原料中雜質(zhì)的控制課件

原料藥中雜質(zhì)的控制TheControlofImpuritiesinDrugSubstances楊仲元（廣州市藥品檢驗所）YangZhong-Yuan（GuangzhouMunicipalInstituteforDrugControl)TheFirstJointUSP-ChPConference15August2004Shanghai原料中雜質(zhì)的控制原料藥中雜質(zhì)的控制

TheControlofImpuritiesinDrugSubstances本部分將討論中國藥典對藥品雜質(zhì)分析的新的指導(dǎo)原則，包括ICH和其他藥典的有關(guān)要求。Thispartoftheprogramwillfocusonthenewguidelineofthe2005ChinesePharmacopoeiafortheanalysisofdrugimpurities,includingrelevantrequirementsofICHandotherpharmacopoeias原料中雜質(zhì)的控制原料藥中雜質(zhì)的控制

TheControlofImpuritiesinDrugSubstances本討論包括：ICH新原料藥中對雜質(zhì)的指導(dǎo)原則ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則原料中雜質(zhì)的控制原料藥中雜質(zhì)的控制

TheControlofImpuritiesinDrugSubstances雖然ICH指導(dǎo)原則是對申報新化學(xué)藥和新生物制品的技術(shù)要求，但經(jīng)ICH三方成員國制藥工業(yè)部門和藥品管理部門的協(xié)調(diào)，其原則切實可行，在保證藥品安全有效，藥品的生產(chǎn)按GMP的要求，起一定作用，逐步為各國采用。不僅作為申報新藥的要求，有的還作為修訂藥典正文的要求。原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstances

文件Q3A（R）為未曾在ICH三方注冊過的化學(xué)合成新原料藥申報時關(guān)于雜質(zhì)的指導(dǎo)原則Thisdocumentisintendedtoprovideguidanceforregistrationapplicationoncontentandqualificationofimpuritiesinnewdrugsubstancesproducedbychemicalsynthesesandnotpreviouslyregisteredinaregionormemberstate.原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstancesQ3A（R）雜質(zhì)分類ClassificationofImpurities有機(jī)雜質(zhì)OrganicImpurities無機(jī)雜質(zhì)InorganicImpurities殘留溶劑Residualsolvents原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstances其中有機(jī)雜質(zhì)包括起始原料、副產(chǎn)物、中間體、降解產(chǎn)物、試劑、配位體、催化劑?？梢允墙?jīng)鑒定或未鑒定的Theorganicimpuritiesincludestartingmaterials,by-products,intermediates,Degradationproducts,reagents,ligandsandcatalysts(identifiedorunidentified)原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstancesQ3A(R)關(guān)于有機(jī)雜質(zhì)的報告和控制中幾點說明Rationalforthereportingandcontroloforganicimpurities原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstances為便于理解，先介紹ICH雜質(zhì)指導(dǎo)原則中的幾個術(shù)語：ReportingThreshold:Alimitabove(>)whichanimpurityshouldbereported.報告限：系指一個限度，大于該限度的雜質(zhì)，應(yīng)該（在申報資料中）報告原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstancesIdentificationThreshold:Alimitabove(>)whichanimpurityshouldbeidentified.鑒定限：系指一個限度，大于該限度的雜質(zhì)，應(yīng)作鑒定原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstancesQualificationThreshold:Alimitabove(>)whichanimpurityshouldbequalified.論證限：系指一個限度，大于該限度的雜質(zhì)應(yīng)進(jìn)行論證原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstancesQualification:Theprocessofacquiringandevaluatingdatathatestablishesthebiologicalsafetyofanindividualimpurityoragivenimpurityprothelevel(s)specified.論證：系指對單個雜質(zhì)，或含規(guī)定量已知或未知雜質(zhì)的新原料藥獲得生物安全性數(shù)據(jù)并進(jìn)行評價的過程原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstancesTheapplicantshouldprovidearationaleforestablishingimpurityacceptancecriteriathatincludessafetyconsiderations.Thelevelofanyimpuritypresentinanewdrugsubstancethathasbeenadequatelytestedinsafetyand/orclinicalstudieswouldbeconsideredqualified.申報者應(yīng)提供設(shè)定雜質(zhì)限度的理由，包括安全性的理由。新原料藥中含有的一定量的任何雜質(zhì)，經(jīng)安全性試驗或臨床研究，即認(rèn)為是論證了的。原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstancesICH規(guī)定的雜質(zhì)報告限<鑒定限<論證限原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstances1.說明在合成、純化和貯存中該新原料藥實際和可能存在的雜質(zhì)Theapplicantshouldsummariestheactualandpotentialimpuritiesmostlikelytoariseduringsynthesis,purificationandstorage應(yīng)依據(jù)合成的化學(xué)反應(yīng)，可能帶來雜質(zhì)的原料，以及降解產(chǎn)物原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstances2.申報者應(yīng)敘述檢測新原料藥中雜質(zhì)的實驗研究Theapplicantshouldsummarizethelaboratorystudiesconductedtodetectimpuritiesinthenewdrugsubstance應(yīng)報告研究開發(fā)規(guī)模和商品規(guī)模批生產(chǎn)結(jié)果，穩(wěn)定性強(qiáng)制試驗的結(jié)果原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstances3.敘述按Q3A（R）附表1對新原料藥中大于鑒定限的實際存在雜質(zhì)進(jìn)行的結(jié)構(gòu)確證研究Thestudiesconductedtocharacterizethestructureofactualimpuritiespresentinthenewdrugsubstanceatalevelgreaterthantheidentificationthresholdgiveninattachment1shouldbedescribed原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstances按擬訂工藝的商業(yè)化生產(chǎn)任一批大于鑒定限的任何雜質(zhì)均應(yīng)做鑒定Anyimpurityatalevelgreaterthantheidentificationthresholdinanybatchmanufacturedbyproposedcommercialprocessshouldbeidentified原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstances在建議貯存條件下進(jìn)行的穩(wěn)定性試驗中發(fā)現(xiàn)的任何大于鑒定限的降解產(chǎn)物均應(yīng)做鑒定(鑒定不成功的，應(yīng)附相關(guān)資料）Anydegradationproductobservedinstabilitystudiesatrecommendedstorageconditionsatalevelgreaterthantheidentificationthresholdshouldbeidentified原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstances對不大于鑒定限的潛在的具顯著毒性或藥理作用的雜質(zhì)，應(yīng)研究分析方法Analyticalproceduresshouldbedevelopedforthosepotentialimpuritiesthatareexpectedtobeunusuallypotent,producingtoxicorpharmacologicaleffectsatalevelnotmorethantheidentificationthreshold原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstancesQ3A（R）對分析的要求在注冊申報中應(yīng)有成文的依據(jù)，說明分析方法經(jīng)過驗證，并適合于雜質(zhì)的檢出和定量Theregistrationapplicationshouldincludedocumentedevidencethattheanalyticalproceduresarevalidatedandsuitableforthedetectionandquantificationofimpurities原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstancesQ3A(R)對定量限的要求分析方法的定量限不能大于報告限Thequantitationlimitfortheanalyticalprocedureshouldbenotmorethanthereportingthreshold原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstancesQ3A（R）對雜質(zhì)對照品的要求分析方法中檢驗雜質(zhì)用的對照品，按其用途，應(yīng)經(jīng)評價并確定（結(jié)構(gòu)）Referencestandardsusedintheanalyticalprocedureforcontrolofimpuritiesshouldbeevaluatedandcharacterizedaccordingtotheirintendeduses原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstancesQ3A(R)對批雜質(zhì)含量報告要求用于臨床、安全、穩(wěn)定性研究的全部批，以及擬訂商業(yè)化生產(chǎn)代表性批的分析結(jié)果均應(yīng)提供在申報資料中，用數(shù)字結(jié)果，不用“符合”字樣Analyticalresultsshouldbeprovidedintheapplicationforallbatchesofthenewdrugsubstanceusedforclinical,safetyandstabilitytesting,aswellasforbatchesrepresentativeofproposedcommercialprocess原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstances大于報告限的雜質(zhì)和雜質(zhì)總量，應(yīng)連同分析方法進(jìn)行報告1.0%以下的結(jié)果,報告到小數(shù)點后2位,1.0%及以上的,報告到小數(shù)點后1位,結(jié)果應(yīng)按規(guī)定進(jìn)行修約雜質(zhì)應(yīng)用代碼或描述符號表示提高報告限應(yīng)經(jīng)說明,全部大于報告限的雜質(zhì)應(yīng)求和報告總量原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstancesQ3A（R）附表1限度表ATTACHMENT1Thresholds原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstances新原料藥的報告應(yīng)包括：批標(biāo)識和量、生產(chǎn)日期、生產(chǎn)場地、生產(chǎn)工藝、雜質(zhì)含量、批的利用、參照的分析方法Thereportshouldinclude:Batchidentityandsize,Dateofmanufacture,Siteofmanufacture,Manufacturingprocess,Impuritycontent(individualandtotal),Useofbatches,Referencetoanalyticalprocedureused原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstances關(guān)于質(zhì)量標(biāo)準(zhǔn)中列出的雜質(zhì)新原料藥的質(zhì)量標(biāo)準(zhǔn)中應(yīng)列出雜質(zhì)。穩(wěn)定性研究、化學(xué)研究開發(fā)、批的常規(guī)分析，可預(yù)測商業(yè)生產(chǎn)產(chǎn)品中的雜質(zhì)。質(zhì)量標(biāo)準(zhǔn)中列出的雜質(zhì)應(yīng)為擬訂商業(yè)生產(chǎn)工藝批中出現(xiàn)的雜質(zhì)Theselectionofimpuritiesinthenewdrugsubstancespecificationshouldbebasedontheimpurityfoundinbatchesmanufacturedbytheproposedcommercialprocess原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstancesQ3A（R）質(zhì)量標(biāo)準(zhǔn)中的指定雜質(zhì)新原料藥質(zhì)量標(biāo)準(zhǔn)中收載的具有規(guī)定限度的單個雜質(zhì)，在本指導(dǎo)原則中稱為指定雜質(zhì)，已知或未知Thoseindividualimpuritieswithspecificacceptancecriteriaincludedinthespecificationforthenewdrugsubstancearereferredtoas“specifiedimpurity”inthisguideline.Specifiedimpuritiescanbeidentifiedorunidentified.原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstancesQ3A（R）對非指定雜質(zhì)限度要求非指定雜質(zhì)的限度一般應(yīng)不大于鑒定限,并應(yīng)有總雜質(zhì)限度Ageneralacceptancecriterionofnotmorethantheidentificationthresholdforanyunspecifiedimpurityandanacceptancecriterionfortotalimpuritiesshouldbeincluded原料中雜質(zhì)的控制ICH新原料藥中的雜質(zhì)指導(dǎo)原則

ICHGuidelineonImpuritiesinNewDrugSubstancesQ3A（R）關(guān)于質(zhì)量標(biāo)準(zhǔn)中列出雜質(zhì)檢查項的要求，有機(jī)雜質(zhì)：每個指定已知雜質(zhì)，每個指定未知雜質(zhì)，非指定雜質(zhì)的限度不得大于鑒定限，總雜質(zhì)Fororganicimpuritiesthefollowingitemsshouldbelistedinthespecification:eachspecifiedidentifiedimpurity,eachspecifiedunidentifiedimpurity,anyunspecifiedimpuritywithanacceptancecriterionofnotmorethantheidentificationthreshold,totalimpurities原料中雜質(zhì)的控制ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用

CitationofICHimpurityguidelinebyforeignpharmacopoeiasICH指導(dǎo)原則為新化合物申報用，通過藥典協(xié)調(diào)，也被國際主要藥典引用TheICHguidelinesareapplicabletothenewchemicalentitiesforregistrationapplication.Afterharmonizationtherequirementsoftheguidelinesareadoptedbyinternationallyrecognizedpharmacopoeias,suchasUSP,EP,BP,etc原料中雜質(zhì)的控制ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用

CitationofICHimpurityguidelinebyforeignpharmacopoeias如：美國藥典關(guān)于法定品種中的雜質(zhì)USP27<1086>Impuritiesinofficialarticles正文原料藥純度檢查通常用下列方法（1）色譜純度檢查，加上非專屬含量測定，（2）用能反映純度的色譜法做含量測定，（3）對已知雜質(zhì)規(guī)定專屬檢查和限度，對已知雜質(zhì)的檢查通常用雜質(zhì)對照標(biāo)準(zhǔn)品Monographsonbulkpharmaceuticalchemicalsusuallyciteoneofthreetypeofpuritytests(1)achromatographicpuritytestcoupledwithanonspecificassay;(2)achromatographicpurity-indicatingmethodthatservesastheassay;or(3)aspecifictestandlimitforaknownimpurity,anapproachthatusuallyrequiresareferencestandardforthatimpurity原料中雜質(zhì)的控制ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用

CitationofICHimpurityguidelinebyforeignpharmacopoeiasUSP制劑正文雜質(zhì)檢查收載原則一般，USP原料正文中檢查的雜質(zhì)，該雜質(zhì)不再增加的，在其制劑中不再重復(fù)檢查Ingeneral,thispharmacopoeiadoesnotrepeatimpuritytestsinsubsequentpreparationswheretheseappearinthemonographofbulkpharmaceuticalchemicalsandwheretheseimpuritiesarenotexpectedtoincrease原料中雜質(zhì)的控制ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用

CitationofICHimpurityguidelinebyforeignpharmacopoeias相關(guān)術(shù)語：外來物質(zhì)（foreignsubstances)，毒性雜質(zhì)（toxicimpurities)，共存物質(zhì)（concomitantcomponents)，信號雜質(zhì)（signalimpurities)，普通雜質(zhì)（ordinaryimpurities)原料中雜質(zhì)的控制ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用

CitationofICHimpurityguidelinebyforeignpharmacopoeias除另有規(guī)定外，正文中用相對方法檢查普通雜質(zhì)，或非專屬檢查Unlessotherwisespecifiedinanindividualmonograph,estimationoftheamountandnumberofordinaryimpuritiesismadebyrelativemethodsratherthanbystrictcomparisontoindividualreferencestandards.Nonspecificdetectionofordinaryimpuritiesisalsoconsistentwiththisclassification原料中雜質(zhì)的控制ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用

CitationofICHimpurityguidelinebyforeignpharmacopoeiasUSP27普通雜質(zhì)的限度，一般為2.0%Thevalueof2.0%wasselectedasthegenerallimitonordinaryimpuritiesinmonographwheredocumentationdidnotsupportadoptionofothervalues原料中雜質(zhì)的控制ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用

CitationofICHimpurityguidelinebyforeignpharmacopoeias如正文設(shè)置共存物、信號雜質(zhì)和毒性雜質(zhì)限度，除另有規(guī)定外，這些不作為普通雜質(zhì)Whereamonographsetslimitsonconcomitantcompounds,signalimpurities,and/ortoxicimpurities,thesespeciesarenottobeincludedintheestimationofordinaryimpuritiesunlesssostatedintheindividualmonograph原料中雜質(zhì)的控制ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用

CitationofICHimpurityguidelinebyforeignpharmacopoeias有關(guān)物質(zhì)-與原料藥結(jié)構(gòu)有關(guān)，有關(guān)物質(zhì)可能是已知或未知的降解產(chǎn)物，或從生產(chǎn)工藝及貯存中產(chǎn)生Relatedsubstancesarestructurallyrelatedtoadrugsubstance.Thesesubstancesmaybeidentifiedorunidentifieddegradationproductsorimpuritiesarisingfromamanufacturingprocessorduringstorageofamaterial原料中雜質(zhì)的控制ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用

CitationofICHimpurityguidelinebyforeignpharmacopoeias工藝污染物-工藝污染物為已知或未知物質(zhì)（有關(guān)物質(zhì)和水分除外），包括試劑、無機(jī)物、原料和溶劑，可能從生產(chǎn)及處置過程中引入Processcontaminantsareidentifiedorunidentifiedsubstances(excludingrelatedsubstancesandwater),includingreagents,inorganics,rawmaterials,andsolvents.Thesesubstancesmaybeintroducedduringmanufacturingorhandlingprocedures原料中雜質(zhì)的控制ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用

CitationofICHimpurityguidelinebyforeignpharmacopoeiasUSP27凡例（GeneralNotices)對其他雜質(zhì)的規(guī)定法定原料藥中出現(xiàn)（正文）未標(biāo)明的雜質(zhì)，其量為0.1%或以上時，且是由于變更工藝或其他可說明原因產(chǎn)生的，檢測方法應(yīng)報USP，申請收載入正文，否則應(yīng)在分析證其他雜質(zhì)項下標(biāo)明，并注明量。其他雜質(zhì)加上正文檢出的雜質(zhì)總量不得過2.0%原料中雜質(zhì)的控制ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用

CitationofICHimpurityguidelinebyforeignpharmacopoeiasThepresenceofanyunlabeledimpurityinanofficialsubstanceisavariancefromthestandardifthecontentis0.1%orgreater.Testssuitablefordetectionandquantitatingunlabeledimpurities,whenpresentastheresultofprocesschangeorotheridentifiable,consistentoccurrence,shallbesubmittedtotheUSPforinclusionintheindividualmonograph.Otherwise,theimpurityshallbeidentified,preferablybyname,andtheamountlistedundertheheadingOtherImpuritiesinthelabeling(COA)oftheofficialsubstance.Thesumofallotherimpuritiescombinedwiththemonograph-detectedimpuritiesdoesnotexceed2.0%,unlessotherwisestatedinthemonograph原料中雜質(zhì)的控制ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用

CitationofICHimpurityguidelinebyforeignpharmacopoeiasUSP關(guān)于修訂USP-NF申報要求指導(dǎo)原則（征求意見稿）中，非復(fù)雜有效成分中雜質(zhì)檢查新要求Newrequirementfortestingofimpuritiesinthenon-complexactivesSeeUSPGuidelineforSubmittingRequestsforRevisiontotheUSP-NF原料中雜質(zhì)的控制ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用

CitationofICHimpurityguidelinebyforeignpharmacopoeias對于新的原料藥正文（Newmonographforadrugsubstance),雜質(zhì)檢查應(yīng)對全部指定雜質(zhì)規(guī)定限度，所有非指定雜質(zhì)的限度均為0.10%Theimpuritytestofadrugsubstancemonographisintendedtolimitallspecifiedimpurities,withafurtherlimitof0.10%forallunspecifiedimpurities原料中雜質(zhì)的控制ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用

CitationofICHimpurityguidelinebyforeignpharmacopoeiasUSP新的正文（newmonographs)的雜質(zhì)將按表中的命名法Fornewmonographs,USPwillfollownomenclatureandapproachesshowninthetable原料中雜質(zhì)的控制ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用

CitationofICHimpurityguidelinebyforeignpharmacopoeias原料中雜質(zhì)的控制ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用

CitationofICHimpurityguidelinebyforeignpharmacopoeiasUSP原料藥正文僅收載檢查實際存在的，而不是理論存在雜質(zhì)的方法USPdrugsubstancemonographswillincludeonlyproceduresthatcontrolactual,nottheoretical,impurities原料中雜質(zhì)的控制ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用

CitationofICHimpurityguidelinebyforeignpharmacopoeias由于合成路線不同，產(chǎn)生不同的雜質(zhì)，需用不同方法檢查，此情況下，在有關(guān)文件上（如COA）應(yīng)說明附加的可行方法Wheredifferentroutesofsynthesisyielddifferentimpurityprofiles,differentimpurityproceduremaybeneeded.Inthiscase,theadditionalapplicableprocedureshouldbeincludedinthelabeling原料中雜質(zhì)的控制ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用

CitationofICHimpurityguidelinebyforeignpharmacopoeias如果申報資料中有FDA未評價過的已知毒性的雜質(zhì)，則在申報資料中應(yīng)包括毒性數(shù)據(jù)IftherequestforrevisiondescribesanimpurityofknowntoxicitythathasnotpreviouslybeenevaluatedbytheFDA,toxicitydatashouldbeincludedintheRequestforRevision原料中雜質(zhì)的控制ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用

CitationofICHimpurityguidelinebyforeignpharmacopoeias對有機(jī)雜質(zhì)（fororganicimpurities)色譜識別和定量用外標(biāo)法Toidentifyandquantifyimpurities,anexternalratherthananinternalstandardispreferred.Theuseofexternalstandardsispreferable,asinternalstandardsmayobscureotherimpurities原料中雜質(zhì)的控制ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用

CitationofICHimpurityguidelinebyforeignpharmacopoeias有機(jī)雜質(zhì)用原料藥對照標(biāo)準(zhǔn)品或外標(biāo)雜質(zhì)對照品比對定量。盡可能用需要限量的指定雜質(zhì)的USP對照標(biāo)準(zhǔn)品對已知雜質(zhì)進(jìn)行定量Thequantificationoforganicimpuritiesshouldbedonebycomparisontoeitherthedrugsubstancereferencestandardortoanexternalimpurityreferencestandard.Wherepossible,officialUSPReferenceStandardsofspecifiedimpuritiestobelimitedarethebestoptionwhenquantifyingidentifiedimpurities原料中雜質(zhì)的控制ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用

CitationofICHimpurityguidelinebyforeignpharmacopoeias雜質(zhì)的限度應(yīng)符合ICHQ3A的要求，并對每個指定雜質(zhì)規(guī)定限度，并在必要時規(guī)定非指定雜質(zhì)的限度，總雜質(zhì)限度，報告限度，雜質(zhì)的限度應(yīng)適應(yīng)于貨架效期AcceptancecriteriashouldcomplywithICHQ3Aandshouldbeprovidedforeachspecifiedimpurity,anyunspecifiedimpurityasappropriate,totalimpurities,andreportthresholds.Theseacceptancecriteriaareapplicablethroughoutshelf-life原料中雜質(zhì)的控制ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用

CitationofICHimpurityguidelinebyforeignpharmacopoeias英國藥典2003版補(bǔ)充附錄“雜質(zhì)檢查”，其中的有關(guān)物質(zhì)ThesupplementarychaptersofBP2003,A.ControlofImpuritiesrelatedsubstances原料中雜質(zhì)的控制ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用

CitationofICHimpurityguidelinebyforeignpharmacopoeias起草正文時，要求企業(yè)提供雜質(zhì)的性質(zhì)、雜質(zhì)存在的理由、按GMP生產(chǎn)條件下雜質(zhì)的量，貯存期變化情況，與原料藥本身有關(guān)的雜質(zhì)毒性說明Whenpreparationofamonographisinitiatedthemanufacturerisaskedtoprovideinformationconcerningthenatureofsuchimpurities,thereasonfortheirpresence,theamountsthatmaybeencounteredinmaterialpreparedunderconditionsofGMPandthemannerinwhichproportionsmayvaryonstorage,togetherwithanindicationofthetoxicityofanyimpuritiesinrelationtothatofthesubstanceitself原料中雜質(zhì)的控制ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用

CitationofICHimpurityguidelinebyforeignpharmacopoeias生產(chǎn)工藝或降解產(chǎn)生的特殊雜質(zhì)，根據(jù)毒性等理由，需規(guī)定限度的，用專屬檢查Aspecifictestisincludedwhereaparticularimpurityarisingfromthemanufacturingprocessorfromdegradationneedstobelimitedongroundoftoxicityorforanotherspecialreason原料中雜質(zhì)的控制ICH關(guān)于雜質(zhì)指導(dǎo)原則在國外藥典中的引用

CitationofICHimpurityguidelinebyforeignpharmacopoeias該補(bǔ)充附錄說明了，與生產(chǎn)企業(yè)有關(guān)的指導(dǎo)原則，見ICHQ3A和Q3BOtherguidancerelatedtomanufacturersisprovidedin,forexample,ICHguidelinesonimpuritiesinnewdrugsubstances(Q3A)andnewdrugpreparations(Q3B)

原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities

本指導(dǎo)原則為參考人用藥品注冊申報技術(shù)要求國際協(xié)調(diào)會，根據(jù)中國的具體情況起草的2005年版中國藥典新增附錄ThisisanewguidelinetobeincludedintheChinesePharmacopoeia2005,draftedonthebasisofICHrelevantrequirementsandrecentprogressinpharmaceuticalresearchanddrugstandarddevelopmentinChina原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities本附錄為藥品質(zhì)量標(biāo)準(zhǔn)中化學(xué)合成或半合成的有機(jī)原料藥及其制劑雜質(zhì)分析的指導(dǎo)原則,供藥品研究、生產(chǎn)、質(zhì)量標(biāo)準(zhǔn)起草和修訂參考

Thisistheguidelineontheanalysisofimpuritiesinsynthesizedorsemi-synthesizedorganicdrugsubstancesandtheirpreparationsfordrugresearch,pharmaceuticalmanufacturing,andrevisionofdrugstandards原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities任何影響藥品純度的物質(zhì)均稱為雜質(zhì)

Anysubstancethataffectsthepurityofadrugisconsideredasanimpurity原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities藥品質(zhì)量標(biāo)準(zhǔn)中的雜質(zhì)系指，在按照經(jīng)國家有關(guān)藥品監(jiān)督管理部門依法審查批準(zhǔn)的規(guī)定工藝和規(guī)定原輔料生產(chǎn)的藥品中，由其生產(chǎn)工藝或原輔料帶入的雜質(zhì)，或經(jīng)穩(wěn)定性試驗確證的在貯存過程中產(chǎn)生的降解產(chǎn)物

Impuritieslistedinadrugstandardmaybeintroducedfromproductionprocess,startingmaterialsorexcipientsofthedrugproducedwithspecifiedprocessandmaterialsofficiallyapprovedbythecompetentdrugregulatoryauthority.Theimpuritiesmaybethedegradationproductsarisinginthestorageperiod,thatisvalidatedbystabilitytesting原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities藥品質(zhì)量標(biāo)準(zhǔn)中的雜質(zhì)不包括變更生產(chǎn)工藝或變更原輔料而產(chǎn)生的新的雜質(zhì)，也不包括摻入或污染的外來物質(zhì)

Thenewimpuritiescausedbychangeofproductionprocessormaterials,orfromforeignsubstancesadulteratedorcontaminatedarenotincludedintheimpuritiesofthedrugstandard原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities藥品生產(chǎn)企業(yè)變更生產(chǎn)工藝或原輔料，并因由此帶進(jìn)新的雜質(zhì)對原質(zhì)量標(biāo)準(zhǔn)的修訂，均應(yīng)依法向有關(guān)藥品監(jiān)督管理部門申報批準(zhǔn)

Applicationforchanginginproductionprocessormaterials,andrequestingforrevisionofthedrugstandardduetonewimpuritiescausedbythechangingshallbesubmittedtothecompetentauthorityforapprovalaccordingtothelaw原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities藥品中不得摻入或污染藥品或其組分以外的外來物質(zhì)。對于假劣藥品，必要時應(yīng)根據(jù)各該具體情況，采用非法定分析方法予以檢測

Drugsshallnotbeadulteratedorcontaminatedbyforeignsubstances.Non-officialmethodscanbeadoptedtomonitorthecounterfeitdrugs原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities

1.雜質(zhì)的分類及其在藥品質(zhì)量標(biāo)準(zhǔn)中的項目名稱

Theclassificationofimpuritiesandtheirtestingitemtitlesinthedrugstandards原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities按化學(xué)類別和特性，雜質(zhì)可分為：有機(jī)雜質(zhì)、無機(jī)雜質(zhì)、有機(jī)揮發(fā)性雜質(zhì)

Accordingtothechemicalcategoryandcharacteristics,impuritiescouldbeclassifiedasorganicimpurities,inorganicimpuritiesandorganicvolatileimpurities原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities按其來源，雜質(zhì)可分為：有關(guān)物質(zhì),其他雜質(zhì)和外來物質(zhì)等

Accordingtothesource,impuritiescouldbeclassifiedasrelatedsubstances(includingdegradationproducts),otherimpurities,foreignsubstances,etc.原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities按結(jié)構(gòu)關(guān)系，雜質(zhì)又可分為：其他甾體、其他生物堿、幾何異構(gòu)體、光學(xué)異構(gòu)體等

Impuritiescouldbeclassifiedasothersteroids,otheralkaloids,geometricisomers,opticalisomers,etcbaseduponthestructurerelationship原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities按其毒性，雜質(zhì)又可分為毒性雜質(zhì)和普通雜質(zhì)等。普通雜質(zhì)即為在存在量下無顯著不良生理作用的雜質(zhì)，而毒性雜質(zhì)為具強(qiáng)烈不良生理作用的雜質(zhì)

Impuritiescouldbeclassifiedastoxicandordinaryimpuritiesaccordingtothetoxicity原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities由于雜質(zhì)的分類方法甚多，所以，藥品質(zhì)量標(biāo)準(zhǔn)中檢查項下雜質(zhì)的項目名稱，應(yīng)根據(jù)國家藥典會編寫的《國家藥品標(biāo)準(zhǔn)工作手冊》的要求進(jìn)行規(guī)范TheitemtitleforaimpurityinadrugspecificationshallbenormalizedbasedontherequirementsoftheManualforRevisingtoNationalDrugStandardspublishedbytheCommissionoftheChinesePharmacopoeia原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities2.質(zhì)量標(biāo)準(zhǔn)中雜質(zhì)檢查項目的確定Selectionofimpuritytestingitemsfordrugstandard新原料藥和新制劑中的雜質(zhì)，應(yīng)按國家有關(guān)新藥申報要求進(jìn)行研究StudiesonimpuritiesinnewdrugsubstancesandnewpreparationsshallbeconductedinaccordwiththerelevantrequirementsforregistrationapplicationofnewdrugsinChina原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities也可參考ICH（人用藥品注冊技術(shù)要求國際協(xié)調(diào)會）的文本Q3A（新原料藥中的雜質(zhì)）和Q3B（新制劑中的雜質(zhì)）進(jìn)行研究，并對雜質(zhì)和降解產(chǎn)物進(jìn)行安全性評價

ThestudiesonimpuritiesinnewdrugsubstancesandnewpreparationscouldbeperformedbyreferringtotheICHguidelinesQ3AorQ3B,too.Thesafetyevaluationforimpuritiesanddegradationproductsshouldbemade原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities新藥研制部門對在合成、純化和貯存中實際存在的雜質(zhì)和潛在的雜質(zhì)，應(yīng)采用有效的分離分析方法進(jìn)行檢測

Effectiveanalyticalmethodofseparationshallbeadoptedbythenewdrugresearchinstitutionsfordeterminingactuallypresentandpotentialimpuritiesarisingfromsynthesis,purificationandstorage原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities對于表觀含量在0.1%及其以上的雜質(zhì)，以及表觀含量在0.1%以下的具強(qiáng)烈藥理作用的雜質(zhì)或毒性雜質(zhì)，予以定性，或確證其結(jié)構(gòu)

Characterizationorstructureconfirmationshallbecarriedoutfortheimpuritythatitsapparentlevelis0.1%orabove,andforthetoxicimpurityorimpuritywithsignificantpharmacologicaleffectthatitsapparentlevelisunder0.1%原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities對在穩(wěn)定性試驗中出現(xiàn)的降解產(chǎn)物，也應(yīng)按上述要求進(jìn)行研究Thedegradationproductsfoundinthestabilitytesting(accelerateandlongterm)shallbestudiedaccordingtotheaboverequirement原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities新藥質(zhì)量標(biāo)準(zhǔn)中的雜質(zhì)檢查項目應(yīng)包括經(jīng)研究和穩(wěn)定性考察檢出的，并在批量生產(chǎn)中出現(xiàn)的雜質(zhì)和降解產(chǎn)物，并包括相應(yīng)的限度

Impuritytestingitemsinthenewdrugstandardshouldincludetheimpuritiesanddegradationproductsdetectedinthequalitystudyandstabilitytesting,andappearedinthebatchesproducedinanindustrialscale.Thecorrespondinglimitshallbeprovided原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities除降解產(chǎn)物和毒性雜質(zhì)外，在原料中已控制的雜質(zhì)，在制劑中一般不再控制

Impuritiescontrolledinthedrugsubstancespecificationwillnotbecontrolledinitspreparationspecificationexceptdegradationproductsandtoxicimpurities原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities原料藥和制劑中的無機(jī)雜質(zhì)，應(yīng)根據(jù)其生產(chǎn)工藝、起始原料情況確定檢查項目，但對于毒性無機(jī)雜質(zhì)，應(yīng)在質(zhì)量標(biāo)準(zhǔn)中規(guī)定其檢查項

Inorganicimpuritytestingitemsfordrugsubstancesandpreparationsshallbeselectedaccordingtothemanufacturingprocessandstartingmaterials.Testingitemsfortoxicinorganicimpuritiesshallbeestablishedforthedrugstandard原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities在仿制藥品的研制和生產(chǎn)中，如發(fā)現(xiàn)其雜質(zhì)模式與其原始開發(fā)藥品的不同，或與已有法定質(zhì)量標(biāo)準(zhǔn)規(guī)定不同，需增加新的雜質(zhì)檢查項目的，應(yīng)按上述方法進(jìn)行研究，申報新的質(zhì)量標(biāo)準(zhǔn)或?qū)υ|(zhì)量標(biāo)準(zhǔn)進(jìn)行修訂，并報有關(guān)藥品監(jiān)督管理部門審批。Wheretheimpurityprointhestudyorproductionofagenericdrugisdifferentfromthatoftheinnovatedoneorfromtheexistingofficialstandard,thenewimpuritiesshallbestudiedaccordingtotheaboverequirements,andanapplicationforrevisingtotheoriginalstandardorestablishinganewstandardshallbesubmittedtotherelevantdrugregulatoryauthorityforreviewandapproval原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities共存的異構(gòu)體和抗生素多組分一般不作為雜質(zhì)檢查項目，作為共存物質(zhì)，必要時，在質(zhì)量標(biāo)準(zhǔn)中規(guī)定其比例，以保證生產(chǎn)用的原料藥與申報注冊時的一致性。但當(dāng)共存物質(zhì)為毒性雜質(zhì)時，該物質(zhì)就不再認(rèn)為是共存物質(zhì)Theconcomitantisomersandtheantibioticsmulti-componentsaregenerallynotthetestingitemsofimpurities.Forconcomitants,theirproportionmaybespecifiedinthespecificationtoensuretheconsistencyofdrugsubstancesusedforproductionandthoseforregistrationapplication.Thetoxicconcomitantswillbeconsideredasimpuritiesinsteadofconcomitants原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities單一對映體藥物，其可能共存的其他對映體，應(yīng)作為雜質(zhì)檢查。消旋體藥物，當(dāng)已有其單一對映體藥物的法定質(zhì)量標(biāo)準(zhǔn)時，應(yīng)在該消旋體藥物的質(zhì)量標(biāo)準(zhǔn)中設(shè)旋光度檢查項目

Wherethedrugisasingleenantiomer,otherco-existentenantiomersshallbeimpurities.Wherethereisanofficialstandardforasingleenantiomerdrug,thetestingitemofopticalrotationshouldbesetforthestandardofthecorrespondingracemicdrug原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities3.雜質(zhì)檢查分析方法和雜質(zhì)的限度

Analyticalmethodsforimpuritytestingandimpuritylimit雜質(zhì)檢查分析方法應(yīng)專屬、靈敏

Theanalyticalmethodsforimpuritytestingshouldbespecificandsensitive原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities雜質(zhì)檢查應(yīng)盡量采用現(xiàn)代分離分析手段，主成分與雜質(zhì)和降解產(chǎn)物均能分開，其檢測限應(yīng)滿足限度檢查的要求

Modernanalyticalmethodsforseparationshouldbeusedforimpuritytesting.Thesubstanceshouldbewellresolvedwithimpuritiesanddegradationproducts,Thedetectionlimitsshallmeettherequirementforthelimittests原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities對于需作定量檢查的雜質(zhì)，方法的定量限應(yīng)滿足相應(yīng)的要求。Fortheimpuritiestobequantified,thequantificationlimitshallmeettheintendedrequirement原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities雜質(zhì)檢查分析方法的建立應(yīng)按本藥典的要求作方法驗證。在研究時，應(yīng)采用幾種不同的分離分析方法或不同測試條件

以便比對結(jié)果，選擇較佳的方法作為質(zhì)量標(biāo)準(zhǔn)的檢查方法

TheanalyticalmethodsforimpuritytestingshouldbevalidatedaccordingtotherequirementsoftheChP.Differentmethodsmaybeadoptedintheresearchstage,resultsshouldbecomparedtoselectasuitablemethodasthecompendiummethod原料中雜質(zhì)的控制中國藥典(2005)藥品雜質(zhì)分析指導(dǎo)原則

ChP(2005)GuidelineonAnalysisofDrugImpurities雜質(zhì)檢查分析方法的建立，應(yīng)考慮普遍適用性，所用的儀器和試材應(yīng)容易獲得。對于特殊試材，應(yīng)在質(zhì)量標(biāo)準(zhǔn)中寫明。Thesuitabilityofanestablishedmethodshouldbeconsidered,equipm