CHALLENGES ASSOCIATED WITH BIOLOGICAL SAFETY ASSESSMENTS FOR DRUG-DEVICE COMBINATION PRODUCTS《药物-器械组合产品生物安全性评估相关挑战》

DownloadedfromonOctober18,2023

CHALLENGESASSOCIATEDWITHBIOLOGICALSAFETYASSESSMENTSFORDRUG-DEVICECOMBINATIONPRODUCTS

CherylLMStults,DianeHarperandDorisZane

PDAJournalofPharmaceuticalScienceandTechnology2023,

Accessthemostrecentversionatdoi:10.5731/pdajpst.2022.012822

DownloadedfromonOctober18,2023

PAGE

10

ChallengesAssociatedwithBiologicalSafetyAssessmentsfor

Drug-DeviceCombinationProducts

CherylLMStults1*,DianeHarper2,DorisZane3

1C&MTechnicalConsulting,LLC,SanMateo,CA

2Immunovant,Inc.,NewYork,NY

3GileadSciences,FosterCity,CA

*Correspondingauthor:CherylLMStults,322W25thAve,SanMateo,CA94403;(650)400-9114;

clm.stults@.

ABSTRACT:Biologicalsafetyassessmentsfordrug-devicecombinationproductsinvolveevaluationofthedrugcontainerclosureandthedeviceconstituentpart.Whenthedeviceconstituentpartisthedrugdeliverysystemaswellasthedrugcontainerclosuresystem,bothdeviceanddrug-basedpackagingstandardshavebeendeemedapplicable.Approachesusedforthebiologicalsafetyassessmentofmedicaldevicesdifferfromthoseusedforpharmaceuticalpackaging/deliverysystems.Oneareaofdifferenceistheextenttowhichchemicalcharacterizationwithtoxicologicalassessmentisusedeitherinadditionto,orinplaceof,biologicalinvivoorinvitrotests.Differencesalsoexistinthewaynonclinicalstudiesareusedtoevaluatethesafetyofmedicaldevicesordrugdeliverysystems.Thelackofalignmentinstandardsandguidancehasresultedinconfusionoverwhatcombinationoftestsandmethodsofevaluationconstituteabiologicalsafetyassessmentthatwillmeetregulatoryexpectationsforadrug-devicecombinationproduct.Theintentofthismanuscriptistodiscussthechallengescreatedwhenthepackagingordeliverysystemisalsoadeviceconstituentpartofadrug-devicecombinationproduct.Suggestionsareofferedregardingapproachesthatmaybeusefulforconductingsuitablebiologicalsafetyassessmentsfordrug-devicecombinationproducts.

Keywords:biologicalreactivity,biocompatibility,analyticalevaluationthreshold(AET),toxicologicalassessment,drug-devicecombinationproducts,extractables,leachables

Introduction

Fordrug-devicecombinationproducts,thedrugpackagingistypicallyalsoamedicaldeviceconstituentpart.Forexample,inaprefilledsyringe,theglassbarrelandplungerstopperbothholdthedrugproductaswellasfunctiontodeliverthedrugproducttothepatient.Forametereddoseinhaler,thedrugcanisterhasavalvethatisinvolvedindeliveringthedrug(deliverysystem)andtogetherwiththemouthpiece/actuatorbecomesanintegralpartofamedicaldevice.FDArecognizesthispotentialdualityofthedrugcontainerasamedicaldeviceforcombinationproducts(1).TheUnitedStatesPharmacopeia(USP)hasimplementedtheterm‘drugpackaging/deliverysystems’todescribethesetypesofsystemsinwhichthepharmaceuticalcontainerclosuremayalsobepartofthedeliverysystem.PerUSP<1663>and

<1664>,drugpackaging/deliverysystemsare“thesumofcomponentsandmaterialsthatareusedtotransportadrugproductfromitspackagingtothepointofadministrationintothepatient.Forexample,anadministrationsetisadeliverysystemthatisusedtotransferliquiddrugproductsfromtheirplasticpackagingsystemtothesiteofadministrationtothepatient.Itisnotedthatinsomecases,thepackagingsystemitselfmayperformthedeliveryfunction.”(2-3).

Asinglestandardforthebiologicalsafetyassessmentofdrug/biologic-devicecombinationproductsdoesnotexist.Ratherseparateapproachesforthebiologicalevaluationofmedicaldevicesandthebiologicalsafetyassessmentofpharmaceuticalpackaginghavebeendeveloped.Whiletheseapproachesshareanumberofcommonelements,theydifferinseveralkeyareasasaresultofthedifferentpathwaysbywhichtheassessmentmethodologieshavebeendeveloped.StandardsforbiologicalreactivitytestingandtheassessmentofextractablesandleachablesfordrugpackaginghavebeendevelopedthroughtheUSP.USPchapters<87>and

<88>providerecommendationsonhowtoperformsafetyassessmentsviaafewbiologicalreactivitytests–cytotoxicity,intracutaneousirritationandacutesystemictoxicity(4-5).

AlthoughUSP<1663>and<1664>provideguidanceontheexperimentaldesignofextractableandleachablestudies,respectively,thereisnoguidanceontoxicologicalassessmentofchemicalsthatareextractedorleachedfrompackagingcomponentsorsystems.

Historically,USPstandardsprecededformaleffortstodevelopbiologicalevaluationapproachesformedicaldevices(6).USPXVIIChapter,BiologicalTests-PlasticContainers(1965),wastheinitialstandardappliedtoimplantsaswellastoparenteraldrugproductcontainersandinfusionassemblies(7).Twentyyearslater,standardizationofmedicaldevicebiologicalevaluationwasinitiated,resultinginthe1986“TripartiteBiocompatibilityGuidanceforMedicalDevices,”issuedbytheToxicologySubgroupoftheTripartiteSubcommitteeonMedicalDevicesformedbyFDA,HealthandWelfareCanada,andHealthandSocialServicesUK.In1987,theFDAOfficeofDeviceEvaluation(ODE)issuedaGeneralProgramMemorandum,G87-1,entitled,“TripartiteBiocompatibilityGuidance,”(April24,1987)thatoutlineduseoftheguidance.Subsequently,ISO10993-1wasdevelopedbytheInternationalOrganizationforStandardization(ISO)TechnicalCommittee(TC)ISO/TC194andfirstpublishedin1992.In1995,FDAreplacedtheG87-1memorandumwithanewODEmemothatformallyadoptedISO10993-1,whichwasdistributedaspartofBlueBookMemorandum#G95-1,“UseofInternationalStandardISO-10993,BiologicalEvaluationofMedicalDevicesPart1:EvaluationandTesting,”(May1,1995).ThroughseveralrevisionsoftheISO10993-1standard(1997,2003,2009,2018),medicaldevicebiologicalsafetyevaluationhasevolvedfromalistofrequiredteststobeperformed,touseofrisk-basedapproachesforbiologicalendpointstobeevaluated.Inconjunction,FDAguidanceonthebiologicalevaluationofmedicaldevicesper

ISO10993-1alsoevolvedsinceitsinitialpublicationin1995.However,theevolutionhasnotalwaysresultedinfullalignmentbetweenFDAguidanceandISOstandards.Forexample,intherecentguidanceupdateinSeptember2020(8),FDAdidnotfullyendorsethe2018ISOstandard.FDAdidnotincludephysicaland/orchemicalinformationasarequiredendpointforbiologicalsafetyevaluation(seethemodifiedmatrixinTableA.1:BiocompatibilityEvaluationEndpoints)butdiddiscussutilizationofphysicalandchemicalinformationintheriskassessmentprocess

(8).Thus,whileUSPinitiallydevelopedbiologicalsafetytestsformedicaldevices,theUSPtestsarenowprimarilyappliedtopharmaceuticalplasticsandelastomericcontainerclosures,andaredifferentfromtheISO10993standardsthatarenowappliedtomedicaldevices.RevisionstoUSP<87>and<88>thatwererecentlyproposedinPharmacopeialForum49(2)acknowledgedthisgapandincludedchangesthatwouldaligntheseUSPchapterstotheISO10993standards.

AsforthehistoricaldevelopmentofbiologicalsafetyevaluationrecommendationsinFDAregulatoryguidancefordrug/biologic-devicecombinationproducts,safetyassessmentfordrugpackagingwaspublishedin1999asGuidanceforIndustry:ContainerClosureSystemsforPackagingHumanDrugsandBiologicsbytwocentersattheUSFoodandDrugAdministration(FDA)―CenterforDrugEvaluationandResearch(CDER)andCenterforBiologicsEvaluationandResearch(CBER).Whilethisguidanceremainseffective,itsrecommendeduseoftoxicologicalevaluationofleachablesand/orUSPBiologicalReactivityTestsasthestandardforsafetyevaluationofdrug-devicecombinationproducts,suchasinhalationandinjectionproducts,tomeetcurrentgoodmanufacturingpractice(cGMP)requirementsunderTitle21oftheCodeofFederalRegulations(CFR)Parts210and211(9)doesnotrepresentthecurrentAgencythinkingoncombinationproducts.

TheUSregulatoryapproachtoproductsthatincludebothadrugorbiologicconstituentpartandadeviceconstituentpart(i.e.,drug/biologic-devicecombinationproduct)wasinitiallyformalizedin2013under21CFRPart4(78FR4307-CurrentGoodManufacturingPracticeRequirementsforCombinationProducts,January22,2013).In2017,allthreecentersatFDApublishedaguidancedescribingandexplainingthefinalruleoncurrentgoodmanufacturingpractice(cGMP)requirementsfordrug/biologic-devicecombinationproducts,whichcitestotheuseofboththedevicestandardISO10993-1andthetraditionaldrugpackagingstandard

USP<87>/<88>forbiologicalsafetyevaluation(10).Likewise,theMeteredDoseInhaler/DryPowderInhaler(MDI/DPI)draftguidancere-publishedin2018(11)alsocitesbothUSP

<87>/<88>andISO10993.ThesetwoguidancedocumentslefttheapplicationofUSPandISOstandardsambiguousanddidnotspecifytheUSregulatoryexpectationsforbiologicalsafetyassessmentofdrugpackagingwhenitisalsoadeviceconstituentindrug-devicecombinationproduct.

Thefundamentalquestionformanufacturersofdrug-devicecombinationproductsiswhetherthesafetyassessmentshouldbeperformedaccordingtothedrugpackaging/deliverysystemstandardsinUSPoraccordingtothemedicaldevicestandardspublishedbyISO,orwhetherhealthauthoritiesexpectthatallorasubsetoftherequirementsofbothstandardsshouldbemet.Whilestandardsexist,theregulatoryauthorityisthefinaldecisionmaker.SinceFDAguidancedoesnotcurrentlyresolvethisissueforcombinationproducts,thepathwayforbiologicalsafetyassessmentbecomesamatterofregulatoryreviewforeachspecificdrug-devicecombinationproduct.

InEurope,theEuropeanPharmacopoeia(12)standardsareeasiertonavigate,andtheregulationsareabitmorestraightforwardregardingtheEuropeanMedicinesAgency(EMA)and

NotifiedBody(NB)reviewofsingleintegraldrug-devicecombinationproducts.ThePh.Eur.,unlikeUSP,doesnotcontaingeneralchaptersforthebiologicalsafetyassessmentofdrugpackagingordevicebiocompatibilitytests.RatherPh.Eur.chaptersfocusonthephysicochemicalattributesofpharmaceuticalcontainers(Ref:Ph.Eur.Chapter3.1Materialsusedforthemanufactureofcontainers,andPh.Eur.Chapter3.2Containers)andthequalityofthematerialscommonlyusedinmedicinalproductpackaging(e.g.,Ph.Eur.3.1.5polyethylene,Ph.Eur.3.1.6polypropylene,Ph.Eur.3.2glass,andPh.Eur.3.2.9rubberclosures).ThePh.Eur.therebyavoidsincongruityinbiologicalsafetyevaluationrecommendationsthathavearisenbetweentheUSPchaptersfordrugpackagingbiologicalreactivity(<87>/<88>)andbiocompatibility(<1031>),andtheISO10993chaptersformedicaldevices.Additionally,theEMAqualityguidelineforsingleintegraldrug-devicecombinationproductsclearlyoutlinestheseparationbetweendrug-basedcontainersafetyevaluationanddevice-basedsafetyevaluation

(13).Sponsorsaretodemonstratesafetyofallmaterialsincontactwiththemedicinalproductduringadministrationanddelivery(e.g.,extractablesandleachables,processingaids)inthemedicinalproductmarketingauthorizationdossier,whichmaysoonbeaidedbytheinternationaleffortscurrentlyunderwayviaICHQ3E.AssessmentofconformityofthedevicepartwiththerelevantGeneralSafetyandPerformanceRequirements(GSPRs)inAnnexItotheEUMedicalDeviceRegulation(14),whichcontainsbiocompatibilityassessment(Chapter1,GeneralRequirement1furtherdetailedinChapterII,GeneralRequirement10),istobesubmittedbytheSponsorinthemarketingdossierthrougheitheranEUDeclarationofConformityorrelevantEUcertificateissuedbyaNotifiedBodyforthemedicaldeviceoropiniononconformityofthedevicetotherelevantGSPRsknownasaNotifiedBodyOpinion(NBOp)(13).SinceEuropeavoidstheconfusionthathasdevelopedintheUSstandardsandguidance,thediscussionbelow

focusesontheregulatory,analytical,andtoxicologicalchallengesinmeetingFDAreviewerexpectationsforthebiologicalsafetyassessmentofcombinationproductsforwhichthedrugcontainerisalsoadeliverydevice.

RegulatoryApproachesfortheSafetyAssessmentofDrug-DeviceCombinationProducts

USFDAregulationsgoverningthestandards,testingrequirements,andoverallmaterialsafetyassessmentstrategytobeappliedtodrug-devicecombinationproductsarechallengingtonavigate,especiallywhenadrugorbiologiciscombinedwithadeviceasasingleentity.Title21oftheCodeofFederalRegulations(CFR)Part4,whichwascodifiedin2013,allowsSponsorstoapplya“streamlinedregulatoryframework”ofbothdrug(orbiologic)productgoodmanufacturingpractice(GMPs)andmedicaldevicequalitysystemsregulations(QSregulation)tomeettherequirementsfordemonstratingcombinationproductsafety,performance,protection,andcompatibility(1;15).Thus,aSponsorofasingleentitycombinationproductwithdrugconstituentastheprimarymodeofaction,suchasaprefilledsyringeormetereddoseinhaler,mayapplyboththedrug-based21CFRPart210or211requirementsaswellasdevice-based

21CFR820.30DesignControls.Ineffect,21CFRPart4moveddevicestandardsintosafetyassessmentsthatwereformerlyconductedusingonlydrugpackagingsafetystandards.

FDAexplainsintheir2017guidanceoncGMPsforcombinationsproducts,thatunderthe“streamlinedapproach,”thedrugisnowconsideredpartofthedevicedesigncontrolprocess:

"[T]hedrugcomesintothedesigncontrolprocessasaninputtothedesignofthesyringetoensurethatthesyringe’sdesignreflectsadequateconsiderationofthedrug’scharacteristics….”Designinputsvia21CFR820.30shouldaddress“theperformanceofthesyringeasacontainer/closuretostorethedrugandtheextent

towhichthecontactbetweenthesyringeandthedrugmayaffectsitsperformanceasadeliverysystem,”and“[n]odegradationofdrugorsyringeovertheexpectedshelf-lifeasaresultofcontactwithoneanother.”(1).

Thus,whatwasonceadrugcontainer-closuresystemevaluatedunderUSPstandardswithreviewbyCDER/CBER,nowhasabroaderscopeofassessmentthatencompassesmedicaldevicedeliverysystemperformance,whichbringsinCDRHreviewandapplicationofISOstandardsthatmaybeadditionaland/orduplicativetoUSPstandards.WhiletheCFRintroduceda“streamlinedregulatoryapproach”thatcombinesdrugrequirementsanddevicerequirements,currentFDAguidancedoesnotclarifywhichstandards,e.g.,USP,ISO,ICH,ASTM,etc.,aretobeappliedinevaluationofthesafetyofthepackaging/deliverysystems(1;8;16).Hence,Sponsorscurrentlydonothaveaguidance-basedresourcetonavigatethevariousstandardsaswellastheinconsistenciespresentwithinthedifferentstandards.

Usingaprefilledsyringeasanexample,therelevantchaptersfrombothUSPandISOthatcouldbeappliedtoaprefilledsyringeforcontainer-closuresuitabilityqualification,i.e.,assessmentofsafety,performance,protectionandcompatibility(9),areprovidedinTableI.Whiletherearenospecificstandardsoncompatibility,thetopicofbiocompatibility(invitro/invivotestsorchemicalcharacterizationwithtoxicologicalassessment)ispartofthesafetyassessment.Thesafety,performance,andprotectionaspectsallhaverelevantdrug-basedUSPchaptersanddevice-basedISOstandardsthatareavailableandcouldbeappliedtotherespectiveassessments,whichmakesitachallengetodiscernwhichstandardtoapplyandwhen.However,itisthebiologicalsafetyassessmentthatisthemostdifficulttonavigate.ApackagingengineeraccustomedtotestingmaterialsaccordingtoUSP<87>/<88>(e.g.,ClassVI)foravialthat

containsadrugproductwilldiscoverthatanevaluationperISO10993-1ispartoftheFDAregulatoryexpectationwhenthatsamedrugproductisdeliveredbyaprefilledsyringe.

TheUSPchaptersandISOstandardsarenotinterchangeable.Thedrug/biologicpackaging/deliverysystemsafetyevaluationisbasedonUSP<87>(invitrocytotoxicity)andincludestoxicologicalevaluationofleachablesinthedrugformulationtoaddresssystemictoxicity(note:USPnolongermandatesinvivotestingforacutesystemictoxicityorintracutaneousirritationwithUSP<88>;seecurrentgeneralchaptersofUSP<381>and<661>).Incontrast,thedeterminationofsafetyofdeviceconstituentpartsunderISO10993-1isbasedonabiologicalevaluationofvariousendpointsthatinvolvesinvitroandinvivotesting.Ataminimumcytotoxicity,irritation,andsensitizationarerequiredtestsperISO10993-1;systemictoxicitymaybeaddressedbyinvivotestingorbytoxicologicalassessmentofextractablesfromthedevice(8).Thus,thesestandardshavedifferingtestmethodologiesthatcannotbesubstitutedforeachother,asdiscussedindetailbelowinsectionEvaluationofPackaging/DeliverySystemsandDeviceConstituentPartsinDrug-DeviceCombinationProducts.SubmissionstoFDAusingtheincorrectchoiceofstandardscanresultinclinicalholdofanInvestigationalNewDrug(IND)submission,inanon-approvalrecommendationforaNewDrugApplication(NDA)submission,orinnon-approvalofachemistry,manufacturingandcontrols(CMC)post-approvalchangesubmission.

UponreviewofFDAguidanceonISO10993-1,thepackagingengineerwhoisseekingapathforwardforthebiologicalsafetyassessmentforaprefilledsyringewilldiscovernoclearacceptedtestingand/orevaluationapproachforcombinationproducts.TheFDAguidanceonISO10993-1statesthat,“detailedguidancespecifictobiocompatibilityevaluationof

combinationproductsarenotwithinthescopeofthisdocument.Assuch,weencourageyoutodiscusscombinationproductswiththeappropriateCenterandreviewdivisionwhowillinitiateproperconsultationoncombinationproduct-specificbiocompatibilityconcernsasappropriate.”

(8).Additionally,asnotedabove,regulatoryguidanceonthebiologicalsafetyassessmentofcombinationproductssuchasaprefilledsyringe,citebothUSP<87>/<88>andISO10993-1asapplicableforbiocompatibilitytesting(10-11).ThepackagingengineerwillalsohavetobeawarethatFDAdoesnotfullyrecognizeISO10993-1:2018Fifthedition(17).WhileISOrecommendschemicalinformation,includingchemicalcharacterizationperISO10993-18asappropriate,asthefirstplacetostartthebiologicalevaluation,FDAdoesnotrecognizeTable

A.1inAnnexAofthestandardandhasinsteadprovidedamodifiedmatrixintheirguidance(8).

WithrespecttothechemicalcharacterizationchaptersofUSP<1663>and<1664>listedinTableI,thesechaptersdescribeanapproachforthedesign,justification,andimplementationoftheassessmentofextractablesandleachablesfrompackaginganddeliverysystemsthatisdifferentfromtheapproachdescribedintheISO10993-18formedicaldevices.DeterminingwhichchemicalcharacterizationstandardappliestotheproductdependsonwhichFDACenter,CBER/CDERorCDRH,istheleadreviewerofthedatapackageassociatedwiththecombinationproductCMCsubmission.

Additionally,thechaptersoftheUSPandISOstandardscontinuetoevolve.Atthetimeofthispaper,revisionstoUSP<87>/<88>/<1031>areunderconsiderationforreviewasoutlinedinthePharmacopeialForumPF47(4)(18).ISO10993-17:2002Establishmentofallowablelimitsforleachablesubstancesisalsoundertechnicalcommitteereview.NotonlydoesaSponsorhavetonavigatechoicesfortheappropriatestandardtouse,butalsomayhaveto

complywithanewerorolderversionofastandardinordertomeettheFDAregulatoryexpectation.

TheFDARecognizedConsensusStandardsdatabaseisavailableonlineforaSponsortryingtomitigaterisksandgainclearerinsightintocurrentFDArecommendationforwhichUSPandISOstandardsandwhichversionoftheUSPorISOstandardmightbeappliedtothesafetyassessmentofdrug-devicecombinationproducts(19).However,thisresourcecanleadtofurtherconfusion.FDAlistsbothdrug-basedUSP<87>anddevice-basedISO10993-1withCDRHastheFDATechnicalContact,aswellasonlypartiallyrecognizesthecontentineachofthesestandards.Foraprefilledsyringe,theRecognizedConsensusStandardsdatabaselistsISO

11040-4GlassbarrelsforinjectablesandsterilizedsubassembledsyringesreadyforfillingandISO11040-5Plungerstoppersforinjectables,however,FDArecommendsthatSponsorsofprefilledsyringedrugproductsuseISO11040-8Requirementsandtestmethodsforfinishedprefilledsyringes,eventhoughthischapterofISOisnotlistedineithertheRecognizedConsensusStandardswebsiteoringuidance(15;19).

MeetingtheexpectationsofFDAreviewerscanappeartobeanever-movingtarget.

Sponsorswillfaceadditionalchallengesforglobalsubmissions,whichmayrequirejustificationandalignmentwithmultipleHealthAuthoritiesindifferentregions.Theregulatoryexpectationscouldalsochangethroughoutthedevelopmentandproductlife-cyclesasthetargetedcountryapprovallistevolvesandtheidentityofthereviewerschangeovertime.

Withthemajorityofbiologic-deviceanddrug-devicecombinationproductsindevelopment(oralreadyapproved)beingcomposedofprefilledsyringes,autoinjectors,andinhalers,thereisanopportunityforfutureFDAregulatoryguidancetofocusonthesethreedrug-

deviceplatformsandresolvethetypesofgapsandinconsistenciesillustratedabove.ItwouldbehelpfultohavepublishedFDArecommendationsregardingwhich(drugand/ordevice)standardsaretobeutilizedforthesethreemainproducttypes,andanyadditionalconsiderationsthatwouldenableaclearprocessformaterialsselection,materialscontrolstrategy,andriskmanagement.

Theresultingguidancewouldprovidearoadmapthatdeviceandpackagingengineerscanuniformlyfollowtoensurebiologicalsafetyforadrug-devicecombinationproduct.

EvaluationofPackaging/DeliverySystemsandDeviceConstituentPartsinDrug-DeviceCombinationProducts

Safetyassessmentofmaterialsusedinacombinationproductusuallybeginswithgatheringinformationonthematerialsandtheprocessesusedtoproducecomponentsandsubsequentassembliesthatcomprisethepackaging/deliverysystemordeviceconstituentpart.Materialcharacterizationinformationistypicallyrequiredformaterialselectionandqualification.Forpackaging/deliverysystems,baselineinformationisobtainedthroughcompendialtesting(e.g.,USP,EP,JP,CP).Inadditiontotestingforgeneralphysicochemicalattributes,biologicalreactivitytestingisoftenperformedtoconfirmthatamaterialconformstotherequirementsofUSPClassVI.Apackaging/deliverysystemthatmeetsbaselinerequirementsisthensubjecttoadditionalproductspecifictestingrequirementsthat,ifmet,wouldqualifythematerialandpackaging/deliverysystemfortheintendeduse.Forapackaging/deliverysystemthetypeandamountoftestingisprescribedintheUSPisbasedontheperceivedrisksassociatedwithvariousproducttypes(e.g.,asdetailedinUSP<1664>).

Incontrast,foramedicaldevice,materialselectionandqualificationfollowsarisk-basedapproachperISO14971andisspecifictotheproduct(20).Thisrisk-basedapproachisinitiatedwithdesigninputrequirementsthatcoverallaspectsincludingsafety(e.g.,functionalattributes,

non-toxic,biocompatible,compatiblewithcontactmaterials).Dependingonalreadyexistinginformationortestreports,testingmayormaynotbeneededforpurposesofqualification.Foradevice,thetypeandamountoftestingisbasedontherisksestimatedthroughtheuseofriskanalysistools(e.g.,FailureModesandEffectsAnalysis)appliedspecificallytotheproductanditsassociatedhazardoussituations.

Whenthedeviceisalsothepackaging/deliverysystem,someoftherequirementsareclearandsomeareambiguous.Withrespecttomaterialsafety,biocompatibility,andtoxicity,therearetwosetsofstandards–onesetforpackaging/deliverysystemsandonesetformedicaldevices.WiththerecentrevisionsoftheISO10993standardsfordeviceandtherecentimplementationofanewstandardforbreathinggaspathways,ISO18562(21),thereissignificantoverlapwithUSPpackaging/deliverysystemstandardsforhighriskproductsforwhichbiologicalreactivitytestingandextractablestestingisrequired.

AnexampleofoverlapbetweenISOstandardsandUSPchaptersisintheareaofcytotoxicityevaluation.AccordingtoISO10993-1cytotoxicityshouldbeevaluatedforalldevicesregardlessofdevicecategory,contactdurationormaterialtype.Iftestingisrequiredbasedontherisk,ISO10993-5istheapplicablestandard(22).CytotoxicitytestingperUSP

<87>isperformedonelastomericandplasticcomponentsaspartofUSP<381>andUSP<661>testing,respectively.InpracticethismeansthataplungerstopperinaprefilledsyringethatistheclosureandalsoadevicecomponentwouldbesubjecttotestingperUSP<87>andevaluationaccordingtoISO10993-5forcytotoxicity.Asimilarsituationwouldbetrueforaplasticreservoirthatisadrugcontainerandanintegralinhalationdevicecomponent.Oneapproachwouldbetoperformeachtestseparatelysincetheyhavedifferentscoringrequirements.

Alternatively,ISO10993-5alonemaybeperformed,sincethesurfaceareatovolume

requirementsarethesameforUSPandISO,whereasISOrequiresmorereplicatesthanUSP

<87>andtheISOscoringcriteriaaremorestringent.Alignmentofthesetwostandards,whichhasrecentlybeenproposedforUSP<87>inPharmacopeialForum49(2),wouldeliminatedifferencesinmildandmoderatereactivitygradeassignmentsalongwithredundanttesting.

AnotherexampleofoverlapbetweenISOandUSPstandardsisintheareaofirritationevaluation.AccordingtoISO10993-1irritationshouldbeevaluatedforalldevicesregardlessofdevicecategory,contactdurationormaterialtype.IrritationtestingintheformofintracutaneousreactivityisrequiredbyUSPonlyforestablishingtheplasticclass(e.g.,USPClassVI)oraspartofperformingUSP<88>foranelastomerasresultofthetwo-stagetestingapproachdescribedinUSP<381