0707基因杂质PhRMA文献综述.docx

0707基因杂质PhRMA文献综述.docx

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0707基因杂质PhRMA文献综述

GenotoxicImpuritiesInPharmaceuticals

SubmittedbypoonmpharonMon,05/24/2010-11:

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Decisionstoapprove,prescribeandconsumemedicinesinvolverisk/benefitassessmentsbyregulatoryagencies,healthcareprofessionalsandconsumers.Forseriousorlifethreateningconditions,drugswithhigherrisksforadverseeffectsorforseriousadverseeffectsaresometimesacceptable.Forexample,somelife-savingcancerchemotherapiesareknownhumancarcinogens.However,ifoneissufferingfromalifethreateningtumor,a5%riskofasecondary,treatment-relatedtumorisgenerallyconsideredacceptable.Arguably,thesameisnottrueforimpuritiesfoundindrugsubstancesanddrugproducts;impuritiesconveyonlyriskwithnoassociatedbenefit.Drugimpuritiesmightbeviewedas“pollutants”inthepharmaceuticalworld.Muchlikepollutantsintheenvironment,fewpeoplebelievethattheycanbeentirelyeliminated.Thechallengeforregulatoryagenciesistopromulgatestandardsthatassurethatunavoidabledrugimpuritiesimpartnooracceptablelevelsofrisk.

Residualimpuritiesresultingfrommanufacturingandformulation,orfromdegradationoftheactivepharmaceuticalingredient（API）andexcipients,maybepresentinpharmaceuticalproducts.Asubsetoftheseimpuritiesmaypresentapotentialforgenotoxicityandthereforeposeanadditionalsafetyconcerntoclinicalsubjectsandpatients.Thepharmaceuticalindustryandthosethatregulateitrecognizetheirrespectiveobligationtolimitgenotoxicimpurities.Therefore,substantialeffortsaremadeduringdevelopmenttocontrolallimpuritiesatsafeconcentrations.However,theeffortmadetolimitimpuritiesmustbecommensuratewiththeriskassessedateachphaseofclinicaldevelopment,takingintoaccounttheextentofthehazard,thediseaseindication,thesizeandcharacteristicsoftheexposedpopulation,andthedurationofthatexposure,aswellasthelikelydelayintheavailabilityofbeneficialmedicinesiftheburdenoflimitingorcontrollingimpuritylevelsisdisproportionate.Abalanceoftheseconsiderationscanbedescribedbestasthe‘‘aslowasreasonablypracticable’’（ALARP）principle.Itfollowsthatthepresenceofimpuritieswithgenotoxic（mutagenic）potentialmaybeunavoidableinclinicaltrialandultimatelyinapprovedandmarketedmaterials.ControlofimpuritiesinthedrugsubstanceanddegradantsindrugproductareaddressedinICHQualityGuidelinesQ3A（R）andQ3B（R）,respectively,andtheQ3Cguidelinethatdealswithresidualsolvents.However,nospecificguidancefordeterminingacceptablelevelsforgenotoxicimpuritiesisprovidedinthesedocumentsotherthantorecognizethefactthatunusuallytoxicimpuritiesmayrequiretighterlimitsofcontrol.

LimitingGenotoxicImpurities:

Amajorchangeinimpuritytestinginvolvesanewregulatoryguidancedesignedtotightlylimitsubstancespossessingpotentialforgenotoxicity.TheEuropeanAgencyfortheEvaluationofMedicinalProducts（EMEA）guidanceongenotoxicimpurities,whichbecameeffectiveonJan.1,2007,nowappliesa1.5μgdailyexposurelimitforsuchsubstancesinmostpharmaceuticalsbasedonaprecedentapplicationofthethresholdoftoxicologicalconcern（TTC）concepttofoodadditivesandfoodcontactmaterials.BeforetheEMEAdraftguidance,genotoxicimpuritieshadbeenaddressedonlyasafootnoteinICHQ3A（R2）"ImpuritiesinNewDrugSubstances".

In2004,thePharmaceuticalResearchandManufacturersofAmerica（PhRMA）formedataskforcetodiscussgenotoxicimpuritylimits.Concernedthe1.5μg/daylimitwouldbeappliedtodrugssynthesizedintheUnitedStates,evenwhilethesedrugswerestillinclinicaldevelopment,thePhRMAgroupproposedastagedTTCapproachthattiespermissibleimpuritylevelstothestageofdevelopment.Becauseclinicalstudiesareconductedwithlimiteddurationofdosing,thegroupreasonedthattotalexposureisverylow,andthushigherintakelevelsshouldbeallowableduringearlyclinicalstudieswithoutanetincreaseinrisk.PhRMA'sstagedTTCapproachappliestoallclinicalroutesandtocompoundsatallstagesofdevelopment,foridentifiedandpredictedimpurities.TheTTClimitswouldnotapplytoalreadymarketedproducts.

USFDAhasconsideredboththeguidelinesinsettinglimitsongenotoxicimpurities.

EmeaGuidelineOnLimitsOfGenotoxicImpurities

TheEuropeanMedicinesAgency's（EMEA）CommitteeforMedicinalProductsforHumanUse（CHMP）publishedaguidelineonthelimitsofgenotoxicimpurities.Thisguidelinerecommendsdichotomizinggenotoxicimpuritiesintothoseforwhichthereis“sufficient（experimental）evidenceforathreshold-relatedmechanism”andthose“withoutsufficient（experimental）evidenceforathreshold-relatedmechanism.

”ThosegenotoxiccompoundswithsufficientevidencewouldberegulatedusingmethodsoutlinedinICHQ3C,forclass2solvents.Thisapproachcalculatesa“permitteddailyexposure”（PDE）whichiscalculatedusingtheNOELorLOELfromthemostrelevantanimalstudyplusincorporationofsafetyfactors.Examplesofgenotoxinsthatmayfallintothisclassincludechemicalsthatinduceaneuploidybyinterferingwiththemitoticspindle,chemicalsinterferingwithactivityoftopoisomeraseorchemicalsthatinhibitDNAsynthesis.

Forgenotoxiccompoundswithoutsufficientevidenceforathreshold-relatedmechanism,theguidelineproposesapolicyofcontrollinglevelsto“aslowasreasonablypracticable”（ALARPprincipal）.Thisapproachspecifiesthateveryeffortshouldbemadetopreventtheformationofsuchcompoundsduringdrugsubstancesynthesisand,ifnotpossible,effortsshouldbemadetoreducesuchimpuritiesthroughtechnicalefforts（e.g.purificationsteps）.CompoundsfallingintothisclassaregenerallythosethatinteractwithDNAeitherdirectlyorindirectlysuchasalkylatingagents,intercalatingagentsoragentsgeneratingfreeradicals.Sinceallexposurestosuchagentstheoreticallyconveysomelevelofcarcinogenicrisk,regulatoryagenciesgenerallyperformquantitativeriskassessmentstocalculatetheincreasedlevelsofadverseevents,suchascancers,thatresultfromparticularexposuresandsetexposurelevelswhichresultin“acceptable”risks;often1in105or1in106additionalcancersfromlifetimeexposures.

Whiletheapproachdescribedabovehassoundscientificsupport,inmostinstancessufficientmechanisticdatawillbelackingwithwhichtodecidewhetherathresholdmechanismisapplicableforgenotoxicimpurities.Furthermore,itisalsounlikelythatdatawillexistonwhichquantitativeriskassessmentscanbeperformed.Theguidelinerecognizestheselimitationsandthereforeproposestheuseofa“thresholdoftoxicologicalconcern”（TTC）forgenotoxicimpurities.TheTTCreferstoathresholdexposureleveltocompoundsthatwillnotposeasignificantriskofcarcinogenicityorothertoxiceffectsandwasoriginallydevelopedasa“thresholdofregulation”forfoodcontactmaterialsbytheFDA.ThedraftguidelineproposesaTTCof1.5µg/day.Thisthresholdcorrespondstoa10-5lifetimeriskofcancer,arisklevelthattheEMEAconsidersjustifiedduetothebenefitsderivedfrompharmaceuticals.Importantly,however,thisdraftguidelineonlyaddresseslevelsofgenotoxicimpuritiesinmarketedproducts;theguidelineissilentonwhatmightconstituteacceptableTTCsfordrugsduringdevelopment,especiallyfortrialsofshortduration.

1-GenotoxicCompoundswithSufficientEvidenceforaThreshold-RelatedMechanism

Examplesofmechanismsofgenotoxicitythatmaybedemonstratedtoleadtonon-linearorthresholdeddose-responserelationshipsincludeinteractionwiththespindleapparatusofcelldivisionleadingtoaneuploidy,topoisomeraseinhibition,inhibitionofDNAsynthesis,overloadingofdefencemechanisms,metabolicoverloadandphysiologicalperturbations（e.g.inductionoferythropoeisis,hyper-orhypothermia）.For（classesof）compoundswithclearevidenceforathresholdedgenotoxicity,exposurelevelswhicharewithoutappreciableriskofgenotoxicitycanbeestablishedaccordingtotheprocedureasoutlinedforclass2solventsintheQ3CNoteforGuidanceonImpurities:

ResidualSolvents.Thisapproachcalculatesa“PermittedDailyExposure”（PDE）,whichisderivedfromtheNOEL,orthelowestobservedeffectlevel（LOEL）inthemostrelevant（animal）studyusing“uncertaintyfactors”（UF）.

2-GenotoxicCompoundswithoutSufficientEvidenceforaThreshold-Related Mechanism

Theassessmentofacceptabilityofgenotoxicimpuritiesforwhichnothresholdmechanismsareidentifiedshouldincludebothpharmaceuticalandtoxicologicalevaluations.Ingeneral,pharmaceuticalmeasurementsshouldbeguidedbyapolicyofcontrollinglevelsto“aslowasreasonablypracticable”（ALARPprinciple）,whereavoidingisnotpossible.LevelsconsideredbeingconsistentwiththeALARPprinciplefollowingpharmaceuticalassessmentshouldbeassessedforacceptabilityfromatoxicologicalpointofview.

2.1PharmaceuticalAssessment

Arationaleoftheproposedformulation/manufacturingstrategyshouldbeprovidedbasedonavailableformulationoptionsandtechnologies.Theapplicantshouldhighlight,withinthechemicalprocessandimpurityprofileofactivesubstance,allchemicalsubstances,usedasreagentsorpresentasintermediates,orside-products,knownasgenotoxicand/orcarcinogenic（e.g.alkylatingagents）.Moregenerally,reactingsubstancesandsubstanceswhichshow“alertingstructure”intermsofgenotoxicitywhicharenotsharedwiththeactivesubstanceshouldbeconsidered.Potentialalternativeswhichdonotleadtogenotoxi