LEACHABLESUBSTANCESincondensate

General

AMEDICALDEVICE,partorACCESSORYshallnotaddtothecondensateLEACHABLESUBSTANCESatlevelsthatcreateanunacceptableRISKtothePATIENT.AllGASPATHWAYSfromwhichthePATIENTinspiresgasinNORMALCONDITION,where

gasintheGASPATHWAYcanreach100%saturationwithwateratsomepointintheGASPATHWAY,

condensatecanformontheGASPATHWAYsurfaces,and

liquidcondensatecanreachthePATIENT,

shallbeevaluatedforcondensateemissions.TheevaluationshouldusetheRISKMANAGEMENTPROCESS

toassessiftestingisrequired.

NOTE1CondensatecanforminGASPATHWAYSandcantaketheformofliquiddropsorafilmofwaterontheGASPATHWAYwalls.Thisliquidwatercanextractsubstancesfromthematerialsofthewallsthatwouldnotbeextractedbythebreathinggasalone.IfthisliquidcondensatecanreachthePATIENT,itcouldpotentiallyconveyharmfulsubstancestothePATIENT.

NOTE2Theevaluationofsomecomponents,whichareidenticalinFORMULATION,processingandpreparationforusetoanexistingcomponentofaMEDICALDEVICEthathasbeenpreviouslytested,mightconcludethatnofurthertestingisrequired.RefertoISO18562-1:2017,Figure2.

SectionsoftheGASPATHWAYfromwhichthePATIENTcannotbeexposedtocondensateneednotbetested.IftheRISKMANAGEMENTPROCESSdeterminesthattestingisrequired,thetestsof.52shallbeperformed.

IftheMEDICALDEVICEunderevaluationhasalreadybeenevaluatedasanexternalcommunicatingMEDICALDEVICEwithcontacttotissue/bone/dentinaccordingtoISO10993-1,thenthefollowingtestsneednotbeperformed.

EXAMPLE Atrachealtube,becauseofitsdirectcontactwiththePATIENT,isevaluatedaccordingtoISO10993-1.Inthiscase,thetestsofthisdocumentarenotrequired.

NOTE3SomeAUTHORITIESHAVINGJURISDICTIONmightrequirethesetestsiftheMEDICALDEVICEisintended

foruseonparticularlyvulnerablePATIENTpopulations,suchasneonates.

*Testmethod

TestforLEACHABLESUBSTANCESincondensateisasfollows.

Tocollectasample,either

produceandcollectcondensateunderclinicallyrelevantconditions,or

circulatethewateroverthesurfaceofthesampleatatemperaturerepresentativeofclinicaluse,or

*performanaqueousextractionontheinternalgascontactsurfacesaccordingtothemethodofISO10993-12:2012,Clause10,withtheextractatclinicallyrelevanttemperatures,foraclinicallyrelevantdurationoftime.

EXAMPLEThereisnoclinicalrelevancetoperforminga24-hextractiononaMEDICALDEVICEthatisonlyintendedtobeusedonaPATIENTfor20min.However,theunderlyingprincipleremains"whatisthedosetothePATIENTin24h".IfaMEDICALDEVICEcouldbeusedmultipletimesina24-hperiod,thenthemaximumlikelycumulativetimeisconsidered.Additionally,iftheMEDICALDEVICEisconsumableandreplacedconsecutively,the24-hexposurecanbehigherduetoadditiveeffects.

NOTE1 SeetherationaleinAnnexAforfurtherconsiderationsifperforminganaqueousextraction.

ThisdocumentisnotintendedtobeprescriptiveintheselectionofMEDICALDEVICEconfiguration,testmethodandconditionsusedtoproducethesample.Choicesshouldbejustifiedanddocumented.

*Determinethecontentofmetalionsinthecondensateorextractusingthemethodofpharmacopeias(e.g.USP<233>[1Zl)oranotherrelevantmethod.EvaluatetheresultsbasedonlimitsdefinedinUSP<232>[1B.]orothervalidatedsources.IfnotallthemetalslistedinUSP<233>arescreenedfor,thenjustifyanddocumenttherationale.

NOTE2Similaranalyticalmethodsareusefultoassessothermetalsofconcern,suchasnickeland

chromium.

Ifexposurelimitsarenotavailableforspecificmetalsidentifiedincondensate,thenderivea

TOLERABLEINTAKEusingthemethodofISO18562-1:2017,Clause7.

Converttheconcentrationofeachmetaliontoatotaldose/daybyconsideringthetotalamountofliquidcondensatethatreachesthePATIENTinadayas1ml.

*Ifrequiredinordertoachievedetectionofconcentrationsatthelimitsspecified,enrichtheorganicimpuritiesinthecondensateorextractusingestablishedmethods,suchasstirbarsorptiveextraction,solidphasemicroextraction,liquid-liquidextractionorademonstrablyequivalentmethod.ThenidentifyandquantifyorganicimpuritiesusingGC-MS(gaschromatography-massspectrometry)oranequivalentmethod.

ConverttheconcentrationofeachsubstancetoatotaldoseperPATIENTperdaybyconsideringthetotalamountofcondensatethatreachesthePATIENTperdayas1ml.

ConfirmthatthedoseofeachidentifiedsubstancedeliveredtothePATIENTin1mlofcondensateorextractislessthantheTOLERABLEINTAKEorTHRESHOLDOFTOXICOLOGICALCONCERNderivedfromthemethodofISO18562-1:2017,Clause7.

Therouteofexposureisintothelungandthereforeconsideredinhalational,notoralingestion.

*PerformacytotoxicitytestaccordingtoISO10993-5onthecondensateorextract.ThereareseveraldifferentmethodsofferedinISO10993-5.Selectamethodsuitableforliquids.

NOTE3TheMEMelutionmethodisasensitivemethod,andisnormallyacceptedbyAUTHORITIESHAVING

JURISDICTIONasanappropriatemethod.

*PerformasensitizationtestaccordingtoISO10993-10onthecondensateorextract.Selectamethodsuitableforliquids.

NOTE4TheLLNAmethodisnormallyacceptedbyAUTHORITIESHAVINGJURISDICTIONasanappropriate

method.However,thereareconcernsthatthisparticulartestmethodmightnotbewhollysuitableif

theMEDICALDEVICEincludesnickel,

theextractcontainsamixtureofsubstances,ratherthanasingleleachedsubstance,

theaqueousextractdoesnotincludeavehicletoensuretheextractisincontactwiththeskin,ornovelmaterialsthatdonotpenetratetheskinarepresent(e.g.nanomaterials).

AnnexA(informative)

Rationaleandguidance

Generalguidance

Thisannexprovidesrationalefortheimportantrequirementsofthisdocumentandisintendedforthosewhoarefamiliarwiththesubjectofthisdocument,butwhohavenotparticipatedinitsdevelopment.Anunderstandingofthereasonsforthemainrequirementsisconsideredtobeessentialforitsproperapplication.Furthermore,asclinicalpracticeandtechnologychange,itisbelievedthatrationaleforthepresentrequirementswillfacilitateanyrevisionofthisdocumentnecessitatedbythosedevelopments.

Theclausesandsubclausesinthisannexhavebeensonumberedtocorrespondtotheclausesandsubclausesinthisdocumenttowhichtheyrefer.Thenumberingis,therefore,notconsecutive.

Rationaleforparticularclausesandsubclauses

.5..2.-Testmethod

3)

Typically,theextractionratiowillbe3cm2ofinnerGASPATHWAYsurfacepermlofwater.

CareshouldbetakenifthebulkmaterialofthewallsoftheGASPATHWAYarenon-homogeneous.Forexample,atubewithacoatingoraco-extrudedtubecouldhavedifferentmaterialsontheinnergascontactsurfacesfromthematerialsformingtheoutersurfaces.Inthiscase,grindingupthebulkmaterialtoperformtheextractionwillnotgiveresultsrepresentativeofanintacttube.

Also,beawarethatwithsomematerials,freshcutsurfacescanhavedifferentpropertiesfromthesurfacesresultingfromtheactualmanufacturingPROCESS.Forexample,extrudedfoamedmaterialstypicallyhaveaclosedfilmsurface,whiletheinnerbulkmaterialhasafoamstructurewithamuchgreatersurfacearea.Thesetwodifferentphysicalformsofthesamematerialmaywellgivedifferentresultswhenatypicalextractionisperformed.

SomeAUTHORITIESHAVINGJURISDICTIONrecommendexhaustiveextractionforprolongedandpermanentdurationMEDICALDEVICES.

andc)

Inanyassessment,themostimportantconsiderationistheactualdose-to-PATIENT,whichiscalculatedbytakingtheconcentrationsmultipliedbythevolumethePATIENTinhalesoringestsperday.

TheexpertsonthecommitteediscussedatlengththeamountofliquidcondensatethatmightreachthePATIENTperday.ThecommitteenotedthatitisestablishedclinicalpracticetohavemethodsinplacetopreventliquidwaterascondensatefromreachingthePATIENT.Thesemethodsincludeheatedbreathinghosesandwatertraps.ThecommitteeconcludedthathavingcondensedwaterreachingthePATIENTwasbadclinicalpracticeandwasananomalousevent,notaregularoccurrence.

ThecommitteedecidedthatasISO14971requiresthemtoconsiderintendedandreasonablyforeseeablemisuse,thedailypermittedvolumeofwaterenteringaPATIENTshouldbesetat1ml.Thisvalueof1mlshouldbeusedinthecalculationstoderivethedosetothePATIEN