EMEA基因毒性杂质限度指南.docx

55.2.2ToXiCOIOgiCalASSeSSment毒理学评价55.2.3ApplicationofaThresholdofToxicologicalCOnCern毒理学担忧阈值应用55.3DecisionTreefor.Assessmentof.AcceptabilityofGenotoxicImpurities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Thetoxicologicalassessmentofgenotoxicimpuritiesandthedeterminationofacceptable1imitsforsuchimpuritiesinactivesubstancesisadifficultissueandnotaddressedinsufficientdetai1intheexistingICHQ3Xguidances.ThedatasetusualIyavailableforgenotoxicimpuritiesisquitevariableandisthemain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generalconceptofqualificationofimpuritiesisdescribedintheguidelinesforactivesubstances(Q3A,ImpuritiesinNewActiveSubstances)ormedicinalproducts(Q3B,ImpuritiesinNewMedicinalProducts),wherebyqualificationisdefineclastheprocessofacquiringandevaluatingdatathatestablishesthebiologicalsafetyofanindividualimpurityoragivenimpurityprothelevel(三)specified.Inthecaseofimpuritieswithagenotoxicpotential,determinationofacceptabledoselevelsisgeneralIyconsideredasaparticularlycriticalissue,whichisnotspecificallycoveredbytheexistingguideines.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平安性数据或杂质在某特定含量水平的探讨概况。而对于遗传毒性杂质限度的确定，通常都认为是特殊关键的问题，但目前尚无相关的指导原则。2. SCOPE范围ThisGuidelinedescribesageneralframeworkandpracticalapproachesonhowtodealwithgenotoxicimpuritiesinnewactivesubstances.Italsorelatestonewapplicationsforexistingactive目前对于基因毒性杂质的分类主要是指：在以DNA反应物质为主要探讨对象的体内体外试验中，假如发觉它们对DNA有潜在的破坏性，那可称之为基因毒性。假如有足够的后续试验，可由单独的体外试验结果，对它的体内关联性进行评估。在缺乏这样的信息时，体外基因毒性物质常常被考虑为假定的体内诱变剂和致癌剂。3. 1.EGA1.BASIS法规依据ThisguidelinehastobereadinconjunctionwithDirective2019/83/EC(asamended)andallrelevantCHMPGuidancedocumentswithspecialemphasison:在阅读该指南时有必要参考"Directive201983ECm以及相关的CHMP指南文件，特殊是以下几个指南：ImpuritiesTestingGuideline:ImpuritiesinNewDrugSubstances(CF,MPICH273799,ICHQ3(R)NoteforGuidanceonImpuritiesinNewDrugProducts(CPMP/ICH/2738/99,ICHQ3B(R)NoteforGuidanceonImpurities:ResidualSolvents(CPMP/ICll/283/95)NoteforGuidanceonGenotoxicity:GuidanceonSpecificAspectsofRegulatoryGenotoxicityTestsforPharmaceuticals(CPMP/ICH/141/95,ICHS2A)然而，对于一些遗传毒性事务，其产生生物学意义的阈值效应的机理正越来越为人所了解。对于非DNA靶点的化合物和潜在致突变剂更是如此,因为它们在及关键靶点接触前就已经去毒化了。对于这些化合物，探讨的基础可以是确定关键的未视察到影响的剂量（NOE1.）和采纳不确定因子。EvenforcompoundswhichareabletoreactwiththeDNAmolecule,extrapolationinalinearmannerfromeffectsinhigh-dosestudiestoverylowlevel（human）exposuremaynotbejustifiedduetoseveralprotectivemechanismsoperatingeffectivelyatlowdoses.However,atpresentitisextremelydifficulttoexperimentallyprovetheexistenceofthresholdforthegenotoxicityofagivenmutagen.Thus,intheabsenceofappropriateevidencesupportingtheexistenceofathresholdforagenotoxiccompoundmakingitdifficulttodefineasafedoseitisnecessarytoadoptaconceptofalevelofexposurethatcarriesanacceptablerisk.即使对能及DNA分子发生反应的化合物，由于低剂量时有多种有效的爱护机制存在，而不能将高剂量卜的影响以线性方式外推到很低的（人）暴露水平。不过，目前要用试验方法证明某诱变剂的遗传毒性阈值仍旧特别困难。所以，在缺乏恰当的证据支持遗传毒性阈值存在的状况卜.，确定平安剂量很困难，因此特别有必要采纳一个可接受风险的暴露水平概念。5.RECOMMENDATIONS建议ASstatedintheQ3guideline,actualandpotentialimpurities指导原则认为这些探讨采纳含有那些需限制杂质的原料药进行是可行的，但用分别出来的杂质进行这些探讨更恰当，也是高度举荐的方法。FordeterminationofacceptablelevelsofexposuretogenotoxiccarcinogensConsiderationsofpossiblemechanismsofactionandofthedose-responserelationshipareimportantcomponents.Basedontheaboveconsiderationsgenotoxicimpuritiesmaybedistinguishedintothefollowingtwoclasses:依据以上论述，遗传毒性杂质可以归纳成以卜两类：-Genotoxiccompoundswithsufficient(experimental)evidenceforathreshold-relatedmechanism有充分阈值相关机理证据(试验)的遗传毒性化合物-Genotoxiccompoundswithoutsufficient(experimental)evidenceforathreshold-relatedmechanism无充分阈值相关机理证据(试验)的遗传毒性化合物5.1 GenotoxicCompoundsWithSufficientEvidenceforaThreshold-RelatedMechanism具有充分证据证明其阈值相关机理的基因毒性化合物Examplesofmechanismsofgenotoxicitythatmaybedemonstratedtoleadtonon-linearorthresholdeddose-responserelationshipsincludeinteractionwiththespindleapparatusofcelldivisiondifferentstartingmaterials.Thismightforinstanceincludecaseswherethestructure,whichisresponsibleforthegenotoxicand/orcarcinogenicpotentialisequivalenttothatneededinchemicalsynthesis(e.g.alkylationreactions).须要供应充分的论证来说明没有可行的替代方法存在，包括可替代的合成路途或配方，不同的起始物料等。比如，应证明具有遗传毒性和/或致癌性的结构在化学合成中(如烷化反应)是必需的。Ifagenotoxicimpurityisconsideredtobeunavoidableinadrugsubstance,technicalefforts(e.g.purificationsteps)shouldbeundertakentoreducethecontentofthegenotoxicresiduesinthefinalproductincompliancewithsafetyneedsortoalevelaslowasreasonablypracticable(seesafetyassessment).DataonchemicalstabiIityofreactiveintermediates,reactants,andothercomponentsshouldbeincludedinthisassessment.假如遗传毒性杂质在原料中不行避开，则应当实行适当的技术(如纯化步骤)降低该杂质的含量，以满意平安性要求，或符合“合理可行的最低限量”原则(见平安评估)。药学评估还应包括反应中间体、反应物和其它组件等的化学稳定性探讨。Detectionand/orquantificationoftheseresiduesshouldbedonebystate-of-the-artanalyticaltechniques.应当运用比较先进的分析检测技术来检测和量化这些残留的杂质。Inmostcasesoftoxicologicalassessmentofgenotoxicimpuritiesonlylimiteddatafrominvitrostudieswiththeimpurity(e.g.Amestest,chromosomalaberrationtest)areavailableandthusestablishedapproachestodetermineacceptableintakelevelscannotbeapplie