Implementation of ICH Q3D Elemental Impurities Guideline Challenges and Opportunities.docx
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Implementation of ICH Q3D Elemental Impurities Guideline Challenges and Opportunities.docx
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ImplementationofICHQ3DElementalImpuritiesGuidelineChallengesandOpportunities
ImplementationofICHQ3DElementalImpuritiesGuideline:
ChallengesandOpportunities
AssessingriskfactorsiskeytoimplementingthenewICHQ3Dguidelines.
Mar02,2015
By AndrewTeasdale, CyrilleC.Chéry, GrahamCook, JohnGlennon, CarlosW.Lee, LaurenceHarris, NancyLewen, SamuelPowell, HelmutRockstroh, LauraRutter, LanceSmallshaw, SarahThompson, VickiWoodward, KatherineUlman
RafeSwan/Cultura/gettyimages
NewguidelinesrelatingtoelementalimpuritiesfromtheInternationalConferenceonHarmonization(ICH),Q3D GuidelineforElementalImpurities
(1)havepresentedthepharmaceuticalindustrywithnewchallenges.Thesechallengesincludethecomplexityofintroducingnewanalyticaltechnology—specificallyinductivelycoupledplasma(ICP)-basedtechniquesreplacingthewetchemical“heavymetals”limittest—alongwithnewandspecificlimitsforindividualelements.Perhapsthemostsignificantchallenges,however,arerelatedtothepracticalimplementationoftheguideline.
ICHQ3Dadvocatestheuseofarisk-basedapproachtoassessingthepotentialpresenceofelementalimpuritiesindrugproducts.Whilesuchassessmentsarecommonwithinotheraspectsofpharmaceuticaldevelopment,applicationtoelementalimpurityassessmentpresentsnewchallenges.Specificchallengesincludedetermininghowtoassessorquantifytherisksassociatedwithfactorssuchaswater,container-closuresystems,andexcipients.Definingwhereintheassessmentprocessdatamayberequiredandidentifyingwhereriskscanbedeterminedtobenegligiblethroughathoroughscientifictheoreticalriskassessmentalsopresentsignificantquestions.Thisarticleseekstoreviewthesequestionsbylookingatthevariousriskfactorsand,wherepossible,weightingtheriskfactorsbasedonappropriateandrelevantconsiderationstoestablishaneffectiveframeworkforthesystematicassessmentofriskandfinalcontrolstrategy.
IntroductionofICHQ3D
TheintroductionofICHQ3D
(1)isoneofthemostcomplexchangesinregulationspertainingtoimpuritiesseenbythepharmaceuticalindustry.Whiletheguidelineisultimatelyintendedtofocusonfinaldrugproductquality,theactualriskassessmentwilltouchallfacetsofthemanufactureofadrugproduct.Theguidelineintroducestoxicologicallyrelevantpermitteddailyexposure(PDE)limitstoindividualelementsreplacingnon-specific19thcenturywetchemical“heavymetal”limittests.ICHQ3Dadvocatestheuseofarisk-basedapproachtoassessingthepotentialforpresenceofelementalimpuritiesindrugproducts.Theprocessofexecutinganddocumentingtheriskassessmentisamajorchallenge,primarilyasaresultofalimitedglobalunderstandingabouthowtoassessorquantifytheriskassociatedwithfactorssuchaswater,container-closuresystems,andexcipients.
Definingwhereintheassessmentprocessdatamayberequiredandidentifyingwhereriskscanbedeterminedtobenegligiblethroughathoroughscientifictheoreticalriskassessmentalsopresentasignificantchallenge.Wheretheriskassessmentidentifiestheneedfortesting,thelevelofthePDEsfortheelement(s)ofconcernmayalsorequirethebroaderintroductionofnew,moresensitive,andspecificanalyticaltechnology,addingstillfurthertothecomplexity.
Thisarticlespecificallyseekstoexaminerelevantriskfactorsand,wherepossible,theweightingoftheserisksbasedonappropriateandrelevantconsiderations.Italsoseekstospecificallydefinewhereintheassessmentprocessdatamayberequiredaswellasseekingtoidentifywhereriskscanbedeterminedtobenegligiblesimplythroughathoroughscientifictheoreticalriskassessment.
Thegeneralprinciplesoutlinedinthisarticlearebelievedtoaddressmostscenariosorproducttypes;however,ultimatelyanydrug-productmanufacturerneedstoconsiderpotentialsourcesofelementalimpuritiesappropriatefortheirspecificproduct.
Riskassessment
Theevaluationofthepotentialriskposedbyelementalimpuritieswithinaformulateddrugproductrequiresaholisticapproachtakingintoaccountallpotentialsourcesofelementalimpurities.Figure1 illustratespotentialsourcesthatshouldbeconsideredinsuchanevaluation.
Figure1:
Sourcesofelementalimpuritiesinfinisheddrugproducts.
Drugsubstance
Aspresentedin Figure1,thedrugsubstanceisakeycomponentthatcancontributeelementalimpuritiestothefinisheddrugproduct.Theriskofinclusionofelementalimpuritiesfromadrugsubstance,therefore,needstobeconsideredwhenconductingadrugproductriskassessment.Controloftheelementalimpuritycontentofadrugsubstancecanbeassuredthroughathoroughunderstandingofthemanufacturingprocessincludingequipmentselection,equipmentqualification,GMPprocesses,packagingcomponents,andtheselectionandapplicationofappropriatecontrolstrategies.
Aprincipalresponsibilityforanydrug-substancemanufactureristodevelopastrategytoensureeffectivecontrolofthelevelsofelementalimpuritiesinthefinisheddrugsubstance.Anapproachbasedonassessingandcontrollingpotentialsourcesofelementalimpurities,coupledwithfocused,limitedtesting,ispreferabletoexhaustivetestingonthefinisheddrugsubstance.Ascientific,risk-basedapproachcombinedwithknowledgeandcontrolofthekeysourcesofelementalimpuritiesinthedrug-substancemanufacturingprocesssuchascatalysts,providesanefficientandcomprehensiveelementalimpuritycontrolstrategyforfinisheddrugsubstances.
Figure2 showspotentialsourcesofelementalimpuritiesinthedrugsubstancemanufacturingprocess.Ofthesourceshighlighted,thegreatestriskcomesfromintentionallyaddedmetals(e.g.,metalcatalystsusedintheprocess).Manufacturingequipment,processingaids,inorganicreagents,water,solvents,andotherorganicmaterialsarelesslikelytoserveasmajorcontributorsofelementalimpuritiesinthefinisheddrugsubstance,butdorequireconsideration.
Figure2:
Primarysourcesofelementalimpuritiesindrugsubstances(DS).
Metalcatalysts. Metalcatalystssuchaspalladiumandplatinumareoftenusedinthedrug-substancemanufacturingprocessandcanthereforebepresentatlowlevelsinthefinisheddrugsubstance.Thesyntheticrouteshouldbereviewedforintentionallyaddedmetals,anddatafrompurgingstudies,includinganysupportivetestingofappropriateisolatedintermediates,shouldbeusedinthedesignofanappropriatecontrolstrategy.
Theabilitytoremovethecatalyst(purgecapacity)willbeinfluencedbycatalystloadingandthenatureofthecatalystusedintheprocess(i.e.,homogeneousvs.heterogeneouscatalysts).Heterogeneouscatalysts,suchaspalladiumoncarbon,areofteneasilyremovedfromreactionmixturesbyfiltration,andtherefore,theriskofcarryoverofelementalimpuritiesintothedrugsubstanceistypicallylow.Evenincaseswheremetalcatalystsareusedinthefinalstagesoftheprocess,goodhistoricaldataand/orunderstandingofcarry-overmaypermitreducedtestingschemes.
Biotechproductsdonotnormallyrelyontheuseofcatalysts.AsICHQ3Dpointsout,typicalpurificationschemesinbiotechdrugsubstancemanufacturingarewellcapableofclearinganyelementsintroducedeitherintentionallyorinadvertently“tonegligiblelevels.”Theprinciplesoutlinedpreviouslymaynonethelessberelevantinsomespecificcases(e.g.,chemicallymodifiedbiotechdrugsubstances).
Whenconsideringtheotherpotentialsourceshighlightedin Figure2,itisrecommendedtofocusprimarilyonthemanufacturingstepsthatoccuraftertheformationofthefinalintermediate.Washes,crystallizations,phaseseparations,chromatography,distillations,andprocessingaids/scavengersaidinpurgingofelementalimpuritiesand,therefore,reducetheriskofcarryoverintothefinisheddrugsubstancefromstagesearlierintheupstreamprocess.Areasforfurtherconsiderationincludemanufacturingequipment,processingaids/inorganicreagents,solvents,water,andpackaging.
Manufacturingequipment. Ingeneral,GMPs,includingequipmentcompatibilityassessmentandqualification,aresufficienttoensurethatsignificantlevelsofelementalimpuritiesarenotleachedfrommanufacturingequipmentintothedrugsubstance.Hastelloy,stainlesssteel,andglassarethemostcommonlyusedmaterialsofconstructionfordrugsubstancemanufacturingequipment,duetotheirsuperiorchemicalresistance.Nickel,cobalt,vanadium,molybdenum,chromium,andcopperarekeyelementsinsomeHastelloyandstainless-steelalloys.Underextreme/corrosivereactionconditions,suchashightemperatureandlow/highpH,theseelementscouldhavethepotentialtoleachfrommanufacturingequipment.Insuchcases,itmaybenecessarytosupplementstandardGMPequipmentcompatibilityassessmentswithspecificstudiestoassesstheelementalimpurity-leachingpropensityfrommanufacturingequipmentduetocorrosivereactionconditions.
Otherpotentialsourcesincludehigh-energyprocessessuchasmilling/micronizationequipment.Thesearealsogenerallyconsideredtobelowrisk,butshouldbeaddressedviaappropriateGMPincludingcleaningrecordsandvisualinspection.ParticlesizereductionisdiscussedintheDrugProductManufacturesection.
Processingaids/inorganicreagents. Processingaidssuchascharcoal,silica,celite,anddarco,andinorganicreagentssuchassodiumchloride,magnesiumsulfate,andsodiumsulfate,areoftenusedindrug-substancemanufacturingprocessesandmaybeusedinsignificantquantities.Dependingontheirspecificcomposition,inorganicreagentsshouldbeconsideredwithintheri
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