切相关的杂质界定限为0.50%，其他杂质的界定限为0.2%。一个相关杂质(非活性物质)被定位是与母体化合物结构相近需要至少提供例如HPLC/质谱/对照品的数据支撑。指南中建议的0.50%/0.2%的限度建议也

60、适用于日服量2g的一些抗生素。Peptidesmanufacturedbyfermentation/semi-synthesis发酵/半合成生产的多肽Forantibioticsthatarepeptides(e.g.gramicidin,tyrothricinandbacitracin)thesamethresholdsasforsyntheticpeptidesasgiveninthePh.Eur.GeneralMonographSubstancesforPharmaceuticalwouldbeconsideredacceptablewithoutanyjustification.Oth