USP-232中英对照PF40(2)

PF40(2)USP232ElementalImpurities-Limits(USP38-NF331S)中英对照USPexpectstherevisionstobecomeofficialonAug.1,2015Page1of9232ELEMENTALIMPURITIES-LIMITSINTRODUCTIONThisgeneralchapterspecifieslimitsfortheamountsofelementalimpuritiesindrugproducts.Elementalimpuritiesincludecatalystsandenvironmentalcontaminantsthatmaybepresentindrugsubstances,excipients,ordrugproducts.Theseimpuritiesmayoccurnaturally,beaddedintentionally,orbeintroducedinadvertently(e.g.,byinteractionswithprocessingequipmentandthecontainerclosuresystem).Whenelementalimpuritiesareknowntobepresent,havebeenadded,orhavethepotentialforintroduction,assuranceofcompliancetothespecifiedlevelsisrequired.Arisk-basedcontrolstrategymaybeappropriatewhenanalystsdeterminehowtoassurecompliancewiththisstandard.Duetotheubiquitousnatureofarsenic,cadmium,lead,andmercuy,they(attheminimum)mustbeconsideredintherisk-basedcontrolstrategy.Regardlessoftheapproachused,compliancewiththelimitsspecifiedisrequiredforalldrugproductsunlessotherwisespecifiedinanindividualmonographorexcludedinparagraphthreeofthisintroduction.Thelimitspresentedinthischapterdonotapplytoexcipientsanddrugsubstances,exceptwherespecifiedinthischapterorintheindividualmonographs.However,elementalimpuritylevelspresentindrugsubstancesandexcipientsmustbeknown,andreporteddocumented,andmadeavailableuponrequest.Thelimitsindicatedinthischapterarenotrequiredforarticlesintendedonlyforveterinaryuseandconventionalvaccines.Requirementslistedinthischapteralso元素杂质-限度介绍本通则规定了制剂中元素杂质的限度。元素杂质包括原料药、辅料或制剂中可能出现的催化剂和环境污染物。这些杂质可能本身就存在，也有可能是有意加入或无意引入的（如生产设备和密封容器的相互作用）。当元素杂质已知存在、已经加入或有可能引入时，必须保证杂质符合规定限度。当分析人员确定是否符合标准时，可以适当采用基于风险的控制策略。由于砷（As）、镉（Cd）、铅（Pb）和汞（Hg）是自然界普遍存在的元素，采用基于风险的控制策略时至少要考虑这四种元素。无论采用何种方法，所有制剂产品必须符合规定限度，除各论另行规定或本介绍章节第三段描述的产品外。本通则所列限度不适用于辅料和原料药，本通则或各论另行规定除外。但是原料药和辅料中的元素杂质水平必须已知、记录、需要时提供。本通则所列限度不适用于兽药和传统疫苗。本通则所述要求也不适用于全胃肠外营养和透析液。膳食补充剂及其成分参见USP2232膳食补充剂中的污染元素。PF40(2)USP232ElementalImpurities-Limits(USP38-NF331S)中英对照USPexpectstherevisionstobecomeofficialonAug.1,2015Page2of9donotapplytototalparenteralnutritions(TPNs)anddialysates.DietarysupplementsandtheiringredientsareaddressedinElementalContaminantsinDietarySupplements2232.SPECIATIONThedeterminationoftheoxidationstate,organiccomplex,orcombinationistermedspeciation.Eachoftheelementalimpuritieshasthepotentialtobepresentindifferingoxidationorcomplexationstates.However,arsenicandmercuryareofparticularconcernbecauseofthedifferingtoxicitiesoftheirinorganicandcomplexedorganicforms.Thearseniclimitsarebasedontheinorganic(mosttoxic)form.Arseniccanbemeasuredusingatotal-arsenicprocedureundertheassumptionthatallarseniccontainedinthematerialundertestisintheinorganicform.Wherethelimitisexceededusingatotalarsenicprocedure,itmaybepossibletoshowviaaprocedurethatquantifiesthedifferentformsthattheinorganicformmeetsthespecification.Themercurylimitsarebasedupontheinorganic(2+)oxidationstate.Themethylmercuryform(mosttoxic)israrelyanissueforpharmaceuticals.Thus,thelimitwasestablishedassumingthemostcommon(mercuric)inorganicform.Limitsforarticlesthathavethepotentialtocontainmethylmercury(e.g.,materialsderivedfromfish)aretobeprovidedinthemonograph.ROUTESOFEXPOSUREThetoxicityofanelementalimpurityisrelatedtoitsextentofexposure(bioavailability).Theextentofexposurehasbeendeterminedforeachoftheelementalimpuritiesofinterestfor杂质形态测定到的氧化态、有机络合物或复合态称为杂质形态。每种元素杂质都可能以不同的氧化态或络合态存在。但是，砷和汞因其无机形态和络合形态均具有不同毒性，故需特别关注。砷的限度是基于其无机形态（毒性最大）。可以用总砷测试法来测定砷，即假设待测物料中的砷均为无机形态。如果用总砷测试法，结果超出限度，可通过其它方法定量检测砷的不同形态，证明无机形态符合质量标准。汞的限度是基于其无机（2+）氧化态。甲基汞形态（毒性最大）在药物中十分罕见，因此，汞的限度是假设其为最常见的无机形态（二价汞）制定的。可能含有甲基汞的产品（如鱼制品），其限度在各论中有规定。接触途径元素杂质的毒性与其接触程度（生物利用度）有关。根据三种给药途径：口服、注射和吸入，每种目标元素杂质的接触程度已经确定。限度是基于长期接触条件制定的。PF40(2)USP232ElementalImpurities-Limits(USP38-NF331S)中英对照USPexpectstherevisionstobecomeofficialonAug.1,2015Page3of9threeroutesofadministration:oral,parenteral,andinhalational.Theselimitsarebasedonchronicexposure.Theothertworoutesofadministration,mucosalandtopical,areconsideredtobethesameasoralforthepurposeofthisstandard,andthePDEsdescribedinTable1wouldapplytotheseproducts.Toaccountforthepotentialapplicationoftopicalproductstoinjuredorbrokenskin,topicalproductpermissibledailyexposures(PDEs)willbethesameasoralTable1,exceptasindicatedintheindividualmonograph.MucosalwillalsouseoralPDEs,exceptwhereotherwisestatedintheindividualmonograph.[NOTE—TheroutesofadministrationofdrugproductsaredefinedingeneralchapterPharmaceuticalDosageForms1151.]DRUGPRODUCTSThelimitsdescribedinthesecondthroughfourthcolumnsofTable1arethebasedailydosePDEsoftheelementalimpuritiesofinterestforadrugproducttakenbythepatientaccordingtoindicatedroutesofadministration.Parenteralswithanintendedmaximumdoseofgreaterthan10mLandnotmorethan100mLmustusetheSummationOption.Large-VolumeParenteralsWhenthedailydoseofaninjectionisgreaterthan100mL[largevolumeparenteral(LVP)],theamountofelementalimpuritiespresentinthedrugproductmustmaybecontrolledthroughtheindividualcomponentsusedtoproducetheproductcomponentoption.TheamountsofelementalimpuritiespresentineachcomponentusedinanLVParele