ISO_10993-3_2014 医疗器械生物学评价——第3部分：遗传毒性、致癌毒性和生殖毒性试验

ISO2014BIOLOGICALEVALUATIONOFMEDICALDEVICESPART3TESTSFORGENOTOXICITY,CARCINOGENICITYANDREPRODUCTIVETOXICITYVALUATIONBIOLOGIQUEDESDISPOSITIFSMDICAUXPARTIE3ESSAISCONCERNANTLAGNOTOXICIT,LACANCROGNICITETLATOXICITSURLAREPRODUCTIONINTERNATIONALSTANDARDISO109933THIRDEDITION20141001REFERENCENUMBERISO1099332014EISO1099332014EIIISO2014ALLRIGHTSRESERVEDCOPYRIGHTPROTECTEDDOCUMENTISO2014ALLRIGHTSRESERVEDUNLESSOTHERWISESPECIFIED,NOPARTOFTHISPUBLICATIONMAYBEREPRODUCEDORUTILIZEDOTHERWISEINANYFORMORBYANYMEANS,ELECTRONICORMECHANICAL,INCLUDINGPHOTOCOPYING,ORPOSTINGONTHEINTERNETORANINTRANET,WITHOUTPRIORWRITTENPERMISSIONPERMISSIONCANBEREQUESTEDFROMEITHERISOATTHEADDRESSBELOWORISOSMEMBERBODYINTHECOUNTRYOFTHEREQUESTERISOCOPYRIGHTOFFICECASEPOSTALE56CH1211GENEVA20TEL41227490111FAX41227490947EMAILCOPYRIGHTISOORGWEBWWWISOORGPUBLISHEDINSWITZERLAND,ISO1099332014EISO2014ALLRIGHTSRESERVEDIIICONTENTSPAGEFOREWORDIVINTRODUCTIONVI1SCOPE12NORMATIVEREFERENCES13TERMSANDDEFINITIONS24REQUIREMENTSFORTESTSTRATEGIES241GENERAL242ADDITIONALREQUIREMENTSFORCARCINOGENICITYTESTING343ADDITIONALREQUIREMENTSFORREPRODUCTIVETOXICITYTESTING35GENOTOXICITYTESTS451GENERAL452TESTSTRATEGY453SAMPLEPREPARATION66CARCINOGENICITYTESTS761GENERAL762EVALUATIONSTRATEGY763SAMPLEPREPARATION864TESTMETHODS87REPRODUCTIVEANDDEVELOPMENTALTOXICITYTESTS971GENERAL972TESTSTRATEGY973SAMPLEPREPARATION1074TESTMETHODS108TESTREPORT11ANNEXAINFORMATIVEGUIDANCEONSELECTINGANAPPROPRIATESAMPLEPREPARATIONPROCEDUREINGENOTOXICITYTESTING12ANNEXBINFORMATIVEFLOWCHARTFORFOLLOWUPEVALUATION20ANNEXCINFORMATIVERATIONALEOFTESTSYSTEMS21ANNEXDINFORMATIVECELLTRANSFORMATIONTESTSYSTEMS23ANNEXENORMATIVECONSIDERATIONSFORCARCINOGENICITYSTUDIESPERFORMEDASIMPLANTATIONSTUDIES24ANNEXFINFORMATIVEINVITROTESTSFOREMBRYOTOXICITY25BIBLIOGRAPHY27,ISO1099332014EFOREWORDISOTHEINTERNATIONALORGANIZATIONFORSTANDARDIZATIONISAWORLDWIDEFEDERATIONOFNATIONALSTANDARDSBODIESISOMEMBERBODIESTHEWORKOFPREPARINGINTERNATIONALSTANDARDSISNORMALLYCARRIEDOUTTHROUGHISOTECHNICALCOMMITTEESEACHMEMBERBODYINTERESTEDINASUBJECTFORWHICHATECHNICALCOMMITTEEHASBEENESTABLISHEDHASTHERIGHTTOBEREPRESENTEDONTHATCOMMITTEEINTERNATIONALORGANIZATIONS,GOVERNMENTALANDNONGOVERNMENTAL,INLIAISONWITHISO,ALSOTAKEPARTINTHEWORKISOCOLLABORATESCLOSELYWITHTHEINTERNATIONALELECTROTECHNICALCOMMISSIONIECONALLMATTERSOFELECTROTECHNICALSTANDARDIZATIONTHEPROCEDURESUSEDTODEVELOPTHISDOCUMENTANDTHOSEINTENDEDFORITSFURTHERMAINTENANCEAREDESCRIBEDINTHEISO/IECDIRECTIVES,PART1INPARTICULARTHEDIFFERENTAPPROVALCRITERIANEEDEDFORTHEDIFFERENTTYPESOFISODOCUMENTSSHOULDBENOTEDTHISDOCUMENTWASDRAFTEDINACCORDANCEWITHTHEEDITORIALRULESOFTHEISO/IECDIRECTIVES,PART2WWWISOORG/DIRECTIVESATTENTIONISDRAWNTOTHEPOSSIBILITYTHATSOMEOFTHEELEMENTSOFTHISDOCUMENTMAYBETHESUBJECTOFPATENTRIGHTSISOSHALLNOTBEHELDRESPONSIBLEFORIDENTIFYINGANYORALLSUCHPATENTRIGHTSDETAILSOFANYPATENTRIGHTSIDENTIFIEDDURINGTHEDEVELOPMENTOFTHEDOCUMENTWILLBEINTHEINTRODUCTIONAND/ORONTHEISOLISTOFPATENTDECLARATIONSRECEIVEDWWWISOORG/PATENTSANYTRADENAMEUSEDINTHISDOCUMENTISINFORMATIONGIVENFORTHECONVENIENCEOFUSERSANDDOESNOTCONSTITUTEANENDORSEMENTTHECOMMITTEERESPONSIBLEFORTHISDOCUMENTISISO/TC194THISTHIRDEDITIONOFISO109933CANCELSANDREPLACESTHESECONDEDITIONISO1099332003,WHICHHASBEENTECHNICALLYREVISEDTHEMAJORTECHNICALCHANGESARETHEFOLLOWINGATESTSTRATEGYCHANGEDBYINCLUSIONOFAINVIVOTESTANDAFOLLOWUPEVALUATIONBNEWANNEXA”GUIDANCEONSELECTINGANAPPROPRIATESAMPLEPREPARATIONPROCEDUREINGENOTOXICITYTESTING”INCLUDEDCINCLUSIONOFFURTHERINVITROANDINVIVOTESTFOREVALUATINGTHEGENOTOXICPOTENTIALOFMEDICALDEVICESDNEWANNEXB“FLOWCHARTFORFOLLOWUPEVALUATION”INCLUDEDEANNEXECHANGEDTO“CONSIDERATIONSFORCARCINOGENICITYSTUDIESPERFORMEDASIMPLANTATIONSTUDIES”ANDMADENORMATIVEFNEWANNEXF“INVITROTESTSFOREMBRYOTOXICITY”INCLUDEDISO10993CONSISTSOFTHEFOLLOWINGPARTS,UNDERTHEGENERALTITLEBIOLOGICALEVALUATIONOFMEDICALDEVICESPART1EVALUATIONANDTESTINGWITHINARISKMANAGEMENTPROCESSPART2ANIMALWELFAREREQUIREMENTSPART3TESTSFORGENOTOXICITY,CARCINOGENICITYANDREPRODUCTIVETOXICITYPART4SELECTIONOFTESTSFORINTERACTIONSWITHBLOODPART5TESTSFORINVITROCYTOTOXICITYPART6TESTSFORLOCALEFFECTSAFTERIMPLANTATIONPART7ETHYLENEOXIDESTERILIZATIONRESIDUALSPART9FRAMEWORKFORIDENTIFICATIONANDQUANTIFICATIONOFPOTENTIALDEGRADATIONPRODUCTSPART10TESTSFORIRRITATIONANDSKINSENSITIZATIONIVISO2014ALLRIGHTSRESERVED,ISO1099332014EPART11TESTSFORSYSTEMICTOXICITYPART12SAMPLEPREPARATIONANDREFERENCEMATERIALSPART13IDENTIFICATIONANDQUANTIFICATIONOFDEGRADATIONPRODUCTSFROMPOLYMERICMEDICALDEVICESPART14IDENTIFICATIONANDQUANTIFICATIONOFDEGRADATIONPRODUCTSFROMCERAMICSPART15IDENTIFICATIONANDQUANTIFICATIONOFDEGRADATIONPRODUCTSFROMMETALSANDALLOYSPART16TOXICOKINETICSTUDYDESIGNFORDEGRADATIONPRODUCTSANDLEACHABLESPART17ESTABLISHMENTOFALLOWABLELIMITSFORLEACHABLESUBSTANCESPART18CHEMICALCHARACTERIZATIONOFMATERIALSPART19PHYSICOCHEMICAL,MORPHOLOGICALANDTOPOGRAPHICALCHARACTERIZATIONOFMATERIALSTECHNICALSPECIFICATIONPART20PRINCIPLESANDMETHODSFORIMMUNOTOXICOLOGYTESTINGOFMEDICALDEVICESTECHNICALSPECIFICATIONTHEFOLLOWINGPARTISUNDERPREPARATIONPART33SUPPLEMENTTOISO109933GUIDANCEONTESTSTOEVALUATEGENOTOXICITYTECHNICALREPORTTHEFOLLOWINGDEFINITIONSAPPLYINUNDERSTANDINGHOWTOIMPLEMENTANISOINTERNATIONALSTANDARDANDOTHERNORMATIVEISODELIVERABLESTS,PAS,IWA“SHALL”INDICATESAREQUIREMENT“SHOULD”INDICATESARECOMMENDATION“MAY”ISUSEDTOINDICATETHATSOMETHINGISPERMITTED“CAN”ISUSEDTOINDICATETHATSOMETHINGISPOSSIBLE,FOREXAMPLE,THATANORGANIZATIONORINDIVIDUALISABLETODOSOMETHINGISO/IECDIRECTIVES,PART2SIXTHEDITION,2011,331,DEFINESAREQUIREMENTASAN“EXPRESSIONINTHECONTENTOFADOCUMENTCONVEYINGCRITERIATOBEFULFILLEDIFCOMPLIANCEWITHTHEDOCUMENTISTOBECLAIMEDANDFROMWHICHNODEVIATIONISPERMITTED”ISO/IECDIRECTIVES,PART2SIXTHEDITION,2011,332,DEFINESARECOMMENDATIONASAN“EXPRESSIONINTHECONTENTOFADOCUMENTCONVEYINGTHATAMONGSEVERALPOSSIBILITIESONEISRECOMMENDEDASPARTICULARLYSUITABLE,WITHOUTMENTIONINGOREXCLUDINGOTHERS,ORTHATACERTAINCOURSEOFACTIONISPREFERREDBUTNOTNECESSARILYREQUIRED,ORTHATINTHENEGATIVEFORMACERTAINPOSSIBILITYORCOURSEOFACTIONISDEPRECATEDBUTNOTPROHIBITED”ISO2014ALLRIGHTSRESERVEDV,ISO1099332014EINTRODUCTIONTHEBASISFORBIOLOGICALEVALUATIONOFMEDICALDEVICESISOFTENEMPIRICALANDDRIVENBYTHERELEVANTCONCERNSFORHUMANSAFETYTHERISKOFSERIOUSANDIRREVERSIBLEEFFECTS,SUCHASCANCERORSECONDGENERATIONABNORMALITIES,ISOFPARTICULARPUBLICCONCERNITISINHERENTINTHEPROVISIONOFSAFEMEDICALDEVICESTHATSUCHRISKSBEMINIMISEDTOTHEGREATESTEXTENTFEASIBLETHEASSESSMENTOFMUTAGENIC,CARCINOGENICANDREPRODUCTIVEHAZARDSISANESSENTIALCOMPONENTOFTHECONTROLOFTHESERISKSNOTALLTESTMETHODSFORTHEASSESSMENTOFGENOTOXICITY,CARCINOGENICITYORREPRODUCTIVETOXICITYAREEQUALLYWELLDEVELOPED,NORISTHEIRVALIDITYWELLESTABLISHEDFORTHETESTINGOFMEDICALDEVICESSIGNIFICANTISSUESWITHTESTSAMPLESIZEANDPREPARATION,SCIENTIFICUNDERSTANDINGOFDISEASEPROCESSESANDTESTVALIDATIONCANBECITEDASLIMITATIONSOFAVAILABLEMETHODSFOREXAMPLE,THEBIOLOGICALSIGNIFICANCEOFSOLIDSTATECARCINOGENESISISPOORLYUNDERSTOODITISEXPECTEDTHATONGOINGSCIENTIFICANDMEDICALADVANCESWILLIMPROVEOURUNDERSTANDINGOFANDAPPROACHESTOTHESEIMPORTANTTOXICOLOGICALEFFECTSATTHETIMETHISDOCUMENTWASPREPARED,THETESTMETHODSPROPOSEDWERETHOSEMOSTACCEPTABLESCIENTIFICALLYSOUNDALTERNATIVESTOTHEPROPOSEDTESTINGMAYBEACCEPTABLEINSOFARASTHEYADDRESSRELEVANTMATTERSOFSAFETYASSESSMENTINTHESELECTIONOFTESTSNEEDEDTOEVALUATEAPARTICULARMEDICALDEVICE,THEREISNOSUBSTITUTEFORACAREFULASSESSMENTOFEXPECTEDHUMANUSESANDPOTENTIALINTERACTIONSOFTHEMEDICALDEVICEWITHVARIOUSBIOLOGICALSYSTEMSTHESECONSIDERATIONSWILLBEPARTICULARLYIMPORTANTINSUCHAREASASREPRODUCTIVEANDDEVELOPMENTALTOXICOLOGYTHISPARTOFISO10993PRESENTSTESTMETHODSFORTHEDETECTIONOFSPECIFICBIOLOGICALHAZARDS,ANDSTRATEGIESFORTHESELECTIONOFTESTS,WHEREAPPROPRIATE,THATWILLASSISTINHAZARDIDENTIFICATIONTESTINGISNOTALWAYSNECESSARYORHELPFULINMANAGINGTOXICOLOGICALRISKSASSOCIATEDWITHEXPOSURETOMEDICALDEVICEMATERIALSBUT,WHEREITISAPPROPRIATE,ITISIMPORTANTTHATMAXIMUMTESTSENSITIVITYISACHIEVEDINVIEWOFTHEMULTITUDEOFPOSSIBLEOUTCOMESANDTHEIMPORTANCEOFFACTORSSUCHASEXTENTOFEXPOSURE,SPECIESDIFFERENCESANDMECHANICALORPHYSICALCONSIDERATIONS,RISKASSESSMENTHAVETOBEPERFORMEDONACASEBYCASEBASISVIISO2014ALLRIGHTSRESERVED,INTERNATIONALSTANDARDISO1099332014EBIOLOGICALEVALUATIONOFMEDICALDEVICESPART3TESTSFORGENOTOXICITY,CARCINOGENICITYANDREPRODUCTIVETOXICITY1SCOPETHISPARTOFISO10993SPECIFIESSTRATEGIESFORRISKESTIMATION,SELECTIONOFHAZARDIDENTIFICATIONTESTSANDRISKMANAGEMENT,WITHRESPECTTOTHEPOSSIBILITYOFTHEFOLLOWINGPOTENTIALLYIRREVERSIBLEBIOLOGICALEFFECTSARISINGASARESULTOFEXPOSURETOMEDICALDEVICESGENOTOXICITYCARCINOGENICITYREPRODUCTIVEANDDEVELOPMENTALTOXICITYTHISPARTOFISO10993ISAPPLICABLEWHENTHENEEDTOEVALUATEAMEDICALDEVICEFORPOTENTIALGENOTOXICITY,CARCINOGENICITY,ORREPRODUCTIVETOXICITYHASBEENESTABLISHEDNOTEGUIDANCEONSELECTIONOFTESTSISPROVIDEDINISO1099312NORMATIVEREFERENCESTHEFOLLOWINGDOCUMENTS,INWHOLEORINPART,ARENORMATIVELYREFERENCEDINTHISDOCUMENTANDAREINDISPENSABLEFORITSAPPLICATIONFORDATEDREFERENCES,ONLYTHEEDITIONCITEDAPPLIESFORUNDATEDREFERENCES,THELATESTEDITIONOFTHEREFERENCEDDOCUMENTINCLUDINGANYAMENDMENTSAPPLIESISO109931,BIOLOGICALEVALUATIONOFMEDICALDEVICESPART1EVALUATIONANDTESTINGWITHINARISKMANAGEMENTPROCESSISO109932,BIOLOGICALEVALUATIONOFMEDICALDEVICESPART2ANIMALWELFAREREQUIREMENTSISO109936,BIOLOGICALEVALUATIONOFMEDICALDEVICESPART6TESTSFORLOCALEFFECTSAFTERIMPLANTATIONISO1099312,BIOLOGICALEVALUATIONOFMEDICALDEVICESPART12SAMPLEPREPARATIONANDREFERENCEMATERIALSISO1099318,BIOLOGICALEVALUATIONOFMEDICALDEVICESPART18CHEMICALCHARACTERIZATIONOFMATERIALSOECD414,PRENATALDEVELOPMENTTOXICITYSTUDYOECD415,ONEGENERATIONREPRODUCTIONTOXICITYSTUDYOECD416,TWOGENERATIONREPRODUCTIONTOXICITYOECD421,REPRODUCTION/DEVELOPMENTALTOXICITYSCREENINGTESTOECD451,CARCINOGENICITYSTUDIESOECD453,COMBINEDCHRONICTOXICITY/CARCINOGENICITYSTUDIESOECD471,BACTERIALREVERSEMUTATIONTESTOECD473,INVITROMAMMALIANCHROMOSOMEABERRATIONTESTISO2014ALLRIGHTSRESERVED1ISO1099332014EOECD476,INVITROMAMMALIANCELLGENEMUTATIONTESTOECD487,INVITROMAMMALIANCELLMICRONUCLEUSTEST3TERMSANDDEFINITIONSFORTHEPURPOSESOFTHISDOCUMENT,THETERMSANDDEFINITIONSGIVENINISO109931,ISO1099312ANDTHEFOLLOWINGAPPLY31CARCINOGENICITYTESTTESTTODETERMINETHECARCINOGENICPOTENTIALOFMEDICALD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