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.Itisimpracticaltolevelsthatareincompliancewithregulatorystandards.evaluate/identifyeveryconceivableimpurity;hence,suchanTheevaluationandcontrolofGTIsinasyntheticprocessisaassessmentthereforeneedstobebasedonprocessunder-multidisciplinaryactivity.Considerationsfromtoxicological,standingoflikely/probableimpurities.IndeedtheEMAprocessing,andanalyticalperspectivesareinvolvedandmustguidelineadvocatessuchanapproach.4

alignwithregulatoryrequirements.Whilecurrentregulatory2.2.TheEvaluationProcess.EvaluationofgenotoxicguidancedoesprovideclearexpectationsregardingtheallowedpotentialisgenerallyperformedinitiallythroughacomparisonlimitsofGTIsduringclinicaldevelopmentandatmarketingofstructuresofreagents/startingmaterials/intermediatesintheapplication,therearestillanumberofareasopentosyntheticschemewiththoseofknowngenotoxins,eitherinterpretation.ExamplesofGTIregulatorygrayareasincludethroughsimplecomparisonwithaknownalertingfunctionality,de ningthescopeofthesearchforGTIs(numberofchemicale.g.Ashby Tennantalerts,7throughsearchesofpublishedstepsbackfromthe naldrugsubstanceinthesynthesisandinformation,orthroughassessingstructuresina(quantitative)considerationofhypotheticalbyproducts),howscienti cstructure/activityrelationshipSAR/QSARsoftwaredatabasejusti cation(basedonchemicalexpertiseandknowledgeofsuchaDEREK(deductiveestimationofriskfromexistingthechemistryofthesyntheticprocess)canbeusedinlieuofknowledge)eofotheranalyticaltesting,expectationsfortypeofanalyticalmethod-sourcesoftoxicologicaldata,e.g.TOXNET,canalsobeuseful,ologyandrequiredlevelofvalidation,anduniversalunder-thisbeingparticularlytruewhenaddressingrelativelycommonstandingofspeci ccontrolsasafunctionofstageofclinicalreagentsforwhichspeci csafetydatamayalreadyexist.development.Abenchmarkingsurvey,issuedbyPharmaceut-ItiscriticalthatanysuchassessmentisaugmentedbyhumanicalResearchknowledgeandexpertise.Forexample,thedatasetunder-

10andManufacturersofAmerica(PhRMA)in2009,re ectsthatmanyoftheseareasareaddressedpinningtheinsilicosystemshouldbeevaluatedinordertodi erentlybyindustryandregulatoryagencies(Table1).ensurethatthereissu cientdatabasecoveragetoallowtheTheproposalsdescribedinthispaperexpandupontheEMAreviewertohavecon denceineitherapositiveoranegativeguidelineandFDAdraftguidancetodescribestrategicresultfromtheSARanalysis.

approachesforevaluationofGTIsthroughoutthevariousThestructuresassessedtypicallyincludestartingmaterials,stagesofpharmaceuticaldevelopment.Itdetailsriskassessmentreagents,intermediates,andknownprocessimpurities.ThisisstrategiesthatcanbeimplementedtoevaluatewhichGTIsoftenfurtheraugmentedduringthedevelopmentprocessbyshouldbemeasuredanalyticallyandwheretestingcanbetheinclusionofadditionalstructuresthatarederivedfromeliminatedorreducedonthebasisofscienti crationale.eitherincreasedknowledgeofthesyntheticprocess(intermsof

2.AQUANTITATIVERISKASSESSMENTFORimpuritiesassociatedwiththeprocess)and/oridenti edEVALUATIONOFGENOTOXICIMPURITYdegradationproductsofthedrugsubstance(andproductCARRYOVERwhereapplicable).Compoundsthatdonotcontainstructuralalertsfor

2.1.ScopeofEvaluation.AsoutlinedintheIntroduction,genotoxicityaretreatedasconventionalimpuritiesthemajorityofGTIsarisefromthesyntheticprocessitself.3andarecontrolledinaccordancewithICHQ3A/3B/3C.1 Com-Syntheticdrugsubstancesaretypicallyconstructedthroughpoundswithstructuralalertsforgenotoxicityrequirefurthersystematicmodi cationofacompound’smolecularframeworkaction.Thesecompoundscanbetestedformutagenicitythroughtheformationandrecon gurationofcarbon carbon,throughinvitromethods,typicallyAmestesting.IftheAmescarbon nitrogen,carbon oxygen,andcarbon sulfurbonds.testisnegative,thentheimpuritycanbetreatedasaCurrentsyntheticmethodologyissuchthattheformationofconventionalimpurityandmanagedasperICHQ3A/3B/3Csuchbondsispredominantlyachievedthroughtheuseofguidelines.