USP 88 生物实验.docx

USP 88 生物实验.docx

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USP88生物实验

88

BIOLOGICALREACTIVITYTESTS,INVIVO

Thefollowingtestsaredesignedtodeterminethebiologicalresponseofanimalstoelastomerics,plastics,andotherpolymericmaterialwithdirectorindirectpatientcontact,orbytheinjectionofspecificextractspreparedfromthematerialundertest、Itisessentialtomakeavailablethespecificsurfaceareaforextraction、Whenthesurfaceareaofthespecimencannotbedetermined,use0、1gofelastomeror0、2gofplasticorothermaterialforeverymLofextractionfluid、Also,itisessentialtoexercisecareinthepreparationofthematerialstobeinjectedorinstilledtopreventcontaminationwithmicroorganismsandotherforeignmatter、Threetestsaredescribed、TheSystemicInjectionTestandtheIntracutaneousTestareusedforelastomericmaterials,especiallytoelastomericclosuresforwhichtheappropriateBiologicalReactivityTests,InVitro

87

haveindicatedsignificantbiologicalreactivity、Thesetwotestsareusedforplasticsandotherpolymers,inadditiontoathirdtest,theImplantationTest,totestthesuitabilityofthesematerialsintendedforuseinfabricatingcontainersandaccessoriesthereto,foruseinparenteralpreparations,andforuseinmedicaldevices,implants,andothersystems、

Thesethreetestsareappliedtomaterialsormedicaldevices,ifthereisaneedforclassificationofplasticsandotherpolymersbasedoninvivobiologicalreactivitytesting、

Forthepurposeofthischapter,thesedefinitionsapply:

theSampleisthespecimenundertestoranextractpreparedfromsuchaspecimen、ABlankconsistsofthesamequantityofthesameextractingmediumthatisusedfortheextractionofthespecimenundertest,treatedinthesamemannerastheextractingmediumcontainingthespecimenundertest、ANegativeControl1isaspecimenthatgivesnoreactionundertheconditionsofthetest、

CLASSIFICATIONOFPLASTICS

SixPlasticClassesaredefined（seeTable1）、Thisclassificationisbasedonresponsestoaseriesofinvivotestsforwhichextracts,materials,androutesofadministrationarespecified、Thesetestsaredirectlyrelatedtotheintendedend-useoftheplasticarticles、Thechoiceofextractantsisrepresentativeofthevehiclesinpreparationswithwhichtheplasticsarelikelytobeincontact、TheTable1classificationfacilitatescommunicationamongsuppliers,users,andmanufacturersofplasticsbysummarizingtheteststobeperformedforcontainersforinjectionsandmedicaldevicesifaneedforclassificationexists、

Table1、ClassificationofPlastics

PlasticClassesa

TeststobeConducted

I

II

III

IV

V

VI

TestMaterial

Animal

Dose

Procedureb

x

x

x

x

x

x

ExtractofSampleinSodiumChlorideInjection

Mouse

50mL/kg

A（IV）

x

x

x

x

x

x

RabbitorGuineaPig

0、2mL/animal

ateachof10or6sites

B（IC）

x

x

x

x

x

ExtractofSamplein1in20SolutionofAlcoholinSodiumChlorideInjection

Mouse

50mL/kg

A（IP）

x

x

x

x

x

RabbitorGuineaPig

0、2mL/animal

ateachof10or6sites

B（IC）

x

x

x

ExtractofSampleinPolyethyleneGlycol400

Mouse

10g/kg

A（IP）

x

x

RabbitorGuineaPig

0、2mL/animal

ateachof10or6sites

B（IC）

x

x

x

x

ExtractofSampleinVegetableOil

Mouse

50mL/kg

A（IP）

x

x

x

RabbitorGuineaPig

0、2mL/animal

ateachof10or6sites

B（IC）

x

x

ImplantstripsofSample

Rabbit

4strips/animal

C

x

x

ImplantSample

Rat

2Samples/animal

C

a 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、

Thisclassificationdoesnotapplytoplasticsthatareintendedforuseascontainersfororalortopicalproducts,orthatmaybeusedasanintegralpartofadrugformulation、Table1doesnotapplytonaturalelastomers,whicharetobetestedinSodiumChlorideInjectionandvegetableoilsonly、

TheSystemicInjectionTestandtheIntracutaneousTestaredesignedtodeterminethesystemicandlocal,respectively,biologicalresponsesofanimalstoplasticsandotherpolymersbythesingle-doseinjectionofspecificextractspreparedfromaSample、TheImplantationTestisdesignedtoevaluatethereactionoflivingtissuetotheplasticandotherpolymersbytheimplantationoftheSampleitselfintoanimaltissue、TheproperpreparationandplacementofthespecimensunderasepticconditionsareimportantintheconductoftheImplantationTest、

Thesetestsaredesignedforapplicationtoplasticsandotherpolymersintheconditioninwhichtheyareused、Ifthematerialistobeexposedtoanycleansingorsterilizationprocesspriortoitsend-use,thenthetestsaretobeconductedonaSamplepreparedfromaspecimenpreconditionedbythesameprocessing、

Factorssuchasmaterialcomposition,processingandcleaningprocedures,contactingmedia,inks,adhesives,absorption,adsorptionandpermeabilityofpreservatives,andconditionsofstoragemayalsoaffectthesuitabilityofamaterialforaspecificuse、Evaluationofsuchfactorsshouldbemadebyappropriateadditionalspecificteststodeterminethesuitabilityofamaterialforitsintendeduse、

USPReferenceStandards

11

—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

ErythemaandEscharFormation

Score

Noerythema

0

Veryslighterythema（barelyperceptible）

1

Well-definederythema

2

Moderatetosevereerythema

3

Severeerythema（beet-redness）toslightescharformation（injuriesindepth）

4

EdemaFormationb

Score

Noedema

0

Veryslightedema（barelyperceptible）

1

Slightedema（edgesofareawelldefinedbydefiniteraising）

2

Moderateedema（raisedapproximately

1mm）

3

Severeedema（raisedmorethan1mmandextendingbeyondtheareaof

exposure）

4

a DraizeJH,WoodwardG,CalveryHO、Methodsforthestudyofirritationandtoxicityofsubstancesappliedtopicallytotheskinandmucousmembranes、JPharmacolExpTher1944;82:

377–390、

b Excludesnoninflammatory（mechanical）edemafromtheblankorextractionfluid、

Apparatus—Theapparatusforthetestsincludesthefollowing、

autoclave—Useanautoclavecapableofmaintainingatemperatureof121±2、0

equippedwithathermometer,apressuregauge,aventcock,arackadequatetoaccommodatethetestcontainersabovethewaterlevel,andawatercoolingsystemthatwillallowforcoolingofthetestcontainerstoabout,butnotbelow,20

immediatelyfollowingtheheatingcycle、

oven—Useanoven,preferablyaforced-circulationmodel,thatwillmaintainoperatingtemperaturesof50

or70

within±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—BoththeSystemicInjectionTestan