2.3.RiskAssessmentofGTICarryover.Ifastartingempiricalapproachestosuchassessmentsbasedonthepointofmaterial,reagent,intermediate,orabyproductisidenti edasaintroductionoftheGTIinquestionandthenumberofstagespossibleGTI,itmayappearthatthebestwaytocontrolitremovedfromtheAPI.Suchanapproach,euphemisticallywouldbetoeliminateitspresencethroughanalternatereferredtoas‘stagecounting’,hasunfortunatelynotbeensynthesisroute.However,inmostcases,thisisanimpracticaluniversallyacceptedbyregulatoryauthorities.Severalregu-approachbecauseanalternatesynthesismayproducelowerlatoryagenciescontinuetoasktheSponsortoprovideyields,havepooreroverallqualitycontrol,andultimatelymayanalyticaldataevenincaseswherecompellingscienti cnotbeeconomicallyfeasible.Moreimportantly,itishighlyargumentswouldsuggestproofofabsence.Suchargumentslikelythatanyalternatesynthesiswillcontainotherimpuritiesshouldbesu cient,particularlywhentheassessmentaddressesthatrequiresimilarcontrolattheTTClevel,andsigni cantthechemistry(reactionsandpuri cations)speci ctoeachstepadditionale ortwillberequiredtodischargetheriskofthosethatisbeing“counted”inaparticularprocess.Nonetheless,itnewimpurities,withoutmateriallyimprovingthesafetyofthewouldbeusefuliftherewereanalternativeapproachthatAPIorreducingtheoverallrisktopatients.ControlofGTIscontainedaquantitative(orsemiquantitative)element,asisratherthaneliminationisthereforestronglyadvocated.Similarpresentedanddescribedinthefollowingsection.considerationsapplytoALARP(aslowasreasonablyItispossibletotakesuchanapproachtoriskassessmentonpracticable)andwereacceptedbyEMAintheQ&Athebasisofthespeci cphysicochemicalpropertiesofaGTI,supplements.8alongwithanunderstandingoftheprocessconditionstowhichTodemonstratecontrol,anassessmentofthepotentialriskitisexposed,toquantitativelyassesstherisk.Theserisk-basedofcarryoverofaGTIatalevelexceedingstagedTTCorTTCassessmentsrelyontheconceptofevaluatingpurgefactorslevelstothedrugsubstanceismade.Thisisalignedwithqualitywhichcanbede nedastheabilityofasyntheticprocesstobydesign(QbD)andtheriskassessmentprinciplesenshrinedpurge(eliminate)aparticularGTI.19,20

inICHQ8andQ9.11,12Aseeminglysimplebutpotentially2.4.PurgeFactors.Theprinciplesupportingthemyopicwaytoaddressthisistodevelopasensitiveanalyticalcalculationofapurgefactorisasimpleone.ItistoidentifymethodandtestforthepossibleGTIinquestionatthepointthekeyphysicochemicalparametersthatin uencetheremovalafterintroduction,atthe naldrugsubstance,oratsomeofaspeci cGTIinaprocess(inQbDterms:criticalqualityintermediatepoint,i.e.QualitybyTesting(QbT).Thisattributes(CQAs))andtousethese,incombinationwiththeapproach,however,canbeatechnicallychallengingandspeci cprocessconditions,todetermineapurgefactor,i.e.howresource-intensiveactivity,especiallywhenappliedtoallthemuchoftheGTIislikelytoberemoved.GTIsthatareassociatedwiththesyntheticprocessandrunsThekeyparametersidenti edarereactivity,solubility,contrarytothetenantsofQbD.Moreoverthisapproachfailstovolatility,ionisability,plusanyadditionalphysicalprocessrecognizethatreactiveGTIswilloftenbedestroyedordesignedtoeliminateimpurities,e.g.chromatography.Theeliminated nalinthesubsequentprocessstepsleadinglatterapproachisoftenemployedinmedicinalchemistrysyntheticroutesemployedforpreparingtestmaterialsfor rstThedrugtotheusesubstance.ofscienti cunderstandinginrelationtoevaluationhumanclinicaltrials.InordertoensurethataconsistentofGTI-relatedriskisgrowing.Severalarticles13,14haveoutlinedapproachistaken,ascoringsystemhasbeendevisedwhichistheuseofQbDprinciplesintheassessmentofGTI-relatedrisk,outlinedinTable2.thesebeingcenteredontheuseofspiking/purgefatestudiesto2.4.1.Reactivity.Thepurposeofthisspeci cparameteristoprovetheabilityofthesyntheticprocessinquestiontoremoveassessthereactivityoftheGTIinquestioninrelationtospeci cGTIs.Suchapproachesareextremelyusefulwhenprocessingconditionstowhichitissubsequentlyexposed.Onappliedinthecontextofa xedprocess.thebasisofreactivitytowardtypicalreagentsWorkconductedbytheProductQualityResearchInstituteencounteredduringworkuporstorage(e.g.,otherchemicals(PQRI)relatingtosulfonateesters15,16(Teasdaleetal.)usedwithintheprocess,water,acid,base,alcohols,etc.)itiscompellinglydemonstratedhowagoodscienti cunder-proposedthatGTIscouldbegenerallyplacedintooneofthreestandingofthepropertiesofacompound,combinedwithacategories(seeTable3).riskassessmentoftheimpactofprocessconditions,canbeusedItiscritical,though,thatanysuchclassi cationmusttakee ectivelytocontrol,oreveneliminatethepotentialGTIriskposed.Suchapproachesasthosedescribedabove,althoughoneforcomprehensive,areimpracticaltoapplytoallpossibleGTIsahighlyreactiveGTI,e.g.acylhalide,andthesecondforalesswithineachandeverysyntheticprocess.Whatissoughtinsteadreactivearylnitrocompound.isarisk-basedmechanismwherebythepotentialriskofThionylchlorideistypicallyusedtoconvertnonreactivecarryovercanbequicklyandsimplyassessed.Formanycarboxylicacidsintoreactiveacylhalides,whichcanthenbeimpurities,chemistry-basedargumentsalonemaybesu cientfurtherprocessed(e.g.,formationofesters,amides,etc.).21toconcludethatanimpuritywouldnotresideinthe nalAPIHowever,duetotheirhighreactivitytheyareverye cientlywithouttheneedforlaboratoryexperimentation.Thisapproachpurgedfromthesubsequentdownstreamchemistryreac-isoftenusedwhenprocessingconditionsforthedownstreamtion(s);thisalsoappliestothionylchlorideitselfwhichreactspurgeordestructionoftheimpurityareobvious.Aconsistentviolentlywithwater.22

frameworkforthistypeofrisk-basedassessmentwherebytheIncontrast,arelativelystablenitrocompoundwouldshowpotentialforcarryovercanbeassessedthroughconsiderationofhighreactivity,undermostreductionconditions,toformanthephysicochemicalpropertiesoftheGTIandtherelevantaromaticamine,butitmaywellbeunreactiveduringprocessingconditionsisrecommended,thepotentialbene tssubsequentstagesoftheprocess.toregulatoryreviewersbeingobvious.SuchanapproachisnotExperimentaldatarelatingtotheprocess(e.g.inprocessanewconcept.BothDobo17andPierson18havedescribedreactionmonitoring)canbeusedtore neth …… 此处隐藏：13702字，全部文档内容请下载后查看。喜欢就下载吧 ……