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.ANegativeControlisaspecimenthatgivesnoreactionundertheconditionsofthetest.

CLASSIFICATIONOFPLASTICS

SixPlasticClassesaredefined（see）.Thisclassificationisbasedonresponsestoaseriesofinvivotestsforwhichextracts,materials,androutesofadministrationarespecified.Thesetestsaredirectlyrelatedtotheintendedend-useoftheplasticarticles.Thechoiceofextractantsisrepresentativeofthevehiclesinpreparationswithwhichtheplasticsarelikelytobeincontact.Theclassificationfacilitatescommunicationamongsuppliers,users,andmanufacturersofplasticsbysummarizingtheteststobeperformedforcontainersforinjectionsandmedicaldevicesifaneedforclassificationexists.

Table1.ClassificationofPlastics

PlasticClasses

TeststobeConducted

I

II

III

IV

V

VI

TestMaterial

Animal

Dose

Procedure

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–VIonlyonthebasisoftheresponsecriteriaprescribedin.

Thisclassificationdoesnotapplytoplasticsthatareintendedforuseascontainersfororalortopicalproducts,orthatmaybeusedasanintegralpartofadrugformulation.doesnotapplytonaturalelastomers,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.EvaluationofSkinReactions

ErythemaandEscharFormation

Score

Noerythema

0

Veryslighterythema（barelyperceptible）

1

Well-definederythema

2

Moderatetosevereerythema

3

Severeerythema（beet-redness）toslightescharformation（injuriesindepth）

4

EdemaFormation

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—BoththeSystemicInjectionTestandtheIntracutaneousTestmaybeperformedusin