EMEA基因毒性杂质限度指南

20060628EMEA/CHMP/QWP/251344/2006基因毒性杂质限度指南（中英文对照）London,28June2006CPMP/SWP/5199/02EMEA/CHMP/QWP/251344/2006TheEuropeanAgencyfortheEvaluationofMedicinalProducts欧洲共同体药物评审委员会(EMEA)COMMITTEEFORMEDICINALPRODUCTSFORHUMANUSE人用药品委员会(CHMP)GUIDLINEONTHELIMITSOFGENOTOXICIMPURITIES基因毒性杂质限度指南DESCUSSIONINTHESAFETYWORKINGPARTY安全工作组之内的讨论June2002-October2002TRANSMISSIONTOCPMPCPMP传递December2002RELEASEFORCONSULTATION专家讨论December2002DEADLINEFORCOMMENTS建议收集最后期限March2003DISCUSSIONINTHESAFETYWORKINGJune2003-February2004PARTYANDQUALITYWORKINGPARTY安全工作组和质量工作组之间的讨论TRANSMISSIONTOCPMP转移给CPMPMarch2004RE-RELEASEFORCONSULTATION再次放行给顾问团June2004DEADLINEFORCOMMENTS收集意见的最后期限December2004DISCUSSIONINTHESAFETYWORKINGPARTYANDQUALITYWORKINGPARTY安全工作组和质量工作组之间的讨论February2005-May2006ADOPTIONBYCHMP被CHMP采用28June2006DATEFORCOMINGINTOEFFECT生效日期01January2007KEYWORDS关键词Impurities;Genotoxicity;Thresholdoftoxicologicalconcern(TTC);Structureactivityrelationship(SAR)GUIDLINEONTHELIMITSOFGENOTOXICIMPURITIES基因毒性杂质限度指南TABLEOFCONTENTS目录EXECUTIVESUMMARY内容摘要..............................................................................................31.INTRODUCTION介绍...............................................................................................................32.SCOPE范围...............................................................................................................................33.LEGALBASIS法律依据............................................................................................................34.TOXICOLOGICALBACKGROUND毒理学背景....................................................................45.RECOMMENDATIONS建议.....................................................................................................45.1GenotoxicCompoundsWithSufficientEvidenceforaThreshold-RelatedMechanism具有充分证据证明其阈值相关机理的基因毒性化合物.........................................................45.2GenotoxicCompoundsWithoutSufficientEvidenceforaThreshold-RelatedMechanism不具备充分证据支持其阈值相关机理的基因毒性化合物......................................................55.2.1PharmaceuticalAssessment药学评价..................................................................................55.2.2ToxicologicalAssessment毒理学评价...................................................................................55.2.3ApplicationofaThresholdofToxicologicalConcern毒理学担忧阈值应用........................55.3DecisionTreeforAssessmentofAcceptabilityofGenotoxicImpurities基因毒性杂质可接受性评价决策树..........................................................................................7REFERENCES.参考文献................................................................................................................8EXECUTIVESUMMARY内容摘要ThetoxicologicalassessmentofgenotoxicimpuritiesandthedeterminationofacceptablelimitsforsuchimpuritiesinactivesubstancesisadifficultissueandnotaddressedinsufficientdetailintheexistingICHQ3Xguidances.Thedatasetusuallyavailableforgenotoxicimpuritiesisquitevariableandisthemainfactorthatdictatestheprocessusedfortheassessmentofacceptablelimits.Intheabsenceofdatausuallyneededfortheapplicationofoneoftheestablishedriskassessmentmethods,i.e.datafromcarcinogenicitylong-termstudiesordataprovidingevidenceforathresholdmechanismofgenotoxicity,implementationofagenerallyapplicableapproachasdefinedbytheThresholdofToxicologicalConcern(TTC)isproposed.ATTCvalueof1.5μg/dayintakeofagenotoxicimpurityisconsideredtobeassociatedwithanacceptablerisk(excesscancerriskof1in100,000overalifetime)formostpharmaceuticals.Fromthisthresholdvalue,apermittedlevelintheactivesubstancecanbecalculatedbasedontheexpecteddailydose.Higherlimitsmaybejustifiedundercertainconditionssuchasshort-termexposureperiods.基因毒性杂质的毒理学评估和这些杂质在活性药物中的可接受标准的测定是一件困难的事情，并且在现有的ICHQ3X指南中也没有详细的规定。现有的关于基因毒性杂质的相关数据是容易变化的，也是对杂质可接受标准如何进行评价的主要影响因素。如果缺少风险评估方法所需要的数据，比如，致癌作用的长期研究数据，或为基因毒性的阀值提供证据的数据，一般建议使用一般通用的被定义为毒理学关注的阈值（TTC）的方法。一个“1.5μg/day”的TTC值，即相当于每天摄入1.5μg的基因毒性杂质，被认为对于大多数药品来说是可以接受的风险（一生中致癌的风险小于十万分之1）。按照这个阀值，可以根据这个预期的每日摄入量计算出活性药物中可接受的杂质水平。较高的临界值可以在特定的条件下，如短期暴露周期等，进行推算。1.INTRODUCTION介绍Ageneralconceptofqualificationofimpuritiesisdescribedintheguidelinesforactivesubstances(Q3A,ImpuritiesinNewActiveSubstances)ormedicinalproducts(Q3B,ImpuritiesinNewMedicinalProducts),wherebyqualificationisdefinedastheprocessofacquiringandevaluatingdatathatestablishesthebiologicalsafetyofanindividualimpurityoragivenimpurityprofileatthelevel(s)specified.Inthecaseofimpuritieswithagenotoxicpotential,determinationofacceptabledoselevelsisgenerallyconsideredasaparticularlycriticalissue,whichisnotspecificallycoveredbytheexistingguidelines.在原料药（Q3A）和药物制剂（Q3B）的杂质指导原则中，杂质限度确定的依据包括各个杂质的生物安全性数据或杂质在某特定含量水平的研究概况。而对于遗传毒性杂质限度的确定，通常都认为是特别关键的问题，但目前尚无相关的指导原则。2.SCOPE范围ThisGuidelinedescribesageneralframeworkandpracticalapproachesonhowtodealwithgenotoxicimpuritiesinnewactivesubstances.Italsorelatestonewapplicationsforexistingactivesubstances,whereassessmentoftherouteofsynthesis,processcontrolandimpurityprofiledoesnotprovidereasonableassurancethatnoneworhigherlevelsofgenotoxicimpuritiesareintroducedascomparedto