1、EUROPEANMEDICINESAGENCYSCIENCEMEDICINESHEALTH30June2012EMA心HMP心VMP/QWP/199250/2009corrCommitteeforMedicinalProductsforHumanUse(CHMP)/CommitteeforMedicinalProductsforVeterinaryUse(CVMP)Guidelineonsettingspecificationsforrelatedimpuritiesinantibiotics抗生素中相關雜質質量標準制定的指導原則Final定稿DraftAgreedbyQualityWorki

2、ngParty2010年5月質量工作中批準草案May2010AdoptionbyCHMPforreleaseforconsultation2010年6月24日被人用藥委員會采納，公布征求意見稿24June2010AdoptionbyCVMPforreleaseforconsultation2010年7月15日被獸用藥委員會采納，公布征求意見稿15July2010Endofconsultation(deadlineforcomments)2011年1月31日結束征求意見31Jan2011AgreedbyQualityWorkingParty2012年5月質量工作組批準May2012Adoptio

3、nbyCHMP2012年5月14日被人用藥委員會采納14May2012AdoptionbyCVMP2012年6月14日被獸用藥委員會采納14June2012Dateforcomingintoeffect2013年6月30日生效30June2013學習之名（譯注）Tableofcontents目錄概要背景介紹范圍法規(guī)依據(jù)一般要求雜質分布以及報告、鑒別和界定閾值新申請和變更制劑產品質量標準分析方法定義附件1：關于閾值的注釋附件2：閾值附件3：利用基于“指紋圖譜”的方法對非常復雜的雜質分布進行控制舉例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.目前上市的抗生素類活性物質是由發(fā)酵、發(fā)酵加一步或幾步合成步驟(半合成)、化學合成制得。與合成工藝相比，發(fā)酵工藝更具多變性，不易控制，因此與單純使用化學合成生產的產品相比，生產工藝含有發(fā)酵步驟的活性物質的雜質分布一般比較復雜和難以預測?；诖嗽颍l(fā)酵產品和半合成產品并不適用于ICHQ3和VICHGL10/GL11指南。因為這兩個指南適用于由化學合成生產的活性物質。Thisguidelinehasbeende

8、velopedinordertoprovideguidanceonhowspecificationsforrelatedimpuritiesinantibioticsthatarefermentationproductsorsemi-syntheticsubstancesderivedfromfermentationproducts,andarethereforenotincludedinthescopeofthe(V)ICHguidelinesmentionedabove,shouldbeset.本指南旨在為不適用于ICHQ3指南的發(fā)酵產品或源于發(fā)酵產品的半合成物質中雜質質量標準的設定提供指

9、導。Thresholdsaregivenintheguidelineforreporting,identificationandqualificationofrelatedimpuritiesforantibioticsmedicinalproductswhoseactivesubstanceisproducedbyfermentationorsemisynthesis.Incaseswheretheactivesubstanceconsistsofamixtureofcloselyrelatedcompounds,whereitmaybedifficulttoapplygeneralthre

10、sholds,generalguidanceisgivenonhowtosetspecificthresholdsandspecificationsandonhowtoqualifyimpurityprofiles.TherelationshipsbetweentherequirementsintheguidelineandtheapplicablePh.Eur.chaptersandmonographsarealsoaddressed.對于活性成分為發(fā)酵或半合成來源的抗生素制劑產品的相關雜質，本指南給出了報告、鑒定和界定閾值。在活性物質由多個密切相關的化合物混合組成情況下，對其應用一般的閾值

11、存在困難。針對此，本指南就如何設定閾值和如何論證雜質分布給出了指導。對于本指南與歐洲藥典要求的關系，本指南也做了闡述。注：界定限(界定閾值)：指超過該限度的雜質需進行論證，包括安全性、設定的限度合理性等。Introduction(background)背景介紹Mostoftheantibioticscurrentlyonthemarketareproducedbyfermentationorchemicalsynthesis.Incertaincasesthechemicalstructureoftheantibioticsobtainedbyfermentationisfurthermodi

12、fiedbysomesyntheticsteps,beforethesubstanceisusedasanactivesubstanceinthemanufactureofmedicinalproducts(semi-syntheticsubstances).目前市售的大多數(shù)抗生素是由發(fā)酵或化學合成生產的。一些情況下，由發(fā)酵生產的抗生素在可用作生產制劑的活性成分前，其結構會經過一些合成步驟進行修改(半合成物質)Fermentationprocessesinvolvebiologicalsystemswhicharelesspredictable,lesscontrollableandmorec

13、omplexthanstraightforwardchemicalreactions.Becauseofthis,thevariabilityinproductsderivedbyfermentationisoftengreaterthaninproductsderivedbychemicalsynthesis.Thus,theimpurityprofileofafermentationproductmaybemorecomplexandlesspredictablethanthatofasyntheticproduct.與直接化學方應相比，發(fā)酵工藝包含不易預測、控制和復雜的生物系統(tǒng)，發(fā)酵產品

14、比化學合成產品更具多變性。因此，發(fā)酵產品的雜質分布會比化學合成產品的更復雜和不易預測。Forthisreason,fermentationproductsandsemi-syntheticsubstancesderivedfromthemarenotincludedinthescopeoftheICHQ3andtheVICHGL10/GL11guidelinesthatsetthresholdsfortheidentification,reportingandqualificationofrelatedimpuritiesinactivesubstancesmanufacturedbychem

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

16、ralmonograph.基于此，發(fā)酵產品和源于發(fā)酵產品的半合成物質并不適用于ICHQ3和VICHGL10/GL11。這兩個指南旨在為化學合成物質的鑒別、報告和界定閾值提供指導。依據(jù)這兩個指南設定的閾值也適用于歐洲藥典總論“藥用物質”。發(fā)酵產品和基于發(fā)酵產品的半合成物質并不適用于總論。Intheabsenceofotherguidance,relatedimpuritiesintheseproductshavebeenassessedonacase-by-casebasis,whichhasresultedintheacceptanceofdifferentimpuritythresholds

17、forthesameantibioticandfordifferentcompoundswithinthesameclass(e.g.cephalosporins).Thereisalsoaneedtoensurethattheauthorisationofnewantibioticsisenabledbyconsistentapproachesinsettinglimitsfortheirimpurities.在以前沒有其他指南的條件下，這些產品中的雜質是基于個案進行評估的，這就導致同一抗生素或同類下不能化合物有不同的雜質閾值。在批準新抗生素時也需要采用一致的方法來設定雜質限度。Itisth

18、ereforenecessarytoprovideguidance,basedoncurrentpracticeandexperience,toformulategeneralrecommendationsforimpuritythresholdsinantibioticsproducedbyfermentationorsemisynthesis.Thesearepresentedinthisguideline.因此，有必要基于目前的實踐和經驗，為發(fā)酵或源于發(fā)酵的半合成產品中雜質閾值設定提供指南。Evenso,itisacknowledgedthatinsomecaseshigherthres

19、holdsmaybeacceptableifnecessaryandjustifiedtakingaccountofuseandexposureofthedrugsubstance/product.Thiswouldalsoincludeanalyticalproblems(seeAnnex1:Explanatorynoteregardingthresholds).盡管如此，若考慮到藥品的使用和用量，如果需要，采用較高的閾值也是可以接受的。見附件1：關于閾值的注釋Scope范圍Thisdocumentprovidesguidanceformarketingauthorisationapplic

20、ationsonsettingspecificationsforrelatedimpuritiesinantibiotics(i.e.antibacterialsubstances)thatarefermentationproductsorsemisyntheticsubstancesderivedfromfermentationproducts.Itisforeseentowidenthescopetootherantibiotics(e.g.antifungalsubstances)atalaterstage.本指南為源于發(fā)酵產品或源于發(fā)酵產品的半合成抗生素(例如抗菌物質)申請銷售許可時，

21、提供相關雜質質量標準的設定指導。可以預見，后續(xù)本指南適用范圍會進一步擴展(例如抗真菌物質)。Itprovidesguidanceforthecontentandqualificationofrelatedimpuritiesinbothactivesubstancesandmedicinalproducts.Theguidelineisnotintendedtoapplytonewactivesubstancesusedininvestigationalmedicinalproductsusedinclinicaltrials.可為活性物質和制劑中相關雜質的含量和界定提供指導。本指南不適用于處

22、在臨床試驗階段的研究用活性物質。Inthisguidelinethresholdsaregivenforreporting,identificationandqualificationofrelatedimpurities.Forantibioticswheretheactivesubstanceconsistsofamixtureofcloselyrelatedcompoundswhereitmaybedifficulttoapplythesegeneralthresholds,generalguidanceisgivenonhowtosetthresholdsandspecificatio

23、nsandhowtoqualifyimpurityprofiles.Thethresholdsgiveninthisguidelinewouldrepresentageneralsetofrequirements,andthiscouldbesubject,forspecificsubstancesorproducts,toadaptationtothespecificsituation.Furtherrequirementsmightbeintroducedwhenconsiderednecessary,e.g.forsafetyreasons.本指南中給出了相關雜質的報告、鑒定和界定閾值。

24、對于活性物質為相近的化合物混合組成的抗生素，由于采用一般的閾值存在困難，指南給出了如何設定閾值和質量標準以及如何確定雜質分布的通用指導。本指南中給出的閾值代表一般的設定要求，對于特定的物質，需要根據(jù)特定情況進行調整。若需要，可將其他要求考慮在內，如安全因素。Thisguidelinedoesnotcoverresiduesfromthefermentationprocess,i.e.residuesfromtheproducermicro-organism,culturemedia,substratesandprecursors;thisiscoveredbythePh.Eur.general

25、monographProductsoffermentation.(Thismonographappliestosubstancesmanufacturedbyfermentationonly,andnottosubstancesmanufacturedbysemi-synthesis).本指南不包括發(fā)酵過程的殘留，如生產菌株、培養(yǎng)基、基質和前體。這些殘留依據(jù)歐洲藥典總論“發(fā)酵產品”進行控制。此總論僅適用于發(fā)酵生產的產品，不包括半合成生產的產品。Thisguidelineappliestonewactivesubstancesandfornewsourcesofexistingactivesub

26、stances.ItistheApplicantsresponsibilitytodemonstratethattheactivesubstancehasalreadybeenmarketedintheEUwhenrelevant.本指南適用于新活性物質或新來源的已存在活性物質。需要時，申請者需說明該物質是否已在歐洲上市。Theguidelineshouldnotbeappliedretrospectively,butitisintendedthatthisguidelinewillactasastimulustoestablishbestpracticeandtoinitiatetherev

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

28、arisonwithimpuritylevels/profilesofactivesubstancesourcesorproductsapprovedintheEUisoneoftheoptionsforqualifyingimpurities.本指南不可回顧性使用注：不適用于已完成注冊上市銷售的產品，但可作為建立最佳實踐或推動歐洲藥典專論修訂的刺激因素(例如，對已注冊的產品，當增加了某專論或修訂了某專論，需依據(jù)情況進行修訂)。對于新來源的已存在的活性物質，本指南閱讀時需要結合相應的藥典準了。需要指出的是，與已在歐洲批準上市的活性物質或制劑進行雜質分布對比，是一個確定雜質分布的方法。Itisf

29、oreseentore-evaluatetheScopewhenmoreexperiencehasbeenobtained.Legalbasis法規(guī)依據(jù)Thisguidelinehastobereadinconjunctionwiththeintroductionandgeneralprinciples(4)andpart1oftheAnnexIstoDirectives2001/82/ECand2001/83/ECasamended.Generalrequirements一般要求Theimpurityprofiledependsverymuchonthemanufacturingproces

30、s;evenforthesamestrainofamicro-organism,impurityprofilesmaybedifferent.Ingeneral,purificationstepsincludingcolumnchromatographyandultra-filtrationstepsmaybecrucialtoachieveasufficientlypureactivesubstance.雜質分布與生產工藝密切相關；甚至同一微生物生產產品的雜質分布也有不同。一般來說，純化步驟包括柱層析和超濾，對獲得一個純品至關重要。Semi-syntheticsubstancesarenot

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

32、rtingmaterials).半合成物質不在歐洲藥典總論“發(fā)酵產品”要求范圍內。然而，如果需要，半合成產品的源于發(fā)酵的起始物料質量標準應當滿足總論“發(fā)酵產品”要求。(本指南中的閾值不適用于源于發(fā)酵的起始物質注：指半合成產品的起始物料)Theshorterthesyntheticrouteafterthefermentationandthemorecomplexthefermentedstartingmaterial,themorerelevancethegeneralmonographhas.Therefore,adetaileddescriptionofthefermentationste

33、psaswellasotheraspectsaddressedinthegeneralmonograph,inparticularpurificationsteps,shouldbepresentedforsemi-syntheticantibiotics,unlessjustifiedbythenoncomplexityofthefermentedstartingmaterialandthenumberand/ornatureofthesyntheticstepsfollowingfermentation.發(fā)酵后合成工藝越短、源于發(fā)酵的起始物料越復雜，越適用于藥典總論“發(fā)酵產品”要求。因此，

34、對于半合成抗生素，應詳細描述發(fā)酵工藝和總論中要求的其他方面，尤其是純化步驟，除非有源于發(fā)酵的起始物料不復雜和發(fā)酵后的合成工藝的證明。Thesesyntheticstepsshouldcontributetoarelevantdepletionandinactivationoffermentationbyproductsinthefinalactivesubstance,soforexample,esterification,etherificationandsalificationoffermentationproducts(e.g.,erythromycinderivativeslikeer

35、ythromycinethylsuccinateorerythromycinlactobionate)arenotconsideredassignificantsyntheticstepswhichwouldjustifyanomissionofadetaileddescriptionofthefermentationprocess,inparticularofthepurification.合成步驟應當可以在一定程度上消耗或使發(fā)酵副產物失活。例如，發(fā)酵產品的酯化、醚化和成鹽步驟，這類操作不認為是重要的合成步驟，此情況下不可省略發(fā)酵工藝的詳細描述，尤其是純化步驟。Incaseswherethe

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

37、houldbeinanycasejustified.Foractivesubstancesmanufacturedbysemi-synthesis,theimpurityprofileofthefermentedstartingmaterialshouldbecriticallyevaluatedforitscontributiontotheimpurityprofileofthefinalactivesubstance.在源于發(fā)酵的起始物料不復雜的情況下，將發(fā)酵后合成工藝的步數(shù)和原理考慮在內，為源于發(fā)酵的起始物料建立包括含量、成分組成和相關雜質(特定雜質、非特定雜質、總雜)在內的質量標準足夠

38、了，這在任何情況下都是合理的。對于半合成生產的活性物質，應當對源于發(fā)酵的起始物料引入的雜質進行充分地評估。Relatedimpuritiesobservedafterfermentationincludeby-products,intermediatesanddegradationproducts.Forsemi-synthesistheimpuritiesalsoincludethefermentedstartingmaterialandrelatedsubstancesinthisstartingmaterial,synthesisby-products(includingthoseder

39、ivedfromimpuritiesinthestartingmaterial),synthesisintermediatesanddegradationproducts.發(fā)酵后的相關雜質包括副產物、中間體和降解產物。對于半合成后的雜質，也包括起始物料、起始物料中的相關雜質、合成副產物(包括來自起始物料的副產物)、合成中間體和降解產物。Specificationsshouldbegivenforanycriticalintermediates(thisalsoincludesintermediatesbetweendifferentpurificationsteps).Thesespecifi

40、cationsshouldincludelimitsforspecifiedandsingleunspecifiedimpurities.Impuritiesthatcontributetotheimpurityprofileoftheactivesubstanceshouldbespecified.Theapplicantshouldprovideadiscussiononpotentialimpurities,howtheyareremovedandwhichimpuritiesappearintheactivesubstance.應當為關鍵中間體建立質量標準(包括不同純化步驟間的中間體)

41、。標準應當包括特定雜質和非特定單一雜質的限度。進入最終活性物質的雜質應當詳細說明。申請人應當提供針對潛在雜質的討論，論述它們是如何除去和哪些雜質會在成品中出現(xiàn)。Evenifmanufacturedbyfermentationorsemi-synthesis,anantibioticmaybestructurallywelldefinedasamonocomponentsubstance,andthusitmaybeefficientlypurified.Foreachclassofantibiotic,itisconsideredpreferabletooptimisepurification

42、stepsasfaraspossible,inordertodecreasethelevelofimpuritytobelowthequalificationthreshold,thantoprovide(additional)safetydata.雖然一個抗生素是由發(fā)酵或半合成生產的，但它仍然可以是一個結構明確的單一組分物質，因它可經過有效地純化。對于每類抗生素，充分利用純化步驟盡可能地使雜質含量低于界定閾值比提供(額外的)安全數(shù)據(jù)更可取。Forantibioticsmanufacturedbyfermentation,theactivesubstancemayconsistofamixtu

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

44、icalandclinicalstudiesunlesstheactivesubstanceisdescribedinaPh.Eur.monographwheretheactivesubstancecomponentsaredefined.Relatedcompoundsthatarenotdefinedtobecomponentsoftheactivesubstanceareregardedasrelatedimpurities.對于由發(fā)酵生產的抗生素，活性物質可能由一組密切相關的化合物混合而成，從而表現(xiàn)出相應的生物活性。這種情況下，在設定質量標準時很難確定某個化合物是有效成分還是作為雜質(

45、例如慶大霉素)。有效成分的界定應當基于預臨床和臨床研究數(shù)據(jù)，除非藥典專論中有相應說明。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學指南中的閾值不適用于發(fā)酵產品和源于發(fā)酵的半合成物質。對于本指南未提及的方面，可以參考這些指南。Inqualifyinganimpurityoragivenimpurityprofileatthelevelspecified,severalpossibilitiesexist:appropriatebatteryofnon-clinicalt

47、ests,literaturebaseddata;comparisonwithimpuritylevels/profilesofactivesubstancesources/productsapprovedintheEU;orprovingthattherelevantimpurityisasignificantmetaboliteoftheactivesubstance.在界定指定的雜質或雜質分布時，存在幾種方案：一套合適的非臨床試驗、文獻數(shù)據(jù)、與已被批準的活性物質/制劑的雜質水平進行對比、或證明相應雜質是活性物質的重要代謝物。Impurityprofilingandreporting,id

48、entificationandqualificationthresholds雜質分布以及雜質的報告、鑒定、界定閾值Forantibioticdrugsubstances,theimpurityprofileshouldbecharacterisedaccordingtotheguidancedescribedinICHQ3A(VICHGL10).對于抗生素原料藥，其雜質分布應當依據(jù)ICHQ3A進行描述。Inaccordancewiththatguidance,withrespecttorelatedsubstances,limitsshouldbesetfor:應當為以下相關物質設定限度：?E

49、achspecifiedidentifiedimpurity;每個特定的已鑒別雜質?Eachspecifiedunidentifiedimpurity;每個特定的未鑒別雜質?Anyunspecifiedimpurity,withanacceptancecriterionofnotmorethantheidentificationthreshold;任意非特定雜質，標準為不高于鑒定閾值?Totalimpurities.總雜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，如果難以鑒定某個單一雜質，應提供其充足的結構證據(jù)（例如，通過HPLC/質譜）證明其可以分類為母體化合物的有關雜質。此情況下，應當采用適當?shù)姆治鰳擞泴ζ溥M行說明，例如HPLC相對保留時間，作為一個特定的未鑒別雜質

52、。參照一般原則，對于在結構上與母體化合物非密切相關的雜質（見5.3部分），應依據(jù)ICHQ3A對其設定閾值，除非后續(xù)部分有特殊闡述。Forthereasonsdiscussedinsection4above,andtakingintoaccountthatthedurationoftreatmentwithantibioticsisinmostcaseslimited,forantibioticrelatedsubstancesthethresholdstobeappliedmaybehigherthanthosestatedinICHQ3A/VICHGL10,andalsodifferentf

53、oreachofthedifferentclassesofantibiotic.Thesethresholdsaregivenbelow.考慮到抗生素的作用時間有限，綜合第4部分闡述的原因，抗生素相關物質的限度可能比ICHQ3A中設定的稍高，并可能不同的抗生素限度不同。這些限度如下：Activesubstancesmanufacturedbysemi-synthesis半合成工藝生產的活性物質Semi-syntheticsubstancesareobtainedfromafermentedstartingmaterialbyaprocessinvolvingatleastcleavageand

54、formationofcovalentbondsandincludingextraction/purificationsteps.Acceptancecriteriaforrelatedimpuritiesshouldbesetinaccordancewiththethresholdsgivenbelow.半合成物質源于發(fā)酵，至少應包含共價鍵的斷裂和形成以及提取純化工藝。雜質的限度設定應符合以下規(guī)定：TheICHQ3Athresholdsforreporting,identificationandqualificationapply.適用ICHQ3A中的報告、鑒定和界定閾值Reportingt

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

56、.Ajustificationshouldbegiven.如果半合成活性物質由密切相關的化合物家族組成，有必要將其閾值提高至為發(fā)酵產品（家族化合物）標準（見5.3部分），并進行合理性說明。Activesubstancesmanufacturedbyfermentation,singlecompound發(fā)酵生產的活性物質（單一化合物）Acceptancecriteriaforrelatedimpuritiesshouldbesetinaccordancewiththethresholdsgivenbelow.Reportingthreshold報告限:0.10%Identificationand

57、qualificationthresholds鑒定限和界定限:0.15%Activesubstancesmanufacturedbyfermentation,familyofcompounds發(fā)酵生產的活性物質（家族化合物）Acceptancecriteriaforrelatedimpuritiesshouldbesetinaccordancewiththethresholdsgivenbelow.Reportingthreshold報告限:0.10%Identificationthreshold鑒定限: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.結構密切相關的雜質界定限為0.50%，其他雜質的界定限為0.2%。一個相關雜質(非活性物質)被定位是與母體化合物結構相近需要至少提供例如HPLC/質譜/對照品的數(shù)據(jù)支撐。指南中建議的0.50%/0.2%的限度建議也

60、適用于日服量2g的一些抗生素。Peptidesmanufacturedbyfermentation/semi-synthesis發(fā)酵/半合成生產的多肽Forantibioticsthatarepeptides(e.g.gramicidin,tyrothricinandbacitracin)thesamethresholdsasforsyntheticpeptidesasgiveninthePh.Eur.GeneralMonographSubstancesforPharmaceuticalwouldbeconsideredacceptablewithoutanyjustification.Oth