./88BIOLOGICALREACTIVITYTESTS,INVIVOThefollowingtestsaredesignedtodeterminethebiologicalresponseofanimalstoelastomerics,plastics,andotherpolymericmaterialwithdirectorindirectpatientcontact,orbytheinjectionofspecificextractspreparedfromthematerialundertest.Itisessentialtomakeavailablethespecificsurfaceareaforextraction.Whenthesurfaceareaofthespecimencannotbedetermined,use0.1gofelastomeror0.2gofplasticorothermaterialforeverymLofextractionfluid.Also,itisessentialtoexercisecareinthepreparationofthematerialstobeinjectedorinstilledtopreventcontaminationwithmicroorganismsandotherforeignmatter.Threetestsaredescribed.TheSystemicInjectionTestandtheIntracutaneousTestareusedforelastomericmaterials,especiallytoelastomericclosuresforwhichtheappropriateBiologicalReactivityTests,InVitro87(http://127.0.0.1:38332/uspnf/pub/data/v38332/usp38nf33s2_c87.xml"\l"usp38nf33s2_c87)haveindicatedsignificantbiologicalreactivity.Thesetwotestsareusedforplasticsandotherpolymers,inadditiontoathirdtest,theImplantationTest,totestthesuitabilityofthesematerialsintendedforuseinfabricatingcontainersandaccessoriesthereto,foruseinparenteralpreparations,andforuseinmedicaldevices,implants,andothersystems.Thesethreetestsareappliedtomaterialsormedicaldevices,ifthereisaneedforclassificationofplasticsandotherpolymersbasedoninvivobiologicalreactivitytesting.Forthepurposeofthischapter,thesedefinitionsapply:theSampleisthespecimenundertestoranextractpreparedfromsuchaspecimen.ABlankconsistsofthesamequantityofthesameextractingmediumthatisusedfortheextractionofthespecimenundertest,treatedinthesamemannerastheextractingmediumcontainingthespecimenundertest.ANegativeControl1(http://127.0.0.1:38332/uspnf/pub/data/v38332/usp38nf33s2_c88.xml"\l"usp38nf33s2_fc00881)isaspecimenthatgivesnoreactionundertheconditionsofthetest.CLASSIFICATIONOFPLASTICSSixPlasticClassesaredefined(seeTable1(http://127.0.0.1:38332/uspnf/pub/data/v38332/usp38nf33s2_c88.xml"\l"usp38nf33s2_c88-tb1)).Thisclassificationisbasedonresponsestoaseriesofinvivotestsforwhichextracts,materials,androutesofadministrationarespecified.Thesetestsaredirectlyrelatedtotheintendedend-useoftheplasticarticles.Thechoiceofextractantsisrepresentativeofthevehiclesinpreparationswithwhichtheplasticsarelikelytobeincontact.TheTable1(http://127.0.0.1:38332/uspnf/pub/data/v38332/usp38nf33s2_c88.xml"\l"usp38nf33s2_c88-tb1)classificationfacilitatescommunicationamongsuppliers,users,andmanufacturersofplasticsbysummarizingtheteststobeperformedforcontainersforinjectionsandmedicaldevicesifaneedforclassificationexists.Table1.ClassificationofPlasticsPlasticClassesa(http://127.0.0.1:38332/uspnf/pub/data/v38332/usp38nf33s2_c88.xml"\l"usp38nf33s2_fc8802)TeststobeConductedIIIIIIIVVVITestMaterialAnimalDoseProcedureb(http://127.0.0.1:38332/uspnf/pub/data/v38332/usp38nf33s2_c88.xml"\l"usp38nf33s2_fc8803)xxxxxxExtractofSampleinSodiumChlorideInjectionMouse50mL/kgA(IV)xxxxxxRabbitorGuineaPig0.2mL/animalateachof10or6sitesB(IC) xxxxxExtractofSamplein1in20SolutionofAlcoholinSodiumChlorideInjectionMouse50mL/kgA(IP) xxxxxRabbitorGuineaPig0.2mL/animalateachof10or6sitesB(IC) x xxExtractofSampleinPolyethyleneGlycol400Mouse10g/kgA(IP) xxRabbitorGuineaPig0.2mL/animalateachof10or6sitesB(IC) xxxxExtractofSampleinVegetableOilMouse50mL/kgA(IP) xxxRabbitorGuineaPig0.2mL/animalateachof10or6sitesB(IC) x xImplantstripsofSampleRabbit4strips/animalC x xImplantSampleRat2Samples/animalCa Testsrequiredforeachclassareindicatedby“x”inappropriatecolumns.b Legend:A(IP)—SystemicInjectionTest(intraperitoneal);B(IC)—IntracutaneousTest(intracutaneous);C—ImplantationTest(intramuscularorsubcutaneousimplantation).WiththeexceptionoftheImplantationTest,theproceduresarebasedontheuseofextractsthat,dependingontheheatresistanceofthematerial,arepreparedatoneofthreestandardtemperatures:50,70,and121.Therefore,theclassdesignationofaplasticmustbeaccompaniedbyanindicationofthetemperatureofextraction(e.g.,IV-121,whichrepresentsaclassIVplasticextractedat121,orI-50,whichrepresentsaclassIplasticextractedat50).PlasticsmaybeclassifiedasUSPPlasticClassesI–VIonlyonthebasisoftheresponsecriteriaprescribedinTable1(http://127.0.0.1:38332/uspnf/pub/data/v38332/usp38nf33s2_c88.xml"\l"usp38nf33s2_c88-tb1).Thisclassificationdoesnotapplytoplasticsthatareintendedforuseascontainersfororalortopicalproducts,orthatmaybeusedasanintegralpartofadrugformulation.Table1(http://127.0.0.1:38332/uspnf/pub/data/v38332/usp38nf33s2_c88.xml"\l"usp38nf33s2_c88-tb1)doesnotapplytonaturalelastomers,whicharetobetestedinSodiumChlorideInjectionandvegetableoilsonly.TheSystemicInjectionTestandtheIntracutaneousTestaredesignedtodeterminethesystemicandlocal,respectively,biologicalresponsesofanimalstoplasticsandotherpolymersbythesingle-doseinjectionofspecificextractspreparedfromaSample.TheImplantationTestisdesignedtoevaluatethereactionoflivingtissuetotheplasticandotherpolymersbytheimplantationoftheSampleitselfintoanimaltissue.TheproperpreparationandplacementofthespecimensunderasepticconditionsareimportantintheconductoftheImplantationTest.Thesetestsaredesignedforapplicationtoplasticsandotherpolymersintheconditioninwhichtheyareused.Ifthematerialistobeexposedtoanycleansingorsterilizationprocesspriortoitsend-use,thenthetestsaretobeconductedonaSamplepreparedfromaspecimenpreconditionedbythesameprocessing.Factorssuchasmaterialcomposition,processingandcleaningprocedures,contactingmedia,inks,adhesives,absorption,adsorptionandpermeabilityofpreservatives,andconditionsofstoragemayalsoaffectthesuitabilityofamaterialforaspecificuse.Evaluationofsuchfactorsshouldbemadebyappropriateadditionalspecificteststodeterminethesuitabilityofamaterialforitsintendeduse.USPReferenceStandards11(http://127.0.0.1:38332/uspnf/pub/data/v38332/usp38nf33s2_c11.xml"\l"usp38nf33s2_c11)—USPHigh-DensityPolyethyleneRS.ExtractingMedia—sodiumchlorideinjection(seemonograph).UseSodiumChlorideInjectioncontaining0.9%ofNaCl.1in20solutionofalcoholinsodiumchlorideinjection.polyethyleneglycol400(seemonograph).vegetableoil—UsefreshlyrefinedSesameOil(seemonograph)orCottonseedOil(seemonograph)orothersuitablevegetableoils.drugproductvehicle(whereapplicable).waterforinjection(seemonograph).Note—TheSesameOilorCottonseedOilorothersuitablevegetableoilmeetsthefollowingadditionalrequirements.Obtain,ifpossible,freshlyrefinedoil.Usethreeproperlypreparedanimals,andinjecttheoilintracutaneouslyinadoseof0.2mLintoeachof10sitesperanimal,andobservetheanimalsat24,48,and72hfollowinginjection.RatetheobservationsateachsiteonthenumericalscaleindicatedinTable2.Forthe3rabbitsorguineapigs(30or18injectionsites),atanyobservationtime,theaverageresponseforerythemaisnotgreaterthan0.5andforedemaisnotgreaterthan1.0,andnositeshowsatissuereactionlargerthan10mminoveralldiameter.Theresidueofoilattheinjectionsiteshouldnotbemisinterpretedasedema.Edematoustissueblancheswhengentlepressureisapplied.Table2.EvaluationofSkinReactionsa(http://127.0.0.1:38332/uspnf/pub/data/v38332/usp38nf33s2_c88.xml"\l"usp38nf33s2_fc8808)ErythemaandEscharFormationScoreNoerythema0Veryslighterythema(barelyperceptible)1Well-definederythema2Moderatetosevereerythema3Severeerythema(beet-redness)toslightescharformation(injuriesindepth)4EdemaFormationb(http://127.0.0.1:38332/uspnf/pub/data/v38332/usp38nf33s2_c88.xml"\l"usp38nf33s2_fc8807)ScoreNoedema0Veryslightedema(barelyperceptible)1Slightedema(edgesofareawelldefinedbydefiniteraising)2Moderateedema(raisedapproximately1mm)3Severeedema(raisedmorethan1mmandextendingbeyondtheareaofexposure)4a DraizeJH,WoodwardG,CalveryHO.Methodsforthestudyofirritationandtoxicityofsubstancesappliedtopicallytotheskinandmucousmembranes.JPharmacolExpTher1944;82:377–390.b Excludesnoninflammatory(mechanical)edemafromtheblankorextractionfluid.Apparatus—Theapparatusforthetestsincludesthefollowing.autoclave—Useanautoclavecapableofmaintainingatemperatureof121±2.0,equippedwithathermometer,apressuregauge,aventcock,arackadequatetoaccommodatethetestcontainersabovethewaterlevel,andawatercoolingsystemthatwillallowforcoolingofthetestcontainerstoabout,butnotbelow,20immediatelyfollowingtheheatingcycle.oven—Useanoven,preferablyaforced-circulationmodel,thatwillmaintainoperatingtemperaturesof50or70within±2.extractioncontainers—Useonlycontainers,suchasampulsorscrew-capculturetesttubes,ofTypeIglass.Ifused,culturetesttubesareclosedwithscrewcapshavingsuitableelastomericliners.Theexposedsurfaceoftheelastomericlineriscompletelyprotectedwithaninertsoliddisk0.05–0.075mminthickness.Asuitablediskmaybefabricatedfromapolytefresin.PreparationofApparatus—Cleanseallglasswarethoroughlywithchromicacidcleansingmixture,orifnecessary,withhotnitricacid,followedbyprolongedrinsingwithwater.Cleancuttingutensilsbyanappropriatemethod(e.g.,successivecleaningwithacetoneandmethylenechloride)priortouseinsubdividingaspecimen.Cleanallotherequipmentbythoroughscrubbingwithasuitabledetergentandprolongedrinsingwithwater.Rendercontainersandequipmentusedforextraction,andintransferandadministrationoftestmaterial,sterileanddrybyasuitableprocess.[Note—Ifethyleneoxideisusedasthesterilizingagent,allowadequatetimeforcompletedegassing.]Procedure—preparationofsample—BoththeSystemicInjectionTestandtheIntracutaneousTestmaybeperformedusingthesameextract,ifdesired,orseparateextractsmaybemadeforeachtest.SelectandsubdivideintoportionsaSampleofthesizeindicatedinTable3(http://127.0.0.1:38332/uspnf/pub/data/v38332/usp38nf33s2_c88.xml"\l"usp38nf33s2_c88-tb3).Removeparticulatematter,suchaslintandfreeparticles,bytreatingeachsubdividedSampleorNegativeControlasfollows.PlacetheSampleintoaclean,glass-stoppered,100-mLgraduatedcylinderofTypeIglass,andaddabout70mLofWaterforInjection.Agitateforabout30s,anddrainoffthewater.Repeatthisstep,anddrythosepiecespreparedfortheextractionwithVegetableOilinanovenatatemperaturenotexceeding50.[Note—DonotcleantheSamplewithadryorwetclothorbyrinsingorwashingwithanorganicsolvent,surfactant,etc.]Table3.SurfaceAreaofSpecimenToBeUseda(http://127.0.0.1:38332/uspnf/pub/data/v38332/usp38nf33s2_c88.xml"\l"usp38nf33s2_fc8804)FormofMaterialThicknessAmountofSampleforeach20mLofExtractingMediumSubdividedintoFilmorsheet<0.5mmEquivalentof120cm2totalsurfacearea(bothsidescombined)Stripsofabout5×0.3cm 0.5–1mmEquivalentof60cm2totalsurfacearea(bothsidescombined) Tubing<0.5mm(wall)Length(incm)=120cm2/(sumofIDandODcircumferences)Sectionsofabout5×0.3cm 0.5–1mm(wall)Length(incm)=60cm2/(sumofIDandODcircumferences) Slabs,tubing,andmoldeditems>1mmEquivalentof60cm2totalsurfacearea(allexposedsurfacescombined)Piecesuptoabout5×0.3cmElastomers>1mmEquivalentof25cm2totalsurfacearea(allexposedsurfacescombined)Donotsubdivideb(http://127.0.0.1:38332/uspnf/pub/data/v38332/usp38nf33s2_c88.xml"\l"usp38nf33s2_fc8805)a Whensurfaceareacannotbedeterminedduetotheconfigurationofthespecimen,use0.1gofelastomeror0.2gofplasticorotherpolymersforevery1mLofextractingfluid.b Moldedelastomericclosuresaretestedintact.preparationofextracts—PlaceaproperlypreparedSampletobetestedinanextractioncontainer,andadd20mLoftheappropriateextractingmedium.Repeatthesedirectionsforeachextractingmediumrequiredfortesting.Also,prepareone20-mLblankofeachmediumforparallelinjectionsandcomparisons.Extractbyheatinginanautoclaveat121for60min,inanovenat70for24h,orat50for72h.Allowadequatetimefortheliquidwithinthecontainertoreachtheextractiontemperature.[Note—TheextractionconditionsshouldnotinanyinstancecausephysicalchangessuchasfusionormeltingoftheSamplepieces,whichresultinadecreaseintheavailablesurfacearea.Aslightadherenceofthepiecescanbetolerated.Alwaysaddthecleanedpiecesindividuallytotheextractingmedium.IfculturetubesareusedforautoclaveextractionswithVegetableOil,sealscrewcapsadequatelywithpressure-sensitivetape.]Cooltoaboutroomtemperaturebutnotbelow20,shakevigorouslyforseveralminutes,anddecanteachextractimmediately,usingasepticprecautions,intoadry,sterilevessel.Storetheextractsatatemperatureof20–30,anddonotusefortestsafter24h.Ofimportancearethecontactoftheextractingmediumwiththeavailablesurfaceareaoftheplasticandthetimeandtemperatureduringextraction,thepropercooling,agitation,anddecantingprocess,andtheaseptichandlingandstorageoftheextractsfollowingextraction.SYSTEMICINJECTIONTESTThistestisdesignedtoevaluatesystemicresponsestotheextractsofmaterialsundertestfollowinginjectionintomice.Alternateroutesofinjectionmaybeusedwithjustification.TestAnimals—Usehealthy,notpreviouslyusedalbinomiceweighing17–23g.Foreachtestgroupuseonlymiceofthesamesource.Allowwaterandfood,commonlyusedforlaboratoryanimalsandofknowncomposition,adlibitum.Procedure—[Note—Agitateeachextractvigorouslypriortowithdrawalofinjectiondosestoensureevendistributionoftheextractedmatter.]InjecteachofthefivemiceinatestgroupwiththeSampleortheBlankasoutlinedinTable4(http://127.0.0.1:38332/uspnf/pub/data/v38332/usp38nf33s2_c88.xml"\l"usp38nf33s2_c88-tb4),excepttodiluteeachgoftheextractoftheSamplepreparedwithPolyethyleneGlycol400,andthecorrespondingBlank,with4.1volumesofSodiumChlorideInjectiontoobtainasolutionhavingaconcentrationofabout200mgofpolyethyleneglycolpermL.Table4.InjectionProcedure—SystemicInjectionTestExtractorBlankDoseperkgRoutea(http://127.0.0.1:38332/uspnf/pub/data/v38332/usp38nf33s2_c88.xml"\l"usp38nf33s2_ft00886)SodiumChlorideInjection50mLIV1in20solutionofAlcoholinSodiumChlorideInjection50mLIVPolyethyleneGlycol40010gIPDrugproductvehicle(whereapplicable)50mLIV50mLIPVegetableOil50mLIPa IV=intravenous(aqueoussampleandblank);IP=intraperitoneal(oleaginoussampleandblank).Observetheanimalsimmediatelyafterinjection,again4hafterinjection,andthenatleastat24,48,and72h.IfduringtheobservationperiodnoneoftheanimalstreatedwiththeextractoftheSampleshowsasignificantlygreaterbiologicalreactivitythantheanimalstreatedwiththeBlank,theSamplemeetstherequirementsofthistest.Iftwoormoremicedie,orifabnormalbehaviorsuchasconvulsionsorprostrationoccursintwoormoremice,orifabodyweightlossgreaterthan2goccursinthreeormoremice,theSampledoesnotmeettherequirementsofthetest.IfanyanimalstreatedwiththeSampleshowonlyslightsignsofbiologicalreactivity,andnotmorethanoneanimalshowsgrosssymptomsofbiologicalreactivityordies,repeatthetestusinggroupsof10mice.Ontherepeattest,all10animalstreatedwiththeSampleshownosignificantbiologicalreactivityabovetheBlankanimalsduringtheobservationperiod.INTRACUTANEOUSTESTThistestisdesignedtoevaluatelocalresponsestotheextractsofmaterialsundertestfollowingintracutaneousinjectionintorabbitsorguineapigs.TestAnimals—Selecthealthy,rabbitsorguineapigswithfurthatcanbeclippedcloselyandskinthatisfreefrommechanicalirritationortrauma.Inhandlingtheanimals,avoidtouchingtheinjectionsitesduringobservationperiods,excepttodiscriminatebetweenedemaandanoilresidue.Procedure—[Note—Agitateeachextractvigorouslypriortowithdrawalofinjectiondosestoensureevendistributionoftheextractedmatter.]Onthedayofthetest,closelyclipthefurontheanimal'sbackonbothsidesofthespinalcolumnoverasufficientlylargetestarea.Avoidmechanicalirritationandtrauma.Removeloosehairbymeansofvacuum.Ifnecessary,swabtheskinlightlywithdilutedalcohol,anddrytheskinpriortoinjection.Morethanoneextractfromagivenmaterialcanbeusedperrabbitorguineapig,ifitisdeterminedthatthetestresultswillnotbeaffected.ForeachSampleusetwoanimalsandinjecteachintracutaneously,usingonesideoftheanimalfortheSampleandtheothersidefortheBlank,asoutlinedinTable5(http://127.0.0.1:38332/uspnf/pub/data/v38332/usp38nf33s2_c88.xml"\l"usp38nf33s2_c88-tb5).[Note—DiluteeachgoftheextractoftheSamplepreparedwithPolyethyleneGlycol400,andthecorrespondingBlank,with7.4volumesofSodiumChlorideInjectiontoobtainasolutionhavingaconcentrationofabout120mgofpolyethyleneglycolpermL.]Table5.IntracutaneousTestExtractorBlankNumberofSites(peranimal)Dose(µLpersite)Sample5200Blank5200Examineinjectionsitesforevidenceofanytissuereactionsuchaserythema,edema,andnecrosis.Swabtheskinlightly,ifnecessary,withdilutedalcoholtofacilitatereadingofinjectionsites.Observeallanimalsat24,48,and72hafterinjection.RatetheobservationsonanumericalscalefortheextractoftheSampleandfortheBlank,usingTable2.Reclipthefurasnecessaryduringtheobservationperiod.TheaverageerythemaandedemascoresforSampleandBlanksitesaredeterminedateveryscoringinterval(24,48,and72h)foreachrabbitorguineapig.Afterthe72-hourscoring,allerythemascoresplusedemascoresaretotalledseparatelyforeachSampleandBlank.Divideeachofthetotalsby12(2animals×3scoringperiods×2scoringcategories)todeterminetheoverallmeanscoreforeachSampleversuseachcorrespondingBlank.TherequirementsofthetestaremetifthedifferencebetweentheSampleandtheBlankmeanscoreis1.0orless.IfatanyobservationperiodtheaveragereactiontotheSampleisquestionablygreaterthantheaveragereactiontotheBlank,repeatthetestusingthreeadditionalrabbitsorguineapigs.TherequirementsofthetestaremetifthedifferencebetweentheSampleandtheBlankmeanscoreis1.0orless.IMPLANTATIONTESTTheimplantationtestisdesignedfortheevaluationofplasticmaterialsandotherpolymericmaterialsindirectcontactwithlivingtissue.Ofimportancearetheproperpreparationoftheimplantstripsandtheirproperimplantationunderasepticconditions.TheintramuscularimplantationtestrequireshealthyadultNewZealandrabbits.Thetestspecimensareplacedintoneedlesasthedeliverysystemforimplantation.Althoughmostmaterialslendthemselvesreadilytothismethod,thereareanumberofmaterialsthatareunsuitableforintramuscularimplantation.Formaterialswithphysicalcharacteristicsunsuitableforroutineintramuscularimplantation,thesubcutaneousratimplantationmodelisaviablealternative.IntramuscularImplantationinRabbitsPrepareforimplantation8stripsoftheSampleand4stripsofUSPHigh-DensityPolyethyleneRS.Eachstripshouldmeasurenotlessthan10×1mm.Theedgesofthestripsshouldbeassmoothaspossibletoavoidadditionalmechanicaltraumauponimplantation.Stripsofthespecifiedminimumsizeareimplantedbymeansofahypodermicneedle(15–19gauge)withintravenouspointandasteriletrocar.Useeitherpresterilizedneedlesintowhichthesterileplasticstripsareasepticallyinserted,orinserteachcleanstripintoaneedle,thecannulaandhubofwhichareprotectedwithanappropriatecover,andthensubjectedtotheappropriatesterilizationprocedure.[Note—Allowforproperdegassingifagentssuchasethyleneoxideareused.]TestAnimals—Selecthealthy,adultrabbitsweighingnotlessthan2.5kg,andwithparavertebralmusclesthataresufficientlylargeinsizetoallowforimplantationoftheteststrips.Donotuseanymusculartissueotherthantheparavertebralsite.Theanimalsmustbeanesthetizedwithacommonlyusedanestheticagenttoadegreedeepenoughtopreventmuscularmovements,suchastwitching.SeetheAssociationforAssessmentandAccreditationofLaboratoryAnimalCare(AAALAC)guidelines.Procedure—Performthetestinacleanarea.Onthedayofthetestorupto20hbeforetesting,clipthefuroftheanimalsonbothsidesofthespinalcolumn.Removeloosehairbymeansofvacuum.Swabtheskinlightlywithdilutedalcohol,anddrytheskinpriortoinjection.ImplantfourstripsoftheSampleintotheparavertebralmuscleononesideofthespineofeachoftworabbits,2.5–5cmfromthemidlineandparalleltothespinalcolumn,andabout2.5cmapartfromeachother.InasimilarfashionimplanttwostripsofUSPHigh-DensityPolyethyleneRSintheoppositemuscleofeachanimal.Insertasterilestyletintotheneedletoholdtheimplantstripinthetissuewhilewithdrawingtheneedle.Ifexcessivebleedingisobservedafterimplantationofastrip,placeaduplicatestripatanothersite.Keeptheanimalsforaperiodofnotlessthan120h,andsacrificethemattheendoftheobservationperiodbyadministeringanoverdoseofananestheticagentorothersuitableagents.Allowsufficienttimetoelapseforthetissuetobecutwithoutbleeding.Examinemacroscopicallytheareaofthetissuesurroundingthecenterportionofeachimplantstrip.Useamagnifyinglensandauxiliarylightsource.ObservetheSampleandControlimplantsitesforhemorrhage,necrosis,discolorations,andinfections,andrecordtheobservations.Measureencapsulation,ifpresent,byrecordingthewidthofthecapsule(fromtheperipheryofthespaceoccupiedbytheimplantControlorSampletotheperipheryofthecapsule)roundedtothenearest0.1mm.ScoreencapsulationaccordingtoTable6(http://
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