新药基因毒性杂质风险分析Risk assessment of genoto
时间:2025-03-10
时间:2025-03-10
RiskAssessmentofGenotoxicImpuritiesinNewChemicalEntities:StrategiesToDemonstrateControl
AndrewandIgnacioTeasdale,H.Sanchez*, DavidFloresElder,
#Sou-JenChang,§SophieWang,∥RichardThompson,⊥NancyBenz,¶
AstraZeneca,CharterWay,SilkRoadBusinessPark,Maccles eld,CheshireSK102NX,UnitedKingdom
GlaxoSmithKline,ParkRoad,Ware,HertfordshireSG120DP,UnitedKingdom
§AbbottLaboratories,200AbbottParkRoad,PA71,BuildingAP-50,AbbottPark,Illinois60064-6220,UnitedStates
∥AmgenInc.,1AmgenCenterDrive,ThousandOaks,California91320,UnitedStates
⊥BenVenueLaboratoriesInc.,BoehringerIngelheim,300North eldRoad,Bedford,Ohio44146,UnitedStates
¶AbbottLaboratoriesDepartmentR45T,BuildingR8-2,1401SheridanRoad,NorthChicago,Illinois60064,UnitedStates#TakedaGlobalResearch&DevelopmentCenter,Inc.,OneTakedaParkway,Deer eld,Illinois60015,UnitedStates
Syntheticprocessesusedtoproducepharmaceuticaldrugcategoriesrangingfromthosewithnostructuralalertsforsubstancestypicallyrequiretheuseofelectrophilicagentstogenotoxicitytothosethatareknowntobecarcinogenic.Thefacilitatecarbon carbon,carbon nitrogen,carbon oxygen,principlesofstructural
andcarbon sulfurbondformation.Examplesincludealkylating7alertswereoriginallyproposedbyAshbyandTennantonthebasisofstructure/Amesmutagenicity/agents,benzylhalidesandMichaelacceptors.Someofthesecarcinogenicitycorrelationsforcompoundscontaininganagentsmayalsopossesstheabilitytoreactwithbiologicalelectrophilicfunctionalgroup(oracompoundthatcouldbesubstratessuchasDNA,whichwouldraiseconcernsaboutmetabolisedtoonecontainingsuchareactiveentity,e.g.sometheirpotentialcarcinogenicity.Anyresiduesofacon rmedaromaticamines).
DNA-reactiveelectrophilicreagentorintermediateinadrugIn2008,theEMAadoptedthestagedTTCapproachinitssubstancewouldbecategorizedasgenotoxicimpurities(GTIs).publishedQ&Adocument,whilereducingtheallowedlimitstoExistingregulatory3guidelinessuchasICHQ3A(R2)/Q3BhalfofthoseproposedbythePhRMAtaskforce.8Asan(R2)/Q3C(R4)1 donotadequatelyaddresstherequire-mentsforcontrollingtracelevelsofGTIs.example,theEMAguidanceallowedalimitofdailyexposureof
60
μμgforclinicaltrialslastinglessthan30
marketingnalizedIn2004versiontheEUapplicationsin2006issuedforthatadraftpharmaceuticals.addressedguidancecontrollingfollowed4ThisEuropeanGTIsbyinastrategygasproposedwasproposedbythePhRMAbythetaskFDAforce.daysinsteadof120inAtheirsimilardraftstagedguidelineTTCMedicinesAgency(EMA)guidelinerecommendedthat,inissuedlaterin2008.9
caseswherespeci csafetydatawereunavailableforaGTI,theGTIsmaybegeneratedduringdrugsubstancesynthesis,GTIshouldbecontrolledtoalevelbasedonathresholdofdrugproductmanufacture,orduringstorageofdrugsubstancetoxicologicalconcern(TTC).Theguidelinerecommendedtheordrugproduct.Inmanycases,GTIscanbecontrolledduringTTCasadefaultlimitofdailyexposuretothepatientof1.5μgthedrugsubstancesyntheticprocessprovidedthattheGTIsinonthebasisofanincreasedcancerriskof10 5.questionarenotgeneratedaseitheradrugsubstanceAlsoin2006,aPhRMAtaskforceissueditswhitepaperdegradationproductorproducedduringdrugproductproposingastagedTTCwhereinexposuretohigherlevelsofmanufacturingorstorage.IncaseswheretheGTIisgeneratedGTIswouldbeacceptableincaseswheredurationofexposurethroughinteractionswithmanufacturingprocessingagentsislimited,asisthecaseduringclinicaldevelopment.5The(e.g.,excipients,residualsolvents,etc.)orduringstorageduringhigherlimitswerebasedonanextrapolationfromdailylifetimenormalconditions,controllingthelevelsoftheGTIinthedrugexposuretoshort-termexposuresoflessthan12months6butproductmayalsoberequired.ManyoftheprincipleswithanadditionalsafetyimplementedforthecontrolofGTIsindrugsubstancewill
6factorapplied,sothecalculatedexcessriskofcancerwas10insteadof10 5,sinceearlyclinicaltrialsoftenincludehealthyvolunteers,andevenforpatientstheReceived:September25,2012
pharmacologicalbene tofthedrugmaynotyethavebeenPublished:January14,2013
Table1.PhRMAsurveyresultsonGTIs
areasofgeneralconsensusareasofdiversity
evaluationoftheAPIsyntheticpathwayforGTIsatthepreclinicalstagepointmonitoringinthesyntheticforGTIsprocesstobeginconsidertheGTIthenumberofstepsbackfromthe nalAPIthattheGTIoriginateswhenprovidingarationalefornottestinguseofofGTIslimittestsvsquantitativereportinguseeliminatedofscienti incjustithedownstream cationinlieuchemistryoftestingorwhenprocessaGTIisintroducedearlyintheprocessandisreactiveenoughtobedegreecontrolofofvalidationGTIs
ofmethodsusedforalsoapplyfordrugproduct.However,thedrugproductprocesselectrophilicreagents.Theirinherentreactivenatureandisoftenconstrainedinitsabilitytopurge(orremove)GTIs.potentialtoreactwithnucleophiles(includingDNA)mayAcriticaltenetofdrugsubstanceprocessdevelopmentistoensurethatGTIsintroducedorgeneratedduringtheprocessraiseconcernsfromtheperspectiveofcarryoverintothe nalarecontrolleddrugsubstance.However,highlyreactiveelectrophilicreagents
4toacceptablelevels.OnthebasisofEMAguidancetheselimitsarecurrentlybasedonthestagedTTC,shouldbee ectivelypurgedfromtheAPIsynthesisbyanyTTC,orcompoundspeci csafetydataassociatedwiththesubsequentdownstreamchemistry.Therefore,anevaluationofimpurity(ies)concerned.GTIcontrolmaybeexecutedthroughtheriskposedbysuchimpuritiesisrequired.TheassessmentofimplementationofsimpleprocessoperationssuchaswashesGTIcarryoverinvolvesidentifyingthepotentialpresence/andcrystallizationstepsandinmanycasesindirectlythroughremovalofsuchentities,asthesyntheticreactionproceedstofurtherdownstreamsyntheticreactions.Thus,thedevelopmentthe nalAPI.ItiscriticalthatsuchanassessmentbalancestheofthedrugsubstanceprocessincludesconsiderationsthatareriskofobservingtheGTIinthe naldrugsubstancewiththebasednotonlyonscale-up,safety,economicandenvironmentalprobabilityofitsremoval(purge)basedonknowledgeofthefactorsbutalsoontheproductionofanAPIwithimpuritychemistryusedinthesyntheticprocess.Itisimpracticaltolevelsthatareincompliancew …… 此处隐藏:7556字,全部文档内容请下载后查看。喜欢就下载吧 ……