中文版VICHTopicGL18IMPURITIESRESIDUALSOLVENTS免費哦

V1cHTopicGL18（VICH的議題中指導原那么8）Step7第七時期IMPURITIES:RESIDUALSOLVENTS雜質：殘留溶劑IMPURITIES:RESIDUALSOLVENTSINNEWVETERINARYMEDICINALPRODUCTS,ACTIVE

SUBSTANCESANDEXCIPIENTS

雜質：新獸藥、活性物質和輔料中的殘留溶劑RecommendedforImplementationatStep7oftheVICHProcesson15June2000by

theVICHSteeringCommitteeVICH指導委員會2000年6月5日由在VICH進程的第七時期通過并推薦THISGUIDELINEHASBEENDEVELOPEDBYTHEAPPROPRIATEVICHEXPERTWORKINGGROUPONTHEBASISOFTHEICHGUIDELINESONTHESAMESUBJECTANDWASSUBJECTTOCONSULTATIONBYTHEPARTIES,INACCORDANCEWITHTHEVICHPROCESS.ATSTEP7OFTHEPROCESSTHEFINALDRAFTISRECOMMENDEDFORADOPTIONTOTHEREGULATORYBODIESOFTHEEUROPEANUNION,JAPANANDUSA.本指南已經(jīng)在ICH指南相同議題的基礎上被適合的VICH專家工作小組更新，參與者會在VICH進程上就不準確的地址進一步磋商。在VICH進程的第7時期，這一最終草案，會被歐盟、日本和美國就調整后的文件正式通過并推薦。INTRODUCTION3簡介SCOPEOFTHEGUIDELINE3范圍GENERALPRINCIPLES4總那么ClassificationofResidualSolventsbyRiskAssessment4風險評估中殘留溶劑的分類MethodsforEstablishingExposureLimits4成立接觸限度的方式OptionsforDescribingLimitsofClass2Solvents4第二類溶劑的相關描述AnalyticalProcedures6分析方式ReportingLevelsofResidualSolvents6報導的殘留溶劑的水平LIMITSOFRESIDUALSOLVENTS6殘留溶劑的限度SolventstobeAvoided6幸免利用的溶劑SolventstobeLimited6限制利用的熔劑SolventswithLowToxicPotential7具有潛在低毒的溶劑SolventsForWhichNoAdequateToxicologicalDataWasFound8尚無足夠的毒理數(shù)據(jù)的溶劑GLOSSARY9術語LISTOFSOLVENTSINCLUDEDINTHEGUIDELINE10附錄1:本指導原那么中的殘留溶劑ADDITIONALBACKGROUND15附錄2:其他背景EnvironmentalRegulationofOrganicVolatileSolvents15有機揮發(fā)性溶劑在環(huán)境方面的規(guī)定ResidualSolventsinPharmaceuticals15藥品中的殘留溶劑METHODSFORESTABLISHINGEXPOSURELIMITS16成立接觸限度的方式TableValuesusedinthecalculationsinthisdocument18表在這篇文檔中用于計算的數(shù)值IMPURITIES:RESIDUALSOLVENTSINNEWVETERINARYMEDICINALPRODUCTS,ACTIVESUBSTANCESANDEXCIPIENTS雜質：新獸藥、活性物質和輔料中的殘留溶劑INTRODUCTION介紹Theobjectiveofthisguidelineistorecommendacceptableamountsforresidualsolventsinpharmaceuticalsforthesafetyofthetargetanimalaswellasforthesafetyofresiduesinproductsderivedfromtreatedfoodproducinganimals.Theguidelinerecommendsuseoflesstoxicsolventsanddescribeslevelsconsideredtobetoxicologicallyacceptableforsomeresidualsolvents.本指導原那么的目的在于推薦患病動物用含可同意的殘留溶劑量的藥物，保證用藥動物的平安同時也適用于生產(chǎn)含殘留物的動物食物制品的平安。Residualsolventsinpharmaceuticalsaredefinedhereasorganicvolatilechemicalsthatareusedorproducedinthemanufactureofactivesubstancesorexcipients,orinthepreparationofveterinarymedicinalproducts.Thesolventsarenotcompletelyremovedbypracticalmanufacturingtechniques.Appropriateselectionofthesolventforthesynthesisofactivesubstancemayenhancetheyield,ordeterminecharacteristicssuchascrystalform,purity,andsolubility.Therefore,thesolventmaysometimesbeacriticalparameterinthesyntheticprocess.Thisguidelinedoesnotaddresssolventsdeliberatelyusedasexcipientsnordoesitaddresssolvates.However,thecontentofsolventsinsuchproductsshouldbeevaluatedandjustified.殘留溶劑在藥品中被概念為被用于活性物質、輔料或是用于獸藥的有機揮發(fā)溶劑。這一溶劑并非能通過實際的生產(chǎn)工藝全數(shù)去除。選擇適當?shù)娜軇┯糜诨钚猿煞莸暮铣捎锌赡軐μ岣弋a(chǎn)品的產(chǎn)量或對產(chǎn)品的特性比如晶型、純度和可溶性起著決定性作用。因此，溶劑有時在合成進程中是一個至觀重要的參數(shù)。本指導原那么不是將溶劑特意概念為應用于輔料或溶劑合物。但是，溶劑的成份在這些產(chǎn)品的生產(chǎn)中應當評估和判定。Sincethereisnotherapeuticbenefitfromresidualsolvents,allresidualsolventsshouldberemovedtotheextentpossibletomeetproductspecifications,goodmanufacturingpractices,orotherquality-basedrequirements.Veterinarymedicinalproductsshouldcontainnohigherlevelsofresidualsolventsthancanbesupportedbysafetydata.Somesolventsthatareknowntocauseunacceptabletoxicities(Class1,Table1)shouldbeavoidedintheproductionofactivesubstances,excipients,orveterinarymedicinalproductsunlesstheirusecanbestronglyjustifiedinarisk-benefitassessment.Somesolventsassociatedwithlessseveretoxicity(Class2,Table2)shouldbelimitedinordertoprotecttargetanimalsandhumanconsumersfrompotentialadverseeffects.Ideally,lesstoxicsolvents(Class3,Table3)shouldbeusedwherepractical.ThecompletelistofsolventsincludedinthisguidelineisgiveninAppendix1.因殘留溶劑并無醫(yī)治的作用，因此所有的溶劑都應當盡可能的去除以便來符合產(chǎn)品特性，GMP或其他大體的質量方面的要求。獸藥所含殘留溶劑量應為具有平安數(shù)據(jù)支持且不高于規(guī)定的殘留溶劑限度。而像一些溶劑因會引發(fā)不可同意的毒性（1類溶劑見表1）應當禁止應用于、活性物質、輔料或獸藥的生產(chǎn)，不然應通過風險-利益評估充分證明。另一些具有較低嚴峻毒性的溶劑（2類溶劑，表2）應當限制利用以防患病動物或患者產(chǎn)生不良反映。最后，具有較低毒性的溶劑（3類，表3）應當應用于生產(chǎn)。本指導原那么中涉及的所有溶劑見附件1。Thelistsarenotexhaustiveandothersolventscanbeusedandlateraddedtothelists.RecommendedlimitsofClass1and2solventsorclassificationofsolventsmaychange,asnewsafetydatabecomesavailable.Supportingsafetydatainamarketingapplicationforanewveterinarymedicinalproductcontaininganewsolventmaybebasedonconceptsinthisguidelineortheconceptofqualificationofimpuritiesasexpressedintheguidelineforactivesubstance（VICHGL10,ImpuritiesinNewVeterinaryDrugSubstances）orveterinarymedicinalproduct,orallthreeguidelines.這一清單并非是詳盡的，其他用到的溶劑能夠添加到清單上來。建議限制利用1類和2類溶劑，或有當新的平安數(shù)據(jù)支持時溶劑的分類能夠作相應改變。當有支持的平安數(shù)據(jù)的應用于新獸藥生產(chǎn)中新的溶劑，能夠依據(jù)本指導原那么或或依照VICHGL10新獸藥中雜質（ImpuritiesinNewVeterinaryDrugSubstances）這一指導原那么中活性物質中雜質的概念，或依照獸藥生產(chǎn)指導原那么在或以上三個指導原那么。SCOPEOFTHEGUIDELINE本指導原那么的范圍Residualsolventsinactivesubstances,excipients,andinveterinarymedicinalproductsarewithinthescopeofthisguideline.Therefore,testingshouldbeperformedforresidualsolventswhenproductionorpurificationprocessesareknowntoresultinthepresenceofsuchsolvents.Itisonlynecessarytotestforsolventsthatareusedorproducedinthemanufactureorpurificationofmedicinalsubstances,excipients,orveterinarymedicinalproducts.Althoughmanufacturersmaychoosetotesttheveterinarymedicinalproduct,acumulativemethodmaybeusedtocalculatetheresidualsolventlevelsintheproductfromthelevelsintheingredientsusedtoproducetheproduct.Ifthecalculationresultsinalevelequaltoorbelowthatrecommendedinthisguideline,notestingoftheveterinarymedicinalproductforresidualsolventsneedbeconsidered.If,however,thecalculatedlevelisabovetherecommendedlevel,theveterinarymedicinalproductshouldbetestedtoascertainwhethertheformulationprocesshasreducedtherelevantsolventleveltowithintheacceptableamount.Theveterinarymedicinalproductshouldalsobetestedifasolventisusedduringitsmanufacture.Thisguidelinedoesnotapplytopotentialnewactivesubstances,excipients,orveterinarymedicinalproductsusedduringtheclinicalresearchstagesofdevelopment,nordoesitapplytoexistingmarketedveterinarymedicinalproducts.本指導原那么包括活性物質、輔料和獸藥中的殘留溶劑。因此，當生產(chǎn)進程或純化工藝會致使存在殘留溶劑時，殘留溶劑應當檢測。僅僅需要檢測在藥物、輔料或獸藥生產(chǎn)或純化進程中被用到的或參與生產(chǎn)的溶劑。盡管生產(chǎn)廠家可能選擇檢測獸藥制劑產(chǎn)品中殘留溶劑，但應當用累加方式計算用于生產(chǎn)產(chǎn)品的各成份殘留溶劑水平到計算產(chǎn)品中殘留溶劑的水平。若是，計算出的殘留溶劑含量在推薦的水平之上，獸藥產(chǎn)品應當檢測來確認各組分通過處置是不是已經(jīng)將殘留溶劑的水平降低至可同意范圍之內。若是某一溶劑用于生產(chǎn)那么獸藥產(chǎn)品應當檢測。此指導原那么不適用于即將準新活性物質、輔料或處于臨床研究時期進展的獸藥，也不適用于存在于已經(jīng)上市的獸藥。Theguidelineappliestoalldosageformsandroutesofadministration.Higherlevelsofresidualsolventsmaybeacceptableincertaincasesortopicalapplication.Justificationfortheselevelsshouldbemadeonacasebycasebasis.這一指導原那么適用于所有的劑型多有給藥途徑的獸品。在某些情形下或局部應歷時，含有較高含量殘留溶劑的獸藥能夠同意。應依照不同情形來評判溶劑的水平。SeeAppendix2foradditionalbackgroundinformationrelatedtoresidualsolvents.殘留溶劑相關的另外一些背景知識能夠參見附錄二。FORIMPLEMENTATIONATSTEP7(FINAL)-06/00Page4of18于第七時期被推薦aEMEA2000歐洲藥品治理局2000GENERALPRINCIPLES總那么ClassificationofResidualSolventsbyRiskAssessment依照危害程度對殘留溶劑的分類Theterm"tolerabledailyintake"(TDI)isusedbytheInternationalProgramonChemicalSafety(IPCS)todescribeexposurelimitsoftoxicchemicalsand"acceptabledailyintake"(ADI)isusedbytheWorldHealthOrganisation(WHO)andothernationalandinternationalhealthauthoritiesandinstitutes.Thenewterm"permitteddailyexposure"(PDE)isdefinedinthepresentguidelineasapharmaceuticallyacceptableintakeofresidualsolventstoavoidconfusionofdifferingvaluesforADIsofthesamesubstance.“可耐受的日攝取量”這一術語被國際化學品平安組織來描述毒性化學藥品接觸限度，同時WHO也用到可接受的日接觸量，其他一些國家或國際衛(wèi)生局、協(xié)會也用到這一術語。本指導原那么頂用“許諾的日接觸量”這一新術語作為藥物中可同意的殘留溶劑的攝入量，以防同一物質的的可同意的日攝入量(ADI)相混淆。ResidualsolventsassessedinthisguidelinearelistedinAppendix1bycommonnamesandstructures.Theywereevaluatedfortheirpossiblerisktohumanhealthandplacedintooneofthreeclassesasfollows:在這一指導原那么中已確信的殘留溶劑的通用名和結構列于附錄1中。Class1solvents:Solventstobeavoided幸免利用的殘留溶劑Knownhumancarcinogens,stronglysuspectedhumancarcinogens,andenvironmentalhazards.已知的人體致癌物質，疑為人體致癌物或環(huán)境污染物。Class2solvents:Solventstobelimited限制利用的溶劑Non-genotoxicanimalcarcinogensorpossiblecausativeagentsofotherirreversibletoxicitysuchasneurotoxicityorteratogenicity.非遺傳毒性動物致癌物或可能致使其他不可逆的毒性如神經(jīng)毒性或致畸性。Solventssuspectedofothersignificantbutreversibletoxicities.疑具有其他嚴峻的但可逆的毒性的溶劑Class3solvents:Solventswithlowtoxicpotential具有潛在的低毒溶劑Solventswithlowtoxicpotentialtoman;nohealth-basedexposurelimitisneeded.Class3solventshavePDEsof50mgormoreperday.對人類有潛在低毒性的溶劑；不需要制丁接觸限度。第3類溶劑的PDE為天天50毫克或更高。MethodsforEstablishingExposureLimits確信接觸限度的方式ThemethodusedtoestablishpermitteddailyexposuresforresidualsolventsispresentedinAppendix3.SummariesofthetoxicitydatathatwereusedtoestablishlimitsarepublishedinPharmeuropa,Vol.9,No.1,Supplement,April1997.確信殘留溶劑PDE的方式見附錄3。用于確信攝取限度的毒性數(shù)據(jù)的總結見1997年4月增補本的VOL9\.OptionsforDescribingLimitsofClass2Solvents第二類溶劑界限的選擇方式ThreeoptionsareavailablewhensettinglimitsforClass2solvents.設定第二類溶劑的界限時有三種選擇Option1:TheconcentrationlimitsinppmstatedinTable2canbeused.Theywerecalculatedusingequation(1)belowbyassumingaproductmassof10gadministereddaily.方式1：可用表2中規(guī)定的濃度限度(單位PPM)。假定一個藥品每日給藥量為10g能夠用下面的公式(1)來進行計算。(1)Concentration(ppm)=1000xPDE/dose=1000xPDE/劑量Here,PDEisgivenintermsofmg/dayanddoseisgivening/day.那個地址PDE為mg/天，劑量為g/天。Theselimitsareconsideredacceptableforresidualsolventsinallsubstances,excipients,orthisoptionmaybeappliedifthedailydoseisnotknownorfixed.IftheresidualsolventsinallexcipientsandactivesubstancesinaformulationmeetthelimitsgiveninOption1,thenthesecomponentsmaybeusedinanyproportion.Nofurthercalculationisnecessaryprovidedthedailydosedoesnotexceed10g.Productsthatareadministeredindosesgreaterthan10gperdayshouldbeconsideredunderOption2.所有的物質、輔料或產(chǎn)品中的殘留有機溶劑的限度以為是能夠同意的。因此若是不明白日劑量或日劑量固定不變也有可用于這一方式。若是所有的輔料和活性物質中殘留溶劑在公式中都符合方式1中給定的限度。那這些成份能夠任何比例來用。不需要進一步的提供每日劑量不超過10g的計算方式。但日服用劑量超過10g的產(chǎn)品應當用方式2。Option2:itisnotconsiderednecessaryforresidualsolventsineachcomponentoftheveterinarymedicinalproducttocomplywiththelimitsgiveninOption1.ThePDEintermsofmg/dayasstatedinTable2canbeusedwiththeknownmaximumdailydoseandequation(1)abovetodeterminetheconcentrationofresidualsolventallowedintheveterinarymedicinalproduct.Suchlimitsareconsideredacceptableprovidedthatithasbeendemonstratedthattheresidualsolventhasbeenreducedtothepracticalminimum.Thelimitsshouldberealisticinrelationtoanalyticalprecision,manufacturingcapability,reasonablevariationinthemanufacturingprocess,andthelimitsshouldreflectcontemporarymanufacturingstandards.方式2：并非需要考慮獸藥產(chǎn)品中的每一組分的殘留溶劑都要符合選項1給出的限度。表2中規(guī)定的PDE（mg/天）和日最大劑量及方程（1）來確信許諾用于獸藥產(chǎn)品的殘留溶劑的濃度。只要能證明殘留溶劑已經(jīng)被降低到實際的最小量，那這些限度被以為是可同意的。這些限度與生產(chǎn)進程中分析的周密度、生產(chǎn)能力和合理的工藝變更有著實際的聯(lián)系，這些限度應當能反映目前生產(chǎn)的標準。Option2maybeappliedbyaddingtheamountsofaresidualsolventpresentineachofthecomponentsoftheveterinarymedicinalproduct.ThesumoftheamountsofsolventperdayshouldbelessthanthatgivenbythePDE.方式2將獸藥制劑產(chǎn)品中每種成份的必然量的殘留溶劑相加來，相加后的溶劑的總量應當?shù)陀赑DE。ConsideranexampleoftheuseofOption1andOption2appliedtoacetonitrileinaveterinarymedicinalproduct.Thepermitteddailyexposuretoacetonitrileismgperday;thus,theOption1limitis410ppm.Themaximumadministereddailymassofaveterinarymedicinalproductisg,andtheveterinarymedicinalproductcontainstwoexcipients.Thecompositionoftheveterinarymedicinalproductandthecalculatedmaximumcontentofresidualacetonitrilearegiveninthefollowingtable.以獸藥產(chǎn)品中乙睛在方式1和方式2中的應用為例，乙睛的PDE為天；方式1的算出限度為410ppm。如天天最大給藥量為，這一獸藥含有2種輔料。獸藥產(chǎn)品中的組分和通過計算取得的殘留乙睛的最大量見下表。Component組分AmountinAcetonitrilecontentDailyexposureActivesubstance活性物g800ppmmgExcipient1輔料1g400ppmmgExcipient2輔料2g800ppmmgVeterinarmedicinalg728ppmmgproductExcipient1meetstheOption1limit,buttheactivesubstance,excipient2,andtheveterinarymedicinalproductdonotmeettheOption1limit.Nevertheless,theproductmeetstheOption2limitofmgperdayandthusconformstotherecommendationsinthisguideline.輔料1要符合方式1中規(guī)定限度，而活性物質，輔料2，和獸藥產(chǎn)品那么不用符合方式1中的規(guī)定。盡管如此產(chǎn)品符合方式2中的天，與這一指導原那么中推薦的一致。Consideranotherexampleusingacetonitrileasresidualsolvent.Themaximumadministereddailymassofaveterinarymedicinalproductisg,andtheveterinarymedicinalproductcontainstwoexcipients.Thecompositionoftheveterinarymedicinalproductandthecalculatedmaximumcontentofresidualacetonitrileisgiveninthefollowingtable.再以乙腈這一殘留溶劑為例。一個獸藥產(chǎn)品天天最大的給藥劑量為，這一獸藥中包括兩種輔料。動物制劑產(chǎn)品的組份和通過計算的最大的殘留乙腈的含量見下表。Component成分AmountinAcetonitrilecontentDailyexposureActivesubstance活性物g800ppmmgExcipient1輔料1g2000ppmmgExcipient2輔料2g800ppmmgVeterinarmedicinalg1016ppmmgproductInthisexample,theproductmeetsneithertheOption1northeOption2limit.Themanufacturercouldtesttheproducttodetermineiftheformulationprocessreducedthelevelofacetonitrile.Ifthelevelofacetonitrilewasnotreducedduringformulationtotheallowedlimit,thenthemanufactureroftheproductshouldtakeotherstepstoreducetheamountofacetonitrileintheproductoroption3shouldbeconsidered.在那個例子中，藥品既不符合方式1規(guī)定的限度也不用符合方式2中的限度。生產(chǎn)商應通過檢測產(chǎn)品中乙腈的含量來確定是不是對處方工藝進行處置來降低乙腈的含量。若是在對處方工藝處置中沒有使乙腈的含量降低至準予的限度，那么生產(chǎn)此產(chǎn)品的生產(chǎn)商應采取其他步驟降低產(chǎn)品中乙腈的總量不然應當考慮方式3。Option3方式3ApplicantsmayjustifyhigherlevelsforthePDEandconcentrationlimitbasedupontheactualdailydose,actualtargetspecies,andrelevanttoxicologicaldataandconsideringconsumersafetyaspects.UseofOption3willbehandledonacasebycasebasisbytheregulatoryauthorities.Thisoptionmaybeappliedas:申請人能夠證明更高的PDE含量，對濃度的限度應基于實際的天天劑量，實際的給藥的物種，相關的毒理學數(shù)據(jù)和應考慮給藥動物的平安因素。3a-Theapplicantmayprovideanappropriatebodyweightfortheactualtargetspeciesand/ortheactualdoseandrecalculatethePDEand/orconcentrationlimitusingtheICHequationsandICHsupportingtoxicologicaldata.3a-申請人要提供給藥物種的適合的體重或實際給藥劑量、和/或從頭計算的PDE、和/或用ICH方程、支持ICH的毒理學數(shù)據(jù)的取得的濃度限度。3b—Theapplicantmayprovidenewtoxicologicaldata(withorwithoutactualtargetanimalanddoseinformation）andrecalculatethePDEandconcentrationlimitusingtheequationprovidedbyICH.Ifallofthesestepsfailtoreducethelevelofresidualsolvent,inexceptionalcasesthemanufacturercouldprovideasummaryofeffortsmadetoreducethesolventleveltomeettheguidelinevalue,andprovidearisk-benefitanalysistosupportallowingtheproducttobeutilisedwithresidualsolventatahigherlevel.3"申請者要提供新的毒理學數(shù)據(jù)（包括或不包括給藥的動物和劑量方面的信息）和再計算后取得PDEsfflHICH公式中提供的濃度限度。若是所有的處置步驟都不能降低殘留溶劑的含量，在特殊情形下制造商能夠提供出為使殘留溶劑含量降低至所要求的限度所做出工作的總結，并提供風險效益分析來支持藥品中許諾存在較高含量的殘留溶劑。AnalyticalProcedures分析方式Residualsolventsaretypicallydeterminedusingchromatographictechniquessuchasgaschromatography.Anyharmonisedproceduresfordetermininglevelsofresidualsolventsasdescribedinthepharmacopoeiasshouldbeused,iffeasible.Otherwise,manufacturerswouldbefreetoselectthemostappropriatevalidatedanalyticalprocedureforaparticularapplication.IfonlyClass3solventsarepresent,anon-specificmethodsuchaslossondryingmaybeused.ValidationofmethodsforresidualsolventsshouldconformtotheVICHguidelines"Validationofanalyticalprocedures:definitionandterminology"and"Validationofanalyticalprocedures:methodology."殘留溶劑專屬檢測方式為色譜法比如GC。若是可行，應與藥典描述的檢測殘留溶劑含量的方式相一致。不然，生產(chǎn)商應為所選的通過驗證最適合的分析方式來做額外的申請。若是僅僅只是3類溶劑，那么能夠應用非專屬法比如干燥失重等方式。體會證的殘留溶劑的方式應與VICH指導原那么中的“分析方式的驗證：概念和術語”和“分析方式的驗證：方式學”一致。ReportingLevelsofResidualSolvents報至ll的殘留溶劑的含量Manufacturersofpharmaceuticalproductsneedcertaininformationaboutthecontentofresidualsolventsinexcipientsoractivesubstancesinordertomeetthecriteriaofthisguideline.Thefollowingstatementsaregivenasacceptableexamplesoftheinformationthatcouldbeprovidedfromasupplierofexcipientsoractivesubstancestoapharmaceuticalmanufacturer.藥劑的生產(chǎn)廠家需要確信關于輔料和活性物質中的殘留溶劑的含量以便能符合本指導原那么中的標準。下面的表述可作為一個供給商提供給制劑生產(chǎn)商輔料和活性物質的可同意案例的信息。Thesuppliermightchooseoneofthefollowingasappropriate:供給商應選擇以下其中之OnlyClass3solventsarelikelytobepresent.Lossondryingislessthan%.僅可能存在第3類溶劑，干燥失重應少于%。OnlyClass2solventsX,Y,...arelikelytobepresent.AllarebelowtheOption1limit.（HerethesupplierwouldnametheClass2solventsrepresentedbyX,Y,...）僅可能存在第2類溶劑X、Y.…，所有的溶劑含量都要在方式1的限度下。（這兒供給商能夠將第2類溶劑以X、Y…表示來命名）OnlyClass2solventsX,Y,...andClass3solventsarelikelytobepresent.ResidualClass2solventsarebelowtheOption1limitandresidualClass3solventsarebelow%.僅可能存在第2類X、Y.…和第3類溶劑，第2類殘留溶劑在方式1規(guī)定的限度下，第3類殘留溶劑要干燥失重應小于%。（別離知足上述條件）IfClass1solventsarelikelytobepresent,theyshouldbeidentifiedandquantified.若是存在第1類溶劑，應進行能辨別并定量。"Likelytobepresent"referstothesolventusedinthefinalmanufacturingstepandtosolventsthatareusedinearliermanufacturingstepsandnotremovedconsistentlybyavalidatedprocess.IfsolventsofClass2orClass3arepresentatgreaterthantheirOption1limitsor%,respectively,theyshouldbeidentifiedandquantified.“Likelytobepresent”可能存在指的是被用于最后一步生產(chǎn)步驟的和前幾道工序且通過確認不能除盡的溶劑。若是第2類和第3類溶劑別離比他們對應的方式1中的限度或干燥失重%限度高，應進行辨別并定量。4.LIMITSOFRESIDUALSOLVENTS殘留溶劑的限度SolventstobeAvoided幸免利用的溶劑SolventsinClass1shouldnotbeemployedinthemanufactureofactivesubstances,excipients,andveterinarymedicinalproductsbecauseoftheirunacceptabletoxicityortheirdeleteriousenvironmentaleffect.However,iftheiruseisunavoidableinordertoproduceaveterinarymedicinalproductwithasignificanttherapeuticadvance,thentheirlevelsshouldberestrictedasshowninTable1,unlessotherwisejustified.1,1,1-TrichloroethaneisincludedinTable1becauseitisanenvironmentalhazard.Thestatedlimitof1500ppmisbasedonareviewofthesafetydata.第1類溶劑由于他們的不可同意的毒性和對環(huán)境的有害阻礙應當幸免用于原料藥和輔料和獸藥產(chǎn)品的生產(chǎn)中。但是，若是為生產(chǎn)出對醫(yī)治成效有著顯著提高的獸藥產(chǎn)品而不可幸免的利歷時，那么它們的含量應當符合表1的規(guī)定，若是不那么應證明其合理性。因為對環(huán)境的危害，三氯甲烷列于表1?；谄桨矓?shù)據(jù)的回憶1500PpM為規(guī)定的限度。Table1:Class1Solventsinpharmaceuticalproducts(solventsthatshouldbeavoided)

藥物制劑中含第1類溶劑的限度(應幸免利用的溶劑)Solvent溶劑名稱ConcentrationLimit(ppm)Concern備注Benzene苯2Carcinogen致癌物Carbontetrachloride4Toxicandenvironmentalhazard1,2-Dichloroethane5Toxic毒性1,1-Dichloroethene8Toxic毒性1，2-二氯乙烯1,1,1-Trichloroethane1500Environmentalhazard環(huán)境公害i，i，1-三氯^乙烷SolventstobeLimited限制利用的溶劑SolventsinTable2shouldbelimitedinpharmaceuticalproductsbecauseoftheirinherenttoxicity.PDEsaregiventothenearestmg/day,andconcentrationsaregiventothenearest10ppm.Thestatedvaluesdonotreflectthenecessaryanalyticalprecisionofdetermination.Precisionshouldbedeterminedaspartofthevalidationofthemethod.在表2中的溶劑應當限制利用因為它們潛在的毒性。PDEs約為天，濃度給定的約10Ppm。列出數(shù)值并非必然反映測定的分析周密度。周密度應看成為方式驗證的一部份來測定。Table2:Class2SolventsinPharmaceuticalProducts表2：藥物制劑中第2類溶劑Solvent溶劑PDE(mg/day)允許日接觸量ConcentrationLimit濃度限制Acetonitrile乙睛410

Chlorobenzene氯苯360Chloroform三氯甲烷60Cyclohexane環(huán)己烷38801,2-Dichloroethene1,2-二氯乙烯1870Dichloromethane二氯甲烷6001,2-Dimethoxyethane100N,N-Dimethylacetamide1090N,N-Dimethylformamide8801,4-Dioxane3802-Ethoxyethanol160Ethylene乙二醇glycolFormamide220Hexane290Methanol甲醇30002-Methoxyethanol50Methylbutylketone50Methylcyclohexane1180N-Methylpyrrolidone4840Nitromethane50Pyridine200Sulfolane160Tetralin100Toluene8901,1,2-Trichloroethene80Xylene二甲苯2170*usually60%m-xylene,14%p-xylene,9%o-xylenewith17%ethylbenzene.*通常含有60%間二甲苯、14%對二甲苯、9%鄰二甲苯和17%乙苯。SolventswithLowToxicPotential具有潛在低毒的溶劑SolventsinClass3(showninTable3)mayberegardedaslesstoxicandoflowerrisktotargetanimalandhumanconsumerhealth.Class3includesnosolventknownasahumanhealthhazardatlevelsnormallyacceptedinpharmaceuticals.However,therearenolong-termtoxicityorcarcinogenicitystudiesformanyofthesolventsinClass3.Availabledataindicatethattheyarelesstoxicinacuteorshort-termstudiesandnegativeingenotoxicitystudies.Itisconsideredthatamountsoftheseresidualsolventsof50mgperdayorless（correspondingto5000ppmor%underOption1）wouldbeacceptablewithoutjustification.Higheramountsmayalsobeacceptableprovidedtheyarerealisticinrelationtomanufacturingcapabilityandgoodmanufacturingpractice.3類溶劑（見表3）被以為可能為低毒性和對患病動物和患者健康有著低風險。3類溶劑不包括已明白的在正常濃度下就會對人健康產(chǎn)生危害的溶劑。但是，在3類溶劑有很多不是用來做長期毒性或致癌研究的。提供的數(shù)據(jù)顯示它們在急性或短時間的研究中為低毒的也無遺傳毒性。這被以為是可同意的：天天給藥50mg/天或更少（符合5000Ppm或方式1下的%）中殘留溶劑的總量是能夠同意的，不用證明其有合理性。提供實際與生產(chǎn)商的生產(chǎn)能力和GMP相關的，教高總量的殘留溶劑也能夠同意。Table3:Class3SolventswhichshouldbelimitedbyGMPorotherquality-basedrequirementsGMP或其他質量相關要求有限度的為3類溶劑Aceticacid乙酸HeptaneAcetone丙酮Isobutylacetate人田50匕苯甲醚Isobutylacetate1-Butanol1-丁酮Methylacetate2-Butanol2-丁醇3-Methyl-1-butanolButylacetate乙酸丁酯，醋酸丁酯Methylethylketonetert-Butylmethyl?由《「甲基叔」基醚MethylisobutylketoneCumene異丙基苯2-Methyl-1-propanolDimethylsulfoxide—甲基亞砜PentaneEthanol乙醇1-PentanolEthylacetate醋酸乙酯，乙酸乙酯1-PropanolEthylether麻醉乙醚2-PropanolEthylformate甲酸乙酯PropylacetateFormicacid甲酸TetrahydrofuranSolventsForWhichNoAdequateToxicologicalDataWasFound尚無足夠毒理學數(shù)據(jù)的溶劑Thefollowingsolvents(Table4)mayalsobeofinteresttomanufacturersofexcipients,activesubstances,orveterinarymedicinalproducts.However,noadequatetoxicologicaldataonwhichtobaseaPDEwasfound.ManufacturersshouldsupplyjustificationforresiduallevelsoftheseandothersolventsforwhichaPDEhasnotbeenestablishedforuseinpharmaceuticalproducts.下面的溶劑(表4)可能對輔料、原料藥或獸藥產(chǎn)品生產(chǎn)的生產(chǎn)廠家有利。但是，沒有足夠的毒理學數(shù)據(jù)來支持確信PDE。生產(chǎn)廠家應當提供這些殘留溶劑的含量和那些存在的合法性和其他還沒確信PDEs用于制劑制備生產(chǎn)的溶劑。Table4:SolventsforwhichnoadequateToxicologicalDatawasfound表4：尚無足夠的毒理學數(shù)據(jù)支持的溶劑

1,1-DiethoxypropaneMethylisopropylketone1,1-DimethoxymethaneMethyltetrahydrofura2,2-DimethoxypropanePetroleumetherIsooctaneTrichloroaceticacidIsopropyletherTrifluoroaceticacid二乙氧基丙烷甲基異丙基二甲基甲烷甲基四氫呋喃二甲丙烷石油醚異辛烷三氯乙酸異丙醚三氟乙酸GLOSSARY辭匯表Genotoxiccarcinogens遺傳毒性致癌物:Carcinogenswhichproducecancerbyaffectinggenesorchromosomes.LOEL可觀看到的最低反映水平的縮寫:Abbreviationforlowest-observedeffectlevel.Lowest-observedeffectlevel最低的可觀看到阻礙的含量:Thelowestdoseofsubstanceinastudyorgroupofstudiesthatproducesbiologicallysignificantincreasesinfrequencyorseverityofanyeffectsintheexposedhumansoranimals.Modifyingfactor修飾因子:Afactordeterminedbyprofessionaljudgementofatoxicologistandappliedtobioassaydatatorelatethatdatasafelytohumans.Neurotoxicity神經(jīng)毒性：Theabilityofasubstancetocauseadverseeffectsonthenervoussystem.NOEL無可觀看到的反映水平的縮寫:Abbreviationforno-observed-effectlevel.No-observed-effectlevel不可觀看到阻礙的含量:Thehighestdoseofsubstanceatwhichtherearenobiologicallysignificantincreasesinfrequencyorseverityofanyeffectsintheexposedhumansoranimals.PDE許諾日接觸量的縮寫：Abbreviationforpermitteddailyexposure.Permitteddailyexposure許諾的日接觸量:Themaximumacceptableintakeperdayofresidualsolventinpharmaceuticalproducts.Reversibletoxicity可逆毒性：Theoccurrenceofharmfuleffectsthatarecausedbyasubstanceandwhichdisappearafterexposuretothesubstanceends.Stronglysuspectedhumancarcinogen超級可疑人體致癌物:Asubstanceforwhichthereisnoepidemiologicalevidenceinhumansofcarcinogenesisbuttherearepositivegenotoxicitydataandclearevidenceofcarcinogenesisinrodents(orotheranimalspecies).Teratogenicity致畸性:Theoccurrenceofstructuralmalformationsinadevelopingfetuswhenasubstanceisadministeredduringpregnancy.APPENDIX1:LISTOFSOLVENTSINCLUDEDINTHEGUIDELINE本指導原那么中包括的殘留溶劑清單（未全數(shù)列出）SclYHnttoei-nniirilB小i啪I日2-ButanalQjmmnmh'bLhaxYbanzanaTriclilaramBihSnHl^pr^pylbHnzenHp-MeLhyljattiylbanzanaQseeoass.26媯i6轉m日B&nzana13日uisniilButylaohtai?ChbrabenzansChhrafarrrOth&rNamsGEihanaicacid2-Prapinen"PropSn-S-cinBMMuM3mh口IEUlsn-2-aIAzolic;acdbutyl咱右ter2-Malh□xy-^-mathykpicp5nbTairachlaramaIhSneCHjGNOa*61Cla&3O3*s.a6擾？ferf-BL+ylmethylaLha,匚自rbcntslrachlarde由riRn-Bu+yl苜bohcilEkilan-1-alStructursCHaCCOHCH3COCH3已由［CHHsOkCHaC卜MH〔口叩TCHacnnpu^jaCHg(CHmQCHmCHC13APPENDIX2:ADDITIONALBACKGROUND附錄2:其他背景EnvironmentalRegulationofOrganicVolatileSolvents揮發(fā)性有機溶劑在環(huán)境方面的規(guī)定SeveraloftheresidualsolventsfrequentlyusedintheproductionofpharmaceuticalsarelistedastoxicchemicalsinEnvironmentalHealthCriteria(EHC)monographsandtheIntegratedRiskinformationSystem(IRIS).TheobjectivesofsuchgroupsastheInternationalProgrammeonChemicalSafety(IPCS),theUnitedStatesEnvironmentalProtectionAgency(USEPA),andtheUnitedStatesFoodandDrugAdministration(USFDA)includethedeterminationofacceptableexposurelevels.Thegoalisprotectionofhumanhealthandmaintenanceofenvironmentalintegrityagainstthepossibledeleteriouseffectsofchemicalsresultingfromlong-termenvironmentalexposure.Themethodsinvolvedintheestimationofmaximumsafeexposurelimitsareusuallybasedonlong-termstudies.Whenlong-termstudydataareunavailable,shortertermstudydatacanbeusedwithmodificationoftheapproachsuchasuseoflargersafetyfactors.Theapproachdescribedthereinrelatesprimarilytolong-termorlife-timeexposureofthegeneralpopulationintheambientenvironment,.ambientair,food,drinkingwaterandothermedia.在制劑生產(chǎn)進程中常經(jīng)常使用到的幾種殘留溶劑在環(huán)境健康標準（EHC）專題論文和危險信息系統(tǒng)大全（IRIS）中被列為毒性化學物。這些物質在這些組織比如國際化學平安組織（IPCS）,美國環(huán)境愛惜機構（USEPA），美國食物藥品監(jiān)督治理局（USFDA）中有可同意的接觸水平的相關規(guī)定。這一目的旨在避免由于長期接觸化學品的環(huán)境下對人類健康和整個環(huán)境的危害。評估最大接觸的平安限度的相關方式應當基于長期的研究。當無長期研究數(shù)據(jù)時，短時間研究數(shù)據(jù)能夠通過如此的途徑比如用較大的平安因素校正后被應用。其中要緊描述的項目與物種長期或一生接觸的環(huán)境有關，即周圍空氣、食物、飲用水和其他介質。ResidualSolventsinPharmaceuticals制劑產(chǎn)品中的殘留溶劑UExposurelimitsinthisguidelineareestablishedbyreferringtomethodologiesandtoxicitydatadescribedinEHCandIRISmonographs.However,somespecificassumptionsaboutresidualsolventstobeusedinthesynthesisandformulationofpharmaceuticalproductsshouldbetakenintoaccountinestablishingexposurelimits.Theyare:本指導原那么中的接觸限度是在參考EHC和IRIS專著中的方式學和毒理學數(shù)據(jù)而成立的。但是,那些被用于制劑產(chǎn)品的合成進程和制劑處方中的殘留溶劑在確信接觸限度時應考慮一些假設。即：Veterinarypatients（ratherthanthegeneralanimalpopulation）receivepharmaceuticalstotreattheirdiseasesorforprophylaxistopreventinfectionordisease.However,therearesomeveterinarymedicinalproductswhichareusedasaidsinagriculturalproductionwhichareunrelatedtothepresenceofinfectionordiseaseintheanimalpopulation.患病動物（不是一樣的動物）服用藥品是為治病或為避免感染和染疾。但是，有一些獸藥產(chǎn)品是用來用于農(nóng)業(yè)生產(chǎn)的和用于動物預防感染和避免疾病的毫不相干。Theassumptionoflife-timeexposureoftheveterinarypatientisnotnecessaryformostpharmaceuticalproductsbutmaybeappropriateasaworkinghypothesistoreducerisktohumanhealthasalife-timeexposureofthehumanconsumertotheedibletissuesoffoodanimalstreatedwiththeveterinarymedicinalproduct.關于大多數(shù)的藥品沒必要假設患病動物終身服藥的接觸量，但作為工作假設適當應用能夠降低對一生都接觸藥品的患者其健康的危害。Residualsolventsareunavoidablecomponentsinpharmaceuticalproductionandwilloftenbeapartofveterinarymedicinalproducts.在制藥的生產(chǎn)中殘留溶劑作為不可幸免的成份將常常被作為獸藥產(chǎn)品中的一部份。Residualsolventsshouldnotexceedrecommendedlevelsexceptinexceptionalcircumstances,andthenshouldbejustified.殘留溶劑不能超過所推薦的水平；除非在特殊的情形下，而且應證明其存在的合理性。Datafromtoxicologicalstudiesthatareusedtodetermineacceptablelevelsforresidualsolventsshouldhavebeengeneratedusingappropriateprotocolsincluding,butnotnecessarilylimitedtothosedescribedbyOECD,EPAandtheFDARedBook.被用于確定殘留溶劑可同意水平的毒理學研究的數(shù)據(jù)應當通過那些適當?shù)脑\斷記錄產(chǎn)生，并非必然在OECD,EPA和FDA紅皮書所描述的限度內。APPENDIX3:METHODSFORESTABLISHINGEXPOSURELIMITS成立攝入限度的方式TheGaylor-Kodellmethodofriskassessment(Gaylor,D.W.andKodell,R.L.:LinearInterpolationalgorithmforlowdoseassessmentoftoxicsubstance.JEnviron.Pathology,4,305,1980)isappropriateforClass1carcinogenicsolvents.Onlyincaseswherereliablecarcinogenicitydataareavailableshouldextrapolationbytheuseofmathematicalmodelsbeappliedtosettingexposurelimits.ExposurelimitsforClass1solventscouldbedeterminedwiththeuseofalargesafetyfactor.,10,000to100,000)withrespecttotheno-observed-effectlevel(NOEL).Detectionandquantitationofthesesolventsshouldbebystate-of-the-artanalyticaltechniques.Gaylor-Kodell的風險評估的方式(Gaylor,D.W.andKodell,R.L.:LinearInterpolationalgorithmforlowdoseassessmentoftoxicsubstance.JEnviron.Pathology,4,305,1980)適用于1類致癌溶劑。僅有靠得住有效的毒理學數(shù)據(jù)的情形下：才能夠應用數(shù)學模型外推來確信接觸限度。第1類溶劑的接觸限度應當依照不可觀看到的反映水平(NOEL)并適用較大平安系數(shù)(即,10,000至100,000)來確定。檢測和定量這些溶劑應當用現(xiàn)代的分析技術。

AcceptableexposurelevelsinthisguidelineforClass2solventswereestablishedbycalculationofPDEvaluesaccordingtotheproceduresforsettingexposurelimitsinpharmaceuticals(PharmacopeialForum,Nov-Dec1989),andthemethodadoptedbyIPCSforAssessingHumanHealthRiskofChemicals(EnvironmentalHealthCriteria170,WHO,1994).ThesemethodsaresimilartothoseusedbytheEnvironmentalHealthCriteriaandothers.ThemethodisoutlinedheretogiveabetterunderstandingoftheoriginofthePDEvalues.ItisnotnecessarytoperformthesecalculationsinordertousethePDEvaluestabulatedinSection4ofthisdocument.本指導原那么中第2類溶劑的可同意接觸限度應當依照藥品中設定接觸限度的規(guī)定(藥典論壇Nov-Dec1989)和IPCS中評估化學品對人類健康的風險(環(huán)境衛(wèi)生標準170,WHO,1994)所采納的方式計算PDE值的而取得的。這些方式與環(huán)境衛(wèi)生標準和其他一些所用的方式相類似。簡述這些方式是為了更好的明白得PDE值的由來。在利用本文件第四節(jié)表中的PDE值時沒必要進行計算。PDEisderivedfromtheno-observed-effectlevel(NOEL),orthelowest-observedeffectlevel(LOEL)inthemostrelevantanimalstudyasfollows:PDE在對大多數(shù)相關動物的研究中從NOEL或可觀看到的最低反映水平(LOEL)取得，如下：PDENOELxWeightAdjustmentPDENOELxWeightAdjustmentF1xF2xF3xF4xF5PDE=NOELx體重調整F1xF2xF3xF4xF5ThePDEisderivedp