usp有机溶剂残留方法

467ORGANICVOLATILEIMPURITIESRESIDUALSOLVENTSLIMITSForpharmacopeialpurposes,residualsolventsinpharmaceuticalsaredefinedasorganicvolatilechemicalsthatareusedorproducedinthemanufactureofdrugsubstancesorexcipients,orinthepreparationofdrugproducts.Theresidualsolventsarenotcompletelyremovedbypracticalmanufacturingtechniques.Appropriateselectionofthesolventforthesynthesisofadrugsubstanceoranexcipientmayenhancetheyield,ordeterminecharacteristicssuchascrystalform,purity,andsolubility.Therefore,thesolventmaysometimesbeacriticalelementinthesyntheticprocess.ThisGeneralChapterdoesnotaddresssolventsdeliberatelyusedasexcipientsnordoesitaddresssolvates.However,thecontentofsolventsinsuchproductsshouldbeevaluatedandjustified.Becauseresidualsolventsdonotprovidetherapeuticbenefit,theyshouldberemoved,totheextentpossible,tomeetingredientandproductspecifications,goodmanufacturingpractices,orotherquality-basedrequirements.Drugproductsshouldcontainnohigherlevelsofresidualsolventsthancanbesupportedbysafetydata.Solventsthatareknowntocauseunacceptabletoxicities(Class1,Table1)shouldbeavoidedintheproductionofdrugsubstances,excipients,ordrugproductsunlesstheirusecanbestronglyjustifiedinarisk-benefitassessment.Solventsassociatedwithlessseveretoxicity(Class2,Table2)shouldbelimitedinordertoprotectpatientsfrompotentialadverseeffects.Ideally,lesstoxicsolvents(Class3,Table3)shouldbeusedwherepractical.ThecompletelistofsolventsincludedinthisGeneralChapterisgiveninAppendix1.Thesetablesandthelistarenotexhaustive.Whereothersolventshavebeenused,basedonapprovalbythecompetentregulatoryauthority,suchsolventsmaybeaddedtothetablesandlist.Testingofdrugsubstances,excipients,anddrugproductsforresidualsolventsshouldbeperformedwhenproductionorpurificationprocessesareknowntoresultinthepresenceofsuchresidualsolvents.Itisonlynecessarytotestforresidualsolventsthatareusedorproducedinthemanufactureorpurificationprocesses.Althoughmanufacturersmaychoosetotestthedrugproduct,acumulativeproceduremaybeusedtocalculatetheresidualsolventlevelsintheproductfromthelevelsinitsingredients.IfthecalculationresultsinalevelequaltoorbelowthatrecommendedinthisGeneralChapter,notestingofthedrugproductforresidualsolventsneedstobeconsidered.If,however,thecalculatedlevelsareabovetherecommendedlevel,thedrugproductshouldbetestedtoascertainwhethertheformulationprocesshasreducedtherelevantsolventlevelstowithinacceptableamounts.Adrugproductshouldalsobetestedifaresidualsolventisusedduringitsmanufacture.SeeAppendix2foradditionalbackgroundinformationrelatedtoresidualsolvents.

CLASSIFICATIONOFRESIDUALSOLVENTSBYRISKASSESSMENTTheterm“tolerabledailyintake”(TDI)isusedbytheInternationalProgramonChemicalSafety(IPCS)todescribeexposurelimitsoftoxicchemicalsandtheterm“acceptabledailyintake”(ADI)isusedbytheWorldHealthOrganization(WHO)andothernationalandinternationalhealthauthoritiesandinstitutes.Theterm“permitteddailyexposure”(PDE)isdefinedasapharmaceuticallyacceptableintakeofresidualsolventstoavoidconfusionofdifferingvaluesforADIsofthesamesubstance.ResidualsolventsspecifiedinthisGeneralChapterarelistedinAppendix1bycommonnamesandstructures.Theywereevaluatedfortheirpossiblerisktohumanhealthandplacedintooneofthreeclassesasfollows:Class1ResidualSolvents:SolventstobeAvoided

Knownhumancarcinogens

Stronglysuspectedhumancarcinogens

EnvironmentalhazardsClass2ResidualSolvents:SolventstobeLimited

Nongenotoxicanimalcarcinogensorpossible

causativeagentsofotherirreversible

toxicity,suchasneurotoxicityorteratoge

nicity.

Solventssuspectedofothersignificantbutrever-

sibletoxicities.Class3ResidualSolvents:SolventswithLowToxicPo-

tential

Solventswithlowtoxicpotentialtohumans;no

health-basedexposurelimitisneeded.

[NOTE—Class3residualsolventsmayhavePDEsofupto50mgormoreperday.]**

ForresidualsolventswithPDEsofmorethan50mgperday,seethediscussioninthesectionClass3underLimitsofResidualSolvents.

PROCEDURESFORESTABLISHINGEXPOSURELIMITSTheprocedureusedtoestablishpermitteddailyexposuresforresidualsolventsispresentedinAppendix3.

OPTIONSFORDETERMININGLEVELSOFCLASS2RESIDUALSOLVENTSTwooptionsareavailabletodeterminelevelsofClass2residualsolvents.Option1TheconcentrationlimitsinppmstatedinTable2areused.Theywerecalculatedusingequation(1)belowbyassumingaproductweightof10gadministereddaily.Here,PDEisgivenintermsofmgperday,anddoseisgiveningperday.Theselimitsareconsideredacceptableforalldrugsubstances,excipients,anddrugproducts.Therefore,thisoptionmaybeappliedifthedailydoseisnotknownorfixed.IfalldrugsubstancesandexcipientsinaformulationmeetthelimitsgiveninOption1,thesecomponentsmaybeusedinanyproportion.Nofurthercalculationisnecessaryprovidedthedailydosedoesnotexceed10g.Productsthatareadministeredindosesgreaterthan10gperdayaretobeconsideredunderOption2.Option2ItisnotnecessaryforeachcomponentofthedrugproducttocomplywiththelimitsgiveninOption1.ThePDEintermsofmgperdayasstatedinTable2canbeusedwiththeknownmaximumdailydoseandequation(1)abovetodeterminetheconcentrationofresidualsolventallowedinadrugproduct.Suchlimitsareconsideredacceptableprovidedthatithasbeendemonstratedthattheresidualsolventhasbeenreducedtothepracticalminimum.Thelimitsshouldberealisticinrelationtoanalyticalprecision,manufacturingcapability,andreasonablevariationinthemanufacturingprocess.Thelimitsshouldalsoreflectcontemporarymanufacturingstandards.Option2maybeappliedbyaddingtheamountsofaresidualsolventpresentineachofthecomponentsofthedrugproduct.ThesumoftheamountsofsolventperdayshouldbelessthanthatgivenbythePDE.ConsideranexampleoftheapplicationofOption1andOption2toacetonitrileconcentrationinadrugproduct.Thepermitteddailyexposuretoacetonitrileis4.1mgperday;thus,theOption1limitis410ppm.Themaximumadministereddailyweightofadrugproductis5.0g,andthedrugproductcontainstwoexcipients.Thecompositionofthedrugproductandthecalculatedmaximumcontentofresidualacetonitrilearegiveninthefollowingtable.ComponentAmount

inFormulation(g)AcetonitrileContent

(ppm)DailyExposure

(mg)Drug

substance0.38000.24Excipient10.94000.36Excipient23.88003.04Drugproduct5.07283.64ExcipientlmeetstheOption1limit,butthedrugsubstance,excipient2,anddrugproductdonotmeettheOption1limit.Nevertheless,thedrugproductmeetstheOption2limitof4.1mgperdayandthusconformstotheacceptancecriteriainthisGeneralChapter.Consideranotherexampleusingacetonitrileastheresidualsolvent.Themaximumadministereddailyweightofadrugproductis5.0g,andthedrugproductcontainstwoexcipients.Thecompositionofthedrugproductandthecalculatedmaximumcontentofresidualacetonitrilearegiveninthefollowingtable.ComponentAmountin

Formulation(g)AcetonitrileContent

(ppm)DailyExposure

(mg)Drug

substance0.38000.24Excipient10.920001.80Excipient23.88003.04Drugproduct5.010165.08Inthisexample,thedrugproductmeetsneithertheOption1northeOption2limit.Themanufacturercouldtestthedrugproducttodetermineiftheformulationprocessreducedthelevelofacetonitrile.Ifthelevelofacetonitrilewasnotreducedtotheallowedlimitduringformulation,theproductfailstherequirementsofthetest.

LIMITSOFRESIDUALSOLVENTSEthyleneOxide[NOTE—Thetestforethyleneoxideisconductedonlywherespecifiedintheindividualmonograph.]Thestandardsolutionparametersandtheprocedurefordeterminationaredescribedintheindividualmonograph.Unlessotherwisespecifiedintheindividualmonograph,thelimitis10µgperg.Class1Class1residualsolvents(Table1)shouldnotbeemployedinthemanufactureofdrugsubstances,excipients,anddrugproductsbecauseoftheunacceptabletoxicitiesordeleteriousenvironmentaleffectsoftheseresidualsolvents.However,ifClass1residualsolventsareused,theirlevelsshouldberestrictedasshowninTable1,unlessotherwisestatedintheindividualmonograph.Thesolvent1,1,1-trichloroethaneisincludedinTable1becauseitisanenvironmentalhazard.Thestatedlimitof1500ppmisbasedonsafetydata.WhenClass1residualsolventsareusedinthemanufactureofadrugsubstance,excipient,ordrugproduct,themethodologydescribedintheIdentification,Control,andQuantificationofResidualSolventssectionofthisGeneralChapteristobeappliedwhereverpossible.Otherwiseanappropriatevalidatedprocedureistobeemployed.SuchprocedureshallbesubmittedtotheUSPforinclusionintherelevantindividualmonograph.Table1.Class1ResidualSolventsSolventConcentrationLimit

(ppm)ConcernBenzene2CarcinogenCarbontetrachloride4Toxicandenviron

mentalhazard1,2-Dichloroethane5Toxic1,1-Dichloroethene8Toxic1,1,1-Trichloroethane1500Environmental

hazardClass2Class2residualsolvents(Table2)shouldbelimitedindrugsubstances,excipients,anddrugproductsbecauseoftheinherenttoxicitiesoftheresidualsolvents.PDEsaregiventothenearest0.1mgperday,andconcentrationsaregiventothenearest10ppm.Thestatedvaluesdonotreflectthenecessaryanalyticalprecisionofthedeterminationprocedure.Precisionshouldbedeterminedaspartoftheprocedurevalidation.IfClass2residualsolventsarepresentatgreaterthantheirOption1limits,theyshouldbeidentifiedandquantified.TheproceduresdescribedintheIdentification,Control,andQuantificationofResidualSolventssectionofthisGeneralChapteraretobeappliedwhereverpossible.Otherwiseanappropriatevalidatedprocedureistobeemployed.SuchprocedureshallbesubmittedtotheUSPforinclusionintherelevantindividualmonograph.NOTE—ThefollowingClass2residualsolventsarenotreadilydetectedbytheheadspaceinjectionconditionsdescribedintheIdentification,Control,andQuantificationofResidualSolventssectionofthisGeneralChapter:formamide,2-ethoxyethanol,2-methoxyethanol,ethyleneglycol,N-methylpyrrolidone,andsulfolane.Otherappropriatevalidatedproceduresaretobeemployedforthecontroloftheseresidualsolvents.SuchproceduresshallbesubmittedtotheUSPforinclusionintherelevantindividualmonograph.Table2.Class2ResidualSolventsSolventPDE

(mg/day)Concentrationlimit

(ppm)Acetonitrile4.1410Chlorobenzene3.6360Chloroform0.660Cyclohexane38.838801,2-Dichloroethene18.718701,2-Dimethoxyethane1.0100N,N-Dimethylacetamide10.91090N,N-Dimethylformamide8.88801,4-Dioxane3.83802-Ethoxyethanol1.6160Ethyleneglycol6.2620Formamide2.2220Hexane2.9290Methanol30.030002-Methoxyethanol0.550Methylbutylketone0.550Methylcyclohexane11.81180Methylenechloride6.0600N-Methylpyrrolidone5.3530Nitromethane0.550Pyridine2.0200Sulfolane1.6160Tetrahydrofuran7.2720Tetralin1.0100Toluene8.9890Trichloroethene0.880Xylene*21.72170*

Usually60%m-xylene,14%p-xylene,9%o-xylenewith17%ethylbenzeneClass3Class3residualsolvents(Table3)mayberegardedaslesstoxicandoflowerrisktohumanhealththanClass1andClass2residualsolvents.Class3includesnosolventknownasahumanhealthhazardatlevelsnormallyacceptedinpharmaceuticals.However,therearenolong-termtoxicityorcarcinogenicitystudiesformanyoftheresidualsolventsinClass3.Availabledataindicatethattheyarelesstoxicinacuteorshort-termstudiesandnegativeingenotoxicitystudies.Unlessotherwisestatedintheindividualmonograph,Class3residualsolventsarelimitedtonotmorethan50mgperday(correspondingto5000ppmor0.5%underOption1).IfaClass3solventlimitinanindividualmonographisgreaterthan50mgperday,thatresidualsolventshouldbeidentifiedandquantified.TheproceduresdescribedintheIdentification,Control,andQuantificationofResidualSolventssectionofthisGeneralChapteraretobeappliedwhereverpossible.Otherwiseanappropriatevalidatedprocedureistobeemployed.SuchprocedureshallbesubmittedtotheUSPforinclusionintherelevantindividualmonograph.Table3.Class3ResidualSolvents

(limitedbyGMPorotherquality-basedrequirementsindrugsubstances,excipients,anddrugproducts)AceticacidHeptaneAcetoneIsobutylacetateAnisoleIsopropylacetate1-ButanolMethylacetate2-Butanol3-Methyl-1-butanolButylacetateMethylethylketonetert-ButylmethyletherMethylisobutylketoneCumene2-Methyl-l-propanolDimethylsulfoxidePentaneEthanol1-PentanolEthylacetate1-PropanolEthylether2-PropanolEthylformatePropylacetateFormicacidOtherResidualSolventsTheresidualsolventslistedinTable4mayalsobeofinteresttomanufacturersofdrugsubstances,excipients,ordrugproducts.However,noadequatetoxicologicaldataonwhichtobaseaPDEwasfound.Specificationsfortheseresidualsolventswillbeprovidedintherespectiveindividualmonograph.Table4.OtherResidualSolvents

(forwhichnoadequatetoxicologicaldatawasfound)1,1-DiethoxypropaneMethylisopropylketone1,1-DimethoxymethaneMethyltetrahydrofuran2,2-DimethoxypropaneSolventHexaneIsooctaneTrichloroaceticacidIsopropyletherTrifluoroaceticacid

IDENTIFICATION,CONTROL,ANDQUANTIFICATIONOFRESIDUALSOLVENTSNOTE—Theorganic-freewaterspecifiedinthefollowingproceduresproducesnosignificantlyinterferingpeakswhenchromatographed.Class1andClass2ResidualSolventsWATER-SOLUBLEARTICLESProcedureA—Class1StandardStockSolution—Transfer1.0mLofUSPClass1ResidualSolventsMixtureRStoa100-mLvolumetricflask,add9mLofdimethylsulfoxide,dilutewithwatertovolume,andmix.Transfer1.0mLofthissolutiontoa100-mLvolumetricflask,dilutewithwatertovolume,andmix.Transfer1.0mLofthissolutiontoa10-mLvolumetricflask,dilutewithwatertovolume,andmix.Class1StandardSolution—Transfer1.0mLofClass1StandardStockSolutiontoanappropriateheadspacevial,add5.0mLofwater,applystopper,cap,andmix.Class2StandardStockSolution—Transfer1.0mLofUSPClass2ResidualSolventsMixtureRStoa100-mLvolumetricflask,dilutewithwatertovolume,andmix.Class2StandardSolution—Transfer1.0mLofClass2StandardStockSolutiontoanappropriateheadspacevial,add5.0mLofwater,applystopper,cap,andmix.TestStockSolution—Transferabout250mgofthearticleundertest,accuratelyweighed,toa25-mLvolumetricflask,dissolveinanddilutewithwatertovolume,andmix.TestSolution—Transfer5.0mLofTestStockSolutiontoanappropriateheadspacevial,add1.0mLofwater,applystopper,cap,andmix.Class1SystemSuitabilitySolution—Transfer1.0mLofClass1StandardStockSolutiontoanappropriateheadspacevial,add5.0mLofTestStockSolution,applystopper,cap,andmix.ChromatographicSystem(seeChromatographyá621ñ)—Thegaschromatographisequippedwithaflame-ionizationdetector,a0.32-mm×30-mfused-silicacolumncoatedwitha1.8-µmlayerofphaseG43ora0.53-mm×30-mwide-borecolumncoatedwitha3.0-µmlayerofphaseG43.Thecarriergasisnitrogenorheliumwithalinearvelocityofabout35cmpersecond,andasplitratioof1:5.Thecolumntemperatureismaintainedat40for20minutes,thenraisedatarateof10perminuteto240,andmaintainedat240for20minutes.Theinjectionportanddetectortemperaturesaremaintainedat140and250,respectively.ChromatographtheClass1StandardSolution,Class1SystemSuitabilitySolution,andClass2StandardSolution,andrecordthepeakresponsesasdirectedforProcedure:thesignal-to-noiseratioof1,1,1-trichloroethaneintheClass1StandardSolutionisnotlessthan5;thesignal-to-noiseratioofeachpeakintheClass1SystemSuitabilitySolutionisnotlessthan3;andtheresolution,R,betweenacetonitrileandmethylenechlorideintheClass2StandardSolutionisnotlessthan1.0.Procedure—Separatelyinject(followingoneoftheheadspaceoperatingparametersetsdescribedinthetablebelow)equalvolumesofheadspace(about1.0mL)oftheClass1StandardSolution,Class2StandardSolution,andtheTestSolutionintothechromatograph,recordthechromatograms,andmeasuretheresponsesforthemajorpeaks.IfapeakresponseofanypeakintheTestSolutionisgreaterthanorequaltoacorrespondingpeakineithertheClass1StandardSolutionortheClass2StandardSolution,proceedtoProcedureBtoverifytheidentityofthepeak;otherwisethearticlemeetstherequirementsofthistest.Table5.HeadspaceOperatingParametersHeadspaceOperating

ParameterSets123Equilibrationtemperature()8010580Equilibrationtime(min.)604545Transfer-linetemperature()85110105Carriergas:nitrogenorheliumatanappropriatepressurePressurizationtime(s)303030Injectionvolume(mL)111ProcedureB—Class1StandardStockSolution,Class1StandardSolution,Class2StandardStockSolution,Class2StandardSolution,TestStockSolution,TestSolution,andClass1SystemSuitabilitySolution—PrepareasdirectedforProcedureA.ChromatographicSystem(seeChromatographyá621ñ)—Thegaschromatographisequippedwithaflame-ionizationdetector,a0.32-mm×30-mfused-silicacolumncoatedwitha0.25-µmlayerofphaseG16,ora0.53-mm×30-mwide-borecolumncoatedwitha0.25-µmlayerofphaseG16.Thecarriergasisnitrogenorheliumwithalinearvelocityofabout35cmpersecondandasplitratioof1:5.Thecolumntemperatureismaintainedat50for20minutes,thenraisedatarateof6perminuteto165,andmaintainedat165for20minutes.Theinjectionportanddetectortemperaturesaremaintainedat140and250,respectively.ChromatographtheClass1StandardSolution,theClass1SystemSuitabilitySolution,andtheClass2StandardSolution,andrecordthepeakresponsesasdirectedforProcedure:thesignal-to-noiseratioofbenzeneintheClass1StandardSolutionisnotlessthan5;thesignal-to-noiseratioofeachpeakintheClass1SystemSuitabilitySolutionisnotlessthan3;theresolution,R,betweenacetonitrileandtrichloroethyleneintheClass2StandardSolutionisnotlessthan1.0.Procedure—Separatelyinject(followingoneoftheheadspaceoperatingparametersetsdescribedinTable5)equalvolumesofheadspace(about1.0mL)oftheClass1SandardSolution,theClass2StandardSolution,andtheTestSolutionintothechromatograph,recordthechromatograms,andmeasuretheresponsesforthemajorpeaks.Ifthepeakresponse(s)intheTestSolutionofthepeak(s)identifiedinProcedureAis/aregreaterthanorequaltoacorrespondingpeak(s)ineithertheClass1StandardSolutionortheClass2StandardSolution,proceedtoProcedureCtoquantifythepeak;otherwisethearticlemeetstherequirementsofthistest.ProcedureC—Class1StandardSolution,Class2StandardSolution,TestStockSolution,TestSolution,andClass1SystemSuitabilitySolution—PrepareasdirectedforProcedureA.StandardSolution—TransferanaccuratelymeasuredvolumeoftheUSPReferenceStandardforeachpeakidentifiedandverifiedbyProceduresAandBtoasuitablecontainer,anddilutequantitatively,andstepwiseifnecessary,withwatertoobtainasolutionhavingafinalconcentrationof1/100ofthevaluestatedinTable1or2(underConcentrationlimit).Transfer5.0mLofthissolutiontoanappropriateheadspacevial,add1.0mLofwater,applystopper,cap,andmix.ChromatographicSystem(seeChromatographyá621ñ)—[NOTE—IftheresultsofthechromatographyfromProcedureAarefoundtobeinferiortothosefoundwithProcedureB,theChromatographicSystemfromProcedureBmaybesubstituted.]Thegaschromatographisequippedwithaflame-ionizationdetector,a0.32-mm×30-mfused-silicacolumncoatedwitha1.8-µmlayerofphaseG43ora0.53-mm×30-mwide-borecolumncoatedwitha3.0-µmlayerofphaseG43.Thecarriergasisnitrogenorheliumwithalinearvelocityofabout35cmpersecond,andasplitratioof1:5.Thecolumntemperatureismaintainedat40for20minutes,thenraisedatarateof10perminuteto240,andmaintainedat240for20minutes.Theinjectionportanddetectortemperaturesaremaintainedat140and250,respectively.ChromatographtheClass1StandardSolution,theClass1SystemSuitabilitySolution,andtheClass2StandardSolution,andrecordthepeakresponsesasdirectedforProcedure:thesignal-to-noiseratioof1,1,1-trichloroethaneintheClass1StandardSolutionisnotlessthan5;thesignal-to-noiseratioofeachpeakintheClass1SystemSuitabilitySolutionisnotlessthan3;andtheresolution,R,betweenacetonitrileandmethylenechlorideintheClass2StandardSolutionisnotlessthan1.0.Procedure—Separatelyinject(followingoneoftheheadspaceoperatingparametersdescribedinTable5)equalvolumesofheadspace(about1.0mL)oftheStandardSolutionandTestSolutionintothechromatograph,recordthechromatograms,andmeasuretheresponsesforthemajorpeaks.Calculatetheamount,inppm,ofeachresidualsolventfoundinthearticleundertestbytheformula:4(C/W)(rU/rS),inwhichCistheconcentration,inppm,oftheappropriateUSPReferenceStandardintheStandardSolution;Wistheweight,ing,ofthearticleundertesttakentopreparetheTestStockSolution;andrUandrSarethepeakresponsesofeachresidualsolventobtainedfromtheTestSolutionandtheStandardSolution,respectively.WATER-INSOLUBLEARTICLESProcedureA—Class1StandardStockSolution,Class1StandardSolution,Class1SystemSuitabilitySolution,Class2StandardStockSolution,Class2StandardSolution,andChromatographicSystem—ProceedasdirectedforProcedureAunderWater-SolubleArticles.TestStockSolution—Transferabout250mgofthearticleundertest,accuratelyweighed,toa25-mLvolumetricflask,dissolveinanddilutewithdimethylformamidetovolume,andmix.TestSolution1—Transfer5.0mLofTestStockSolutiontoanappropriateheadspacevial,add1.0mLofdimethylformamide,applystopper,cap,andmix.TestSolution2—Transferabout250mgofthearticleundertest,accuratelyweighed,toa25-mLvolumetricflask,dissolveinanddilutewith1,3-dimethyl-2-imidazolidinonetovolume,andmix.Transfer5.0mLofthissolutiontoanappropriateheadspacevial,add1.0mLof1,3-dimethyl-2-imidazolidinone,applystopper,cap,andmix.Procedure—Separatelyinject(followingoneoftheheadspaceoperatingparametersdescribedinTable5)equalvolumesofheadspace(about1.0mL)oftheClass1StandardSolution,theClass2StandardSolution,TestSolution1,andTestsolution2intothechromatograph,recordthechromatograms,andmeasuretheresponsesforthemajorpeaks.IfapeakresponseofanypeakinTestsolution1isgreaterthanorequaltoacorrespondingpeakineithertheClass1StandardSolutionortheClass2StandardSolution,proceedtoProcedureBtoverifytheidentityofthepeak;otherwisethearticlemeetstherequirementsofthistest.IfthepeakresponsefordimethylformamideorN,N-dimethylacetamideinTestSolution2isgreaterthanorequaltothecorrespondingpeakintheClass2StandardSolution,proceedtoProcedureBtoverifytheidentityofthepeak;otherwisethearticlemeetstherequirementsofthistest.ProcedureB—Class1StandardStockSolution,Class1StandardSolution,Class2StandardStockSolution,Class2StandardSolution,andClass1SystemSuitabilitySolution—PrepareasdirectedforProcedureAunderWater-SolubleArticles.TestStockSolution,TestSolution1,andTestSolution2—ProceedasdirectedforProcedureA.ChromatographicSystem—ProceedasdirectedforProcedureBunderWater-SolubleArticles.Procedure—Separatelyinject(followingoneoftheheadspaceoperatingparametersdescribedinTable5)equalvolumesofheadspace(about1.0mL)oftheClass1StandardSolution,Class2StandardSolution,TestSolution1,and/orTestSolution2intothechromatograph,recordthechromatograms,andmeasuretheresponsesforthemajorpeaks.Ifthepeakresponse(s)inTestSolution1ofthepeak(s)identifiedinProcedureAis/aregreaterthanorequaltoacorrespondingpeak(s)ineithertheClass1StandardSolutionortheClass2StandardSolution,proceedtoProcedureCtoquantifythepeak;otherwisethearticlemeetsthe