肼杂质限度论证及控制策略研究—以水合肼用于药物合成工艺实际运作为例

摘要为了将化学合成类新药的安全风险控制在可接受状态，进行杂质遗传毒性评估判断十分重要。遗传毒性杂质极低的限度要求，对工艺和检测分析提出了更高的挑战，也成为药品进入欧美市场的技术挑战和潜在壁垒。国内目前合成类首创新药相对较少，若是合成药产业继续发展首创新药的比例提高，监管机构将来可能会有这方面关注与考量。设定遗传毒性杂质的可接受限度，需考虑研发所处的阶段，包括风险管理，适当的检测仪器与技艺精湛的检验人员，对杂质的认识和对工艺的理解，熟悉相应的法规与指南。本论文以肼杂质为例，检索文献数据，对杂质认识评估归类，运用风险管理工具，确定其可接受限度。遗传毒性物质分两种情况：一种情况是无法获得试验数据支持某一阈值的，通常基于风险的TTC（毒理学关注阈值）；另一种情况是已有文献试验数据阈值支持某一限度的。第二种情况表明细胞自身保护机制能起作用，遗传毒性风险相对要小，允许摄入的限度通常比TTC更高。若是出现推算结果比TTC更低的情况，需理解这些数据的含义，结合其它领域的信息，论证应用TTC限度的合理性。通过分析归纳总结，肼杂质按TTC控制可满足要求。再基于药品最大日剂量以及具体生产工艺，明确风险控制限度目标，确定控制策略。为选取合适的合成工艺，识别关键质量属性、确定关键工艺参数，规避或控制遗传毒性杂质方面的风险提供参考。关键词:遗传毒性；肼杂质；可接受限度；毒理学关注阈值（TTC）2StudyontheControlStrategiesandJustificationfortheAcceptanceLimitsofHydrazinesinActivePharmaceuticalIngredients--HydrazineHydrateUsedinSyntheticProcessasPerspectiveInordertoassessandcontrolthesafetyriskofnewchemicallysynthesizeddrugs,itisverycriticaltoinvestigateanddeterminethepotentialgenotoxicimpurities,whichwillrequirethewell-controlledmanufactureprocessandwell-developedanalyticalmethodologiestosupport.EvaluationandinvestigationofpotentialgenotoxicimpuritiesisbecomingacriticaltechnicalchallengeandpotentialbarrierfornewdrugsenteringintotheUSandEUregulatorydrugmarkets.AlmostallofthechemicallysynthesizeddrugsmarketedinChinahadalsobeenapprovedbyEUand/orUSandmarketedformanyyearsandbeenprovedtobesafe,andSFDAhasnotpaidtoomucheffort/attentiontothistopicoverthoseapproveddrugs.Howtosetupanappropriategenetoxicimpurityacceptancelimitduringthedrugdevelopmentphaserequiresalltheconsiderationsrelatedtodrugdevelopment,includingriskcontrolconcept,adequateequipments,skilfulanalysts,understandingtheregulationandguidelines,investigatingandevaluatingtheimpurityitself,fullknowledgetothemanufactureprocess.Inthisarticle,thegenotoxichydrazinesisusedasanexampletodemonstrateanddiscusshowtoclassify,qualitycontrolandsetupanacceptablelimit.Therearetwoconsiderablesituationsindealingwithgenotoxiccompounds:oneiswithoutsufficient(experimental)evidenceforathreshold-relatedmechanism;anotheristhegenotoxiccompoundswithsufficient(experimental)evidenceforathreshold-relatedmechanism.Usually,aThresholdofToxicologicalConcern(TTC)isestablishedforthefirstsituation,andapermissibledailyexposure(PDE)iscalculatedfromthenoobservableeffectslimit(NOEL)orthelowestobservedeffectlevel(LOEL)forthesecondsituation.IfahigherthanTTCacceptancelimitlevelcouldbesupportedbytheNOELorLOELdata,thenthisacceptancelimitisconsideredtobewelljustifiedandacceptable.Ifahigherlimitcould3notbesupportedbyNOELorLOEL,then,additionalinformationshouldbeprovidedtojustifywhethertheimpuritycanbecontrolledbyTTC.Ingeneral,controllingtheindividualhydrazinesimpuritybyTTClimitisacceptable.AndthenbasedupontheTTClimitandthemaxdailydosage,itisveryimportanttodesignanddeveloptheprocessandstudyingtherelationshipofthegenotoxicimpuritycontrolduringthechoiceofsynthesisroute.Alloftheseworkswillprovideimportantinformationtoestablishtheanalyticalproceduresanddeterminethegenotoxicimpuritiescontrolstrategy.Keywords:Genotoxicity,Hydrazines,AcceptanceCriteriaLimit,ThresholdofToxicologicalConcern(TTC)4目录第1章前言.........................................................................................................................................5第2章综述及背景介绍...........................................................................................................................82.1杂质的概念及相关指南...........................................................................................................82.2选题背景...................................................................................................................................92.3研究的意义.............................................................................................................................10第3章杂质风险评估流程.....................................................................................................................12第4章杂质结构评估与归类.................................................................................................................144.1杂质结构毒性风险归类.........................................................................................................144.2肼结构杂质归类.....................................................................................................................18第5章肼物质现行认可限度.................................................................................................................205.1药典现有产品的检索.............................................................................................................205.2肼的允许暴露量.....................................................................................................................205.3分析检测方法.........................................................................................................................21第6章其它途径摄入肼的允许限度.....................................................................................................276.1工作场所空气中的肼.............................................................................................................276.2呼吸途径日摄入量.......................