新药基因毒性杂质风险分析Risk assessment of genoto(5)

parisonofpredictedandmeasuredpurgefactorsfornitro-anilineimpurity(I)

identity/structureofGIofconcernstagedetailsreactivity(HL==100,1)M=10,solubilityL(F==1)10,M=3,volatility(LH==1)10,M=3,purge/stagefactormeasuredfactorpurgenitro-anilinereduction1001nonisolated1100

nitro-anilinecyclisation10101100not<5detectedppm

overallcalculatedpurgefactor10,000

Scheme5.Synthesisofomeprazolepotassium

saltScheme6.SynthesisofanAPIinvolvingtheuseofhydrazineandasubstitutedhydrazineintermediate(compound

2)

counting’approachtaken.Againariskassessmentwasmade,andthisgaveapredictedpurgefactorof10,000(comparedtoameasuredpurgefactorof40,000).Putinthecontextofthelevelformed(5%=50,000ppm)thenwithapredictedpurgefactorof10,000,thiswouldindicateapredictedlevelof<5ppm,apredictionsupportedbytheactualanalyticalresults.3.3.3.AZD9056Chloride.Thisexampleisperhapsthemost

interestingasitprovidestestamenttotheabilityofthisriskassessmenttooltogainacriticalinsightintotheprocess.Inthisinstancetheimpurityformedisunreactive,relativelyinsoluble,andnonvolatile,suchthatthecalculatedpurgefactorof3indicatesthattheprocessisthereforeunlikelytoe ectivelypurgethisimpurity.Thisagaintallieswiththeobservedfactorof10.Thus,inthisinstancethepredictionindicatestheneedforadditionalcontrol,eithertocontrolformationoftheimpuritythroughprocesscontrolormodi cationoftheprocesstofacilitateitsremoval.underpredictsthepurgecapacityoftheprocessbyafactorof3.4.CaseStudy4:GIinaRegisteredStartingMaterial.

10.Hadalessconservativevalueof100beenappliedtotheThefollowingexampleisderivedfromthesynthesisofareactivetermforthereductiveaminationstep,thentheregisteredstartingmaterialandrelatestoanassessmentofthepredictivevaluewouldhavematchedtheactualobservedvalue.riskofGIsbeingpresentwithinitasaresultofitssynthesis3.3.2.IsopropylChloride(IPC).Theexperimentalmeasure-(Scheme4).Theimpurityofconcernisthenitroprecursor(I)mentsshowedthatlevelsofIPCinsolutionexceeded5%w/w.InthisexampletheoverallcalculatedpurgefactorwasGiventhefactthatsuchahighlevelofaPGIisformedinthe10,000,thusindicatingalowprobabilityofcarryoverintothelatterstagesofthesynthesis,thiswouldgenerallybeastartingmaterial(<100ppm).Thispredictionwasshowntobesigni cantcauseforconcern.Thisiscertainlytruewerea‘stepcorrectwhentheactualpurgefactorwasmeasured,parisonofpredictedandmeasuredpurgefactorsfornitropyridylN-oxideimpurity(A)

identity/structureGIofconcernofstagedetails(H=reactivity100,L=1)M=10,(F=solubility10,M=3,(H=volatility

L=1)L10,=1)M=3,totalpermultiplestagemeasured(ppm)level

nitropyridyl(A)stagechloride1:formation11nonisolated11

nitropyridyl(A)stage2:coupling11nonisolated1120003000(basedspike)onnitropyridyl(A)stageformation3:oxidation/salt110110<1