20141216 ICH Q3D 元素杂质指南

INTERNATIONALCONFERENCEONHARMONISATIONOFTECHNICALREQUIREMENTSFORREGISTRATIONOFPHARMACEUTICALSFORHUMANUSEICHHARMONISEDGUIDELINEGUIDELINEFORELEMENTALIMPURITIES元素杂质指南Q3DCurrentStep4versiondated16December2014ThisGuidelinehasbeendevelopedbytheappropriateICHExpertWorkingGroupandhasbeensubjecttoconsultationbytheregulatoryparties,inaccordancewiththeICHProcess.AtStep4oftheProcessthefinaldraftisrecommendedforadoptiontotheregulatorybodiesoftheEuropeanUnion,Switzerland,Japan,USAandCanada.

Q3DDocumentHistoryCodeHistoryDateQ3DApprovalbytheSteeringCommitteeunderStep2a.6June2013Q3DApprovalbytheSteeringCommitteeunderStep2bandreleaseforpublicconsultation.6June2013Q3DPostsign-offcorrigendumin:Table4.1WandA1wereremovedfromthelistofincludedelementalimpuritiesinClass2Band3respectively.TableA2.1theClassforNiwaschangedtoread3insteadof214June2013Q3DPostsign-offminoreditorialcorrectionsincluding:removalofreferencestoAppendix5(pgsi&13);deletionofredundanttext(pg4);changeofOption2toOption2a(pg10);insertionoftextunderSafetyLimitingToxicity(pg35);referenceto"metals"intextand"metal"inTableA4.7titlewith"elementals"and"elements"(pg73);anddeletionofheaderTableA4.10(pg75).26July2013Q3DAdditionoflinenumberstofacilitatetheprovisionofcommentsbystakeholders.30September2013Q3DApprovalbytheSteeringCommitteeunderStep4andrecommendation12November2014foradoptiontotheICHregulatorybodies.CurrentStep4VersionCodeHistoryDateQ3DCorrigendumtocorrect:themodifyingfactorinthetextofthesafetyassessmentforSelenium(changedto2insteadof10consistentwithSection3.1);andtworeferencesforconsistencyinthesafetyassessmentsforBarium(deletedreference)andVanadium(reviewedreference).16December2014Legalnotice:Thisdocumentisprotectedbycopyrightandmaybeused,reproduced,incorporatedintootherworks,adapted,modified,translatedordistributedunderapubliclicenseprovidedthatICH'scopyrightinthedocumentisacknowledgedatalltimes.Incaseofanyadaption,modificationortranslationofthedocument,reasonablestepsmustbetakentoclearlylabel,demarcateorotherwiseidentifythatchangesweremadetoorbasedontheoriginaldocument.Anyimpressionthattheadaption,modificationortranslationoftheoriginaldocumentisendorsedorsponsoredbytheICHmustbeavoided.Thedocumentisprovided"asis"withoutwarrantyofanykind.InnoeventshalltheICHortheauthorsoftheoriginaldocumentbeliableforanyclaim,damagesorotherliabilityarisingfromtheuseofthedocument.Theabove-mentionedpermissionsdonotapplytocontentsuppliedbythirdparties.Therefore,fordocumentswherethecopyrightvestsinathirdparty,permissionforreproductionmustbeobtainedfromthiscopyrightholder.GUIDELINEFORELEMENTALIMPURITIESICHHarmonisedGuidelineHavingreachedStep4oftheICHProcessattheICHSteeringCommitteemeetingon12

November2014,thisguidelineisrecommendedforadoptiontotheregulatorypartiestoICH.TABLEOFCONTENTSINTRODUCTIONSCOPESAFETYASSESSMENTOFPOTENTIALELEMENTALIMPURITIESPrinciplesoftheSafetyAssessmentofElementalImpuritiesforOral,ParenteralandInhalationRoutesofAdministrationOtherRoutesofAdministrationJustificationforElementalImpurityLevelsHigherthananEstablishedPDEParenteralProducts.ELEMENTCLASSIFICATIONRISKASSESSMENTANDCONTROLOFELEMENTALIMPURITIESGeneralPrinciplesPotentialSourcesofElementalImpuritiesIdentificationofPotentialElementalImpuritiesRecommendationsforElementstobeConsideredintheRiskAssessmentEvaluationSummaryofRiskAssessmentProcessSpecialConsiderationsforBiotechnologically-DerivedProductsCONTROLOFELEMENTALIMPURITIES目录刖言范围潜在元素杂质的安全评估口服、注射和吸入给药中元素杂质安全评估的原则其它给药途径元素杂质水平高于已建立的PDE时的论证注射用药元素分类元素杂质的风险评估和控制通用原则元素杂质的潜在来源潜在元素杂质的识别建议中风险评估中考虑的元素评估风险评估过程总结生物技术衍生产品特殊考虑元素杂质的控制CONVERTINGBETWEENPDESANDCONCENTRATIONLIMITSPDE和关注限度之间的转换SPECIATIONANDOTHERCONSIDERATIONSANALYTICALPROCEDURESLIFECYCLEMANAGEMENTGLOSSARYREFERENCESAppendix1:MethodforEstablishingExposureLimitsAppendix2:EstablishedPDEsforElementalImpuritiesAppendix3:IndividualSafetyAssessmentsAppendix4:IllustrativeExamples物种形成和其它考虑分析方法生命周期管理术语参考文献附录1：建立暴露限度的方法附录2：已建立的元素杂质PDE附录3：单独安全评估附录4：举例说明GUIDELINEFORELEMENTALIMPURITIES元素杂质指南Q3DINTRODUCTION介绍Elementalimpuritiesindrugproductsmayarisefromseveralsources;theymayberesidualcatalyststhatwereaddedintentionallyinsynthesisormaybepresentasimpurities(e.g.,throughinteractionswithprocessingequipmentorcontainer/closuresystemsorbybeingpresentincomponentsofthedrugproduct).Becauseelementalimpuritiesdonotprovideanytherapeuticbenefittothepatient,theirlevelsinthedrugproductshouldbecontrolledwithinacceptablelimits.Therearethreepartsofthisguideline:theevaluationofthetoxicitydataforpotentialelementalimpurities;theestablishmentofaPermittedDailyExposure(PDE)foreachelementoftoxicologicalconcern;andapplicationofarisk-basedapproachtocontrolelementalimpuritiesindrugproducts.Anapplicantisnotexpectedtotightenthelimitsbasedonprocesscapability,providedthattheelementalimpuritiesindrugproductsdonotexceedthePDEs.ThePDEsestablishedinthisguidelineareconsideredtobeprotectiveofpublichealthforallpatientpopulations.Insomecases,lowerlevelsofelementalimpuritiesmaybewarrantedwhenlevelsbelowtoxicitythresholdshavebeenshowntohaveanimpactonotherqualityattributesofthedrugproduct(e.g.,elementcatalyzeddegradationofdrugsubstances).Inaddition,forelementswithhighPDEs,otherlimitsmayhavetobeconsideredfromapharmaceuticalqualityperspectiveandotherguidelinesshouldbeconsulted(e.g.,ICHQ3A).药品中的元素杂质可能会有几个来源，它们可能是有意加入合成反应的催化剂的残留，也可能是作为杂质出现(例如，通过与工艺设备或容器/密闭系统相互反应，或出现在药品的组分中)。由于元素杂质并不给患者提供任何治疗益处，其在药品中的水平应被控制在可接受限度以内。本指南分为三个部分：潜在元素杂质毒性数据的评估、为每个毒性关注元素建立PDE值，以及应用基于风险的方法来控制药品中的元素杂质。如果药品中的元素杂质没有超过PDE阈值的话，申报人不需要根据其工艺能力加严限度。本指南中建立的PDE阈值足以保护所有患者人群的公共健康。在有些情况下，如果毒性阈值以下的元素杂质水平表示出对药品的其它质量属性有影响(例如，对药品降解有催化作用的元素)，则可能需要保证一个更低的元素杂质水平。另外，对于具有较高PDE值的元素，可能需要从药品质量的角度，以及要参照的其它指南（例如ICHQ3A）来考虑其它限度。ThisguidelinepresentsaprocesstoassessandcontrolelementalimpuritiesinthedrugproductusingtheprinciplesofriskmanagementasdescribedinICHQ9.Thisprocessprovidesaplatformfordevelopingarisk-basedcontrolstrategytolimitelementalimpuritiesinthedrugproduct.本指南给出一个采用ICHQ9中所述风险管理原则来评估和控制药品中元素杂质的方法。该方法提供了一个基于风险控制策略的平台来限制药品中的元素杂质。SCOPE范围Theguidelineappliestonewfinisheddrugproducts(asdefinedinICHQ6AandQ6B)andnewdrugproductscontainingexistingdrugsubstances.Thedrugproductscontainingpurifiedproteinsandpolypeptides(includingproteinsandpolypeptidesproducedfromrecombinantornon-recombinantorigins),theirderivatives,andproductsofwhichtheyarecomponents(e.g.,conjugates)arewithinthescopeofthisguideline,asaredrugproductscontainingsyntheticallyproducedpolypeptides,polynucleotides,andoligosaccharides.本指南适用于新的制剂产品(如ICHQ6A和Q6B定义)和含有已有原料药的新药品。含有纯化后的蛋白质和多肽(包括采用复合或非复合来源生产的蛋白质和多肽)的药品、其衍生物，以及其复方药品(例如，偶合物)在本指南适用范围内。含有合成多肽、多核苷酸和低聚糖的药品也适用本指南。Thisguidelinedoesnotapplytoherbalproducts,radiopharmaceuticals,vaccines,cellmetabolites,DNAproducts,allergenicextracts,cells,wholeblood,cellularbloodcomponentsorbloodderivativesincludingplasmaandplasmaderivatives,dialysatesolutionsnotintendedforsystemiccirculation,andelementsthatareintentionallyincludedinthedrugproductfortherapeuticbenefit.Thisguidelinedoesnotapplytoproductsbasedongenes(genetherapy),cells(celltherapy)andtissue(tissueengineering).Insomeregions,theseproductsareknownasadvancedtherapymedicinalproducts.本指南不适用于草药产品、放射性药品、疫苗、细胞代谢物、DNA产品、过敏提取物、细胞、全血、细胞血成分或血液制品，包括血浆和血浆制品、非系统循环用透析液，和用于治疗用途加入的元素。本指南不适用于基于基因(基因治疗)、细胞(细胞治疗)和组织(组织工程)的药品。在有些地区，这些产品是作为先进治疗药品的。Thisguidelinedoesnotapplytodrugproductsusedduringclinicalresearchstagesofdevelopment.Asthecommercialprocessisdeveloped,theprinciplescontainedinthisguidelinecanbeusefulinevaluatingelementalimpuritiesthatmaybepresentinanewdrugproduct.本指南不适用于研发的临床研究阶段药品。由于商业过程是在不断发展的，评估新药中可能出现的元素杂质时也可应用本指南中的原则。ApplicationofQ3Dtoexistingproductsisnotexpectedpriorto36monthsafterpublicationoftheguidelinebyICH.在本指南由ICH发布后36个月内，不需要对已有产品应用Q3D。SAFETYASSESSMENTOFPOTENTIALELEMENTALIMPURITIES潜在元素杂质的安全评估PrinciplesoftheSafetyAssessmentofElementalImpuritiesforOral,ParenteralandInhalationRoutesofAdministration口服、注射和吸入给药途径的元素杂质安全评估原则ThemethodusedforestablishingthePDEforeachelementalimpurityisdiscussedindetailinAppendix1.Elementsevaluatedinthisguidelinewereassessedbyreviewingthepubliclyavailabledatacontainedinscientificjournals,governmentresearchreportsandstudies,internationalregulatorystandards(applicabletodrugproducts)andguidance,andregulatoryauthorityresearchandassessmentreports.ThisprocessfollowstheprinciplesdescribedinICHQ3C:ResidualSolvents.Theavailableinformationwasreviewedtoestablishtheoral,parenteralandinhalationPDEs.Forpracticalpurposes,thePDEstobeappliedtothedrugproductthatarepresentedinAppendix2TableA.2.1havebeenroundedto1or2significantfigures.用于建立各元素杂质的方法在附录1中进行了讨论。在本指南中评估的元素，是通过对科学杂质、政府研发报告和研究、国际法规标准(适用于药品)和指南、以及法规当局研究和评估报告里公众可以获得的数据进行审核得到的。该方法是根据ICHQ3C：残留溶剂中所述的原则制订的。对可以获得的资料进行审核以建立口服、注射和吸入PDE值。为了实用，附录2里表A.2.1中适用于药品的PDE阈值被修约至1位或2位有效数字。AsummarysafetyassessmentidentifyingthecriticalstudyforsettingaPDEforeachelementisincludedinAppendix3.ThereareinsufficientdatatosetPDEsbyanyrouteofadministrationforiridium,osmium,rhodium,andruthenium.ThePDEsfortheseelementswereestablishedonthebasisoftheirsimilaritytopalladium.附录3包括了一份各元素PDE设定的关键研究识别安全评估总结。对于铱、锇、铑和铷没有足够的数据设定口服给药途径的PDE阈值。这些元素的PDE值是基于其与钯的相似性上建立的。ThefactorsconsideredinthesafetyassessmentforestablishingthePDEarelistedbelowinapproximateorderofrelevance:在建立PDE所进行的安全评估中考虑的因素按大致的相关性顺序列出如下：Thelikelyoxidationstateoftheelementinthedrugproduct;-药品中的元素可能的氧化状态Humanexposureandsafetydatawhenitprovidedapplicableinformation;-当其提供可用信息时，人类暴露量和安全数据Themostrelevantanimalstudy;-最相关的动物研究Routeofadministration;-给药途径Therelevantendpoint(s).-相关终点Standardsfordailyintakeforsomeoftheelementalimpuritiesdiscussedinthisguidelineexistforfood,water,air,andoccupationalexposure.Whereappropriate,thesestandardswereconsideredinthesafetyassessmentandestablishmentofthePDEs.在本指南中讨论的有些元素杂质日服用量的标准ThelongestdurationanimalstudywasgenerallyusedtoestablishthePDE.Whenashorterdurationanimalstudywasconsideredthemostrelevant,therationalewasprovidedintheindividualsafetyassessment.一般使用最长的动物研究时长来建立PDE值。如果有一个较短的动物研究时长被认为是最为相关的，则在单个安全评估中给出了其理由。Inhalationstudiesusingsolublesalts(whenavailable)werepreferredoverstudiesusingparticulatesforinhalationsafetyassessmentandderivationofinhalationPDEs.Dependingonavailabledata,inhalationPDEswerebasedoneitherlocal(respiratorysystem)orsystemictoxicity.ForPDEsestablishedforinhalation(andoralorparenteralroutesasapplicable),doseswerenormalizedtoa24-hour,7-dayexposure.相对使用粒子的研究，使用可溶性盐（可获得时）进行的吸入研究优先用于吸入安全性评估和计算吸入PDE值。根据可获得的数据，吸入PDE值是基于局部（喷雾系统）或系统性毒性的。对于为了吸入给药建立的PDE值（适用时，和口服或注射途径），剂量一般统一为24小时7天暴露时长。Intheabsenceofdataand/orwheredataareavailablebutnotconsideredsufficientforasafetyassessmentfortheparenteralandorinhalationrouteofadministration,modifyingfactorsbasedonoralbioavailabilitywereusedtoderivethePDEfromtheoralPDE:如果没有数据，和/或有数据但认为不足以用于注射和/或吸入途径的安全评估，则基于口服生物利用度的修正因子用于从口服PDE来推导PDE：?Oralbioavailability<1%:dividebyamodifyingfactorof100;?Oralbioavailability>1%and<50%:dividebyamodifyingfactorof10;?Oralbioavailability>50%and<90%:dividebyamodifyingfactorof2;and?Oralbioavailability>90%:dividebyamodifyingfactorof1.?口服生物利用度<1%:除以100作为修正因子；?口服生物利用度>1%and<50%:除以10作为修正因子；?口服生物利用度>50%and<90%:除以2作为修正因子；以及?口服生物利用度>90%:除以1作为修正因子。Whereoralbioavailabilitydataoroccupationalinhalationexposurelimitswerenotavailable,acalculatedPDEwasusedbasedontheoralPDEdividedbyamodifyingfactorof100（Ref.1）.如果没有口服生物利用度数据或职业吸入暴露限，则在根据口服PDE值计算出PDE值后除以修正因子100（参考文献1）。OtherRoutesofAdministratio其它摄入途径PDEswereestablishedfororal,parenteralandinhalationroutesofadministration.WhenPDEsarenecessaryforotherroutesofadministration,theconceptsdescribedinthisguidelinemaybeusedtoderivePDEs.AnassessmentmayeitherincreaseordecreaseanestablishedPDE.TheprocessofderivationofthePDEforanotherrouteofadministrationmayincludethefollowing:PDE是针对口服、注射和吸入给药途径建立的。如果需要其它给药途径的PDE，则可以使用本指南的概念来推导PDE。评估结果可能会升高或降低已建立的PDE值。从一种给药途径推导出另一种给药途径的PDE值的计算过程包括以下：?ConsidertheoralPDEinAppendix3asastartingpointindevelopingaroute-specificPDE.Basedonascientificevaluation,theparenteralandinhalationPDEsmaybeamoreappropriatestartingpoint.将附录3中的口服PDE作为建立摄入途径特定PDE的起始点。基于科学评价，注射和吸入PDE可能是一个更适当的起始点。?Assessiftheelementalimpurityisexpectedtohavelocaleffectswhenadministeredbytheintendedrouteofadministration:评估该元素杂质在通过预定给药途径摄入时是否预期产生局部影响Iflocaleffectsareexpected,assesswhetheramodificationtoanestablishedPDEisnecessary.•如果预期有局部影响，需要评估是否要对已建立的PDE进行修正Considerthedoses/exposuresatwhichtheseeffectscanbeexpectedrelativetotheadverseeffectthatwasusedtosetanestablishedPDE.•考虑预期产生这些影响时的剂量/暴露量，与用于设定已建立的PDE所用的不良反应相比较Iflocaleffectsarenotexpected,noadjustmenttoanestablishedPDEisnecessary.•如果预期没有局部影响，则对于已建立的PDE不需要进行调整■Ifavailable,evaluatethebioavailabilityoftheelementviatheintendedrouteofadministrationandcomparethistothebioavailabilityoftheelementbytheroutewithanestablishedPDE:■如果可以，应评估该元素的通过预定给药途径的生物利用度，并将此与该元素通过已建立PDE的给药途径的生物利用度进行比较Whenadifferenceisobserved,acorrectionfactormaybeappliedtoanestablishedPDE.Forexample,whennolocaleffectsareexpected,iftheoralbioavailabilityofanelementis50%andthebioavailabilityofanelementbytheintendedrouteis10%,acorrectionfactorof5maybeapplied.•如果观察到差异，则可能需要对已建立的PDE值使用校正因子。例如，如果预期有局部影响，如果一种元素的口服生物利用度为50%，一种元素的生物利用度在预定的给药途径为10%，则可以使用5作为校正因子■IfaPDEproposedforthenewrouteisincreasedrelativetoanestablishedPDE,qualityattributesmayneedtobeconsidered.如果提议一种新的给药途径的PDE相对于已建立的PDE有增加，则可能需要考虑对质量属性JustificationforElementalImpurityLevelsHigherthananEstablishedPDE元素杂质水平高于已建立的PDE水平时的论证LevelsofelementalimpuritieshigherthananestablishedPDE(seeTableA.2.1)maybeacceptableincertaincases.Thesecasescouldinclude,butarenotlimitedto,thefollowingsituations:元素杂质水平高于已建立的PDE时(参见表A.2.1)，在特定情况下可能也可以接受。这些情况可能包括但不仅限于以下情形：-Intermittentdosing;-间歇给药Shorttermdosing(i.e.,30daysorless);-短期给药(即，30天或更短)Specificindications(e.g.,life-threatening,unmetmedicalneeds,rarediseases).-特定指示(例如，生命威胁、药品供给不足、罕见病)Examplesofjustifyinganincreasedlevelofanelementalimpurityusingasubfactorapproachofamodifyingfactor(Ref.2,3)areprovidedbelow.Otherapproachesmayalsobeusedtojustifyanincreasedlevel.AnyproposedlevelhigherthananestablishedPDEshouldbejustifiedonacase-by-casebasis.以下提供了使用修正因子的子因子方法(参见2.3)对升高的元素杂质水平进行论证的例子。其它方法也可以用来论证较高的杂质水平。提议任何高于已建立的PDE的杂质水平均需根据各案进行论证。Example1:elementXispresentinanoraldrugproduct.FromtheelementXmonographinAppendix3,aNo-Observed-Adverse-EffectLevel(NOAEL)of1.1mg/kg/daywasidentified.ModifyingfactorsF1-F5havebeenestablishedas5,10,5,1and1,respectively.UsingthestandardapproachformodifyingfactorsasdescribedinAppendix1,thePDEiscalculatedasfollows:例1：元素X出现在口服药品中。元素X各论见附录3,其NOAEL水平为1.1mg/kg/天。修正因子F1-F5分别设定为5、10、5、1和1。使用附录1中所述的修正因子标准方法，PDE计算如下：PDE=1.1mg/kg/dx50kg/5x10x5x1x1=220pg/dayModifyingfactorF2(default=10)canbesubdividedintotwosubfactors,onefortoxicokinetics(TK)andonefortoxicodynamics,eachwitharangefrom1to3.16.Usingtheplasmahalf-lifeof5days,theTKadjustmentfactorcouldbedecreasedto1.58foronceweeklyadministration(~1half-life),andto1foradministrationonceamonth(~5half-lives).UsingthesubfactorapproachforF2,theproposedlevelforelementXadministeredonceweeklycanbecalculatedasfollows:修正因子F2(默认=10)可以分成2个子因子，一个作为毒性动力学(TK)，另一个作为毒理动力学，2个因子范围均为1-3.16。采用5天使用血浆半衰期，对于每次一周摄入(-1半衰期)TK调整因子可以降低为1.58,对于每次一个月摄入(-5个半衰期)可以降低为1。通过对F2使用子因子方法，元素X每次一周摄入建议水平可以计算如下：Proposedlevel建议水平=1.1mg/kg/dx50kg/5x(1.6x3.16)x5x1x1=440pg/dayForpracticalpurposes,thisvalueisroundedto400pg/day.为了实用，该值修约为400pg/day。Example2:TheTKadjustmentfactorapproachmayalsobeappropriateforelementalimpuritiesthatwerenotdevelopedusingthemodifyingfactorapproach.ForelementZ,aMinimalRiskLevel(MRL)of0.02mg/kg/daywasusedtoderivetheoralPDE.Fromliteraturesources,theplasmahalf-lifewasreportedtobe4days.Thiselementisanimpurityinanoraldrugproductadministeredonceevery3weeks(~5half-lives).Usingfirst-orderkinetics,theestablishedPDEof1000pg/dayismodifiedasfollows:例2：TK调整因子方法可能也适用于未采用修正因子方法建立的元素杂质。对于元素乙最低风险水平(MRL)为0.02mg/kg/天用以计算口服PDE值。从文献来看，血浆半衰期报道为4天。该元素是口服给药中的一个杂质，药品每三周给药一次(-5个半衰期)。使用一级动力学，已建立的PDE为1000pg/天修正如下：Proposedlevel提议的水平=0.02mg/kg/dx50kg/1/3.16=3.16mg/dayForpracticalpurposes,thisvalueisroundedto3000pg/day.为实用起见，该值修约为3000pg/天。ParenteralProducts注射用药Parenteraldrugproductswithmaximumdailyvolumesupto2litersmayusethemaximumdailyvolumetocalculatepermissibleconcentrationsfromPDEs.Forproductswhosedailyvolumes,asspecifiedbylabelingand/orestablishedbyclinicalpractice,mayexceed2liters(e.g.,saline,dextrose,totalparenteralnutrition,solutionsforirrigation),a2-litervolumemaybeusedtocalculatepermissibleconcentrationsfromPDEs.(Ref.4)注射用药如果最大日给药体积达到2L,则可以使用最大日给药体积来计算PDE的允许浓度。对于日剂量在标签上注明和/或临床确定的药品，可以超过2L(例如，生理盐水、葡萄糖、总注射用营养、冲注洗剂)，2L的体积可以用于计算PDE的允许浓度(参考文献4)。ELEMENTCLASSIFICATION元素分类Theelementsincludedinthisguidelinehavebeenplacedintothreeclassesbasedontheirtoxicity(PDE)andlikelihoodofoccurrenceinthedrugproduct.Thelikelihoodofoccurrenceisderivedfromseveralfactorsincluding:probabilityofuseinpharmaceuticalprocesses,probabilityofbeingaco-isolatedimpuritywithotherelementalimpuritiesinmaterialsusedinpharmaceuticalprocesses,andtheobservednaturalabundanceandenvironmentaldistributionoftheelement.Forthepurposesofthisguideline,anelementwithlownaturalabundancereferstoanelementwithareportednaturalabundanceof<1atom/106atomsofsilicon(Ref.5).Theclassificationschemeisintendedtofocustheriskassessmentonthoseelementsthatarethemosttoxicbutalsohaveareasonableprobabilityofinclusioninthedrugproduct(seeTable5.1).Theelementalimpurityclassesare:本指南中包括的元素已根据其毒性(PDE)及在药品中出现的可能性分入三类。出现可能性是从几个因素中推导出的，包括：在制药工艺中使用的可能性、制药工艺中使用的原料里含有的杂质会产生共析的杂质可能性，以及观察到自然中富含的元素和在环境中广泛分布的元素。根据本指南的目的，一种在自然中存量较低的元素指其自然含量<1个原子/106个硅原子(参考文献5)。分类表目的是将风险评估的焦点集中在那些最毒，且最可能出现在药品中的元素上(参见表5.1)。元素杂质分类为：Class1:Theelements,As,Cd,Hg,andPb,arehumantoxicantsthathavelimitedornouseinthemanufactureofpharmaceuticals.Theirpresenceindrugproductstypicallycomesfromcommonlyusedmaterials(e.g.,minedexcipients).Becauseoftheiruniquenature,thesefourelementsrequireevaluationduringtheriskassessment,acrossallpotentialsourcesofelementalimpuritiesandroutesofadministration.TheoutcomeoftheriskassessmentwilldeterminethosecomponentsthatmayrequireadditionalcontrolswhichmayinsomecasesincludetestingforClass1elements.ItisnotexpectedthatallcomponentswillrequiretestingforClass1elementalimpurities;testingshouldonlybeappliedwhentheriskassessmentidentifiesitastheappropriatecontroltoensurethatthePDEwillbemet.第1类：元素砷、镉、汞和铅是对人有毒性的物质，已限制或不再用于药品生产中。其在药品中出现一般是来自于通常使用的物料(例如，矿物质辅料)。由于其独特的属性，这四种元素需要在风险评估中进行评价，要针对元素杂质的所有潜在来源以及所有的摄入途径。风险评估的结果将决定这些组成是否需要增加控制，在有些情况下要包括对一类元素的检测。不需要对所有成分进行一类元素杂质的检测，只有在风险评估认为需要对其进行适当控制以保证符合PDE要求时才要进行检测。Class2:Elementsinthisclassaregenerallyconsideredasroute-dependenthumantoxicants.Class2elementsarefurtherdividedinsub-classes2Aand2Bbasedontheirrelativelikelihoodofoccurrenceinthedrugproduct.第2类：本类别中的元素一般被认为是与摄入途径相关的人类有毒物质。根据其出现在药品的相对可能性，2类元素又被分为2A和2B两个子类。?Class2Aelementshaverelativelyhighprobabilityofoccurrenceinthedrugproductandthusrequireriskassessmentacrossallpotentialsourcesofelementalimpuritiesandroutesofadministration(asindicated).Theclass2Aelementsare:Co,NiandV.2A类：在药品中出现可能性相对较高的元素，因而需要对所有元素杂质的潜在来源及所有摄入途径(如所指)进行风险评估。2A类元素为钻、镍和钒。?Class2Belementshaveareducedprobabilityofoccurrenceinthedrugproductrelatedtotheirlowabundanceandlowpotentialtobeco-isolatedwithothermaterials.Asaresult,theymaybeexcludedfromtheriskassessmentunlesstheyareintentionallyaddedduringthemanufactureofdrugsubstances,excipientsorothercomponentsofthedrugproduct.Theelementalimpuritiesinclass2Binclude:Ag,Au,Ir,Os,Pd,Pt,Rh,Ru,SeandTl.2B类：由于自然含量较低、与其它物料共存可能性较低，在药品中出现的可能性较低的元素。因此，除非其在原料药、辅料或药品的其它成分生产中被有意加入，否则可能被排除在风险评估以外。2B类的元素杂质包括：银、金、铱、锇、钯、伯、铑、铷、硒和铊。Class3:Theelementsinthisclasshaverelativelylowtoxicitiesbytheoralrouteofadministration(highPDEs,generally>500以g/day)butmayrequireconsiderationintheriskassessmentforinhalationandparenteralroutes.Fororalroutesofadministration,unlesstheseelementsareintentionallyadded,theydonotneedtobeconsideredduringtheriskassessment.Forparenteralandinhalationproducts,thepotentialforinclusionoftheseelementalimpuritiesshouldbeevaluatedduringtheriskassessment,unlesstheroutespecificPDEisabove500pg/day.Theelementsinthisclassinclude:Ba,Cr,Cu,Li,Mo,Sb,andSn.第3类：本类的中元素在口服摄入时具有相对较低的毒性(高PDE，通常＞500pg/day),但可能在吸入和注射给药的风险评估中需要进行考虑。对于口服摄入，除非这些元素被有意加入，否则不需要在风险评估中进行考虑。对于注射和吸入给药药品，除非给药途径的PDE超过500pg/day，否则在风险评估中要评价这些元素杂质出现的可能性。本类中的元素包括钡、铬、铜、锂、钼、锑和锡。Otherelements:SomeelementalimpuritiesforwhichPDEshavenotbeenestablishedduetotheirlowinherenttoxicityand/ordifferencesinregionalregulationsarenotaddressedinthisguideline.Iftheseelementalimpuritiesarepresentorincludedinthedrugproducttheyareaddressedbyotherguidelinesand/orregionalregulationsandpracticesthatmaybeapplicableforparticularelements(e.g.,Alforcompromisedrenalfunction;MnandZnforpatientswithcompromisedhepaticfunction),orqualityconsiderations(e.g.,presenceofWimpuritiesintherapeuticproteins)forthefinaldrugproduct.Someoftheelementsconsideredinclude:Al,B,Ca,Fe,K,Mg,Mn,Na,WandZn.其它元素：有些元素杂质因为其较低的毒性和/或在地方法规中的要求不同，其PDE还没有建立，在本指南中并未说明。如果这些元素杂质出现或包括在药品中，其它指南和/或地方性法规和规范可能适用于特殊的元素(例如，铝，损害肾功能，锰和锌对于肝功能不全的病人)，或对药品成品的质量考虑(例如，钨杂质在治疗性蛋白质中出现)。这些特殊考虑的元素包括：铝、硼、钙、铁、钾、镁、锰、钠、钨和锌。RISKASSESSMENTANDCONTROLOFELEMENTALIMPURITIES元素杂质的风险评估和控制Indevelopingcontrolsforelementalimpuritiesindrugproducts,theprinciplesofqualityriskmanagement,describedinICHQ9,shouldbeconsidered.Theriskassessmentshouldbebasedonscientificknowledgeandprinciples.Itshouldlinktosafetyconsiderationsforpatientswithanunderstandingoftheproductanditsmanufacturingprocess(ICHQ8andQ11).Inthecaseofelementalimpurities,theproductriskassessmentwouldthereforebefocusedonassessingthelevelsofelementalimpuritiesinadrugproductinrelationtothePDEspresentedinthisguidance.Informationforthisriskassessmentincludesbutisnotlimitedto:datageneratedbytheapplicant,informationsuppliedbydrugsubstanceand/orexcipientmanufacturersand/ordataavailableinpublishedliterature.在建立药品中元素杂质的控制方式时，要考虑ICHQ9中所述的质量风险管理的原则。风险评估应基于科学知识和原则，应将对产品和其生产工艺的了解（ICHQ8和Q11）与对患者的安全考虑相关联。对于元素杂质来说，药品风险分析就应聚焦于结合本指南中所给出的PDE来评估一种药品中的元素杂质水平。风险评估的资料包括，但不仅限于：申请人产生的数据、原料药和/或辅料生产商提供的资料，和/或在公开的文献中可以获得的数据。Theapplicantshoulddocumenttheriskassessmentandcontrolapproachesinanappropriatemanner.Thelevelofeffortandformalityoftheriskassessmentshouldbeproportionaltothelevelofrisk.Itisneitheralwaysappropriatenoralwaysnecessarytouseaformalriskmanagementprocess（usingrecognizedtoolsand/orformalprocedures,e.g.,standardoperatingprocedures.）Theuseofinformalriskmanagementprocesses（usingempiricaltoolsand/orinternalprocedures）mayalsobeconsideredacceptable.ToolstoassistintheriskassessmentaredescribedinICHQ8andQ9andwillnotbepresentedinthisguideline.申报者应以适当的方式记录风险评估和控制方法。风险评估和努力水平和正式程度应与风险水平相称。没有必要每次都使用正式的风险管理过程（使用已知的工具和/或正式程序，例如，标准操作程序）。也可以使用非正式的风险评估过程（使用经验工具和或内部程序）。风险评估中辅助工具在ICHQ8和Q9中已有描述，本指南中不再赘述。GeneralPrinciple通则Forthepurposesofthisguideline,theriskassessmentprocesscanbedescribedinthreesteps:出于本指南的目的，风险评估过程可以描述为以下三步：-Identifyknownandpotentialsourcesofelementalimpuritiesthatmayfindtheirwayintothedrugproduct.-识别已知和潜在可能进入药品的元素杂质来源，-EvaluatethepresenceofaparticularelementalimpurityinthedrugproductbydeterminingtheobservedorpredictedleveloftheimpurityandcomparingwiththeestablishedPDE.-通过测试已知或预期杂质，将其水平与已有PDE值比较，评估药品中特殊的元素杂质出现的可能性Summarizeanddocumenttheriskassessment.Identifyifcontrolsbuiltintotheprocessaresufficientoridentifyadditionalcontrolstobeconsideredtolimitelementalimpuritiesinthedrugproduct.-总结和记录风险评估。识别出工艺中嵌入控制是否充分，或识别出要考虑增加控制来限制药品中的元素杂质Inmanycases,thestepsareconsideredsimultaneously.TheoutcomeoftheriskassessmentmaybetheresultofiterationstodevelopafinalapproachtoensurethepotentialelementalimpuritiesdonotexceedthePDE.在很多情况下，这些步骤其实是同步的。风险评估的结果，可以是一个迭代的结果，用以建立一种方法来保证潜在元素杂质不超过PDE值。PotentialSourcesofElementalImpuriti元素杂质的潜在来源Inconsideringtheproductionofadrugproduct,therearebroadcategoriesofpotentialsourcesofelementalimpurities.在考虑一种药品的生产时，元素杂质的潜在来源有很多。Residualimpuritiesresultingfromelementsintentionallyadded(e.g.,catalysts)intheformationofthedrugsubstance,excipientsorotherdrugproductcomponents.Theriskassessmentofthedrugsubstanceshouldaddressthepotentialforinclusionofelementalimpuritiesinthedrugproduct.-在生产原料药、辅料或其它药品成分时有意加入的元素的残留杂质(例如催化剂)。原料药的风险评估要说明元素杂质出现在药品中的可能性Elementalimpuritiesthatarenotintentionallyaddedandarepotentiallypresentinthedrugsubstance,waterorexcipientsusedinthepreparationofthedrugproduct.-非有意加入，可能会在药品制备过程中出现在原料药、水或辅料中的元素杂质Elementalimpuritiesthatarepotentiallyintroducedintothedrugsubstanceand/ordrugproductfrommanufacturingequipment.-可能从生产设备引入原料药和/或制剂的元素杂质Elementalimpuritiesthathavethepotentialtobeleachedintothedrugsubstanceanddrugproductfromcontainerclosuresystems.-可能从容器密闭系统中溶出至原料药和制剂的元素杂质Thefollowingdiagramshowsanexampleoftypicalmaterials,equipmentandcomponentsusedintheproductionofadrugproduct.Eachofthesesourcesmaycontributeelementalimpuritiestothedrugproduct,throughanyindividualoranycombinationofthepotentialsourceslistedabove.Duringtheriskassessment,thepotentialcontributionsfromeachofthesesourcesshouldbeconsideredtodeterminetheoverallcontributionofelementalimpuritiestothedrugproduct.下图表示了一种药品生产中所用的典型物料、设备和成分的一个例子。通过单独或上列潜在来源的联合，每种来源均可能引起药品中的元素杂质污染。在风险评估中，任何一种来源的潜在作用均应进行考虑，以确定对药品造成的总体元素杂质污染。*Theriskofinclusionofelementalimpuritiescanbereducedthroughprocessunderstanding,equipmentselection,equipmentqualificationandGoodManufacturingPractice(GMP)processes.通过对工艺的了解、设备的选择、设备确认和GMP，可以降低元素杂质引入风险。**Theriskofinclusionofelementalimpuritiesfromwatercanbereducedbycomplyingwithcompendial(e.g.,EuropeanPharmacopoeia,JapanesePharmacopoeia,USPharmacopeialConvention)waterqualityrequirements,ifpurifiedwaterorwaterforinjectionisusedinthemanufacturingprocess(es).如果在生产工艺中使用了纯化水或注射用水，从水中引入元素杂质的风险可能通过符合药典水质量来降低(例如，欧洲药典、日本药典、美国药典)。IdentificationofPotentialElementalImpurities潜在元素杂质的识别Potentialelementalimpuritiesderivedfromintentionallyaddedcatalystsandinorganicreagents:IfanyelementlistedinTable5.1isintentionallyadded,itshouldbeconsideredintheriskassessment.Forthiscategory,theidentityofthepotentialimpuritiesisknownandtechniquesforcontrollingtheelementalimpuritiesareeasilycharacterizedanddefined.来自有意加入的催化剂和无机试剂的潜在元素杂质：如果有意地加入了表5.1中的任何元素，则应在风险评估中考虑。对此类情况，潜在杂质是已知的，控制元素杂质的技术易于制订。Potentialelementalimpuritiesthatmaybepresentindrugsubstancesand/orexcipients:Whilenotintentionallyadded,someelementalimpuritiesmaybepresentinsomedrugsubstancesand/orexcipients.Thepossibilityforinclusionoftheseelementsinthedrugproductshouldbereflectedintheriskassessment.可能会出现在原料药和/或辅料中的潜在元素杂质：在非有意加入情况下，有些元素杂质可能会出在有些原料药和/或辅料中。在风险评估中要反映药品中含有这些元素的可能性。Fortheoralrouteofadministration,theriskassessmentshouldevaluatethepossibilityforinclusionofClass1andClass2Aelementalimpuritiesinthedrugproduct.Forparenteralandinhalationroutesofadministration,theriskassessmentshouldevaluatethepossibilityforinclusionoftheClass1,Class2AandClass3elementalimpuritiesasshowninTable5.1.对于口服给药途径，风险评估应评价药品中含有1类和2A类元素杂质的可能性。对于注射和吸入给药途径，风险评估应评价含有1类、2A类和3类元素杂质的可能性，如表5.1所示。Potentialelementalimpuritiesderivedfrommanufacturingequipment:Thecontributionofelementalimpuritiesfromthissourcemaybelimitedandthesubsetofelementalimpuritiesthatshouldbeconsideredintheriskassessmentwilldependonthemanufacturingequipmentusedintheproductionofthedrugproduct.Applicationofprocessknowledge,