20141216 ICH Q3D 元素雜質(zhì)指南

INTERNATIONALCONFERENCEONHARMONISATIONOFTECHNICALREQUIREMENTSFORREGISTRATIONOFPHARMACEUTICALSFORHUMANUSEICHHARMONISEDGUIDELINEGUIDELINEFORELEMENTALIMPURITIES元素雜質(zhì)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目錄刖言范圍潛在元素雜質(zhì)的安全評估口服、注射和吸入給藥中元素雜質(zhì)安全評估的原則其它給藥途徑元素雜質(zhì)水平高于已建立的PDE時的論證注射用藥元素分類元素雜質(zhì)的風險評估和控制通用原則元素雜質(zhì)的潛在來源潛在元素雜質(zhì)的識別建議中風險評估中考慮的元素評估風險評估過程總結(jié)生物技術衍生產(chǎn)品特殊考慮元素雜質(zhì)的控制CONVERTINGBETWEENPDESANDCONCENTRATIONLIMITSPDE和關注限度之間的轉(zhuǎn)換SPECIATIONANDOTHERCONSIDERATIONSANALYTICALPROCEDURESLIFECYCLEMANAGEMENTGLOSSARYREFERENCESAppendix1:MethodforEstablishingExposureLimitsAppendix2:EstablishedPDEsforElementalImpuritiesAppendix3:IndividualSafetyAssessmentsAppendix4:IllustrativeExamples物種形成和其它考慮分析方法生命周期管理術語參考文獻附錄1：建立暴露限度的方法附錄2：已建立的元素雜質(zhì)PDE附錄3：單獨安全評估附錄4：舉例說明GUIDELINEFORELEMENTALIMPURITIES元素雜質(zhì)指南Q3DINTRODUCTION介紹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).藥品中的元素雜質(zhì)可能會有幾個來源，它們可能是有意加入合成反應的催化劑的殘留，也可能是作為雜質(zhì)出現(xiàn)(例如，通過與工藝設備或容器/密閉系統(tǒng)相互反應，或出現(xiàn)在藥品的組分中)。由于元素雜質(zhì)并不給患者提供任何治療益處，其在藥品中的水平應被控制在可接受限度以內(nèi)。本指南分為三個部分：潛在元素雜質(zhì)毒性數(shù)據(jù)的評估、為每個毒性關注元素建立PDE值，以及應用基于風險的方法來控制藥品中的元素雜質(zhì)。如果藥品中的元素雜質(zhì)沒有超過PDE閾值的話，申報人不需要根據(jù)其工藝能力加嚴限度。本指南中建立的PDE閾值足以保護所有患者人群的公共健康。在有些情況下，如果毒性閾值以下的元素雜質(zhì)水平表示出對藥品的其它質(zhì)量屬性有影響(例如，對藥品降解有催化作用的元素)，則可能需要保證一個更低的元素雜質(zhì)水平。另外，對于具有較高PDE值的元素，可能需要從藥品質(zhì)量的角度，以及要參照的其它指南（例如ICHQ3A）來考慮其它限度。ThisguidelinepresentsaprocesstoassessandcontrolelementalimpuritiesinthedrugproductusingtheprinciplesofriskmanagementasdescribedinICHQ9.Thisprocessprovidesaplatformfordevelopingarisk-basedcontrolstrategytolimitelementalimpuritiesinthedrugproduct.本指南給出一個采用ICHQ9中所述風險管理原則來評估和控制藥品中元素雜質(zhì)的方法。該方法提供了一個基于風險控制策略的平臺來限制藥品中的元素雜質(zhì)。SCOPE范圍Theguidelineappliestonewfinisheddrugproducts(asdefinedinICHQ6AandQ6B)andnewdrugproductscontainingexistingdrugsubstances.Thedrugproductscontainingpurifiedproteinsandpolypeptides(includingproteinsandpolypeptidesproducedfromrecombinantornon-recombinantorigins),theirderivatives,andproductsofwhichtheyarecomponents(e.g.,conjugates)arewithinthescopeofthisguideline,asaredrugproductscontainingsyntheticallyproducedpolypeptides,polynucleotides,andoligosaccharides.本指南適用于新的制劑產(chǎn)品(如ICHQ6A和Q6B定義)和含有已有原料藥的新藥品。含有純化后的蛋白質(zhì)和多肽(包括采用復合或非復合來源生產(chǎn)的蛋白質(zhì)和多肽)的藥品、其衍生物，以及其復方藥品(例如，偶合物)在本指南適用范圍內(nèi)。含有合成多肽、多核苷酸和低聚糖的藥品也適用本指南。Thisguidelinedoesnotapplytoherbalproducts,radiopharmaceuticals,vaccines,cellmetabolites,DNAproducts,allergenicextracts,cells,wholeblood,cellularbloodcomponentsorbloodderivativesincludingplasmaandplasmaderivatives,dialysatesolutionsnotintendedforsystemiccirculation,andelementsthatareintentionallyincludedinthedrugproductfortherapeuticbenefit.Thisguidelinedoesnotapplytoproductsbasedongenes(genetherapy),cells(celltherapy)andtissue(tissueengineering).Insomeregions,theseproductsareknownasadvancedtherapymedicinalproducts.本指南不適用于草藥產(chǎn)品、放射性藥品、疫苗、細胞代謝物、DNA產(chǎn)品、過敏提取物、細胞、全血、細胞血成分或血液制品，包括血漿和血漿制品、非系統(tǒng)循環(huán)用透析液，和用于治療用途加入的元素。本指南不適用于基于基因(基因治療)、細胞(細胞治療)和組織(組織工程)的藥品。在有些地區(qū)，這些產(chǎn)品是作為先進治療藥品的。Thisguidelinedoesnotapplytodrugproductsusedduringclinicalresearchstagesofdevelopment.Asthecommercialprocessisdeveloped,theprinciplescontainedinthisguidelinecanbeusefulinevaluatingelementalimpuritiesthatmaybepresentinanewdrugproduct.本指南不適用于研發(fā)的臨床研究階段藥品。由于商業(yè)過程是在不斷發(fā)展的，評估新藥中可能出現(xiàn)的元素雜質(zhì)時也可應用本指南中的原則。ApplicationofQ3Dtoexistingproductsisnotexpectedpriorto36monthsafterpublicationoftheguidelinebyICH.在本指南由ICH發(fā)布后36個月內(nèi)，不需要對已有產(chǎn)品應用Q3D。SAFETYASSESSMENTOFPOTENTIALELEMENTALIMPURITIES潛在元素雜質(zhì)的安全評估PrinciplesoftheSafetyAssessmentofElementalImpuritiesforOral,ParenteralandInhalationRoutesofAdministration口服、注射和吸入給藥途徑的元素雜質(zhì)安全評估原則ThemethodusedforestablishingthePDEforeachelementalimpurityisdiscussedindetailinAppendix1.Elementsevaluatedinthisguidelinewereassessedbyreviewingthepubliclyavailabledatacontainedinscientificjournals,governmentresearchreportsandstudies,internationalregulatorystandards(applicabletodrugproducts)andguidance,andregulatoryauthorityresearchandassessmentreports.ThisprocessfollowstheprinciplesdescribedinICHQ3C:ResidualSolvents.Theavailableinformationwasreviewedtoestablishtheoral,parenteralandinhalationPDEs.Forpracticalpurposes,thePDEstobeappliedtothedrugproductthatarepresentedinAppendix2TableA.2.1havebeenroundedto1or2significantfigures.用于建立各元素雜質(zhì)的方法在附錄1中進行了討論。在本指南中評估的元素，是通過對科學雜質(zhì)、政府研發(fā)報告和研究、國際法規(guī)標準(適用于藥品)和指南、以及法規(guī)當局研究和評估報告里公眾可以獲得的數(shù)據(jù)進行審核得到的。該方法是根據(jù)ICHQ3C：殘留溶劑中所述的原則制訂的。對可以獲得的資料進行審核以建立口服、注射和吸入PDE值。為了實用，附錄2里表A.2.1中適用于藥品的PDE閾值被修約至1位或2位有效數(shù)字。AsummarysafetyassessmentidentifyingthecriticalstudyforsettingaPDEforeachelementisincludedinAppendix3.ThereareinsufficientdatatosetPDEsbyanyrouteofadministrationforiridium,osmium,rhodium,andruthenium.ThePDEsfortheseelementswereestablishedonthebasisoftheirsimilaritytopalladium.附錄3包括了一份各元素PDE設定的關鍵研究識別安全評估總結(jié)。對于銥、鋨、銠和銣沒有足夠的數(shù)據(jù)設定口服給藥途徑的PDE閾值。這些元素的PDE值是基于其與鈀的相似性上建立的。ThefactorsconsideredinthesafetyassessmentforestablishingthePDEarelistedbelowinapproximateorderofrelevance:在建立PDE所進行的安全評估中考慮的因素按大致的相關性順序列出如下：Thelikelyoxidationstateoftheelementinthedrugproduct;-藥品中的元素可能的氧化狀態(tài)Humanexposureandsafetydatawhenitprovidedapplicableinformation;-當其提供可用信息時，人類暴露量和安全數(shù)據(jù)Themostrelevantanimalstudy;-最相關的動物研究Routeofadministration;-給藥途徑Therelevantendpoint(s).-相關終點Standardsfordailyintakeforsomeoftheelementalimpuritiesdiscussedinthisguidelineexistforfood,water,air,andoccupationalexposure.Whereappropriate,thesestandardswereconsideredinthesafetyassessmentandestablishmentofthePDEs.在本指南中討論的有些元素雜質(zhì)日服用量的標準ThelongestdurationanimalstudywasgenerallyusedtoestablishthePDE.Whenashorterdurationanimalstudywasconsideredthemostrelevant,therationalewasprovidedintheindividualsafetyassessment.一般使用最長的動物研究時長來建立PDE值。如果有一個較短的動物研究時長被認為是最為相關的，則在單個安全評估中給出了其理由。Inhalationstudiesusingsolublesalts(whenavailable)werepreferredoverstudiesusingparticulatesforinhalationsafetyassessmentandderivationofinhalationPDEs.Dependingonavailabledata,inhalationPDEswerebasedoneitherlocal(respiratorysystem)orsystemictoxicity.ForPDEsestablishedforinhalation(andoralorparenteralroutesasapplicable),doseswerenormalizedtoa24-hour,7-dayexposure.相對使用粒子的研究，使用可溶性鹽（可獲得時）進行的吸入研究優(yōu)先用于吸入安全性評估和計算吸入PDE值。根據(jù)可獲得的數(shù)據(jù)，吸入PDE值是基于局部（噴霧系統(tǒng)）或系統(tǒng)性毒性的。對于為了吸入給藥建立的PDE值（適用時，和口服或注射途徑），劑量一般統(tǒng)一為24小時7天暴露時長。Intheabsenceofdataand/orwheredataareavailablebutnotconsideredsufficientforasafetyassessmentfortheparenteralandorinhalationrouteofadministration,modifyingfactorsbasedonoralbioavailabilitywereusedtoderivethePDEfromtheoralPDE:如果沒有數(shù)據(jù)，和/或有數(shù)據(jù)但認為不足以用于注射和/或吸入途徑的安全評估，則基于口服生物利用度的修正因子用于從口服PDE來推導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作為修正因子；?口服生物利用度>1%and<50%:除以10作為修正因子；?口服生物利用度>50%and<90%:除以2作為修正因子；以及?口服生物利用度>90%:除以1作為修正因子。Whereoralbioavailabilitydataoroccupationalinhalationexposurelimitswerenotavailable,acalculatedPDEwasusedbasedontheoralPDEdividedbyamodifyingfactorof100（Ref.1）.如果沒有口服生物利用度數(shù)據(jù)或職業(yè)吸入暴露限，則在根據(jù)口服PDE值計算出PDE值后除以修正因子100（參考文獻1）。OtherRoutesofAdministratio其它攝入途徑PDEswereestablishedfororal,parenteralandinhalationroutesofadministration.WhenPDEsarenecessaryforotherroutesofadministration,theconceptsdescribedinthisguidelinemaybeusedtoderivePDEs.AnassessmentmayeitherincreaseordecreaseanestablishedPDE.TheprocessofderivationofthePDEforanotherrouteofadministrationmayincludethefollowing:PDE是針對口服、注射和吸入給藥途徑建立的。如果需要其它給藥途徑的PDE，則可以使用本指南的概念來推導PDE。評估結(jié)果可能會升高或降低已建立的PDE值。從一種給藥途徑推導出另一種給藥途徑的PDE值的計算過程包括以下：?ConsidertheoralPDEinAppendix3asastartingpointindevelopingaroute-specificPDE.Basedonascientificevaluation,theparenteralandinhalationPDEsmaybeamoreappropriatestartingpoint.將附錄3中的口服PDE作為建立攝入途徑特定PDE的起始點?；诳茖W評價，注射和吸入PDE可能是一個更適當?shù)钠鹗键c。?Assessiftheelementalimpurityisexpectedtohavelocaleffectswhenadministeredbytheintendedrouteofadministration:評估該元素雜質(zhì)在通過預定給藥途徑攝入時是否預期產(chǎn)生局部影響Iflocaleffectsareexpected,assesswhetheramodificationtoanestablishedPDEisnecessary.?如果預期有局部影響，需要評估是否要對已建立的PDE進行修正Considerthedoses/exposuresatwhichtheseeffectscanbeexpectedrelativetotheadverseeffectthatwasusedtosetanestablishedPDE.?考慮預期產(chǎn)生這些影響時的劑量/暴露量，與用于設定已建立的PDE所用的不良反應相比較Iflocaleffectsarenotexpected,noadjustmenttoanestablishedPDEisnecessary.?如果預期沒有局部影響，則對于已建立的PDE不需要進行調(diào)整■Ifavailable,evaluatethebioavailabilityoftheelementviatheintendedrouteofadministrationandcomparethistothebioavailabilityoftheelementbytheroutewithanestablishedPDE:■如果可以，應評估該元素的通過預定給藥途徑的生物利用度，并將此與該元素通過已建立PDE的給藥途徑的生物利用度進行比較Whenadifferenceisobserved,acorrectionfactormaybeappliedtoanestablishedPDE.Forexample,whennolocaleffectsareexpected,iftheoralbioavailabilityofanelementis50%andthebioavailabilityofanelementbytheintendedrouteis10%,acorrectionfactorof5maybeapplied.?如果觀察到差異，則可能需要對已建立的PDE值使用校正因子。例如，如果預期有局部影響，如果一種元素的口服生物利用度為50%，一種元素的生物利用度在預定的給藥途徑為10%，則可以使用5作為校正因子■IfaPDEproposedforthenewrouteisincreasedrelativetoanestablishedPDE,qualityattributesmayneedtobeconsidered.如果提議一種新的給藥途徑的PDE相對于已建立的PDE有增加，則可能需要考慮對質(zhì)量屬性JustificationforElementalImpurityLevelsHigherthananEstablishedPDE元素雜質(zhì)水平高于已建立的PDE水平時的論證LevelsofelementalimpuritieshigherthananestablishedPDE(seeTableA.2.1)maybeacceptableincertaincases.Thesecasescouldinclude,butarenotlimitedto,thefollowingsituations:元素雜質(zhì)水平高于已建立的PDE時(參見表A.2.1)，在特定情況下可能也可以接受。這些情況可能包括但不僅限于以下情形：-Intermittentdosing;-間歇給藥Shorttermdosing(i.e.,30daysorless);-短期給藥(即，30天或更短)Specificindications(e.g.,life-threatening,unmetmedicalneeds,rarediseases).-特定指示(例如，生命威脅、藥品供給不足、罕見病)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(參見2.3)對升高的元素雜質(zhì)水平進行論證的例子。其它方法也可以用來論證較高的雜質(zhì)水平。提議任何高于已建立的PDE的雜質(zhì)水平均需根據(jù)各案進行論證。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出現(xiàn)在口服藥品中。元素X各論見附錄3,其NOAEL水平為1.1mg/kg/天。修正因子F1-F5分別設定為5、10、5、1和1。使用附錄1中所述的修正因子標準方法，PDE計算如下：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(默認=10)可以分成2個子因子，一個作為毒性動力學(TK)，另一個作為毒理動力學，2個因子范圍均為1-3.16。采用5天使用血漿半衰期，對于每次一周攝入(-1半衰期)TK調(diào)整因子可以降低為1.58,對于每次一個月攝入(-5個半衰期)可以降低為1。通過對F2使用子因子方法，元素X每次一周攝入建議水平可以計算如下：Proposedlevel建議水平=1.1mg/kg/dx50kg/5x(1.6x3.16)x5x1x1=440pg/dayForpracticalpurposes,thisvalueisroundedto400pg/day.為了實用，該值修約為400pg/day。Example2:TheTKadjustmentfactorapproachmayalsobeappropriateforelementalimpuritiesthatwerenotdevelopedusingthemodifyingfactorapproach.ForelementZ,aMinimalRiskLevel(MRL)of0.02mg/kg/daywasusedtoderivetheoralPDE.Fromliteraturesources,theplasmahalf-lifewasreportedtobe4days.Thiselementisanimpurityinanoraldrugproductadministeredonceevery3weeks(~5half-lives).Usingfirst-orderkinetics,theestablishedPDEof1000pg/dayismodifiedasfollows:例2：TK調(diào)整因子方法可能也適用于未采用修正因子方法建立的元素雜質(zhì)。對于元素乙最低風險水平(MRL)為0.02mg/kg/天用以計算口服PDE值。從文獻來看，血漿半衰期報道為4天。該元素是口服給藥中的一個雜質(zhì)，藥品每三周給藥一次(-5個半衰期)。使用一級動力學，已建立的PDE為1000pg/天修正如下：Proposedlevel提議的水平=0.02mg/kg/dx50kg/1/3.16=3.16mg/dayForpracticalpurposes,thisvalueisroundedto3000pg/day.為實用起見，該值修約為3000pg/天。ParenteralProducts注射用藥Parenteraldrugproductswithmaximumdailyvolumesupto2litersmayusethemaximumdailyvolumetocalculatepermissibleconcentrationsfromPDEs.Forproductswhosedailyvolumes,asspecifiedbylabelingand/orestablishedbyclinicalpractice,mayexceed2liters(e.g.,saline,dextrose,totalparenteralnutrition,solutionsforirrigation),a2-litervolumemaybeusedtocalculatepermissibleconcentrationsfromPDEs.(Ref.4)注射用藥如果最大日給藥體積達到2L,則可以使用最大日給藥體積來計算PDE的允許濃度。對于日劑量在標簽上注明和/或臨床確定的藥品，可以超過2L(例如，生理鹽水、葡萄糖、總注射用營養(yǎng)、沖注洗劑)，2L的體積可以用于計算PDE的允許濃度(參考文獻4)。ELEMENTCLASSIFICATION元素分類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據(jù)其毒性(PDE)及在藥品中出現(xiàn)的可能性分入三類。出現(xiàn)可能性是從幾個因素中推導出的，包括：在制藥工藝中使用的可能性、制藥工藝中使用的原料里含有的雜質(zhì)會產(chǎn)生共析的雜質(zhì)可能性，以及觀察到自然中富含的元素和在環(huán)境中廣泛分布的元素。根據(jù)本指南的目的，一種在自然中存量較低的元素指其自然含量<1個原子/106個硅原子(參考文獻5)。分類表目的是將風險評估的焦點集中在那些最毒，且最可能出現(xiàn)在藥品中的元素上(參見表5.1)。元素雜質(zhì)分類為：Class1:Theelements,As,Cd,Hg,andPb,arehumantoxicantsthathavelimitedornouseinthemanufactureofpharmaceuticals.Theirpresenceindrugproductstypicallycomesfromcommonlyusedmaterials(e.g.,minedexcipients).Becauseoftheiruniquenature,thesefourelementsrequireevaluationduringtheriskassessment,acrossallpotentialsourcesofelementalimpuritiesandroutesofadministration.TheoutcomeoftheriskassessmentwilldeterminethosecomponentsthatmayrequireadditionalcontrolswhichmayinsomecasesincludetestingforClass1elements.ItisnotexpectedthatallcomponentswillrequiretestingforClass1elementalimpurities;testingshouldonlybeappliedwhentheriskassessmentidentifiesitastheappropriatecontroltoensurethatthePDEwillbemet.第1類：元素砷、鎘、汞和鉛是對人有毒性的物質(zhì)，已限制或不再用于藥品生產(chǎn)中。其在藥品中出現(xiàn)一般是來自于通常使用的物料(例如，礦物質(zhì)輔料)。由于其獨特的屬性，這四種元素需要在風險評估中進行評價，要針對元素雜質(zhì)的所有潛在來源以及所有的攝入途徑。風險評估的結(jié)果將決定這些組成是否需要增加控制，在有些情況下要包括對一類元素的檢測。不需要對所有成分進行一類元素雜質(zhì)的檢測，只有在風險評估認為需要對其進行適當控制以保證符合PDE要求時才要進行檢測。Class2:Elementsinthisclassaregenerallyconsideredasroute-dependenthumantoxicants.Class2elementsarefurtherdividedinsub-classes2Aand2Bbasedontheirrelativelikelihoodofoccurrenceinthedrugproduct.第2類：本類別中的元素一般被認為是與攝入途徑相關的人類有毒物質(zhì)。根據(jù)其出現(xiàn)在藥品的相對可能性，2類元素又被分為2A和2B兩個子類。?Class2Aelementshaverelativelyhighprobabilityofoccurrenceinthedrugproductandthusrequireriskassessmentacrossallpotentialsourcesofelementalimpuritiesandroutesofadministration(asindicated).Theclass2Aelementsare:Co,NiandV.2A類：在藥品中出現(xiàn)可能性相對較高的元素，因而需要對所有元素雜質(zhì)的潛在來源及所有攝入途徑(如所指)進行風險評估。2A類元素為鉆、鎳和釩。?Class2Belementshaveareducedprobabilityofoccurrenceinthedrugproductrelatedtotheirlowabundanceandlowpotentialtobeco-isolatedwithothermaterials.Asaresult,theymaybeexcludedfromtheriskassessmentunlesstheyareintentionallyaddedduringthemanufactureofdrugsubstances,excipientsorothercomponentsofthedrugproduct.Theelementalimpuritiesinclass2Binclude:Ag,Au,Ir,Os,Pd,Pt,Rh,Ru,SeandTl.2B類：由于自然含量較低、與其它物料共存可能性較低，在藥品中出現(xiàn)的可能性較低的元素。因此，除非其在原料藥、輔料或藥品的其它成分生產(chǎn)中被有意加入，否則可能被排除在風險評估以外。2B類的元素雜質(zhì)包括：銀、金、銥、鋨、鈀、伯、銠、銣、硒和鉈。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類：本類的中元素在口服攝入時具有相對較低的毒性(高PDE，通常＞500pg/day),但可能在吸入和注射給藥的風險評估中需要進行考慮。對于口服攝入，除非這些元素被有意加入，否則不需要在風險評估中進行考慮。對于注射和吸入給藥藥品，除非給藥途徑的PDE超過500pg/day，否則在風險評估中要評價這些元素雜質(zhì)出現(xiàn)的可能性。本類中的元素包括鋇、鉻、銅、鋰、鉬、銻和錫。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：有些元素雜質(zhì)因為其較低的毒性和/或在地方法規(guī)中的要求不同，其PDE還沒有建立，在本指南中并未說明。如果這些元素雜質(zhì)出現(xiàn)或包括在藥品中，其它指南和/或地方性法規(guī)和規(guī)范可能適用于特殊的元素(例如，鋁，損害腎功能，錳和鋅對于肝功能不全的病人)，或?qū)λ幤烦善返馁|(zhì)量考慮(例如，鎢雜質(zhì)在治療性蛋白質(zhì)中出現(xiàn))。這些特殊考慮的元素包括：鋁、硼、鈣、鐵、鉀、鎂、錳、鈉、鎢和鋅。RISKASSESSMENTANDCONTROLOFELEMENTALIMPURITIES元素雜質(zhì)的風險評估和控制Indevelopingcontrolsforelementalimpuritiesindrugproducts,theprinciplesofqualityriskmanagement,describedinICHQ9,shouldbeconsidered.Theriskassessmentshouldbebasedonscientificknowledgeandprinciples.Itshouldlinktosafetyconsiderationsforpatientswithanunderstandingoftheproductanditsmanufacturingprocess(ICHQ8andQ11).Inthecaseofelementalimpurities,theproductriskassessmentwouldthereforebefocusedonassessingthelevelsofelementalimpuritiesinadrugproductinrelationtothePDEspresentedinthisguidance.Informationforthisriskassessmentincludesbutisnotlimitedto:datageneratedbytheapplicant,informationsuppliedbydrugsubstanceand/orexcipientmanufacturersand/ordataavailableinpublishedliterature.在建立藥品中元素雜質(zhì)的控制方式時，要考慮ICHQ9中所述的質(zhì)量風險管理的原則。風險評估應基于科學知識和原則，應將對產(chǎn)品和其生產(chǎn)工藝的了解（ICHQ8和Q11）與對患者的安全考慮相關聯(lián)。對于元素雜質(zhì)來說，藥品風險分析就應聚焦于結(jié)合本指南中所給出的PDE來評估一種藥品中的元素雜質(zhì)水平。風險評估的資料包括，但不僅限于：申請人產(chǎn)生的數(shù)據(jù)、原料藥和/或輔料生產(chǎn)商提供的資料，和/或在公開的文獻中可以獲得的數(shù)據(jù)。Theapplicantshoulddocumenttheriskassessmentandcontrolapproachesinanappropriatemanner.Thelevelofeffortandformalityoftheriskassessmentshouldbeproportionaltothelevelofrisk.Itisneitheralwaysappropriatenoralwaysnecessarytouseaformalriskmanagementprocess（usingrecognizedtoolsand/orformalprocedures,e.g.,standardoperatingprocedures.）Theuseofinformalriskmanagementprocesses（usingempiricaltoolsand/orinternalprocedures）mayalsobeconsideredacceptable.ToolstoassistintheriskassessmentaredescribedinICHQ8andQ9andwillnotbepresentedinthisguideline.申報者應以適當?shù)姆绞接涗涳L險評估和控制方法。風險評估和努力水平和正式程度應與風險水平相稱。沒有必要每次都使用正式的風險管理過程（使用已知的工具和/或正式程序，例如，標準操作程序）。也可以使用非正式的風險評估過程（使用經(jīng)驗工具和或內(nèi)部程序）。風險評估中輔助工具在ICHQ8和Q9中已有描述，本指南中不再贅述。GeneralPrinciple通則Forthepurposesofthisguideline,theriskassessmentprocesscanbedescribedinthreesteps:出于本指南的目的，風險評估過程可以描述為以下三步：-Identifyknownandpotentialsourcesofelementalimpuritiesthatmayfindtheirwayintothedrugproduct.-識別已知和潛在可能進入藥品的元素雜質(zhì)來源，-EvaluatethepresenceofaparticularelementalimpurityinthedrugproductbydeterminingtheobservedorpredictedleveloftheimpurityandcomparingwiththeestablishedPDE.-通過測試已知或預期雜質(zhì)，將其水平與已有PDE值比較，評估藥品中特殊的元素雜質(zhì)出現(xiàn)的可能性Summarizeanddocumenttheriskassessment.Identifyifcontrolsbuiltintotheprocessaresufficientoridentifyadditionalcontrolstobeconsideredtolimitelementalimpuritiesinthedrugproduct.-總結(jié)和記錄風險評估。識別出工藝中嵌入控制是否充分，或識別出要考慮增加控制來限制藥品中的元素雜質(zhì)Inmanycases,thestepsareconsideredsimultaneously.TheoutcomeoftheriskassessmentmaybetheresultofiterationstodevelopafinalapproachtoensurethepotentialelementalimpuritiesdonotexceedthePDE.在很多情況下，這些步驟其實是同步的。風險評估的結(jié)果，可以是一個迭代的結(jié)果，用以建立一種方法來保證潛在元素雜質(zhì)不超過PDE值。PotentialSourcesofElementalImpuriti元素雜質(zhì)的潛在來源Inconsideringtheproductionofadrugproduct,therearebroadcategoriesofpotentialsourcesofelementalimpurities.在考慮一種藥品的生產(chǎn)時，元素雜質(zhì)的潛在來源有很多。Residualimpuritiesresultingfromelementsintentionallyadded(e.g.,catalysts)intheformationofthedrugsubstance,excipientsorotherdrugproductcomponents.Theriskassessmentofthedrugsubstanceshouldaddressthepotentialforinclusionofelementalimpuritiesinthedrugproduct.-在生產(chǎn)原料藥、輔料或其它藥品成分時有意加入的元素的殘留雜質(zhì)(例如催化劑)。原料藥的風險評估要說明元素雜質(zhì)出現(xiàn)在藥品中的可能性Elementalimpuritiesthatarenotintentionallyaddedandarepotentiallypresentinthedrugsubstance,waterorexcipientsusedinthepreparationofthedrugproduct.-非有意加入，可能會在藥品制備過程中出現(xiàn)在原料藥、水或輔料中的元素雜質(zhì)Elementalimpuritiesthatarepotentiallyintroducedintothedrugsubstanceand/ordrugproductfrommanufacturingequipment.-可能從生產(chǎn)設備引入原料藥和/或制劑的元素雜質(zhì)Elementalimpuritiesthathavethepotentialtobeleachedintothedrugsubstanceanddrugproductfromcontainerclosuresystems.-可能從容器密閉系統(tǒng)中溶出至原料藥和制劑的元素雜質(zhì)Thefollowingdiagramshowsanexampleoftypicalmaterials,equipmentandcomponentsusedintheproductionofadrugproduct.Eachofthesesourcesmaycontributeelementalimpuritiestothedrugproduct,throughanyindividualoranycombinationofthepotentialsourceslistedabove.Duringtheriskassessment,thepotentialcontributionsfromeachofthesesourcesshouldbeconsideredtodeterminetheoverallcontributionofelementalimpuritiestothedrugproduct.下圖表示了一種藥品生產(chǎn)中所用的典型物料、設備和成分的一個例子。通過單獨或上列潛在來源的聯(lián)合，每種來源均可能引起藥品中的元素雜質(zhì)污染。在風險評估中，任何一種來源的潛在作用均應進行考慮，以確定對藥品造成的總體元素雜質(zhì)污染。*Theriskofinclusionofelementalimpuritiescanbereducedthroughprocessunderstanding,equipmentselection,equipmentqualificationandGoodManufacturingPractice(GMP)processes.通過對工藝的了解、設備的選擇、設備確認和GMP，可以降低元素雜質(zhì)引入風險。**Theriskofinclusionofelementalimpuritiesfromwatercanbereducedbycomplyingwithcompendial(e.g.,EuropeanPharmacopoeia,JapanesePharmacopoeia,USPharmacopeialConvention)waterqualityrequirements,ifpurifiedwaterorwaterforinjectionisusedinthemanufacturingprocess(es).如果在生產(chǎn)工藝中使用了純化水或注射用水，從水中引入元素雜質(zhì)的風險可能通過符合藥典水質(zhì)量來降低(例如，歐洲藥典、日本藥典、美國藥典)。IdentificationofPotentialElementalImpurities潛在元素雜質(zhì)的識別Potentialelementalimpuritiesderivedfromintentionallyaddedcatalystsandinorganicreagents:IfanyelementlistedinTable5.1isintentionallyadded,itshouldbeconsideredintheriskassessment.Forthiscategory,theidentityofthepotentialimpuritiesisknownandtechniquesforcontrollingtheelementalimpuritiesareeasilycharacterizedanddefined.來自有意加入的催化劑和無機試劑的潛在元素雜質(zhì)：如果有意地加入了表5.1中的任何元素，則應在風險評估中考慮。對此類情況，潛在雜質(zhì)是已知的，控制元素雜質(zhì)的技術易于制訂。Potentialelementalimpuritiesthatmaybepresentindrugsubstancesand/orexcipients:Whilenotintentionallyadded,someelementalimpuritiesmaybepresentinsomedrugsubstancesand/orexcipients.Thepossibilityforinclusionoftheseelementsinthedrugproductshouldbereflectedintheriskassessment.可能會出現(xiàn)在原料藥和/或輔料中的潛在元素雜質(zhì)：在非有意加入情況下，有些元素雜質(zhì)可能會出在有些原料藥和/或輔料中。在風險評估中要反映藥品中含有這些元素的可能性。Fortheoralrouteofadministration,theriskassessmentshouldevaluatethepossibilityforinclusionofClass1andClass2Aelementalimpuritiesinthedrugproduct.Forparenteralandinhalationroutesofadministration,theriskassessmentshouldevaluatethepossibilityforinclusionoftheClass1,Class2AandClass3elementalimpuritiesasshowninTable5.1.對于口服給藥途徑，風險評估應評價藥品中含有1類和2A類元素雜質(zhì)的可能性。對于注射和吸入給藥途徑，風險評估應評價含有1類、2A類和3類元素雜質(zhì)的可能性，如表5.1所示。Potentialelementalimpuritiesderivedfrommanufacturingequipment:Thecontributionofelementalimpuritiesfromthissourcemaybelimitedandthesubsetofelementalimpuritiesthatshouldbeconsideredintheriskassessmentwilldependonthemanufacturingequipmentusedintheproductionofthedrugproduct.Applicationofprocessknowledge,