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MEDDEV2.5_9 rev1含天然橡胶的医疗器械评估指南

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MEDDEV2.5_9 rev1含天然橡胶的医疗器械评估指南1EUROPEANCOMMISSIONENTERPRISEDIRECTORATE-GENERALSingleMarket:regulatoryenvironment,standardisationandNewApproachPressureequipment,medicaldevices,metrologyMEDDEV.2.5/9rev.1February2004GUIDELINESONMEDICALDEVICESIMPLICATIONSOFTHEMEDICALDEVICESDIRECTIVES(93/42/EEC)INREL...
MEDDEV2.5_9 rev1含天然橡胶的医疗器械评估指南
1EUROPEANCOMMISSIONENTERPRISEDIRECTORATE-GENERALSingleMarket:regulatoryenvironment,standardisationandNewApproachPressureequipment,medicaldevices,metrologyMEDDEV.2.5/9rev.1February2004GUIDELINESONMEDICALDEVICESIMPLICATIONSOFTHEMEDICALDEVICESDIRECTIVES(93/42/EEC)INRELATIONTOMEDICALDEVICESCONTAININGNATURALRUBBERLATEX:AGUIDEFORMANUFACTURERSANDNOTIFIEDBODIESNoteThepresentGuidelinesarepartofasetofGuidelinesrelatingtoquestionsofapplicationofEC-Directivesonmedicaldevices.Theyarelegallynotbinding.TheGuidelineshavebeencarefullydraftedthroughaprocessofintensiveconsultationofthevariousinterestparties(competentauthorities,Commissionservices,industries,otherinterestedparties)duringwhichintermediatedraftswerecirculatedandcommentsweretakenupinthedocument.Therefore,thisdocumentreflectspositionstakenbyrepresentativesofinterestpartiesinthemedicaldevicessector.Ref.Ares(2015)2057675-18/05/20152BackgroundandScopeDuetothecombinationofitssuperiorbarrierqualities,strength,flexibilityandcomfort,naturalrubberlatex(NRL)hasbeenincreasinglyusedinavarietyofmedicaldevices.Inparticular,thepropertiesofNRLmakeitapreferredmaterialformedicalgloves.Theclinicaluseoflatexgloveshasincreasedconsiderablyduringthelast20years,duemainlytoescalatingrisksassociatedwithblood-borneinfectiousagents.Themainfunctionoftheseglovesistocreateaprotectivebarrierbetweenthepatientandhealthcareworkerandalsotofacilitategeneralhandhygiene.InresponsetothegrowingapprehensionsurroundingmedicaldevicescontainingNRL,theDirectorateGeneralforEnterpriseoftheEuropeanCommissionpresentedquestionstotheScientificCommitteeonMedicinalProductsandMedicalDevices(SCMPMD).ThecommitteepreparedanopinioninJune2000basedoninformationavailablefromscientificliteratureandvariouspublicreports.TheCommission’sMedicalDevicesExpertsGroupsubsequentlysetupaWorkingGrouponNaturalRubberLatex,composedofrepresentativesfromtheMemberStates,toconsideranddiscusstheSCMPMDopinionandexplorethepossibilitiesforminimisingproblemsrelatingtotheuseofNRLinmedicaldevices.Afterhearingrepresentationsfromindustryandusers,theWorkingGroupwassatisfiedthattheMedicalDevicesDirectivecontainedadequateprovisionstoensurethesafetyofhealthcareworkersandpatientsexposedtoNRLmedicaldevices.However,theWorkingGroupwasconcernedthattheinterpretationoftheDirectiveintermsoftheriskcontrolmeasuresapplicabletoNRL-containingproductsappearedtobeinsomedoubt.AguidancedocumentwasthereforeconsiderednecessarytoclarifytheimplicationsoftherelevantEssentialRequirements.Tomeetthisobjective,theWorkingGroupfeltitnecessarytoidentify,inthisdocument,thehazardsandexposuresassociatedwithNRL,anddiscusstheeffectsofthelimitationsinthecurrentstateoftheart.ThedocumentisbasedontheprinciplethattheappropriatewaytomanagetherisksarisingfromNRListoreduceallergenicproteinlevelstoalevelaslowasreasonablypracticableandprovidewarningsabouttheresidualrisks.Thisdocumentthereforeprovidesguidanceformanufacturers,NotifiedBodiesandCompetentAuthoritiesontheinterpretationoftheEssentialRequirementsoftheMedicalDevicesDirective,astheyrelatetotheriskofallergytonaturalrubberlatex(NRL).Theriskcontrolmeasuresrecommendedinthisdocumentdonotapplytodevicesmadefromothermaterials.However,similarmeasures,commensuratewiththedegreeofrisk,maybeapplicabletocontrolrisksarisingfromothermaterialspresentinghazardsofasimilarnature(forexampledrynaturalrubber(DNR)).3TheMedicalDevicesDirectiveAswithallproductswhichmeetthedefinitionofamedicaldevice(asdetailedinArticle1oftheMedicalDevicesDirective93/42/EEC)NRL-containingmedicaldevices(i.e.examinationandsurgeons’gloves,condoms,catheters,etc.)mustmeetcertainconditionsasspecifiedbytherelevantEssentialRequirementsunderAnnex1oftheDirective.ThisrepresentstheminimumstandardamanufacturerisexpectedtodemonstratewhenclaimingconformityofaproductwiththeDirective.DuetothenatureoftheconcernsraisedaboutNRL(i.e.theinherentbiologicalhazards),thoseEssentialRequirementsthatrelatetobiologicalsafetyareofparticularrelevancetothisguidancedocument.TheEssentialRequirementsthataremostrelevanttothissituationare1,2,6,7.1,7.2,7.5and13.Toxicologicalrisksneedtobeassessedthroughanexpertscientificassessmentthattakesintoaccounttheextent,relevanceandqualityoftheavailabledata(suchasthatprovidedbytheSCMPMDinrelationtoallergenicrisks).Theconclusionsfromthescientificassessment,andthelevelofconfidenceinit,areusedtodetermineappropriatecontrolmeasurestoensurethesafetyofthoseexposedtothetoxichazardsidentified.EN/ISO10993-17providesamethodofdeterminationofacceptablelevelsofexposurerelevanttotoxicsubstancesthatcanleachoutofmedicaldevices.IndeterminingwhetheraproductmeetstheseEssentialRequirements,itisnecessarytobalancetherisksarisingfromthebiologicalhazardsknowntobeassociatedwithNRLagainstthebenefitsattributedtotheuseofNRL,particularlyinrespectofeffectivenessasabarriertoinfection.EN/ISO14971specifiesanappropriateprocessforjudgingoftheacceptabilityofrisk.EssentialRequirement2indicatesthatthefirstpriorityistheeliminationofrisk.Itisrecognised,however,thatnomedicalprocedureiswithoutriskanditisinevitablethatsomeriskmustbeacceptedintheinterestsofimprovingthehealthorprognosisofthepatient.Inpractice,theelimination,orminimisationofriskistakentomeanthattheriskcanbeconsideredtobesolowthatthereis“noneedtobotheraboutit”.Suchrisksaretermed“broadlyacceptable”(seeAnnexEofEN/ISO14971)Ifitisimpossibletoimplementcontrolsthatensurethatariskisbroadlyacceptable,theMedicalDevicesDirectiverequiresthattheriskmustbereducedasfaraspossible.Insuchcasesitisnecessarytoimplementriskcontrolmeasurestoensurethattheriskisreducedtoalevel“aslowasreasonablypracticable”(ALARP).Thatistosaytheriskisplacedinthe“ALARP”regionofthechartinAnnexEofEN/ISO14971.TheALARPconceptrecognisesthatexposuretoanappreciabledegreeofriskisinherentintheuseofmanymedicaldevices.Theexpectationisthattheriskshouldbereducedtothelowestpracticallevel,bearinginmindthepracticalityofanyfurtherriskreduction,thebenefitsarisingfromtheuseoftheproductandthestateoftheart.Becausethe“stateoftheart”isamovingtargetandtheEssentialRequirements’preferredoptionof“broadlyacceptablerisk”isnotyetachieved,riskcontrolmeasuresneedtobereviewedregularly.ChangesinthestateoftheartcouldlowertheALARPlevels.4ForrisksintheALARPregion,assessmentsofrisks,benefitsandthefeasibilityofriskcontrolareindispensablecomponentsoftheconformityassessmentprocess.Amanufacturerhastodeterminewhatriskcontrolmeasurescanreasonablybeadoptedtoachievetheoptimumbalanceofrisksandbenefits.Anyriskremainingafterallapplicableriskcontrolmeasureshavebeentakenistermedthe“residualrisk”.Theresidualriskmustbeoutweighedbybenefits.Themanufacturerhasaresponsibilitytocommunicateeffectivelywithuserstoinformthemaboutresidualriskstoallowthemtomanagetheseriskseffectively.Thereforeitisnecessarytoincludeappropriatewarningsinthedocumentsaccompanyingtheproduct.Thismayincludetheprovisionofspecificadvicetousersandhealthcaremanagersonanymeasuresthatshouldbetakentomitigatetherisk.Usersmaytakeriskcontrolmeasuresinadditiontothoseadvisedbythemanufacturer,suchastheestablishmentoflocalpoliciesonthepurchaseanduseofNRL-containingproducts,howeverthisaspectofriskmanagementliesoutsidethescopeoftheMedicalDevicesDirective.HazardidentificationAllergytonaturalrubberlatexVariousstudieshaveverifiedthatimmediate(TypeI)hypersensitivitytoNRLappearstobecausedbycertainnaturallyoccurringsolubleallergenicproteinsfoundinlatex.Reportedsymptomsencounteredrangefrommildwhealandflarereactionstogloves,tofatalanaphylaxisfromlatexballoonsusedwithbariumenemaexaminations.TheidentityofmostoftheclinicallyrelevantallergenicproteinsinNRL(bothmajorandminorallergens)nowappearstohavebeenestablished,andtherehasbeenaprogressivedeclineofgloveallergencontent.Althoughthemanufacturingprocessincludeswashingphasesfortheremovalofexcessproteinsandchemicals,residuesofproteinsandchemicalsremaininthematerial.MorecompleteremovaloflatexproteinsfromNRL-containingproductsmanufacturedusingcurrenttechnologymayadverselyeffecttheirproperties,suchaselasticity,tensilestrengthandbarrierfunction.TheprevalenceofNRLsensitisationvariesbetweenthedifferentpopulationsthathavebeenstudied.PrincipalriskgroupsforNRLallergyincludeatopicindividuals,patientswithhanddermatitisandatopicchildren,especiallythosewithfoodallergy.Amonghealthcareworkersthereportedprevalenceratesrangefrom2.7%to15%inmoststudies,dependingonthemethodsusedfordiagnosisandontheallergenicityofthelatexglovesused,althoughstudiesdonotalwaysdistinguishbetweenthosewhoarepositiveinskinpricktestingandthosewithclinicalallergy.NRLallergyhasbeendescribedinseveralotheroccupationsinwhichprotectiveglovesareused(e.g.housekeepingpersonnel,hairdressers,greenhouseworkersandworkersintextilefactories).ThefrequencyofTypeINRLallergyinthegeneralpopulation,basedonskinpricktestingandstringentdiagnosticcriteria,isrelativelylow,clearlyunder1%.Thereisevidencesuggestingthatlatexdeviceswithlowlevelsofleachableallergenicproteindonotinducesensitisation.5TheuseofpowderinlatexglovesTheuseofmodifiedcornstarchpowderasaglovedonning/manufacturingaidhasalsobeenthesubjectofparticularanxietyinrecentyears.Latexproteinsbindtocornstarchpowderparticlesinglovesandthepowdercanthusactasacarrieroftheallergen.Thedustaerosolthatcanbecreatedwhendonningandremovingpowderedglovesmayincreasetheriskofallergicreactionsbecauseuptake,viathelungs,bypeopleinthevicinityrepresentsanadditionalrouteofexposure.Casereportshadbeenpublishedtoindicatethatthissortofexposuremayprovokeallergicsymptoms(asthma,rhinoconjunctivitis,urticaria,anaphylaxis)inlatexsensitisedindividuals.However,theSCMPMD1reportedthattherehasbeennoconclusivescientificstudytoindicatethattheuseofpowderedlatexglovesincreasesthefrequencyorrateofsensitisationwhencomparedtopowder-freegloves,solongasthepowderedglovehasanequivalenttotalextractableallergenicproteinconcentration.Thus,theextenttowhichpowdercanplayaroleinallergicreactionsislimitedtoitsactivityasanairbornecarrierofallergens.Concernshavebeenexpressedregardingtheuseofpowderedglovesinsurgicaloperationsandtheformationofadhesionsorstarchgranuloma,howeveracausativerelationshiphasnotbeenfirmlyestablished.NRLadditivesAwiderangeofhazardousprocessingchemicalsisusedduringthemanufactureofNRLproducts.Theseincludeacceleratorssuchasthiurams,carbamatesandmercaptobenzothiazoles,whichareknowncontactsensitisersposingariskforthedevelopmentofTypeIVallergiccontactdermatitis.Currentlyonlyonestudyisavailablerankingtherelativehazardpotentialofthesechemicals.Quantificationofchemicalspresentinlatexmedicaldevicesanddeterminationoftheirbioavailabilityareproblematic.Thecompositionofthefinalproductishighlydependentontheinitialingredients,whichfluctuatesmorethanwithsyntheticpolymers,andthechemicalreactionsandleachingthatoccursduringprocessing.Theuptakeofchemicalresiduesbytheskinortissuesisdependentonthephysicochemicalpropertiesofthesubstancesandtheconditionsofuseofthedevices.Forexample,chemicaluptakeviamucosalmembraneexposuresuchasforcondoms,islikelytoexceedthatofexposureofanequalconcentrationtointactskin.However,regardlessofthesevariables,areductionintheamountofchemicalresiduesinrubberproductshasbeenshowntoalsoresultinareductioninthebioavailableamountsofchemicalsandintheTypeIVsensitisingcapacityofthematerial.TheriskofTypeIVallergiccontactdermatitisisnotconfinedtoNRLproducts;thecurrentlyavailablesyntheticalternativesmayposeasimilarrisk,dependingonthechemicalsusedfortheirproduction.1EuropeanCommissionScientificCommitteeonMedicinalProductsandMedicalDevices(SCMPMD);OpiniononNaturalRubberLatexAllergy;Adopted27June,2000.Doc.SANCO/SCMPMD/2000/0009Final6ExposureAssessmentExposuretoNRLmaycomefromdermal(cutaneous)ormucousmembranecontact.Thelatterincludesinhalation,andgenito-urinarytractexposure(e.g.fromcondoms,wounddrains,tracheostomytubes,balloonsusedinbariumenemaexaminationsandurinarycatheters).Directtissueorintra-vascularexposurealsooccursviaanopensurgicalwoundthroughtheuseofsurgeons’glovesandcontainersofinjectablematerials.ExposuretoallergenicproteinsTheriskofsensitisationorallergicreactiontoNRLcanbereducedbyminimisingtheamountofleachableallergenicproteintowhichasubjectisexposed.Adistinctionshouldbemade,however,betweenthepreventionofsensitisationandthepreventionofallergenicreactionsinthoseindividualsalreadysensitisedtolatexallergenicproteins.OnceapersonissensitisedtoNRL,anysubsequentexposuretolatexmaytriggeranallergicreaction.Itisnotcurrentlypossibletoestablishathresholdlevelofexposureforsensitisation,butitisgenerallyunderstoodthatgreaterexposureisrequiredtosensitiseanindividualthantoelicitaresponseinasensitisedindividual.Studieshaveshownthatlatexgloveswithalowleachableproteincontentelicitalowerpercentageofpositiveresponsesinlatexsensitisedindividualsthangloveswithhigherproteinresidues.However,thecorrelationbetweenproteincontentandallergencontentisnotstrongenoughtojustifyselectionoflowallergenglovesonthebasisofleachableproteincontent.Nevertheless,itcanbeexpectedthatlowerlevelsofleachableproteinwillalsoresultinalowerprevalenceofinductionofsensitisation.Apreciseindicationofanindividual’ssusceptibilitytolatexallergyisdifficulttoachieve.OnestandardisedextractforskinpricktestingisavailableinEuropeandCanada,butnotintheU.S.Extractsoflatexmaterials(e.g.gloves)canbeusefulbutarefarfromstandardisedandcanonlyprovideinformationonallergenicproteinsorallergenspresentinaparticularextractfromaparticularproduct.Considerableprogresshasbeenmadeintheidentificationandcharacterisationoflatexallergens,indicatedbythefactthat15allergenshadreceivedWHO/IUISAllergenNomenclaturedesignationbyAugust20022.Exposureassessmentis,however,hamperedbythelackofvalidatedmethodsfortheirdirectdetection.Whiledirectallergenmeasurementwouldbethepreferredoption,specificassayscurrentlyavailablearewaitingforinternationalvalidation.Sincearelationshipbetweenleachableproteinlevelsandtheriskofallergicreactionorsensitisationhasbeendemonstratedinseveralstudies,leachableproteinlevelsarecurrentlyusedasasurrogateforallergenexposure.Twomethods,themodifiedLowryandanaminoacidanalysis,bothmeasuringtotalextractableprotein,havebeendescribedandstandardizedforsometypesofproducts,makingthecomparisonbetweenalternativebrandsofproductspossible.However,neitherofthesemethodsdistinguishesbetweensensitisingandnon-sensitisingproteins.AlthoughsomeEuropeanlaboratoriesmayproduceratherconsistentresultsintheirmodifiedLowrytests,experiencefrommanyround-robintestsperformedinhigh-2www.allergen.org7standardlaboratoriesbothintheUSandinEuropehasrevealedseriousproblemsinthereproducibilityoftheresults.ImmunoassaysbasedontheuseofhumanIgEantibodiesrecognisingspecificNRLallergenshavebeendevelopedandusedinalimitedscaletomeasuretotalallergencontentsoflatexglovesandotherNRLdevices.Themajordrawbackinsuchassaysisthelimitedavailabilityofproperhumanseraandproblemsinstandardisation.Specifictestsformeasuringindividuallatexallergensinmedicaldeviceshaverecentlybeendevelopedandarecurrentlyunderinternationalevaluation.Interimrecommendationsnowarethusnotwellgrounded.ExposuretopowderAstandardisedtechniqueforthedeterminationofthepowdercontentofmedicalglovesisavailable.Relevantstandardsrequirethatsurgeons’glovescarrylabellingadvisingusersthatpowdermustberemovedbywashingpriortouse.Somestudieshavequestionedtheeffectivenessofsuchwashing.ExposuretochemicalresiduesSeveraltechniquesareavailableforthedetectionofthechemicalspresentinlatexproductssuchasmedicalgloves.AlthoughthesemethodsallowtheidentificationofthechemicalspresentinNRLproducts,thisdoesnotmeanthatthesechemicalsarealsobioavailablefortheinductionofallergyortheelicitationofaresponse.Crossreactivitycanoccurbetweenvariouschemicalsandmixturesofchemicalsmayalsobepresent.Thereseemstobenoagreementonthebestapplicablemethodofanalysis.Invitroteststhatmeasureclinicallyrelevant,bioavailableresiduesofrubberchemicalsintheproductsarenotyetavailable.RiskEstimationandEvaluationExtractableProteinStudiesthatsuggestacorrelationbetweenthepresenceofleachableproteininNRLglovesandtheriskofallergicreactionorsensitisationleadtotheconclusionthatreducingtheamountofavailableleachableproteincanreducetherisk.Determinationofaleachableproteinlevelthatrepresentsanacceptableriskisproblematic,however,becauseofthesignificantuncertaintiesthatlimittheextenttowhichthisriskcanbeanalysed.WhiletheSCMPMDwasabletoreachclearconclusionsonanumberofimportantissuesrelevanttothemanagementofrisksarisingfrommedicaldevicesmanufacturedfromNRL,thenumberofgoodqualityscientificstudiesrelevanttothecurrentsituationacrosstheEUislimited.Moreover,exposureassessmentsareinaccuratebecauseanalyticalmethodsavailabletodaydonotdifferentiatebetweenallergenic8andnon-allergenicproteins,butdetecttheamountoftotalproteininstead.Asaresult,theriskofsensitisationorelicitationarisingfromcontactwithNRL-containingproductscannotbeestimatedwithanyconfidence.Evenifamoremeaningfulriskestimatewerepossible,limitsforelicitationandsensitisationarelikelytobeclosetoorbelowthequantificationlimitsoftheproteinassayscurrentlyavailable,sotheproteinlevelcannotbeusedtodefinealevelofexposurethatcouldbedeemed“safe”witharealisticmarginofsafety.Inadditiontothelackofasufficientlysensitiveanalysismethod,itisrecognisedthatthereiscurrentlynotoxicologicalmethodavailabletoidentifyathresholdforeitheroftheseendpoints.Oneimplicationofthisisthattermsimplyingminimalallergenicrisk(e.g.hypoallergenic)areinappropriate.Becausetheprobabilityofharmoccurringatlowlevelsofexposurecannotbeestimatedonthebasisofscientificdata,therisktopatientsoruserscannotbeestimated.Forasignificanthazard,suchassensitisation,nolevelofexposurecanthereforebedeterminedthatcorrespondstoabroadlyacceptablerisk.Eliminationoftherisk(inlinewiththeprimaryexpectationofthefirstbulletpointofEssentialRequirement2)isthusnotpossible.Fortheabovereasons,therationalebehindvariousproposedlimitsissubjecttostrongcriticism:biologicallysignificantamountsofrelevantallergensmaybeoverlookedand,ontheotherhand,theamountsofirrelevantnon-allergenicproteinsmayexceedanyselectedupperlimits.UnderthesecircumstancesitisinappropriatetosetanallowablelimitforleachableproteincontentinmedicaldevicescontainingNRL.Failingtheimplementationofcontrolsthatensureabroadlyacceptablerisk,itisnecessarytoreducetheallergicriskarisingfromNRLtoalevelaslowasisreasonablypracticable(ALARP)andconsiderthepresenceofproteinresiduestobearesidualrisk.FormedicalglovescontainingNRL,boththeireffectivenessasabarriertoinfectionandthecostoftheirproductionhavepublichealthimplicationsthatarerelevanttotherisk:benefitassessment.EffortstoreducetheleachableproteincontentofNRLglovesmustthereforebebalancedagainstanyreductioninpropertiesoftheproductthatarecriticaltotheirfunctionandanyfinancialimplicationsthathaveanimpactuponthepreservation,promotionorimprovementofhumanhealth.StarchPowderWhilepowder-freeproductsexistforwhichacceptableperformanceisclaimed,itdoesnotnecessarilyfollowthattheseareappropriateforalluses.Itisimportanttorecognisethatbothrisksandbenefitscanvaryappreciablywiththeintendeduseofaproduct.Thisisparticularlysointhecaseofpowderedmedicalgloves,whererisksandbenefitsneedtobeconsideredinrelationtheiruseinsurgicalinterventionandnon-invasiveprocedures.Theuseofpowderdoesnotincreasetheallergenicityofthegloves,butallowsairborneexposuretotheallergen.Thus,thereisanadditionalriskofreactionsto9respiratoryexposureinsensitisedindividuals.HoweverthepopulationatriskisthesameasthatatriskofallergicreactiontoNRLalone.Ifthecontentoflatexallergensintheglovesislow,theuseofpowderedgloveshasnotincreasedsensitisationrates,implyingthatcontrollingthepowdercontentofglovesprovidesnoadditionalprotectiontonon-sensitisedindividuals.Theriskofadhesionsorgranulomaformationisrelevantonlytopatientsundergoingsurgicalprocedures.TheSCMPMDwasnotaskedtoadviseonthisriskand,intheabsenceofclearevidencethatpowdercausesthesecomplications,itisnotappropriatetointroduceregulatorymeasurestopreventtheuseofpowderedsurgeons’gloves.However,inviewofthescientificuncertainty,thepresenceofpowderremainsaresidualrisk.Thepresenceofglovepowderdoesnotsignificantlyaffectthebarrierpropertiesofglovessoalackofglovepowderdoesnotitselfintroducearisktopati
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