中文版VICHTopicGL18IMPURITIESRESIDUALSOLVENTS免费哦

V1cHTopicGL18（VICH的议题中指导原那么8）Step7第七时期IMPURITIES:RESIDUALSOLVENTS杂质：残留溶剂IMPURITIES:RESIDUALSOLVENTSINNEWVETERINARYMEDICINALPRODUCTS,ACTIVE

SUBSTANCESANDEXCIPIENTS

杂质：新兽药、活性物质和辅料中的残留溶剂RecommendedforImplementationatStep7oftheVICHProcesson15June2000by

theVICHSteeringCommitteeVICH指导委员会2000年6月5日由在VICH进程的第七时期通过并推荐THISGUIDELINEHASBEENDEVELOPEDBYTHEAPPROPRIATEVICHEXPERTWORKINGGROUPONTHEBASISOFTHEICHGUIDELINESONTHESAMESUBJECTANDWASSUBJECTTOCONSULTATIONBYTHEPARTIES,INACCORDANCEWITHTHEVICHPROCESS.ATSTEP7OFTHEPROCESSTHEFINALDRAFTISRECOMMENDEDFORADOPTIONTOTHEREGULATORYBODIESOFTHEEUROPEANUNION,JAPANANDUSA.本指南已经在ICH指南相同议题的基础上被适合的VICH专家工作小组更新，参与者会在VICH进程上就不准确的地址进一步磋商。在VICH进程的第7时期，这一最终草案，会被欧盟、日本和美国就调整后的文件正式通过并推荐。INTRODUCTION3简介SCOPEOFTHEGUIDELINE3范围GENERALPRINCIPLES4总那么ClassificationofResidualSolventsbyRiskAssessment4风险评估中残留溶剂的分类MethodsforEstablishingExposureLimits4成立接触限度的方式OptionsforDescribingLimitsofClass2Solvents4第二类溶剂的相关描述AnalyticalProcedures6分析方式ReportingLevelsofResidualSolvents6报导的残留溶剂的水平LIMITSOFRESIDUALSOLVENTS6残留溶剂的限度SolventstobeAvoided6幸免利用的溶剂SolventstobeLimited6限制利用的熔剂SolventswithLowToxicPotential7具有潜在低毒的溶剂SolventsForWhichNoAdequateToxicologicalDataWasFound8尚无足够的毒理数据的溶剂GLOSSARY9术语LISTOFSOLVENTSINCLUDEDINTHEGUIDELINE10附录1:本指导原那么中的残留溶剂ADDITIONALBACKGROUND15附录2:其他背景EnvironmentalRegulationofOrganicVolatileSolvents15有机挥发性溶剂在环境方面的规定ResidualSolventsinPharmaceuticals15药品中的残留溶剂METHODSFORESTABLISHINGEXPOSURELIMITS16成立接触限度的方式TableValuesusedinthecalculationsinthisdocument18表在这篇文档中用于计算的数值IMPURITIES:RESIDUALSOLVENTSINNEWVETERINARYMEDICINALPRODUCTS,ACTIVESUBSTANCESANDEXCIPIENTS杂质：新兽药、活性物质和辅料中的残留溶剂INTRODUCTION介绍Theobjectiveofthisguidelineistorecommendacceptableamountsforresidualsolventsinpharmaceuticalsforthesafetyofthetargetanimalaswellasforthesafetyofresiduesinproductsderivedfromtreatedfoodproducinganimals.Theguidelinerecommendsuseoflesstoxicsolventsanddescribeslevelsconsideredtobetoxicologicallyacceptableforsomeresidualsolvents.本指导原那么的目的在于推荐患病动物用含可同意的残留溶剂量的药物，保证用药动物的平安同时也适用于生产含残留物的动物食物制品的平安。Residualsolventsinpharmaceuticalsaredefinedhereasorganicvolatilechemicalsthatareusedorproducedinthemanufactureofactivesubstancesorexcipients,orinthepreparationofveterinarymedicinalproducts.Thesolventsarenotcompletelyremovedbypracticalmanufacturingtechniques.Appropriateselectionofthesolventforthesynthesisofactivesubstancemayenhancetheyield,ordeterminecharacteristicssuchascrystalform,purity,andsolubility.Therefore,thesolventmaysometimesbeacriticalparameterinthesyntheticprocess.Thisguidelinedoesnotaddresssolventsdeliberatelyusedasexcipientsnordoesitaddresssolvates.However,thecontentofsolventsinsuchproductsshouldbeevaluatedandjustified.残留溶剂在药品中被概念为被用于活性物质、辅料或是用于兽药的有机挥发溶剂。这一溶剂并非能通过实际的生产工艺全数去除。选择适当的溶剂用于活性成份的合成有可能对提高产品的产量或对产品的特性比如晶型、纯度和可溶性起着决定性作用。因此，溶剂有时在合成进程中是一个至观重要的参数。本指导原那么不是将溶剂特意概念为应用于辅料或溶剂合物。但是，溶剂的成份在这些产品的生产中应当评估和判定。Sincethereisnotherapeuticbenefitfromresidualsolvents,allresidualsolventsshouldberemovedtotheextentpossibletomeetproductspecifications,goodmanufacturingpractices,orotherquality-basedrequirements.Veterinarymedicinalproductsshouldcontainnohigherlevelsofresidualsolventsthancanbesupportedbysafetydata.Somesolventsthatareknowntocauseunacceptabletoxicities(Class1,Table1)shouldbeavoidedintheproductionofactivesubstances,excipients,orveterinarymedicinalproductsunlesstheirusecanbestronglyjustifiedinarisk-benefitassessment.Somesolventsassociatedwithlessseveretoxicity(Class2,Table2)shouldbelimitedinordertoprotecttargetanimalsandhumanconsumersfrompotentialadverseeffects.Ideally,lesstoxicsolvents(Class3,Table3)shouldbeusedwherepractical.ThecompletelistofsolventsincludedinthisguidelineisgiveninAppendix1.因残留溶剂并无医治的作用，因此所有的溶剂都应当尽可能的去除以便来符合产品特性，GMP或其他大体的质量方面的要求。兽药所含残留溶剂量应为具有平安数据支持且不高于规定的残留溶剂限度。而像一些溶剂因会引发不可同意的毒性（1类溶剂见表1）应当禁止应用于、活性物质、辅料或兽药的生产，不然应通过风险-利益评估充分证明。另一些具有较低严峻毒性的溶剂（2类溶剂，表2）应当限制利用以防患病动物或患者产生不良反映。最后，具有较低毒性的溶剂（3类，表3）应当应用于生产。本指导原那么中涉及的所有溶剂见附件1。Thelistsarenotexhaustiveandothersolventscanbeusedandlateraddedtothelists.RecommendedlimitsofClass1and2solventsorclassificationofsolventsmaychange,asnewsafetydatabecomesavailable.Supportingsafetydatainamarketingapplicationforanewveterinarymedicinalproductcontaininganewsolventmaybebasedonconceptsinthisguidelineortheconceptofqualificationofimpuritiesasexpressedintheguidelineforactivesubstance（VICHGL10,ImpuritiesinNewVeterinaryDrugSubstances）orveterinarymedicinalproduct,orallthreeguidelines.这一清单并非是详尽的，其他用到的溶剂能够添加到清单上来。建议限制利用1类和2类溶剂，或有当新的平安数据支持时溶剂的分类能够作相应改变。当有支持的平安数据的应用于新兽药生产中新的溶剂，能够依据本指导原那么或或依照VICHGL10新兽药中杂质（ImpuritiesinNewVeterinaryDrugSubstances）这一指导原那么中活性物质中杂质的概念，或依照兽药生产指导原那么在或以上三个指导原那么。SCOPEOFTHEGUIDELINE本指导原那么的范围Residualsolventsinactivesubstances,excipients,andinveterinarymedicinalproductsarewithinthescopeofthisguideline.Therefore,testingshouldbeperformedforresidualsolventswhenproductionorpurificationprocessesareknowntoresultinthepresenceofsuchsolvents.Itisonlynecessarytotestforsolventsthatareusedorproducedinthemanufactureorpurificationofmedicinalsubstances,excipients,orveterinarymedicinalproducts.Althoughmanufacturersmaychoosetotesttheveterinarymedicinalproduct,acumulativemethodmaybeusedtocalculatetheresidualsolventlevelsintheproductfromthelevelsintheingredientsusedtoproducetheproduct.Ifthecalculationresultsinalevelequaltoorbelowthatrecommendedinthisguideline,notestingoftheveterinarymedicinalproductforresidualsolventsneedbeconsidered.If,however,thecalculatedlevelisabovetherecommendedlevel,theveterinarymedicinalproductshouldbetestedtoascertainwhethertheformulationprocesshasreducedtherelevantsolventleveltowithintheacceptableamount.Theveterinarymedicinalproductshouldalsobetestedifasolventisusedduringitsmanufacture.Thisguidelinedoesnotapplytopotentialnewactivesubstances,excipients,orveterinarymedicinalproductsusedduringtheclinicalresearchstagesofdevelopment,nordoesitapplytoexistingmarketedveterinarymedicinalproducts.本指导原那么包括活性物质、辅料和兽药中的残留溶剂。因此，当生产进程或纯化工艺会致使存在残留溶剂时，残留溶剂应当检测。仅仅需要检测在药物、辅料或兽药生产或纯化进程中被用到的或参与生产的溶剂。尽管生产厂家可能选择检测兽药制剂产品中残留溶剂，但应当用累加方式计算用于生产产品的各成份残留溶剂水平到计算产品中残留溶剂的水平。若是，计算出的残留溶剂含量在推荐的水平之上，兽药产品应当检测来确认各组分通过处置是不是已经将残留溶剂的水平降低至可同意范围之内。若是某一溶剂用于生产那么兽药产品应当检测。此指导原那么不适用于即将准新活性物质、辅料或处于临床研究时期进展的兽药，也不适用于存在于已经上市的兽药。Theguidelineappliestoalldosageformsandroutesofadministration.Higherlevelsofresidualsolventsmaybeacceptableincertaincasesortopicalapplication.Justificationfortheselevelsshouldbemadeonacasebycasebasis.这一指导原那么适用于所有的剂型多有给药途径的兽品。在某些情形下或局部应历时，含有较高含量残留溶剂的兽药能够同意。应依照不同情形来评判溶剂的水平。SeeAppendix2foradditionalbackgroundinformationrelatedtoresidualsolvents.残留溶剂相关的另外一些背景知识能够参见附录二。FORIMPLEMENTATIONATSTEP7(FINAL)-06/00Page4of18于第七时期被推荐aEMEA2000欧洲药品治理局2000GENERALPRINCIPLES总那么ClassificationofResidualSolventsbyRiskAssessment依照危害程度对残留溶剂的分类Theterm"tolerabledailyintake"(TDI)isusedbytheInternationalProgramonChemicalSafety(IPCS)todescribeexposurelimitsoftoxicchemicalsand"acceptabledailyintake"(ADI)isusedbytheWorldHealthOrganisation(WHO)andothernationalandinternationalhealthauthoritiesandinstitutes.Thenewterm"permitteddailyexposure"(PDE)isdefinedinthepresentguidelineasapharmaceuticallyacceptableintakeofresidualsolventstoavoidconfusionofdifferingvaluesforADIsofthesamesubstance.“可耐受的日摄取量”这一术语被国际化学品平安组织来描述毒性化学药品接触限度，同时WHO也用到可接受的日接触量，其他一些国家或国际卫生局、协会也用到这一术语。本指导原那么顶用“许诺的日接触量”这一新术语作为药物中可同意的残留溶剂的摄入量，以防同一物质的的可同意的日摄入量(ADI)相混淆。ResidualsolventsassessedinthisguidelinearelistedinAppendix1bycommonnamesandstructures.Theywereevaluatedfortheirpossiblerisktohumanhealthandplacedintooneofthreeclassesasfollows:在这一指导原那么中已确信的残留溶剂的通用名和结构列于附录1中。Class1solvents:Solventstobeavoided幸免利用的残留溶剂Knownhumancarcinogens,stronglysuspectedhumancarcinogens,andenvironmentalhazards.已知的人体致癌物质，疑为人体致癌物或环境污染物。Class2solvents:Solventstobelimited限制利用的溶剂Non-genotoxicanimalcarcinogensorpossiblecausativeagentsofotherirreversibletoxicitysuchasneurotoxicityorteratogenicity.非遗传毒性动物致癌物或可能致使其他不可逆的毒性如神经毒性或致畸性。Solventssuspectedofothersignificantbutreversibletoxicities.疑具有其他严峻的但可逆的毒性的溶剂Class3solvents:Solventswithlowtoxicpotential具有潜在的低毒溶剂Solventswithlowtoxicpotentialtoman;nohealth-basedexposurelimitisneeded.Class3solventshavePDEsof50mgormoreperday.对人类有潜在低毒性的溶剂；不需要制丁接触限度。第3类溶剂的PDE为天天50毫克或更高。MethodsforEstablishingExposureLimits确信接触限度的方式ThemethodusedtoestablishpermitteddailyexposuresforresidualsolventsispresentedinAppendix3.SummariesofthetoxicitydatathatwereusedtoestablishlimitsarepublishedinPharmeuropa,Vol.9,No.1,Supplement,April1997.确信残留溶剂PDE的方式见附录3。用于确信摄取限度的毒性数据的总结见1997年4月增补本的VOL9\.OptionsforDescribingLimitsofClass2Solvents第二类溶剂界限的选择方式ThreeoptionsareavailablewhensettinglimitsforClass2solvents.设定第二类溶剂的界限时有三种选择Option1:TheconcentrationlimitsinppmstatedinTable2canbeused.Theywerecalculatedusingequation(1)belowbyassumingaproductmassof10gadministereddaily.方式1：可用表2中规定的浓度限度(单位PPM)。假定一个药品每日给药量为10g能够用下面的公式(1)来进行计算。(1)Concentration(ppm)=1000xPDE/dose=1000xPDE/剂量Here,PDEisgivenintermsofmg/dayanddoseisgivening/day.那个地址PDE为mg/天，剂量为g/天。Theselimitsareconsideredacceptableforresidualsolventsinallsubstances,excipients,orthisoptionmaybeappliedifthedailydoseisnotknownorfixed.IftheresidualsolventsinallexcipientsandactivesubstancesinaformulationmeetthelimitsgiveninOption1,thenthesecomponentsmaybeusedinanyproportion.Nofurthercalculationisnecessaryprovidedthedailydosedoesnotexceed10g.Productsthatareadministeredindosesgreaterthan10gperdayshouldbeconsideredunderOption2.所有的物质、辅料或产品中的残留有机溶剂的限度以为是能够同意的。因此若是不明白日剂量或日剂量固定不变也有可用于这一方式。若是所有的辅料和活性物质中残留溶剂在公式中都符合方式1中给定的限度。那这些成份能够任何比例来用。不需要进一步的提供每日剂量不超过10g的计算方式。但日服用剂量超过10g的产品应当用方式2。Option2:itisnotconsiderednecessaryforresidualsolventsineachcomponentoftheveterinarymedicinalproducttocomplywiththelimitsgiveninOption1.ThePDEintermsofmg/dayasstatedinTable2canbeusedwiththeknownmaximumdailydoseandequation(1)abovetodeterminetheconcentrationofresidualsolventallowedintheveterinarymedicinalproduct.Suchlimitsareconsideredacceptableprovidedthatithasbeendemonstratedthattheresidualsolventhasbeenreducedtothepracticalminimum.Thelimitsshouldberealisticinrelationtoanalyticalprecision,manufacturingcapability,reasonablevariationinthemanufacturingprocess,andthelimitsshouldreflectcontemporarymanufacturingstandards.方式2：并非需要考虑兽药产品中的每一组分的残留溶剂都要符合选项1给出的限度。表2中规定的PDE（mg/天）和日最大剂量及方程（1）来确信许诺用于兽药产品的残留溶剂的浓度。只要能证明残留溶剂已经被降低到实际的最小量，那这些限度被以为是可同意的。这些限度与生产进程中分析的周密度、生产能力和合理的工艺变更有着实际的联系，这些限度应当能反映目前生产的标准。Option2maybeappliedbyaddingtheamountsofaresidualsolventpresentineachofthecomponentsoftheveterinarymedicinalproduct.ThesumoftheamountsofsolventperdayshouldbelessthanthatgivenbythePDE.方式2将兽药制剂产品中每种成份的必然量的残留溶剂相加来，相加后的溶剂的总量应当低于PDE。ConsideranexampleoftheuseofOption1andOption2appliedtoacetonitrileinaveterinarymedicinalproduct.Thepermitteddailyexposuretoacetonitrileismgperday;thus,theOption1limitis410ppm.Themaximumadministereddailymassofaveterinarymedicinalproductisg,andtheveterinarymedicinalproductcontainstwoexcipients.Thecompositionoftheveterinarymedicinalproductandthecalculatedmaximumcontentofresidualacetonitrilearegiveninthefollowingtable.以兽药产品中乙睛在方式1和方式2中的应用为例，乙睛的PDE为天；方式1的算出限度为410ppm。如天天最大给药量为，这一兽药含有2种辅料。兽药产品中的组分和通过计算取得的残留乙睛的最大量见下表。Component组分AmountinAcetonitrilecontentDailyexposureActivesubstance活性物g800ppmmgExcipient1辅料1g400ppmmgExcipient2辅料2g800ppmmgVeterinarmedicinalg728ppmmgproductExcipient1meetstheOption1limit,buttheactivesubstance,excipient2,andtheveterinarymedicinalproductdonotmeettheOption1limit.Nevertheless,theproductmeetstheOption2limitofmgperdayandthusconformstotherecommendationsinthisguideline.辅料1要符合方式1中规定限度，而活性物质，辅料2，和兽药产品那么不用符合方式1中的规定。尽管如此产品符合方式2中的天，与这一指导原那么中推荐的一致。Consideranotherexampleusingacetonitrileasresidualsolvent.Themaximumadministereddailymassofaveterinarymedicinalproductisg,andtheveterinarymedicinalproductcontainstwoexcipients.Thecompositionoftheveterinarymedicinalproductandthecalculatedmaximumcontentofresidualacetonitrileisgiveninthefollowingtable.再以乙腈这一残留溶剂为例。一个兽药产品天天最大的给药剂量为，这一兽药中包括两种辅料。动物制剂产品的组份和通过计算的最大的残留乙腈的含量见下表。Component成分AmountinAcetonitrilecontentDailyexposureActivesubstance活性物g800ppmmgExcipient1辅料1g2000ppmmgExcipient2辅料2g800ppmmgVeterinarmedicinalg1016ppmmgproductInthisexample,theproductmeetsneithertheOption1northeOption2limit.Themanufacturercouldtesttheproducttodetermineiftheformulationprocessreducedthelevelofacetonitrile.Ifthelevelofacetonitrilewasnotreducedduringformulationtotheallowedlimit,thenthemanufactureroftheproductshouldtakeotherstepstoreducetheamountofacetonitrileintheproductoroption3shouldbeconsidered.在那个例子中，药品既不符合方式1规定的限度也不用符合方式2中的限度。生产商应通过检测产品中乙腈的含量来确定是不是对处方工艺进行处置来降低乙腈的含量。若是在对处方工艺处置中没有使乙腈的含量降低至准予的限度，那么生产此产品的生产商应采取其他步骤降低产品中乙腈的总量不然应当考虑方式3。Option3方式3ApplicantsmayjustifyhigherlevelsforthePDEandconcentrationlimitbasedupontheactualdailydose,actualtargetspecies,andrelevanttoxicologicaldataandconsideringconsumersafetyaspects.UseofOption3willbehandledonacasebycasebasisbytheregulatoryauthorities.Thisoptionmaybeappliedas:申请人能够证明更高的PDE含量，对浓度的限度应基于实际的天天剂量，实际的给药的物种，相关的毒理学数据和应考虑给药动物的平安因素。3a-Theapplicantmayprovideanappropriatebodyweightfortheactualtargetspeciesand/ortheactualdoseandrecalculatethePDEand/orconcentrationlimitusingtheICHequationsandICHsupportingtoxicologicaldata.3a-申请人要提供给药物种的适合的体重或实际给药剂量、和/或从头计算的PDE、和/或用ICH方程、支持ICH的毒理学数据的取得的浓度限度。3b—Theapplicantmayprovidenewtoxicologicaldata(withorwithoutactualtargetanimalanddoseinformation）andrecalculatethePDEandconcentrationlimitusingtheequationprovidedbyICH.Ifallofthesestepsfailtoreducethelevelofresidualsolvent,inexceptionalcasesthemanufacturercouldprovideasummaryofeffortsmadetoreducethesolventleveltomeettheguidelinevalue,andprovidearisk-benefitanalysistosupportallowingtheproducttobeutilisedwithresidualsolventatahigherlevel.3"申请者要提供新的毒理学数据（包括或不包括给药的动物和剂量方面的信息）和再计算后取得PDEsfflHICH公式中提供的浓度限度。若是所有的处置步骤都不能降低残留溶剂的含量，在特殊情形下制造商能够提供出为使残留溶剂含量降低至所要求的限度所做出工作的总结，并提供风险效益分析来支持药品中许诺存在较高含量的残留溶剂。AnalyticalProcedures分析方式Residualsolventsaretypicallydeterminedusingchromatographictechniquessuchasgaschromatography.Anyharmonisedproceduresfordetermininglevelsofresidualsolventsasdescribedinthepharmacopoeiasshouldbeused,iffeasible.Otherwise,manufacturerswouldbefreetoselectthemostappropriatevalidatedanalyticalprocedureforaparticularapplication.IfonlyClass3solventsarepresent,anon-specificmethodsuchaslossondryingmaybeused.ValidationofmethodsforresidualsolventsshouldconformtotheVICHguidelines"Validationofanalyticalprocedures:definitionandterminology"and"Validationofanalyticalprocedures:methodology."残留溶剂专属检测方式为色谱法比如GC。若是可行，应与药典描述的检测残留溶剂含量的方式相一致。不然，生产商应为所选的通过验证最适合的分析方式来做额外的申请。若是仅仅只是3类溶剂，那么能够应用非专属法比如干燥失重等方式。体会证的残留溶剂的方式应与VICH指导原那么中的“分析方式的验证：概念和术语”和“分析方式的验证：方式学”一致。ReportingLevelsofResidualSolvents报至ll的残留溶剂的含量Manufacturersofpharmaceuticalproductsneedcertaininformationaboutthecontentofresidualsolventsinexcipientsoractivesubstancesinordertomeetthecriteriaofthisguideline.Thefollowingstatementsaregivenasacceptableexamplesoftheinformationthatcouldbeprovidedfromasupplierofexcipientsoractivesubstancestoapharmaceuticalmanufacturer.药剂的生产厂家需要确信关于辅料和活性物质中的残留溶剂的含量以便能符合本指导原那么中的标准。下面的表述可作为一个供给商提供给制剂生产商辅料和活性物质的可同意案例的信息。Thesuppliermightchooseoneofthefollowingasappropriate:供给商应选择以下其中之OnlyClass3solventsarelikelytobepresent.Lossondryingislessthan%.仅可能存在第3类溶剂，干燥失重应少于%。OnlyClass2solventsX,Y,...arelikelytobepresent.AllarebelowtheOption1limit.（HerethesupplierwouldnametheClass2solventsrepresentedbyX,Y,...）仅可能存在第2类溶剂X、Y.…，所有的溶剂含量都要在方式1的限度下。（这儿供给商能够将第2类溶剂以X、Y…表示来命名）OnlyClass2solventsX,Y,...andClass3solventsarelikelytobepresent.ResidualClass2solventsarebelowtheOption1limitandresidualClass3solventsarebelow%.仅可能存在第2类X、Y.…和第3类溶剂，第2类残留溶剂在方式1规定的限度下，第3类残留溶剂要干燥失重应小于%。（别离知足上述条件）IfClass1solventsarelikelytobepresent,theyshouldbeidentifiedandquantified.若是存在第1类溶剂，应进行能辨别并定量。"Likelytobepresent"referstothesolventusedinthefinalmanufacturingstepandtosolventsthatareusedinearliermanufacturingstepsandnotremovedconsistentlybyavalidatedprocess.IfsolventsofClass2orClass3arepresentatgreaterthantheirOption1limitsor%,respectively,theyshouldbeidentifiedandquantified.“Likelytobepresent”可能存在指的是被用于最后一步生产步骤的和前几道工序且通过确认不能除尽的溶剂。若是第2类和第3类溶剂别离比他们对应的方式1中的限度或干燥失重%限度高，应进行辨别并定量。4.LIMITSOFRESIDUALSOLVENTS残留溶剂的限度SolventstobeAvoided幸免利用的溶剂SolventsinClass1shouldnotbeemployedinthemanufactureofactivesubstances,excipients,andveterinarymedicinalproductsbecauseoftheirunacceptabletoxicityortheirdeleteriousenvironmentaleffect.However,iftheiruseisunavoidableinordertoproduceaveterinarymedicinalproductwithasignificanttherapeuticadvance,thentheirlevelsshouldberestrictedasshowninTable1,unlessotherwisejustified.1,1,1-TrichloroethaneisincludedinTable1becauseitisanenvironmentalhazard.Thestatedlimitof1500ppmisbasedonareviewofthesafetydata.第1类溶剂由于他们的不可同意的毒性和对环境的有害阻碍应当幸免用于原料药和辅料和兽药产品的生产中。但是，若是为生产出对医治成效有着显著提高的兽药产品而不可幸免的利历时，那么它们的含量应当符合表1的规定，若是不那么应证明其合理性。因为对环境的危害，三氯甲烷列于表1。基于平安数据的回忆1500PpM为规定的限度。Table1:Class1Solventsinpharmaceuticalproducts(solventsthatshouldbeavoided)

药物制剂中含第1类溶剂的限度(应幸免利用的溶剂)Solvent溶剂名称ConcentrationLimit(ppm)Concern备注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环境公害i，i，1-三氯^乙烷SolventstobeLimited限制利用的溶剂SolventsinTable2shouldbelimitedinpharmaceuticalproductsbecauseoftheirinherenttoxicity.PDEsaregiventothenearestmg/day,andconcentrationsaregiventothenearest10ppm.Thestatedvaluesdonotreflectthenecessaryanalyticalprecisionofdetermination.Precisionshouldbedeterminedaspartofthevalidationofthemethod.在表2中的溶剂应当限制利用因为它们潜在的毒性。PDEs约为天，浓度给定的约10Ppm。列出数值并非必然反映测定的分析周密度。周密度应看成为方式验证的一部份来测定。Table2:Class2SolventsinPharmaceuticalProducts表2：药物制剂中第2类溶剂Solvent溶剂PDE(mg/day)允许日接触量ConcentrationLimit浓度限制Acetonitrile乙睛410

Chlorobenzene氯苯360Chloroform三氯甲烷60Cyclohexane环己烷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%间二甲苯、14%对二甲苯、9%邻二甲苯和17%乙苯。SolventswithLowToxicPotential具有潜在低毒的溶剂SolventsinClass3(showninTable3)mayberegardedaslesstoxicandoflowerrisktotargetanimalandhumanconsumerhealth.Class3includesnosolventknownasahumanhealthhazardatlevelsnormallyacceptedinpharmaceuticals.However,therearenolong-termtoxicityorcarcinogenicitystudiesformanyofthesolventsinClass3.Availabledataindicatethattheyarelesstoxicinacuteorshort-termstudiesandnegativeingenotoxicitystudies.Itisconsideredthatamountsoftheseresidualsolventsof50mgperdayorless（correspondingto5000ppmor%underOption1）wouldbeacceptablewithoutjustification.Higheramountsmayalsobeacceptableprovidedtheyarerealisticinrelationtomanufacturingcapabilityandgoodmanufacturingpractice.3类溶剂（见表3）被以为可能为低毒性和对患病动物和患者健康有着低风险。3类溶剂不包括已明白的在正常浓度下就会对人健康产生危害的溶剂。但是，在3类溶剂有很多不是用来做长期毒性或致癌研究的。提供的数据显示它们在急性或短时间的研究中为低毒的也无遗传毒性。这被以为是可同意的：天天给药50mg/天或更少（符合5000Ppm或方式1下的%）中残留溶剂的总量是能够同意的，不用证明其有合理性。提供实际与生产商的生产能力和GMP相关的，教高总量的残留溶剂也能够同意。Table3:Class3SolventswhichshouldbelimitedbyGMPorotherquality-basedrequirementsGMP或其他质量相关要求有限度的为3类溶剂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异丙基苯2-Methyl-1-propanolDimethylsulfoxide—甲基亚砜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尚无足够毒理学数据的溶剂Thefollowingsolvents(Table4)mayalsobeofinteresttomanufacturersofexcipients,activesubstances,orveterinarymedicinalproducts.However,noadequatetoxicologicaldataonwhichtobaseaPDEwasfound.ManufacturersshouldsupplyjustificationforresiduallevelsoftheseandothersolventsforwhichaPDEhasnotbeenestablishedforuseinpharmaceuticalproducts.下面的溶剂(表4)可能对辅料、原料药或兽药产品生产的生产厂家有利。但是，没有足够的毒理学数据来支持确信PDE。生产厂家应当提供这些残留溶剂的含量和那些存在的合法性和其他还没确信PDEs用于制剂制备生产的溶剂。Table4:SolventsforwhichnoadequateToxicologicalDatawasfound表4：尚无足够的毒理学数据支持的溶剂

1,1-DiethoxypropaneMethylisopropylketone1,1-DimethoxymethaneMethyltetrahydrofura2,2-DimethoxypropanePetroleumetherIsooctaneTrichloroaceticacidIsopropyletherTrifluoroaceticacid二乙氧基丙烷甲基异丙基二甲基甲烷甲基四氢呋喃二甲丙烷石油醚异辛烷三氯乙酸异丙醚三氟乙酸GLOSSARY辞汇表Genotoxiccarcinogens遗传毒性致癌物:Carcinogenswhichproducecancerbyaffectinggenesorchromosomes.LOEL可观看到的最低反映水平的缩写:Abbreviationforlowest-observedeffectlevel.Lowest-observedeffectlevel最低的可观看到阻碍的含量:Thelowestdoseofsubstanceinastudyorgroupofstudiesthatproducesbiologicallysignificantincreasesinfrequencyorseverityofanyeffectsintheexposedhumansoranimals.Modifyingfactor修饰因子:Afactordeterminedbyprofessionaljudgementofatoxicologistandappliedtobioassaydatatorelatethatdatasafelytohumans.Neurotoxicity神经毒性：Theabilityofasubstancetocauseadverseeffectsonthenervoussystem.NOEL无可观看到的反映水平的缩写:Abbreviationforno-observed-effectlevel.No-observed-effectlevel不可观看到阻碍的含量:Thehighestdoseofsubstanceatwhichtherearenobiologicallysignificantincreasesinfrequencyorseverityofanyeffectsintheexposedhumansoranimals.PDE许诺日接触量的缩写：Abbreviationforpermitteddailyexposure.Permitteddailyexposure许诺的日接触量:Themaximumacceptableintakeperdayofresidualsolventinpharmaceuticalproducts.Reversibletoxicity可逆毒性：Theoccurrenceofharmfuleffectsthatarecausedbyasubstanceandwhichdisappearafterexposuretothesubstanceends.Stronglysuspectedhumancarcinogen超级可疑人体致癌物:Asubstanceforwhichthereisnoepidemiologicalevidenceinhumansofcarcinogenesisbuttherearepositivegenotoxicitydataandclearevidenceofcarcinogenesisinrodents(orotheranimalspecies).Teratogenicity致畸性:Theoccurrenceofstructuralmalformationsinadevelopingfetuswhenasubstanceisadministeredduringpregnancy.APPENDIX1:LISTOFSOLVENTSINCLUDEDINTHEGUIDELINE本指导原那么中包括的残留溶剂清单（未全数列出）SclYHnttoei-nniirilB小i啪I日2-ButanalQjmmnmh'bLhaxYbanzanaTriclilaramBihSnHl^pr^pylbHnzenHp-MeLhyljattiylbanzanaQseeoass.26妫i6转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扰？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附录2:其他背景EnvironmentalRegulationofOrganicVolatileSolvents挥发性有机溶剂在环境方面的规定SeveraloftheresidualsolventsfrequentlyusedintheproductionofpharmaceuticalsarelistedastoxicchemicalsinEnvironmentalHealthCriteria(EHC)monographsandtheIntegratedRiskinformationSystem(IRIS).TheobjectivesofsuchgroupsastheInternationalProgrammeonChemicalSafety(IPCS),theUnitedStatesEnvironmentalProtectionAgency(USEPA),andtheUnitedStatesFoodandDrugAdministration(USFDA)includethedeterminationofacceptableexposurelevels.Thegoalisprotectionofhumanhealthandmaintenanceofenvironmentalintegrityagainstthepossibledeleteriouseffectsofchemicalsresultingfromlong-termenvironmentalexposure.Themethodsinvolvedintheestimationofmaximumsafeexposurelimitsareusuallybasedonlong-termstudies.Whenlong-termstudydataareunavailable,shortertermstudydatacanbeusedwithmodificationoftheapproachsuchasuseoflargersafetyfactors.Theapproachdescribedthereinrelatesprimarilytolong-termorlife-timeexposureofthegeneralpopulationintheambientenvironment,.ambientair,food,drinkingwaterandothermedia.在制剂生产进程中常经常使用到的几种残留溶剂在环境健康标准（EHC）专题论文和危险信息系统大全（IRIS）中被列为毒性化学物。这些物质在这些组织比如国际化学平安组织（IPCS）,美国环境爱惜机构（USEPA），美国食物药品监督治理局（USFDA）中有可同意的接触水平的相关规定。这一目的旨在避免由于长期接触化学品的环境下对人类健康和整个环境的危害。评估最大接触的平安限度的相关方式应当基于长期的研究。当无长期研究数据时，短时间研究数据能够通过如此的途径比如用较大的平安因素校正后被应用。其中要紧描述的项目与物种长期或一生接触的环境有关，即周围空气、食物、饮用水和其他介质。ResidualSolventsinPharmaceuticals制剂产品中的残留溶剂UExposurelimitsinthisguidelineareestablishedbyreferringtomethodologiesandtoxicitydatadescribedinEHCandIRISmonographs.However,somespecificassumptionsaboutresidualsolventstobeusedinthesynthesisandformulationofpharmaceuticalproductsshouldbetakenintoaccountinestablishingexposurelimits.Theyare:本指导原那么中的接触限度是在参考EHC和IRIS专著中的方式学和毒理学数据而成立的。但是,那些被用于制剂产品的合成进程和制剂处方中的残留溶剂在确信接触限度时应考虑一些假设。即：Veterinarypatients（ratherthanthegeneralanimalpopulation）receivepharmaceuticalstotreattheirdiseasesorforprophylaxistopreventinfectionordisease.However,therearesomeveterinarymedicinalproductswhichareusedasaidsinagriculturalproductionwhichareunrelatedtothepresenceofinfectionordiseaseintheanimalpopulation.患病动物（不是一样的动物）服用药品是为治病或为避免感染和染疾。但是，有一些兽药产品是用来用于农业生产的和用于动物预防感染和避免疾病的毫不相干。Theassumptionoflife-timeexposureoftheveterinarypatientisnotnecessaryformostpharmaceuticalproductsbutmaybeappropriateasaworkinghypothesistoreducerisktohumanhealthasalife-timeexposureofthehumanconsumertotheedibletissuesoffoodanimalstreatedwiththeveterinarymedicinalproduct.关于大多数的药品没必要假设患病动物终身服药的接触量，但作为工作假设适当应用能够降低对一生都接触药品的患者其健康的危害。Residualsolventsareunavoidablecomponentsinpharmaceuticalproductionandwilloftenbeapartofveterinarymedicinalproducts.在制药的生产中残留溶剂作为不可幸免的成份将常常被作为兽药产品中的一部份。Residualsolventsshouldnotexceedrecommendedlevelsexceptinexceptionalcircumstances,andthenshouldbejustified.残留溶剂不能超过所推荐的水平；除非在特殊的情形下，而且应证明其存在的合理性。Datafromtoxicologicalstudiesthatareusedtodetermineacceptablelevelsforresidualsolventsshouldhavebeengeneratedusingappropriateprotocolsincluding,butnotnecessarilylimitedtothosedescribedbyOECD,EPAandtheFDARedBook.被用于确定残留溶剂可同意水平的毒理学研究的数据应当通过那些适当的诊断记录产生，并非必然在OECD,EPA和FDA红皮书所描述的限度内。APPENDIX3:METHODSFORESTABLISHINGEXPOSURELIMITS成立摄入限度的方式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的风险评估的方式(Gaylor,D.W.andKodell,R.L.:LinearInterpolationalgorithmforlowdoseassessmentoftoxicsubstance.JEnviron.Pathology,4,305,1980)适用于1类致癌溶剂。仅有靠得住有效的毒理学数据的情形下：才能够应用数学模型外推来确信接触限度。第1类溶剂的接触限度应当依照不可观看到的反映水平(NOEL)并适用较大平安系数(即,10,000至100,000)来确定。检测和定量这些溶剂应当用现代的分析技术。

AcceptableexposurelevelsinthisguidelineforClass2solventswereestablishedbycalculationofPDEvaluesaccordingtotheproceduresforsettingexposurelimitsinpharmaceuticals(PharmacopeialForum,Nov-Dec1989),andthemethodadoptedbyIPCSforAssessingHumanHealthRiskofChemicals(EnvironmentalHealthCriteria170,WHO,1994).ThesemethodsaresimilartothoseusedbytheEnvironmentalHealthCriteriaandothers.ThemethodisoutlinedheretogiveabetterunderstandingoftheoriginofthePDEvalues.ItisnotnecessarytoperformthesecalculationsinordertousethePDEvaluestabulatedinSection4ofthisdocument.本指导原那么中第2类溶剂的可同意接触限度应当依照药品中设定接触限度的规定(药典论坛Nov-Dec1989)和IPCS中评估化学品对人类健康的风险(环境卫生标准170,WHO,1994)所采纳的方式计算PDE值的而取得的。这些方式与环境卫生标准和其他一些所用的方式相类似。简述这些方式是为了更好的明白得PDE值的由来。在利用本文件第四节表中的PDE值时没必要进行计算。PDEisderivedfromtheno-observed-effectlevel(NOEL),orthelowest-observedeffectlevel(LOEL)inthemostrelevantanimalstudyasfollows:PDE在对大多数相关动物的研究中从NOEL或可观看到的最低反映水平(LOEL)取得，如下：PDENOELxWeightAdjustmentPDENOELxWeightAdjustmentF1xF2xF3xF4xF5PDE=NOELx体重调整F1xF2xF3xF4xF5ThePDEisderivedp