ISO 10993-1：2018(现行)

©ISO2018Biologicalevaluationofmedicaldevices—Part1:EvaluationandtestingwithinariskmanagementprocessÉvaluationbiologiquedesdispositifsmédicaux—Partie1:Évaluationetessaisauseind'unprocessusdegestiondurisqueINTERNATIONALSTANDARDISO10993-1Fifthedition2018-08ReferencenumberISO10993-1:2018(E)CopyrightInternationalOrganizationforStandardizationProvidedbyIHSMarkitunderlicensewithANSINotforResale,08/20/201820:10:24MDTNoreproductionornetworkingpermittedwithoutlicensefromIHS--`,``,,`,,```,`,`,,`,,`,,`````,-`-`,,`,,`,`,,`---ISO10993-1:2018(E)ii©ISO2018–AllrightsreservedCOPYRIGHTPROTECTEDDOCUMENT©ISO2018Allrightsreserved.Unlessotherwisespecified,orrequiredinthecontextofitsimplementation,nopartofthispublicationmaybereproducedorutilizedotherwiseinanyformorbyanymeans,electronicormechanical,includingphotocopying,orpostingontheinternetoranintranet,withoutpriorwrittenpermission.PermissioncanberequestedfromeitherISOattheaddressbeloworISO’smemberbodyinthecountryoftherequester.ISOcopyrightofficeCP401•Ch.deBlandonnet8CH-1214Vernier,GenevaPhone:+41227490111Fax:+41227490947Email:copyright@iso.orgWebsite:www.iso.orgPublishedinSwitzerlandCopyrightInternationalOrganizationforStandardizationProvidedbyIHSMarkitunderlicensewithANSINotforResale,08/20/201820:10:24MDTNoreproductionornetworkingpermittedwithoutlicensefromIHS--`,``,,`,,```,`,`,,`,,`,,`````,-`-`,,`,,`,`,,`---ISO10993-1:2018(E)Foreword........................................................................................................................................................................................................................................ivIntroduction..................................................................................................................................................................................................................................v1Scope.................................................................................................................................................................................................................................12Normativereferences.....................................................................................................................................................................................13 Terms and definitions.....................................................................................................................................................................................24Generalprinciplesapplyingtobiologicalevaluationofmedicaldevices.................................................55Categorizationofmedicaldevices......................................................................................................................................................95.1General...........................................................................................................................................................................................................95.2Categorizationbynatureofbodycontact........................................................................................................................95.2.1Non-contactingmedicaldevices.........................................................................................................................95.2.2Surface-contactingmedicaldevices.............................................................................................................105.2.3Externallycommunicatingmedicaldevices..........................................................................................105.2.4Implantmedicaldevices.........................................................................................................................................115.3Categorizationbydurationofcontact.............................................................................................................................115.3.1Contactdurationcategories................................................................................................................................115.3.2Transitory-contactingmedicaldevices.....................................................................................................115.3.3Medicaldeviceswithmultiplecontactdurationcategories....................................................116Biologicalevaluationprocess..............................................................................................................................................................126.1Physicalandchemicalinformationforbiologicalriskanalysis.................................................................126.2Gapanalysisandselectionofbiologicalendpointsforassessment.......................................................126.3Biologicaltesting................................................................................................................................................................................136.3.1General...................................................................................................................................................................................136.3.2Testingforevaluation...............................................................................................................................................147Interpretationofbiologicalevaluationdataandoverallbiologicalriskassessment...............18AnnexA(informative)Endpointstobeaddressedinabiologicalriskassessment.........................................20AnnexB(informative)Guidanceontheconductofbiologicalevaluationwithinariskmanagementprocess....................................................................................................................................................................................25AnnexC(informative)Suggestedprocedureforliteraturereview...................................................................................38Bibliography.............................................................................................................................................................................................................................40©ISO2018–AllrightsreservediiiContentsPageCopyrightInternationalOrganizationforStandardizationProvidedbyIHSMarkitunderlicensewithANSINotforResale,08/20/201820:10:24MDTNoreproductionornetworkingpermittedwithoutlicensefromIHS--`,``,,`,,```,`,`,,`,,`,,`````,-`-`,,`,,`,`,,`---ISO10993-1:2018(E)ForewordISO(theInternationalOrganizationforStandardization)isaworldwidefederationofnationalstandardsbodies(ISOmemberbodies).TheworkofpreparingInternationalStandardsisnormallycarriedoutthroughISOtechnicalcommittees.Eachmemberbodyinterestedinasubjectforwhichatechnicalcommitteehasbeenestablishedhastherighttoberepresentedonthatcommittee.Internationalorganizations,governmentalandnon-governmental,inliaisonwithISO,alsotakepartinthework.ISOcollaboratescloselywiththeInternationalElectrotechnicalCommission(IEC)onallmattersofelectrotechnicalstandardization.TheproceduresusedtodevelopthisdocumentandthoseintendedforitsfurthermaintenancearedescribedintheISO/IECDirectives,Part1.InparticularthedifferentapprovalcriterianeededforthedifferenttypesofISOdocumentsshouldbenoted.ThisdocumentwasdraftedinaccordancewiththeeditorialrulesoftheISO/IECDirectives,Part2(seewww.iso.org/directives).Attentionisdrawntothepossibilitythatsomeoftheelementsofthisdocumentmaybethesubjectofpatentrights.ISOshallnotbeheldresponsibleforidentifyinganyorallsuchpatentrights.DetailsofanypatentrightsidentifiedduringthedevelopmentofthedocumentwillbeintheIntroductionand/orontheISOlistofpatentdeclarationsreceived(seewww.iso.org/patents).Anytradenameusedinthisdocumentisinformationgivenfortheconvenienceofusersanddoesnotconstituteanendorsement.Foranexplanationonthevoluntarynatureofstandards,themeaningofISOspecifictermsandexpressionsrelatedtoconformityassessment,aswellasinformationaboutISO'sadherencetotheWorldTradeOrganization(WTO)principlesintheTechnicalBarrierstoTrade(TBT)seethefollowingURL:www.iso.org/iso/foreword.html.ThisdocumentwaspreparedbyTechnicalCommitteeISO/TC194,Biologicalandclinicalevaluationofmedicaldevices.Thisfiftheditioncancelsandreplacesthefourthedition(ISO10993-1:2009),whichhasbeentechnicallyrevised.ItalsoincorporatestheTechnicalCorrigendumISO10993-1:2009/Cor.1:2010.Themainchangescomparedtothepreviouseditionareasfollows:a)revisedAnnexA“Endpointstobeaddressedinabiologicalriskassessment”withnewcolumnsfor“physicaland/orchemicalinformation”and“materialmediatedpyrogenicity”aswellascolumnsfor“chronictoxicity,”“carcinogenicity,”“reproductive/developmentaltoxicity,”and“degradation”whichnowindicates“endpoints”tobeconsideredwith“E”(insteadof“tests”tobeconductedwithan“X”);b)replacedAnnexB“Guidanceontheriskmanagementprocess”with“Guidanceontheconductofbiologicalevaluationwithinariskmanagementprocess”(formerlyISOTR15499);c)additionaldefinitionsfortermsusedthroughouttheISO10993seriesofstandards;d)additionalinformationontheevaluationof“Non-contactingmedicaldevices”andnewinformationontheevaluationof“Transitory-contactingmedicaldevices”;e)additionalinformationontheevaluationofnanomaterials,andabsorbablematerials;f)additionalreferencetoISO18562(allparts)for“Biocompatibilityevaluationofbreathinggaspathwaysinhealthcareapplications”;g)significanteditingchangesthroughoutthedocument;AlistofallpartsintheISO10993seriescanbefoundontheISOwebsite.iv©ISO2018–AllrightsreservedCopyrightInternationalOrganizationforStandardizationProvidedbyIHSMarkitunderlicensewithANSINotforResale,08/20/201820:10:24MDTNoreproductionornetworkingpermittedwithoutlicensefromIHS--`,``,,`,,```,`,`,,`,,`,,`````,-`-`,,`,,`,`,,`---ISO10993-1:2018(E)IntroductionTheprimaryaimofthisdocumentistheprotectionofhumansfrompotentialbiologicalrisksarisingfromtheuseofmedicaldevices.ItiscompiledfromnumerousInternationalandnationalstandardsandguidelinesconcerningthebiologicalevaluationofmedicaldevices.Itisintendedtodescribethebiologicalevaluationofmedicaldeviceswithinariskmanagementprocess,aspartoftheoverallevaluationanddevelopmentofeachmedicaldevice.Thisapproachcombinesthereviewandevaluationofexistingdatafromallsourceswith,wherenecessary,theselectionandapplicationofadditionaltests,thusenablingafullevaluationtobemadeofthebiologicalresponsestoeachmedicaldevice,relevanttoitssafetyinuse.Theterm“medicaldevice”iswide-rangingand,atoneextreme,consistsofasinglematerial,whichcanexistinmorethanonephysicalform,andattheotherextreme,ofamedicaldeviceconsistingofnumerouscomponentsmadeofmorethanonematerial.Thisdocumentaddressesthedeterminationofthebiologicalresponsetomedicaldevices,mostlyinageneralway,ratherthaninaspecificdevice-typesituation.Thus,foracompletebiologicalevaluation,itclassifiesmedicaldevicesaccordingtothenatureanddurationoftheiranticipatedcontactwithhumantissueswheninuseandindicates,inamatrix,thebiologicalendpointsthatarethoughttoberelevantintheconsiderationofeachmedicaldevicecategory.Seealso3.14,Note1toentry.Therangeofbiologicalhazardsiswideandcomplex.Thebiologicalresponsetoaconstituentmaterialalonecannotbeconsideredinisolationfromtheoverallmedicaldevicedesign.Thus,indesigningamedicaldevice,thechoiceofthebestmaterialwithrespecttoitsbiocompatibilitymightresultinalessfunctionalmedicaldevice,biocompatibilitybeingonlyoneofanumberofcharacteristicstobeconsideredinmakingthatchoice.Whereamaterialisintendedtointeractwithtissueinordertoperformitsfunction,thebiologicalevaluationneedstoaddressthis.Biologicalresponsesthatareregardedasadverse,causedbyamaterialinoneapplication,mightnotberegardedassuchinadifferentsituation.Biologicaltestingisbasedupon,amongotherthings,invitroandexvivotestmethodsanduponanimalmodels,sothattheanticipatedbehaviourwhenamedicaldeviceisusedinhumanscanbejudgedonlywithcaution,asitcannotbeunequivocallyconcludedthatthesamebiologicalresponsewillalsooccurinthisspecies.Inaddition,differencesinthemannerofresponsetothesamematerialamongindividualsindicatethatsomepatientscanhaveadversereactions,eventowell-establishedmaterials.Theprimaryroleofthisdocumentistoserveasaframeworkinwhichtoplanabiologicalevaluation.Asecondaryroleistoutilizescientificadvancesinourunderstandingofbasicmechanisms,tominimizethenumberandexposureoftestanimalsbygivingpreferencetoinvitromodelsandtochemical,physical,morphological,andtopographicalcharacterizationtesting,insituationswherethesemethodsyieldequallyrelevantinformationtothatobtainedfrominvivomodels.Itisnotintendedthatthisdocumentprovidearigidsetoftestmethods,includingpass/failcriteria,asthismightresultineitheranunnecessaryconstraintonthedevelopmentanduseofnovelmedicaldevices,orafalsesenseofsecurityinthegeneraluseofmedicaldevices.Whereaparticularapplicationwarrantsit,expertsintheproductorintheareaofapplicationconcernedcanchoosetoestablishspecifictestsandcriteria,describedinaproduct-specificverticalstandard.ISO10993seriesisintendedforusebyprofessionals,appropriatelyqualifiedbytrainingandexperience,whoareabletointerpretitsrequirementsandjudgetheoutcomeoftheevaluationforeachmedicaldevice,takingintoconsiderationallthefactorsrelevanttothemedicaldevice,itsintendeduseandthecurrentknowledgeofthemedicaldeviceprovidedbyreviewofthescientificliteratureandpreviousclinicalexperience.InformativeAnnexAcontainsatablethatisgenerallyhelpfulinidentifyingendpointsrecommendedinthebiocompatibilityevaluationofmedicaldevices,accordingtotheircategoryofbodycontactanddurationofclinicalexposure.InformativeAnnexBcontainsguidancefortheapplicationoftheriskmanagementprocesstomedicaldeviceswhichencompassesbiologicalevaluation.©ISO2018–AllrightsreservedvCopyrightInternationalOrganizationforStandardizationProvidedbyIHSMarkitunderlicensewithANSINotforResale,08/20/201820:10:24MDTNoreproductionornetworkingpermittedwithoutlicensefromIHS--`,``,,`,,```,`,`,,`,,`,,`````,-`-`,,`,,`,`,,`---CopyrightInternationalOrganizationforStandardizationProvidedbyIHSMarkitunderlicensewithANSINotforResale,08/20/201820:10:24MDTNoreproductionornetworkingpermittedwithoutlicensefromIHS--`,``,,`,,```,`,`,,`,,`,,`````,-`-`,,`,,`,`,,`---Biologicalevaluationofmedicaldevices—Part1:Evaluationandtestingwithinariskmanagementprocess1ScopeThisdocumentspecifies:—thegeneralprinciplesgoverningthebiologicalevaluationofmedicaldeviceswithinariskmanagementprocess;—thegeneralcategorizationofmedicaldevicesbasedonthenatureanddurationoftheircontactwiththebody;—theevaluationofexistingrelevantdatafromallsources;—theidentificationofgapsintheavailabledatasetonthebasisofariskanalysis;—theidentificationofadditionaldatasetsnecessarytoanalysethebiologicalsafetyofthemedicaldevice;—theassessmentofthebiologicalsafetyofthemedicaldevice.Thisdocumentappliestoevaluationofmaterialsandmedicaldevicesthatareexpectedtohavedirectorindirectcontactwith:—thepatient'sbodyduringintendeduse;—theuser’sbody,ifthemedicaldeviceisintendedforprotection(e.g.,surgicalgloves,masksandothers).Thisdocumentisapplicabletobiologicalevaluationofalltypesofmedicaldevicesincludingactive,non-active,implantableandnon-implantablemedicaldevices.Thisdocumentalsogivesguidelinesfortheassessmentofbiologicalhazardsarisingfrom:—risks,suchaschangestothemedicaldeviceovertime,asapartoftheoverallbiologicalsafetyassessment;—breakageofamedicaldeviceormedicaldevicecomponentwhichexposesbodytissuetonewornovelmaterials.OtherpartsofISO10993coverspecificaspectsofbiologicalassessmentsandrelatedtests.Device-specificorproductstandardsaddressmechanicaltesting.Thisdocumentexcludeshazardsrelatedtobacteria,moulds,yeasts,viruses,transmissiblespongiformencephalopathy(TSE)agentsandotherpathogens.2NormativereferencesThefollowingdocumentsarereferredtointhetextinsuchawaythatsomeoralloftheircontentconstitutesrequirementsofthisdocument.Fordatedreferences,onlytheeditioncitedapplies.Forundatedreferences,thelatesteditionofthereferenceddocument(includinganyamendments)applies.ISO10993-2:2006,Biologicalevaluationofmedicaldevices—Part2:AnimalwelfarerequirementsINTERNATIONALSTANDARDISO10993-1:2018(E)©ISO2018–Allrightsreserved1CopyrightInternationalOrganizationforStandardizationProvidedbyIHSMarkitunderlicensewithANSINotforResale,08/20/201820:10:24MDTNoreproductionornetworkingpermittedwithoutlicensefromIHS--`,``,,`,,```,`,`,,`,,`,,`````,-`-`,,`,,`,`,,`---ISO10993-1:2018(E)ISO10993-3,Biologicalevaluationofmedicaldevices—Part3:Testsforgenotoxicity,carcinogenicityandreproductivetoxicityISO10993-4,Biologicalevaluationofmedicaldevices—Part4:SelectionoftestsforinteractionswithbloodISO10993-5,Biologicalevaluationofmedicaldevices—Part5:TestsforinvitrocytotoxicityISO10993-6,Biologicalevaluationofmedicaldevices—Part6:TestsforlocaleffectsafterimplantationISO10993-7,Biologicalevaluationofmedicaldevices—Part7:EthyleneoxidesterilizationresidualsISO10993-9,Biologicalevaluationofmedicaldevices—Part9:FrameworkforidentificationandquantificationofpotentialdegradationproductsISO10993-10,Biologicalevaluationofmedicaldevices—Part10:TestsforirritationandskinsensitizationISO10993-11:2017,Biologicalevaluationofmedicaldevices—Part11:TestsforsystemictoxicityISO10993-12,Biologicalevaluationofmedicaldevices—Part12:SamplepreparationandreferencematerialsISO10993-13,Biologicalevaluationofmedicaldevices—Part13:IdentificationandquantificationofdegradationproductsfrompolymericmedicaldevicesISO10993-14,Biologicalevaluationofmedicaldevices—Part14:IdentificationandquantificationofdegradationproductsfromceramicsISO10993-15,Biologicalevaluationofmedicaldevices—Part15:IdentificationandquantificationofdegradationproductsfrommetalsandalloysISO10993-16,Biologicalevaluationofmedicaldevices—Part16:ToxicokineticstudydesignfordegradationproductsandleachablesISO10993-17,Biologicalevaluationofmedicaldevices—Part17:EstablishmentofallowablelimitsforleachablesubstancesISO10993-18,Biologicalevaluationofmedicaldevices—Part18:ChemicalcharacterizationofmaterialsISO/TS10993-20,Biologicalevaluationofmedicaldevices—Part20:PrinciplesandmethodsforimmunotoxicologytestingofmedicaldevicesISO14971:2007,Medicaldevices—Applicationofriskmanagementtomedicaldevices3 Terms and definitionsForthepurposesofthisdocument,thefollowingtermsanddefinitionsapply.ISOandIECmaintainterminologicaldatabasesforuseinstandardizationatthefollowingaddresses:—IECElectropedia:availableathttp://www.electropedia.org/—ISOOnlinebrowsingplatform:availableathttps://www.iso.org/obp3.1biocompatibilityabilityofamedicaldevice(3.14)ormaterial(3.12)toperformwithanappropriatehostresponseinaspecificapplication3.2biologicalriskcombinationoftheprobabilityofharmtohealthoccurringasaresultofadversereactionsassociatedwithmedicaldevice(3.14)ormaterial(3.12)interactions,andtheseverityofthatharm2©ISO2018–AllrightsreservedCopyrightInternationalOrganizationforStandardizationProvidedbyIHSMarkitunderlicensewithANSINotforResale,08/20/201820:10:24MDTNoreproductionornetworkingpermittedwithoutlicensefromIHS--`,``,,`,,```,`,`,,`,,`,,`````,-`-`,,`,,`,`,,`---ISO10993-1:2018(E)3.3biologicalsafetyfreedomfromunacceptablebiologicalrisk(3.2)inthecontextoftheintendeduse3.4chemicalconstituentanysyntheticornaturalsubstancethatisusedinaprocessformanufacturingmaterials(3.12)and/ormedicaldevices(3.14),includingthebasematerial(s),additives(antioxidants,UVstabilizers,coloradditives,dyes,etc.),andprocessingaids(solvents,lubricants,antifoamingagents,etc.)3.5datasetinformation,suchasphysicaland/orchemicalcharacterization,toxicitydata,etc.fromavarietyofsourcesnecessarytocharacterizethebiologicalresponsetoamedicaldevice3.6directcontactmedicaldevice(3.14)ormedicaldevicecomponentthatcomesintophysicalcontactwithbodytissue3.7externallycommunicatingmedica