原料中杂质的控制

原料药中杂质的控制TheControlofImpuritiesinDrugSubstances杨仲元（广州市药品检验所）YangZhong-Yuan（GuangzhouMunicipalInstituteforDrugControl)TheFirstJointUSP-ChPConference15August2004Shanghai原料药中杂质的控制TheControlofImpuritiesinDrugSubstances•本部分将讨论中国药典对药品杂质分析的新的指导原则，包括ICH和其他药典的有关要求。•Thispartoftheprogramwillfocusonthenewguidelineofthe2005ChinesePharmacopoeiafortheanalysisofdrugimpurities,includingrelevantrequirementsofICHandotherpharmacopoeias原料药中杂质的控制TheControlofImpuritiesinDrugSubstances•本讨论包括：•ICH新原料药中对杂质的指导原则•ICH关于杂质指导原则在国外药典中的引用•中国药典(2005)药品杂质分析指导原则原料药中杂质的控制TheControlofImpuritiesinDrugSubstances•虽然ICH指导原则是对申报新化学药和新生物制品的技术要求，但经ICH三方成员国制药工业部门和药品管理部门的协调，其原则切实可行，在保证药品安全有效，药品的生产按GMP的要求，起一定作用，逐步为各国采用。不仅作为申报新药的要求，有的还作为修订药典正文的要求。ICH新原料药中的杂质指导原则ICHGuidelineonImpuritiesinNewDrugSubstances•文件Q3A（R）为未曾在ICH三方注册过的化学合成新原料药申报时关于杂质的指导原则•Thisdocumentisintendedtoprovideguidanceforregistrationapplicationoncontentandqualificationofimpuritiesinnewdrugsubstancesproducedbychemicalsynthesesandnotpreviouslyregisteredinaregionormemberstate.ICH新原料药中的杂质指导原则ICHGuidelineonImpuritiesinNewDrugSubstances•Q3A（R）杂质分类•ClassificationofImpurities•有机杂质OrganicImpurities•无机杂质InorganicImpurities•残留溶剂ResidualsolventsICH新原料药中的杂质指导原则ICHGuidelineonImpuritiesinNewDrugSubstances•其中有机杂质包括起始原料、副产物、中间体、降解产物、试剂、配位体、催化剂。可以是经鉴定或未鉴定的•Theorganicimpuritiesincludestartingmaterials,by-products,intermediates,•Degradationproducts,reagents,ligandsandcatalysts(identifiedorunidentified)ICH新原料药中的杂质指导原则ICHGuidelineonImpuritiesinNewDrugSubstances•Q3A(R)关于有机杂质的报告和控制中几点说明•RationalforthereportingandcontroloforganicimpuritiesICH新原料药中的杂质指导原则ICHGuidelineonImpuritiesinNewDrugSubstances•为便于理解，先介绍ICH杂质指导原则中的几个术语：•ReportingThreshold:Alimitabove()whichanimpurityshouldbereported.•报告限：系指一个限度，大于该限度的杂质，应该（在申报资料中）报告ICH新原料药中的杂质指导原则ICHGuidelineonImpuritiesinNewDrugSubstances•IdentificationThreshold:Alimitabove()whichanimpurityshouldbeidentified.•鉴定限：系指一个限度，大于该限度的杂质，应作鉴定ICH新原料药中的杂质指导原则ICHGuidelineonImpuritiesinNewDrugSubstances•QualificationThreshold:Alimitabove()whichanimpurityshouldbequalified.•论证限：系指一个限度，大于该限度的杂质应进行论证ICH新原料药中的杂质指导原则ICHGuidelineonImpuritiesinNewDrugSubstances•Qualification:Theprocessofacquiringandevaluatingdatathatestablishesthe•biologicalsafetyofanindividualimpurityoragivenimpurityprofileatthelevel(s)•specified.•论证：系指对单个杂质，或含规定量已知或未知杂质的新原料药获得生物安全性数据并进行评价的过程ICH新原料药中的杂质指导原则ICHGuidelineonImpuritiesinNewDrugSubstances•Theapplicantshouldprovidearationaleforestablishingimpurityacceptancecriteriathatincludessafetyconsiderations.Thelevelofanyimpuritypresentinanewdrugsubstancethathasbeenadequatelytestedinsafetyand/orclinicalstudieswouldbeconsideredqualified.•申报者应提供设定杂质限度的理由，包括安全性的理由。新原料药中含有的一定量的任何杂质，经安全性试验或临床研究，即认为是论证了的。ICH新原料药中的杂质指导原则ICHGuidelineonImpuritiesinNewDrugSubstances•ICH规定的杂质报告限鉴定限论证限ICH新原料药中的杂质指导原则ICHGuidelineonImpuritiesinNewDrugSubstances•1.说明在合成、纯化和贮存中该新原料药实际和可能存在的杂质•Theapplicantshouldsummariestheactualandpotentialimpuritiesmostlikelytoariseduringsynthesis,purificationandstorage•应依据合成的化学反应，可能带来杂质的原料，以及降解产物ICH新原料药中的杂质指导原则ICHGuidelineonImpuritiesinNewDrugSubstances•2.申报者应叙述检测新原料药中杂质的实验研究•Theapplicantshouldsummarizethelaboratorystudiesconductedtodetectimpuritiesinthenewdrugsubstance•应报告研究开发规模和商品规模批生产结果，稳定性强制试验的结果ICH新原料药中的杂质指导原则ICHGuidelineonImpuritiesinNewDrugSubstances•3.叙述按Q3A（R）附表1对新原料药中大于鉴定限的实际存在杂质进行的结构确证研究•Thestudiesconductedtocharacterizethestructureofactualimpuritiespresentinthenewdrugsubstanceatalevelgreaterthantheidentificationthresholdgiveninattachment1shouldbedescribedICH新原料药中的杂质指导原则ICHGuidelineonImpuritiesinNewDrugSubstances•按拟订工艺的商业化生产任一批大于鉴定限的任何杂质均应做鉴定•AnyimpurityatalevelgreaterthantheidentificationthresholdinanybatchmanufacturedbyproposedcommercialprocessshouldbeidentifiedICH新原料药中的杂质指导原则ICHGuidelineonImpuritiesinNewDrugSubstances•在建议贮存条件下进行的稳定性试验中发现的任何大于鉴定限的降解产物均应做鉴定(鉴定不成功的，应附相关资料）•AnydegradationproductobservedinstabilitystudiesatrecommendedstorageconditionsatalevelgreaterthantheidentificationthresholdshouldbeidentifiedICH新原料药中的杂质指导原则ICHGuidelineonImpuritiesinNewDrugSubstances•对不大于鉴定限的潜在的具显著毒性或药理作用的杂质，应研究分析方法•Analyticalproceduresshouldbedevelopedforthosepotentialimpuritiesthatareexpectedtobeunusuallypotent,producingtoxicorpharmacologicaleffectsatalevelnotmorethantheidentificationthresholdICH新原料药中的杂质指导原则ICHGuidelineonImpuritiesinNewDrugSubstances•Q3A（R）对分析的要求•在注册申报中应有成文的依据，说明分析方法经过验证，并适合于杂质的检出和定量•TheregistrationapplicationshouldincludedocumentedevidencethattheanalyticalproceduresarevalidatedandsuitableforthedetectionandquantificationofimpuritiesICH新原料药中的杂质指导原则ICHGuidelineonImpuritiesinNewDrugSubstances•Q3A(R)对定量限的要求•分析方法的定量限不能大于报告限•ThequantitationlimitfortheanalyticalprocedureshouldbenotmorethanthereportingthresholdICH新原料药中的杂质指导原则ICHGuidelineonImpuritiesinNewDrugSubstances•Q3A（R）对杂质对照品的要求•分析方法中检验杂质用的对照品，按其用途，应经评价并确定（结构）•ReferencestandardsusedintheanalyticalprocedureforcontrolofimpuritiesshouldbeevaluatedandcharacterizedaccordingtotheirintendedusesICH新原料药中的杂质指导原则ICHGuidelineonImpuritiesinNewDrugSubstances•Q3A(R)对批杂质含量报告要求•用于临床、安全、稳定性研究的全部批，以及拟订商业化生产代表性批的分析结果均应提供在申报资料中，用数字结果，