INTERNATIONALCONFERENCEONHARMONISATIONOFTECHNICALREQUIREMENTSFORREGISTRATIONOFPHARMACEUTICALSFORHUMANUSEICHHarmonisedTripartitESuidelineIMPURITIESINNEWDRUGSUBSTANCESQ3A(R2)CurrentStep4version

dated25October2006ThisGuidelinehasbeendevelopedbytheappropriateICHExpertWorkingGroupandhasbeensubjecttoconsultationbytheregulatoryparties,inaccordancewiththeICHProcess.AtStep4oftheProcessthefinaldraftisrecommendedforadoptiontotheregulatorybodiesoftheEuropeanUnion,JapanandUSA.Q3A(R2)DocumentHistoryFirstCodificationHistoryDateNewCodificationNovember2005Q3ApprovalbytheSteeringCommitteeunderStep2andreleaseforpublicconsultation.15March1994Q3AQ3AApprovalbytheSteeringCommitteeunderStep4andrecommendationforadoptiontothethreeICHregulatorybodies.Q3wasrenamedQ3A.30March1995Q3AQ3A(R)ApprovalbytheSteeringCommitteeofthefirstRevisionunderStep2andreleaseforpublicconsultation.7October1999Q3A(R1)Q3A(R)ApprovalbytheSteeringCommitteeofthefirstRevisionunderStep4andrecommendationforadoptiontothethreeICHregulatorybodies.6February2002Q3A(R1)CurrentStep4versionQ3A(R2)ApprovalbytheSteeringCommitteeoftherevisionoftheAttachment2directlyunderStep4withoutfurtherpublicconsultation.25October2006Q3A(R2)ImpuritiesInNewDrugSubstancesICHHarmonisedTripartiteGuidelineHavingreachedStep4oftheICHProcessattheICHSteeringCommitteemeeting

on7February2002,thisguidelineisrecommendedfor

adoptiontothethreeregulatorypartiestoICH.Attachment2hasbeenrevisedon25October2006.tableofcontentsTOC\o"1-5"\h\zPREAMBLE4CLASSIFICATIONOFIMPURITIES4....RATIONALEFORTHEREPORTINGANDCONTROLIMPURITIES6OrganicImpurities6InorganicImpurities7Solvents7ANALYTICALPROCEDURES8....REPORTINGIMPURITYCONTENTOFBATCHES9LISTINGOFIMPURITIESINSPECIFICATIONS.1.1....QUALIFICATIONOFIMPURITIES13GLOSSARY.15181922ImpuritiesInNewDrugSubstances

新原料藥中的雜質PREAMBLE序言Thisdocumentisintendedtoprovideguidanceforregistrationapplicationsonthecontentandqualificationofimpuritiesinnewdrugsubstancesproducedbychemicalsynthesesandnotpreviouslyregisteredinaregionormemberstate.Itisnotintendedtoapplytonewdrugsubstancesusedduringtheclinicalresearchstageofdevelopment.Thefollowingtypesofdrugsubstancesarenotcoveredinthisguideline:biological/biotechnological,peptide,oligonucleotide,radiopharmaceutical,fermentationproductandsemi-syntheticproductsderivedtherefrom,herbalproducts,andcrudeproductsofanimalorplantorigin.本文件旨在為那些尚未在任何地區或成員國注冊的化學合成的新原料藥在注冊時，對其雜質的含量和界定的申報提供指導。本報導原則不適用于臨床研究期間所用的新原料藥，不涵蓋生物及生物技術產品、肽、寡聚核甘酸、放射性藥物、發酵和半合成產品、草藥以及來源于動植物的粗制品。Impuritiesinnewdrugsubstancesareaddressedfromtwoperspectives:新原料藥中的雜質分兩個方面闡述：ChemistryAspectsincludeclassificationandidentificationofimpurities,reportgeneration,listingofimpuritiesinspecifications,andabriefdiscussionofanalyticalprocedures;and化學方面：包括對雜質的分類和鑒定、報告生成、規范中雜質的檢查項目以及對分析方法的簡要討論。SafetyAspectsincludespecificguidanceforqualifyingthoseimpuritiesthatwerenotpresent,orwerepresentatsubstantiallylowerlevels,inbatchesofanewdrugsubstanceusedinsafetyandclinicalstudies.安全性方面：對用于安全性研究和臨床研究的新原料藥批次中不存在或含量很低的那些雜質的界定的指南。classificationofimpurities質的分類Impuritiescanbeclassifiedintothefollowingcategories:雜質可分為下歹！J類型:Organicimpurities(process-anddrug-related)有機雜質(與工藝和藥物有關的)Inorganicimpurities無機雜質Residualsolvents殘留溶劑Organicimpuritiescanariseduringthemanufacturingprocessand/orstorageofthenewdrugsubstance.Theycanbeidentifiedorunidentified,volatileornon-volatile,andinclude:有機雜質可能會在新原料藥的生產過程和（或）儲存期間有所增加。這些雜質可能是已鑒定的或者是未鑒定的、揮發性的或者非揮發性的。它包括：Startingmaterials起始物By-products副產物Intermediates中間體Degradationproducts降解產物Reagents,ligandsandcatalyst虱齊1J、配位體、催化齊1JInorganicimpuritiescanresultfromthemanufacturingprocess.Theyarenormallyknownandidentifiedandinclude:無機雜質可能來源于生產過程，它們一般是已知的和已鑒定的。包括：Reagents,ligandsandcatalysts試齊1J、配位體、催化齊1JHeavymetalsorotherresidualmetals重金屬或其他殘留金屬Inorganicsalts無機鹽Othermaterials（e.g.,filteraids,charcoal）其他物質（例如：過濾介質、活性炭等）Solventsareinorganicororganicliquidsusedasvehiclesforthepreparationofsolutionsorsuspensionsinthesynthesisofanewdrugsubstance.Sincethesearegenerallyofknowntoxicity,theselectionofappropriatecontrolsiseasilyaccomplished（seeICHGuidelineQ3ConResidualSolvents）.溶劑是在新原料藥合成過程中用于制備溶液或混懸液的有機或無機液體，由于它們一般具有已知毒性，故容易選擇控制方法（見ICH指導原則Q3c殘留溶劑項下）。Excludedfromthisdocumentare:（1）extraneouscontaminantsthatshouldnotoccurinnewdrugsubstancesandaremoreappropriatelyaddressedasGoodManufacturingPractice（GMP）issues,（2）polymorphicforms,and（3）enantiomericimpurities.不包括在本文件中的雜質為：（1）外源性污染物（不應該存在于新原料藥中，可以用GMP來控制）；（2）多晶型；（3）對映體雜質。RATIONALEFORTHEREPORTINGANDCONTROLOFIMPURITIES雜質報告和控制的說明OrganicImpurities有機雜質Theapplicantshouldsummarisetheactualandpotentialimpuritiesmostlikelytoariseduringthesynthesis,purification,andstorageofthenewdrugsubstance.Thissummaryshouldbebasedonsoundscientificappraisalofthechemicalreactionsinvolvedinthesynthesis,impuritiesassociatedwithrawmaterialsthatcouldcontributetotheimpurityprofileofthenewdrugsubstance,andpossibledegradationproducts.Thisdiscussioncanbelimitedtothoseimpuritiesthatmightreasonablybeexpectedbasedonknowledgeofthechemicalreactionsandconditionsinvolved.申報者應對新原料藥在合成、精制和儲存過程中最可能產生的那些實際存在的和潛在的雜質進行綜述。該描述應建立在對合成所涉及的化學反應、由原材料引入的雜質及可能的降解產物進行合理地、科學地評估的基礎上。可以局限于根據化學反應以及相關條件下可能會產生的雜質進行討論。Inaddition,theapplicantshouldsummarisethelaboratorystudiesconductedtodetectimpuritiesinthenewdrugsubstance.Thissummaryshouldincludetestresultsofbatchesmanufacturedduringthedevelopmentprocessandbatchesfromtheproposedcommercialprocess,aswellastheresultsofstresstesting(seeICHGuidelineQ1AonStability)usedtoidentifypotentialimpuritiesarisingduringstorage.Theimpurityprofileofthedrugsubstancebatchesintendedformarketingshouldbecomparedwiththoseusedindevelopment,andanydifferencesdiscussed.此外，申報者還應對新原料藥中雜質檢測的實驗室研究工作進行綜述，其內容包括對研制期間和模擬上市的所有批次產品的試驗結果、以及為鑒定在儲存期間可能產生的潛在雜質而進行強力破壞試驗的結果(見ICH指導原則Q1A穩定性項下)。同時應對那些模擬上市的原料批次中的雜質概況和用于研制開發過程的原料批次中的雜質概況進行比較，任何不同之處均應加以討論。Thestudiesconductedtocharacterisethestructureofactualimpuritiespresentinthenewdrugsubstanceatalevelgreaterthan(>)theidentificationthresholdgiveninAttachment1(e.g.,calculatedusingtheresponsefactorofthedrugsubstance)shouldbedescribed.Notethatanyimpurityatalevelgreaterthan(>)theidentificationthresholdinanybatchmanufacturedbytheproposedcommercialprocessshouldbeidentified.Inaddition,anydegradationproductobservedinstabilitystudiesatrecommendedstorageconditionsatalevelgreaterthan(>)theidentificationthresholdshouldbeidentified.Whenidentificationofanimpurityisnotfeasible,asummaryofthelaboratorystudiesdemonstratingtheunsuccessfuleffortshouldbeincludedintheapplication.Whereattemptshavebeenmadetoidentifyimpuritiespresentatlevelsofnotmorethan（＜）theidentificationthresholds,itisusefulalsotoreporttheresultsofthesestudies.申報資料中還應對那些在新原料藥中實際存在的、含量大于（＞）附錄1中鑒定閾值的雜質（例如：以原料藥的響應因子計算）的結構特征進行描述。應該注意，在模擬上市生產的批次中，所有出現的大于（＞）鑒定閾值的雜質應予鑒定；也應同樣鑒定在推薦的放置條件下的穩定性研究中發現大于（＞）鑒定閾值的降解產物；當某個雜質無法鑒定時，中報資料中應包括對該雜質所進行的不成功的試驗研究的概述。如果已嘗試過鑒定含量不大于（0鑒定閾值的雜質，那么把這些研究結果也報告進去是很有用的。Identificationofimpuritiespresentatanapparentlevelofnotmorethan(<)theidentificationthresholdisgenerallynotconsiderednecessary.However,analyticalproceduresshouldbedevelopedforthosepotentialimpuritiesthatareexpectedtobeunusuallypotent,producingtoxicorpharmacologicaleffectsatalevelnotmorethan(_)theidentificationthreshold.Allimpuritiesshouldbequalifiedasdescribedlaterinthisguideline.通常沒有必要對含量在閾值以下(0的雜質進行鑒定。然而，對那些含量不大于(0閾值但可能產生不尋常功效或毒性藥理作用的潛在雜質，仍應建立分析方法。所有雜質均應按照本指導原則后續章節中的要求來界定。InorganicImpurities無機雜質Inorganicimpuritiesarenormallydetectedandquantifiedusingpharmacopoeialorotherappropriateprocedures.Carry-overofcatalyststothenewdrugsubstanceshouldbeevaluatedduringdevelopment.Theneedforinclusionorexclusionofinorganicimpuritiesinthenewdrugsubstancespecificationshouldbediscussed.Acceptancecriteriashouldbebasedonpharmacopoeialstandardsorknownsafetydata.無機雜質通常按藥典或其他適當的方法來檢測和定量。在新藥的研制過程中應對遺留在新原料藥中的催化劑進行評估。在新原料藥規范中是否收載無機雜質檢查項目，應進行討論。認可標準應根據藥典標準或已知的安全性數據來制定。Solvents容劑ThecontrolofresiduesofthesolventsusedinthemanufacturingprocessforthenewdrugsubstanceshouldbediscussedandpresentedaccordingtotheICHQ3CGuidelineforResidualSolvents.應按ICHQ3C殘留溶劑”指導原則的要求，對新原料藥生產過程中所用的溶劑的殘留量的控制進行討論和申報。ANALYTICALPROCEDURES方法Theregistrationapplicationshouldincludedocumentedevidencethattheanalyticalproceduresarevalidatedandsuitableforthedetectionandquantificationofimpurities(seeICHQ2AandQ2BGuidelinesforAnalyticalValidation).Technicalfactors(e.g.,manufacturingcapabilityandcontrolmethodology)canbeconsideredaspartofthejustificationforselectionofalternativethresholdsbasedonmanufacturingexperiencewiththeproposedcommercialprocess.Theuseoftwodecimalplacesforthresholds(SeeAttachment1)doesnotnecessarilyreflecttheprecisionoftheanalyticalprocedureusedforroutinequalitycontrolpurposes.Thus,theuseoflowerprecisiontechniques(e.g.,thin-layerchromatography)canbeacceptablewherejustifiedandappropriatelyvalidated.Differencesintheanalyticalproceduresusedduringdevelopmentandthoseproposedforthecommercialproductshouldbediscussedintheregistrationapplication.注冊申請中應提供書面文件，證明分析方法是經過論證并適用于雜質的檢測和定量(見ICHQ2A及Q2B分析方法論證指導原則項下)，技術因素(如生產能力與質控方法)可用于說明為什么在擬上市產品中采用其他的閾值。閾值采用兩位小數(見附錄1)并不代表常規質量控制中分析方法的精度。因此，只需經過驗證和論證，可以使用較低精度的技術(如薄層色譜法)。如果研發中所采用的分析方法和準備上市產品的分析方法不同，在中報資料中應予以討論。Thequantitationlimitfortheanalyticalprocedureshouldbenotmorethan(<)thereportingthreshold.分析方法的定量限度應不大于(當報告閾值。Organicimpuritylevelscanbemeasuredbyavarietyoftechniques,includingthosethatcompareananalyticalresponseforanimpuritytothatofanappropriatereferencestandardortotheresponseofthenewdrugsubstanceitself.Referencestandardsusedintheanalyticalproceduresforcontrolofimpuritiesshouldbeevaluatedandcharacterisedaccordingtotheirintendeduses.Thedrugsubstancecanbeusedasastandardtoestimatethelevelsofimpurities.Incaseswheretheresponsefactorsofthedrugsubstanceandtherelevantimpurityarenotclose,thispracticecanstillbeappropriate,providedacorrectionfactorisappliedortheimpuritiesare,infact,beingoverestimated.Acceptancecriteriaandanalyticalproceduresusedtoestimateidentifiedorunidentifiedimpuritiescanbebasedonanalyticalassumptions(e.g.,equivalentdetectorresponse).Theseassumptionsshouldbediscussedintheregistrationapplication.可用各種技術測定有機雜質的含量，這些技術包括把雜質的響應值與適當的參比標準品的響應值比較或與藥物本身的響應值比較。應根據使用目的，對分析過程中用于控制雜質的參比標準品進行定性和定量。可用原料藥作為標準物質來估計雜質的量，如果原料藥和雜質的響應因子不接近，只要應用了校正因子或測得的雜質量高于實際的雜質量，該方法仍是可行的。用于評估已鑒定或未鑒定雜質的認可標準和分析方法可基于分析的假設（例如：相同的檢測響應等）。為此，這些假設也應在注冊申請中加以討論。REPORTINGIMPURITYCONTENTOFBATCHES^產品雜質含量的報告Analyticalresultsshouldbeprovidedintheapplicationforallbatchesofthenewdrugsubstanceusedforclinical,safety,andstabilitytesting,aswellasforbatchesrepresentativeoftheproposedcommercialprocess.Quantitativeresultsshouldbepresentednumerically,andnotingeneraltermssuchas"complies”,“meetslimit"etc.Anyimpurityatalevelgrea（＞）thereportingthreshold（seeAttachment1）andtotalimpuritiesobservedinthesebatchesofthenewdrugsubstanceshouldbereportedwiththeanalyticalproceduresindicated.Below1.0%,theresultsshouldbereportedtotwodecimalplaces（e.g.,0.06%,0.13%）;atandabove1.0%,theresultsshouldbereportedtoonedecimalplace（e.g.,1.3%）.Resultsshouldberoundedusingconventionalrules（seeAttachment2）.Atabulation（e.g.,spreadsheet）ofthedataisrecommended.Impuritiesshouldbedesignatedbycodenumberorbyanappropriatedescriptor,e.g.,retentiontime.Ifahigherreportingthresholdisproposed,itshouldbefullyjustified.Allimpuritiesatalevelgreaterthan（＞）thereportingthresholdshouldbesummedandreportedastotalimpurities.注冊申請應提供用于臨床、安全性研究、穩定性試驗的所有新原料藥批次產品的分析結果以及用于準備上市產品的分析結果。定量測定結果應數字化，不應用符合規定”，符合限度”等一般性術語。在新原料藥的所有批次中，應報告檢測到的大于（＞）報告閾值（見附錄1）的任何雜質和總雜質，并附所用的分析方法。若低于1.0%,結果應報告至小數點后兩位（如0.06%,0.13%）,若大于或等于1.0%,結果報告至小數點后1位（如1.3%）o結果應按傳統規則修約（見附錄2）o建議使用數據表格（如電子數據表），各雜質均應以編號或合適的描述表示（如保留時間）。如果采用較高的報告閾值，應進行充分論證。所有大于（＞）報告閾值的雜質應進行累加，報告為總雜質”。Whenanalyticalprocedureschangeduringdevelopment,reportedresultsshouldbelinkedtotheprocedureused,withappropriatevalidationinformationprovided.Representativechromatogramsshouldbeprovided.Chromatogramsofrepresentativebatchesfromanalyticalvalidationstudiesshowingseparationanddetectabilityofimpurities（e.g.,onspikedsamples）,alongwithanyotherimpuritytestsroutinelyperformed,canserveastherepresentativeimpurityprofiles.Theapplicantshouldensurethatcompleteimpurityprofiles（e.g.,chromatograms）ofindividualbatchesareavailable,ifrequested.若在研制期間，分析方法發生了變化，報告測試結果應附上所用的分析方法。并提供相應的方法學論證資料。應提供有代表性的色譜圖。方法學論證中，顯示雜質分離度和檢測靈敏度的、具有代表性批次（例如：加樣試驗）的色譜圖和常規雜質檢測得到的色譜圖，可以反映出有代表性的雜質概況。申報者應保證：如需要，可提供各個批次產品的完整的雜質概況（例如；色譜圖）。Atabulationshouldbeprovidedthatlinksthespecificnewdrugsubstancebatchtoeachsafetystudyandeachclinicalstudyinwhichthenewdrugsubstancehasbeenused.另外，申報者還應提供應用在每個安全性研究和臨床研究中的新原料藥的每個批次一一對應的名單。Foreachbatchofthenewdrugsubstance,thereportshouldinclude:對每批新原料藥、報告內容應包括：Batchidentityandsize批號與批量Dateofmanufacture生產日期Siteofmanufacture生產地點Manufacturingprocess生產工藝Impuritycontent,individualandtotal單個雜質含量和總雜質含量Useofbatches批次的用途Referencetoanalyticalprocedureused所采用分析方法的闡釋LISTINGOFIMPURITIESINSPECIFICATIONS中所列的雜質檢查項目Thespecificationforanewdrugsubstanceshouldincludealistofimpurities.Stabilitystudies,chemicaldevelopmentstudies,androutinebatchanalysescanbeusedtopredictthoseimpuritieslikelytooccurinthecommercialproduct.Theselectionofimpuritiesinthenewdrugsubstancespecificationshouldbebasedontheimpuritiesfoundinbatchesmanufacturedbytheproposedcommercialprocess.Thoseindividualimpuritieswithspecificacceptancecriteriaincludedinthespecificationforthenewdrugsubstancearereferredtoas"specifiedimpurities"inthisguideline.Specifiedimpuritiescanbeidentifiedorunidentified.在新原料藥的規范中應包括雜質檢查項目。穩定性研究、化學方面的開發研究以及日常批次分析檢驗的結果有助于預測在市售產品中可能出現的雜質。在新原料藥規范中收載的雜質應根據在擬上市生產的批次中所發現的雜質來選擇。在本指導原則中。列入新原料藥規范中、具有特定的認可標準的各個雜質稱為特定雜質。特定雜質可以是已鑒定的，也可以是未鑒定的。Arationalefortheinclusionorexclusionofimpuritiesinthespecificationshouldbepresented.Thisrationaleshouldincludeadiscussionoftheimpurityprofilesobservedinthesafetyandclinicaldevelopmentbatches,togetherwithaconsiderationoftheimpurityprofileofbatchesmanufacturedbytheproposedcommercialprocess.Specifiedidentifiedimpuritiesshouldbeincludedalongwithspecifiedunidentifiedimpuritiesestimatedtobepresentatalevelgreaterthan(>)theidentificationthresholdgiveninAttachment1.Forimpuritiesknowntobeunusuallypotentortoproducetoxicorunexpectedpharmacologicaleffects,thequantitation/detectionlimitoftheanalyticalproceduresshouldbecommensuratewiththelevelatwhichtheimpuritiesshouldbecontrolled.Forunidentifiedimpurities,theprocedureusedandassumptionsmadeinestablishingtheleveloftheimpurityshouldbeclearlystated.Specified,unidentifiedimpuritiesshouldbereferredtobyanappropriatequalitativeanalyticaldescriptivelabel（e.g.,“unidentifiedA",“unidentifiedwithrelativeretentionof0.9acceptancecriterionofnotmorethan（＜）theidentificationthreshold（Attachment1）foranyunspecifiedimpurityandanacceptancecriterionfortotalimpuritiesshouldbeincluded.應對用于安全性和臨床研究中的批次中所發現雜質情況，以及對擬上市生產的原料中雜質概況綜合進行考慮后，再對規范中列入或不列入哪些雜質的理由進行說明。特定的已鑒定雜質應與特定的其含量估計大于（＞）鑒定閾值（附錄1）的未鑒定雜質一起考慮。對于那些具有特殊功效或產生毒性或為預料到的藥理作用的雜質，其分析方法的定量限或檢測限度必須與該雜質應被控制的量相當。對于未鑒定的雜質，所使用的檢測方法和確定雜質量時所采用的假設應予明確說明。特定的未鑒定的雜質應采用適當的方法描述標記（例如：朱鑒定雜質A”相對保留時間為0.9的雜質”）。對于任何一個非特定雜質應有一個不大于（0鑒定閾值（附錄1）的認可標準，對總雜質也應建立一個認可標準。Acceptancecriteriashouldbesetnohigherthanthelevelthatcanbejustifiedbysafetydata,andshouldbeconsistentwiththelevelachievablebythemanufacturingprocessandtheanalyticalcapability.Wherethereisnosafetyconcern,impurityacceptancecriteriashouldbebasedondatageneratedonbatchesofthenewdrugsubstancemanufacturedbytheproposedcommercialprocess,allowingsufficientlatitudetodealwithnormalmanufacturingandanalyticalvariationandthestabilitycharacteristicsofthenewdrugsubstance.Althoughnormalmanufacturingvariationsareexpected,significantvariationinbatch-to-batchimpuritylevelscanindicatethatthemanufacturingprocessofthenewdrugsubstanceisnotadequatelycontrolledandvalidated(seeICHQ6AGuidelineonSpecifications,DecisionTree#1,forestablishinganacceptancecriterionforaspecifiedimpurityinanewdrugsubstance).Theuseoftwodecimalplacesforthresholds(SeeAttachment1)doesnotnecessarilyindicatetheprecisionoftheacceptancecriteriaforspecifiedimpuritiesandtotalimpurities.建立認可標準不能高于經安全資料界定合理的水平，并且必須與生產工藝和分析能力所能達到的水平一致。如果沒有安全性方面的問題，雜質認可標準應根據擬上市生產的新原料藥批次測定的數據來建立，并應為常規生產和分析上的正常變異及藥物的穩定性特性留有足夠的余地。盡管常規生產中的變化是可以預料的，然而批與批之間雜質水平的顯著變化可能預示著新原料藥的生產工藝尚未得到充分的控制和論證(見ICHQ6A規范”指南判斷流程圖1,建立新原料藥中的特殊雜質的認可標準)。閾值的兩位小數(見附錄1)并不代表特定雜質和總雜質認可標準的精度。Insummary,thenewdrugsubstancespecificationshouldinclude,whereapplicable,thefollowinglistofimpurities:總之，新原料藥規范中應包括以下雜質檢查項：OrganicImpurities有機雜質：Eachspecifiedidentifiedimpurity每種特定的已鑒定雜質Eachspecifiedunidentifiedimpurity每種特定的未鑒定的雜質Anyunspecifiedimpuritywithanacceptancecriterionofnotmorethan（＜）theidentificationthreshold任何不大于（當鑒定閾值認可標準的非特定雜質。Totalimpurities雜質總量ResidualSolvents^留溶劑InorganicImpurities無機雜質。QUALIFICATIONOFIMPURITIES質的界定Qualificationistheprocessofacquiringandevaluatingdatathatestablishesthebiologicalsafetyofanindividualimpurityoragivenimpurityprofileatthelevel（s）specified.Theapplicantshouldprovidearationaleforestablishingimpurityacceptancecriteriathatincludessafetyconsiderations.Thelevelofanyimpuritypresentinanewdrugsubstancethathasbeenadequatelytestedinsafetyand/orclinicalstudieswouldbeconsideredqualified.Impuritiesthatarealsosignificantmetabolitespresentinanimaland/orhumanstudiesaregenerallyconsideredqualified.Alevelofaqualifiedimpurityhigherthanthatpresentinanewdrugsubstancecanalsobejustifiedbasedonananalysisoftheactualamountofimpurityadministeredinpreviousrelevantsafetystudies.雜質的界定是獲得和評估數值的過程，這些數值用于建立安全的閾值（水平），單個的或某些已明確的雜質含量在這個閾值水平下是可以確保生物安全性的。中報者應對所選定的雜質限度提供包括安全性研究在內的理由。對于一個通過充分的安全性研究和臨床研究的新原料藥，其中任何一個雜質的水平即被認為是已經通過界定了的。對于是動物和/或人體中的重要代謝物的那些雜質，也認為已通過界定。雜質的界定限量（水平）如果高于藥物實際所含的雜質量，則同樣可以根據對已完成的安全性研究中使用藥物中的實際雜質量來判斷其合理性。Ifdataareunavailabletoqualifytheproposedacceptancecriterionofanimpurity,studiestoobtainsuchdatacanbeappropriatewhentheusualqualificationthresholdsgiveninAttachment1areexceeded.如果可獲得的數據不能界定某一雜質擬定的認可標準，而且當該認可標準超過了附錄1所列的界定閾值時，則必須進行進一步的研究，去獲得必要的數據。Higherorlowerthresholdsforqualificationofimpuritiescanbeappropriateforsomeindividualdrugsbasedonscientificrationaleandlevelofconcern,includingdrugclasseffectsandclinicalexperience.Forexample,qualificationcanbeespeciallyimportantwhenthereisevidencethatsuchimpuritiesincertaindrugsortherapeuticclasseshavepreviouslybeenassociatedwithadversereactionsinpatients.Intheseinstances,alowerqualificationthresholdcanbeappropriate.Conversely,ahigherqualificationthresholdcanbeappropriateforindividualdrugswhenthelevelofconcernforsafetyislessthanusualbasedonsimilarconsiderations(e.g.,patientpopulation,drugclasseffects,clinicalconsiderations).Proposalsforalternativethresholdswouldbeconsideredonacase-by-casebasis.對于某些藥物，可以根據科學原理并考慮藥物的類別和臨床經驗，對其雜質界定閾值進行適當調整。例如，某些雜質在一些藥物中或治療類別中已證明與病人的不良反應有關，則該雜質的界定是非常重要的。在這種情況下，應制訂更低的界定閾值。反之，如果考慮相似情況(病例數、藥物類別、臨床情況)后，對安全性的顧慮比通常情況小，那么這些藥物的界定閾值可以高一些。對限度的改變應具體情況具體對待。The"DecisionTreeforIdentificationandQualification"(Attachment3)describesconsiderationsforthequalificationofimpuritieswhenthresholdsareexceeded.Insomecases,decreasingthelevelofimpuritytonotmorethanthethresholdcanbesimplerthanprovidingsafetydata.Alternatively,adequatedatacouldbeavailableinthescientificliteraturetoqualifyanimpurity.Ifneitheristhecase,additionalsafetytestingshouldbeconsidered.Thestudiesconsideredappropriatetoqualifyanimpuritywilldependonanumberoffactors,includingthepatientpopulation,dailydose,androuteanddurationofdrugadministration.Suchstudiescanbeconductedonthenewdrugsubstancecontainingtheimpuritiestobecontrolled,althoughstudiesusingisolatedimpuritiescansometimesbeappropriate.鑒定和界定判斷圖(附件3)描述了當雜質含量超過了界定閾值時所應考慮到的事項。在一些情況下降低雜質含量使其低于閾值要比提供安全性數據來的簡單。或者可以選擇文獻資料提供的充分數據來界定某一雜質。如果兩者均不可行，則應考慮進行附加的安全性試驗。合理的界定一個雜質的研究將取決于許多因素，包括病例數，每日劑量、給藥途徑與療程。這類試驗雖然可用分離出來的雜質進行研究，但通常是用含有被控制的雜質的新原料藥來進行研究。Althoughthisguidelineisnotintendedtoapplyduringtheclinicalresearchstageofdevelopment,inthelaterstagesofdevelopmentthethresholdsinthisguidelinecanbeusefulinevaluatingnewimpuritiesobservedindrugsubstancebatchespreparedbytheproposedcommercialprocess.Anynewimpurityobservedinlaterstagesofdevelopmentshouldbeidentifiedifitslevelisgreaterthan(>)theidentificationthresholdgiveninAttachment1(seethe“DecisiorTreeforIdentificationandQualificationin"Attachment3).Similarly,thequalificationoftheimpurityshouldbeconsideredifitslevelisgreaterthan(>)thequalificationthresholdgiveninAttachment1.Safetyassessmentstudiestoqualifyanimpurityshouldcomparethenewdrugsubstancecontainingarepresentativeamountofthenewimpuritywithpreviouslyqualifiedmaterial.Safetyassessmentstudiesusingasampleoftheisolatedimpuritycanalsobeconsidered.雖然本指導原則在研發的臨床研究階段并不適用，但在研究后期，本指南的閾值對于評價擬上市新原料藥生產過程中的各批次中出現的新雜質是有用的。在研究后期，任何含量大于（＞）附件1中鑒定閾值（見附件3鑒定和界定流程圖）的新的雜質均需鑒定。同樣，如果雜質量大于（＞）附錄1中的界定閾值，應考慮雜質的界定。界定某雜質的安全性評價研究應將含有一定代表量新雜質的新原料藥與以前界定過的原料進行比較。也可考慮用已分離出來的雜質樣本進行安全性研究。GLOSSARY語ChemicalDevelopmentStudiesStudiesconductedtoscale-up,optimise,andvalidatethemanufacturingprocessforanewdrugsubstance.化學方面的開發研究：對新原料藥合成工藝進行放大、優化以及論證的研究。EnantiomericImpurityAcompoundwiththesamemolecularformulaasthedrugsubstancethatdiffersinthespatialarrangementofatomswithinthemoleculeandisanon-superimposablemirrorimage.對映體雜質：與藥物具有相同的分子式，但其分子中原子的空間排列不同并且為非鏡像疊加的化合物。ExtraneousContaminantAnimpurityarisingfromanysourceextraneoustothemanufacturingprocess.外源物質：來源于生產工藝以外的雜質。HerbalProductsMedicinalproductscontaining,exclusively,plantmaterialand/orvegetabledrugpreparationsasactiveingredients.Insometraditions,materialsofinorganicoranimalorigincanalsobepresent.草藥:以植物和/或植物藥制品為活性組分制成的藥物制劑。在一些傳統藥中，可能也含有無機物或動物組織。IdentifiedImpurity:Animpurityforwhichastructuralcharacterisationhasbeenachieved.已鑒定的雜質：已確證了其結構特征的雜質。IdentificationThresholdAlimitabove(>)whichanimpurityshouldbeidentified.鑒定閾值：雜質應被鑒定的限度值。Impurity:Anycomponentofthenewdrugsubstancethatisnotthechemicalentitydefinedasthenewdrugsubstance.雜質：存在于新原料藥中，但其化學結構與新原料藥不一樣的任何一種成分。ImpurityProfileAdescriptionoftheidentifiedandunidentifiedimpuritiespresentinanewdrugsubstance.雜質概況：對存在于某一新原料藥中的已鑒定或未鑒定雜質情況的描述。Intermediate:Amaterialproducedduringstepsofthesynthesisofanewdrugsubstancethatundergoesfurtherchemicaltransformationbeforeitbecomesanewdrugsubstance.中間體：化學合成新原料藥的過程中所產生的某一成分，必須進一步進行結構改變才能成為新原料藥。LigandAnagentwithastrongaffinitytoametalion.配位體：對金屬離子具有很強親和力的試劑。NewDrugSubstanceThedesignatedtherapeuticmoietythathasnotbeenpreviouslyregisteredinaregionormemberstate(alsoreferredtoasanewmolecularentityornewchemicalentity).Itcanbeacomplex,simpleester,orsaltofapreviouslyapproveddrugsubstance.新原料藥：先前尚無在某一地區或成員國注冊的具有治療作用的活性部分(或為新分子體或新化學體)。它可以是某種已獲批準的藥物的一種復合物、簡單的酯或鹽。PolymorphicFormsDifferentcrystallineformsofthesamedrugsubstance.Thesecanincludesolvationorhydrationproducts(alsoknownaspseudo-polymorphs)andamorphousforms.多品型：某一藥物的不同結晶形態。包括溶劑化或水合物(偽晶體及無定型)。PotentialImpurity:Animpuritythattheoreticallycanariseduringmanufactureorstorage.Itmayormaynotactuallyappearinthenewdrugsubstance.潛在雜質：按照理論推測在生產過程中可能引入或產生的雜質。其在新原料藥中可能存在，也可能是不存在的。QualificationTheprocessofacquiringandevaluatingdatathatestablishesthebiologicalsafetyofanindividualimpurityoragivenimpurityprofileatthelevel(s)specified.界定：是獲得和評價一些數據的過程，這些數據用于建立安全的閾值(水平)，單個的或一些已確定的雜質的含量在這個閾值下可以確保生物安全性。QualificationThresholdAlimitabove(>)whichanimpurityshouldbequalified.界定閾值：雜質應被界定的限度值。ReagentAsubstanceotherthanastartingmaterial,intermediate,orsolventthatisusedinthemanufactureofanewdrugsubstance.試劑：一種與起始物、中間體或溶劑不同的物質，在新原料藥的生產中使用ReportingThreshold:Alimitabove（＞）whichanimpurityshouldbereported.ReportingthresholdisthesameasreportinglevelinQ2B.報告閾值：雜質應報告的限度，即Q2B中的報告水平”。Solvent:Aninorganicoranorganicliquidusedasavehicleforthepreparationofsolutionsorsuspensionsinthesynthesisofanewdrugsubstance.溶劑：在新原料藥合成中用于制備溶液或混懸液的無機或有機液體。SpecifiedImpurityAnimpuritythatisindividuallylistedandlimitedwithaspecificacceptancecriterioninthenewdrugsubstancespecification.Aspecifiedimpuritycanbeeitheridentifiedorunidentified.特定雜質：在新原料藥規范（標準）中規定要檢測并有特定的認可標準的雜質。它可以是已鑒定或未鑒定的雜質。StartingMaterial:Amaterialusedinthesynthesisofanewdrugsubstancethatisincorporatedasanelementintothestructureofanintermediateand/orofthenewdrugsubstance.Startingmaterialsarenormallycommerciallyavailableandofdefinedchemicalandphysicalpropertiesandstructure.起始物：在新藥的合成中，作為一種成分結合到中間體或新藥中的物質。起始物通常市場上有供應，并具有確定的化學物理性質及結構。UnidentifiedImpurity:Animpurityforwhichastructuralcharacterisationhasnotbeenachievedandthatisdefinedsolelybyqualitativeanalyticalproperties（e.g.,chromatographicretentiontime）.未鑒定雜質：未獲得結構特征，僅通過定性手段（例如：色譜保留時間）來定義的雜質。Unspecifiedimpurity:Animpuritythatislimitedbyageneralacceptancecriterion,butnotindividuallylistedwithitsownspecificacceptancecriterion,inthenewdrugsubstancespecification.非特定雜質：在新原料藥規范（標準）中，其限度在總認可標準中控制而不單獨控制的雜質O

最大日劑量報告閾值鑒定閾值界定閾值<2克/天最大日劑量報告閾值鑒定閾值界定閾值<2克/天0.05%0.10%或每天攝入1.0mg（取閾值?）0.15%^￡每天攝入1.0mg（取閾值低者）>2克/大0.03%0.05%0.05%iTheamountofdrugsubstanceadministeredperday每日使用的原料藥的量。Higherreportingthresholdsshouldbescientificallyjustified能否制定較高的報告閾值，應經過科學驗證。Maximum一??一iDailyDoseReportingThresh01cpIdentificationThresholci,3.QualificationThreshold<2g/day0.05%0.10%or1.0mgperdayintake(whicheverislower)0.15%or1.0mgperdayintake(whicheverislower)>2g/day0.03%0.05%0.05%Lowerthresholdscanbeappropriateiftheimpurityisunusuallytoxic如果雜質具有特殊毒性，可以采用較低的閾值ATTACHMENT2IllustrationofReportingImpurityResultsforIdentificationandQualificationinanApplication附件2申請文件中雜質鑒定或界定結果報告實例Theattachmentisonlyillustrativeandisnotintendedtoserveastemplatehowresultsonimpuritiesshouldbepresentedinanapplicationfile.Normallyrawdataarenotpresented.本附件只是作為說明，并不作為雜質檢測結果在申請文件中呈報的模板。原始數據通常不呈報。0.5gMaximumDailyDoseReportingthreshold=0.05%Identificationthreshold=0.10%Qualificationthreshold=0.15%"Raw"Result(%)ReportedResult(%)Reportingthreshold=0.05%CalculatedTotalDailyIntake(TDI)(mg)oftheimpurity(roundedresultinmg)ActionIdentification(Threshold0.10%exceeded?)Qualification(Threshold0.15%exceeded?)0.044Notreported0.2NoneNone0.09630.100.5NoneNone0.120.121)0.6Yes21)None0.16490.161)0.8YesV1)Yes例1:0.5g最大日劑量報告閾值=0.05%鑒定閾值=0.10%界定閾值=0.15%原始”結果（%）報告結果（％）報告閾值=0.05%計算的雜質每日總攝入量（TDD（mg）（修約至mg）反應鑒定（口閾值0.10%%?）界定（大于閾值0.15%?）0.044不報告0.2否否0.09630.100.5否否0.120.121)0.6是否1)0.16490.161)0.8是是1)0.8gMaximumDailyDoseReportingthreshold=0.05%Identificationthreshold=0.10%Qualificationthreshold=1.0mgTDI“RaWResu(%)tReportedResult(%)Reportingthreshold=0.05%CalculatedTotalDailyIntake(TDI)(mg)oftheimpurity(roundedresult