原料药中基因毒性杂质控制的研究进展

20151321ChinJModApplPharm,2015January,Vol.32No.1119(322002)(activepharmaceuticalingredientAPI)R284.1A1007-7693(2015)01-0119-08DOI:10.13748/j.cnki.issn1007-7693.2015.01.032DevelopmentofGenotoxicImpuritiesControlinActivePharmaceuticalIngredientWANGPing,XUCaihong,CHENXian,HUAiling,LOUChao,JINXiufang,GONGJunqiang,CHENYiqun(ZhejiangHuayiPharmaceuticalCo.,Ltd.,Yiwu322002,China)ABSTRACT:OBJECTIVETointroducethebackgroundofregulatoryguidance,valuationandcontrolstrategyofgenotoxicimpuritiesinactivepharmaceuticalingredient(API).METHODSBasedontheunderstandingofregulatoryexpectationsonthecontrolofgenotoxicimpuritybystudyingofthehistoryofEuropeanandUSregulations,proposemethodsforassessing&controllinggenotoxicimpuritiesindrugsubstance.RESULT&CONCLUSIONThemosteffectivewaytoachievetheregulatoryexpectationsistoestablishcontrolstrategiesbasedonacombinationofsemi-quantitativeassessment,alliedtoanalyticalresultsanddatafromappropriatepurgingstudies.Suchanapproachshouldensurethatanyactualgenotoxicimpurityrelatedriskisclearlyidentifiedandmanaged.KEYWORDS:genotoxicimpurities;API;riskassessmentTel:[phone]E-mail:[e-mail](activepharmaceuticalingre-dientAPI)11.12000PharmEuropa[1]200212EMEA(SafetyWorkingPartySWP)(CommitteeforProprietaryMedicinalProductsCPMPCommitteeforHumanMedicinalProductsCHMP)[2]ICHQ3C(R5)120ChinJModApplPharm,2015January,Vol.32No.120151321[3](aslowastechnicallyfeasibleALATF)2004()(aslowasreasonablypracticalALARP)ALATF(thresholdoftoxicologicalconcernTTC)(1.5µg·d1)[4](70)1.5µg(1/100000)(ppm)=TTC(µg·d1)/(g·d1)TTC[5]50%TD50730TD50TD5010-6500000DNATTCTTCTTC1.5µg·d1TTC(PharmaceuticalResearchandManufacturersofAmericaPhRMA)LutzMueller20061PhRMA[6]TTC11GTIsTab.1Proposedallowabledailyintakeforgenotoxicimpuritiesduringclinicaldevelopmentdependingonthedurationofexposure/µg·d1()1120a0.5%c1~340a0.5%c3~620a0.5%c6~1210a0.5%c121.5bca10693%b10593%70c()Note:aProbabilityofnotexceedinga106riskis93%;bProbabilityofnotexceedinga105riskis93%,whichconsidersa70-yearexposure;cOtherlimits(higherorlower)maybeappropriateandtheapproachesusedtoidentify,qualify,andcontrolordinaryimpuritiesduringdevelopedshouldbeapplied.121/1000000TTC1/100000522Tab.2Clarificationofgenotoxicimpurities()()2-TD50(MTD)()NOEL(LOEL)DNA(DNADNA)TTCAPI()AmesAPIAmesAPIppmAPI()APIAPIAPI20151321ChinJModApplPharm,2015January,Vol.32No.112120066EMEA[7]2008CHMP(CHMPSafetyWorkingParty,SWP)Q&A[8]TTCSWPTTCLutzMuellerTTC33TTCTab.3AstagedTTCapproach/g1201601~3203~6106~125121.5SWPEDQM44Tab.4EDQMdecisiontableforuseduringelaborationorrevisionofmonographsCHMPCHMPCHMP()()CHMPCHMPCHMPSWP()1.5µg·d1TTCALARPSWPQ&AICHICHSWPICHQ3aICHQ3a122ChinJModApplPharm,2015January,Vol.32No.1201513211.2FDAEMEAQ&AFDAEMEA2008FDA200812FDA[9]FDAEMEATTCSARFDAICHEMEAQ&AALARPFDAEUTTCFDA120µg·d1(14d)ICHICHM7201326[10]TTCAPIGTIs422.1EDQM2006[11]EDQMTOP102011552011EDQM[12]Tab.5TopthreedeficienciesfornewapplicationforCEP(2011)[12]0.10%330%TTC2.2EMEA20151321ChinJModApplPharm,2015January,Vol.32No.1123API(API)API(API)()APIAPI2.3EMEAFDADEREKMcaseAshbyTennant[13]11Fig.1Structuralalerts2.4LutzMueller52SARSAR(Ames)TOXNET(HazardousSubstancesDatabankHSDB)(ChemicalCarcinogenesisResearchInformationSystemCCRIS)(IntegratedRiskInformationSystemIRIS)BerkeleyTTC2.52.5.12124ChinJModApplPharm,2015January,Vol.32No.1201513212Fig.2Reactionschemeexample66Tab.6GenotoxicCompoundsClassifiedbasedonReactivitya/////NS/Michael//aNote:aSusceptibletoattackbyawiderangeofpotentialnucleophiles.2.5.2-()2.5.3/2.5.4APIpH()4-[14]2.5.5API()()Bandichhor[15]5-HT0.01%pH20151321ChinJModApplPharm,2015January,Vol.32No.112540000ppm40~80ppm(95%)2.5.6APIAPI2.5.72.6(spiking)(purging)Liu[16]/53()35Fig.3FivepotentialgenotoxicimpuritesintheprocessofpazopanibHCl(5%)1670ppmii223ppm3APIAPI1.7ppm(ii)3EMEAFDAICHM7REFERENCES[1]EuropeanDirectoratefortheQualityofMedicinesandHealthcareAlkylmesilate(methanesulfonate)impuritiesinmesilatesalts[S].Pharmeuropa,2000,12(1):27.[2]SafetyWorkingParty.Positionpaperonthelimitsofgenotoxicimpurities(CPMP/SWP/5199/02/draft2)[S].London:CommitteeforProprietaryMedicinalProducts,2002.[3]ICHExpertWorkingGroup.Impurities:GuidelineforResidualSolventsQ3C,(R5)step4version[S].EuropeanUnion,JapanandUSA:ICHHARMONISEDTRIPARTITE(ICH),2011:6-7.[4]MUNROIC,RENWICKAG,DANIELEWSKA-NIKIEIB.Thethresholdoftoxicologicalconcern(TTC)inriskassessment[J].ToxicolLett,2008,180(2):151-156.[5]KROESR,RENWICKAG,CHEESEMANNM,etal.Structure-basedthresholdsoftoxicologicalconcern(TTC):126ChinJModApplPharm,2015January,Vol.32No.120151321Guidanceforapplicationtosubstancespresentatlowlevelsinthediet[J].FoodChemToxiccol,2004(42):65-83.[6]MULLERL,MAUTHERJ,RILEYCM,etal.Arationaleforspecificimpuritiesinpharmaceuticalsthatpossesspotentialforgonotoxicity[J].RegulatToxicolPharmacol,2006(44):198-211.[7]CommitteeforMedicinalProductsforHumanUse(CHMP)Guidelinesonthelimitsofgenotoxicimpurities(CPMP/SWP/5199/02)[S].London:EuropeanMedicinesAgencyEvaluationofMedicinesforHumanUse(EMEA),2006.[8]CHMPSafetyWorkingParty(SWP).Question&answerontheCHMPguid