重金属残留EMEA指导原则

EuropeanMedicinesAgencyPre-authorisationEvaluationofMedicinesforHumanUse7WestferryCircus,CanaryWharf,London,E144HB,UKTel.(44-20)74188400Fax(44-20)74188613E-mail:mail@emea.europa.euhttp://www.emea.europa.eu©EMEA2007Reproductionand/ordistributionofthisdocumentisauthorisedfornoncommercialpurposesonlyprovidedtheEMEAisacknowledgedLondon,January2007Doc.Ref.CPMP/SWP/QWP/4446/00corr.COMMITTEEFORHUMANMEDICINALPRODUCTS(CHMP)DraftGUIDELINEONTHESPECIFICATIONLIMITSFORRESIDUESOFMETALCATALYSTSDRAFTAGREEDBYTHESAFETYWORKINGPARTYJune1998-November2000ADOPTIONBYCHMPFORRELEASEFORCONSULTATIONJanuary2001ENDOFCONSULTATION(DEADLINEFORCOMMENTS)July2001DISCUSSIONINTHESWPOctober2001–June2002ADOPTIONBYCHMPFORRE-RELEASEFORCONSULTATIONJune2002DISCUSSIONINTHESWPFebruary2003–December2006ADOPTIONBYCHMPFORRE-RELEASEFORCONSULTATIONJanuary2007ENDOFCONSULTATION(DEADLINEFORCOMMENTS)23rdMay2007Commentsshouldbeprovidedusingthistemplatetoemea-h.swp@emea-h.eudra.orgFax+442074188613KEYWORDSMetalcatalysts,classification,concentrationlimitsofmetals,drugsubstance,excipients,PDE,administrationroutes,testingstrategies,reportinglevelsGUIDELINEONTHESPECIFICATIONLIMITSFORRESIDUESOFMETALCATALYSTSTABLEOFCONTENTSEXECUTIVESUMMARY...................................................................................................................31.INTRODUCTION(BACKGROUND)........................................................................................32.SCOPE............................................................................................................................................43.LEGALBASIS..............................................................................................................................44.MAINGUIDELINETEXT..........................................................................................................44.1CLASSIFICATIONOFMETALS...................................................................................................44.2EXPOSURELIMITS...................................................................................................................54.3SETTINGCONCENTRATIONLIMITSOFMETALS:ORALANDPARENTERALROUTES...............64.4OTHERADMINISTRATIONROUTES..........................................................................................74.5ACTIVESUBSTANCESUSEDFORSHORT-TERMONLY.............................................................74.6TESTINGSTRATEGY.................................................................................................................74.7ANALYTICALPROCEDURES.....................................................................................................84.8REPORTINGLEVELSOFMETALLICRESIDUES.........................................................................85.GLOSSARY...................................................................................................................................8REFERENCES(SCIENTIFICAND/ORLEGAL).........................................................................9APPENDIX1:RATIONALEFORPDESETTING..................................................................10APPENDIX2:MONOGRAPHSONELEMENTS...................................................................11PLATINUM(PT)...............................................................................................................................11PALLADIUM(PD)...........................................................................................................................13IRIDIUM(IR)....................................................................................................................................15RHODIUM(RH)...............................................................................................................................16RUTHENIUM(RU)..........................................................................................................................16OSMIUM(OS)..................................................................................................................................17MOLYBDENUM(MO)....................................................................................................................18NICKEL(NI).....................................................................................................................................19CHROMIUM(CR)............................................................................................................................21VANADIUM(V)..............................................................................................................................23COPPER(CU)...................................................................................................................................24MANGANESE(MN)........................................................................................................................26ZINC(ZN).........................................................................................................................................27IRON(FE).........................................................................................................................................29APPENDIX3:EXAMPLECALCULATIONSFORCONCENTRATIONLIMITS............30©EMEA20077Page2/32EXECUTIVESUMMARYThisguidelinerecommendsmaximumacceptablelimitsofmetalresiduesindrugsubstancesandexcipients.Residualmetalsusedasprocesscatalystsdonotprovideanytherapeuticbenefitandshouldthereforebeevaluatedandrestrictedonthefoundationofsafety-andquality-basedcriteria.Metalswillbeclassifiedinthreecategoriesbasedontheirindividuallevelsofsafetyconcernandconcentrationlimitswillbesetonthebasesofthemaximaldailydose,durationoftreatment,routeofadministrationandpermitteddailyexposure(PDE).Guidanceisalsogivenontestingstrategies,analyticalproceduresandreportinglevelsinexcipientsanddrugsubstances.1.INTRODUCTION(background)Theobjectiveofthisguidelineistorecommend,forthesafetyofthepatient,maximumacceptablemetalresiduesarisingfromtheuseofmetalsascatalystsorreagentsinthesynthesisofdrugsubstancesandexcipients.Sincethereisnotherapeuticbenefitfromresidualmetals,specificationacceptancecriteriashouldbeappliedtothosemetalspresentinthesepharmaceuticalsubstancesinamannerthatisconsistentwithsafety-andquality-basedcriteria.Sincetheuseofcatalystsorreagentsisrestrictedtodefinedchemicalreactionsinthesynthesisofpharmaceuticalsubstances,limitationofresiduesinthesesubstancesissufficient,andingeneralthereisnoneedtosetlimitsformetalresiduesinthefinalmedicinalproductscontainingthesesubstances.Thisguidelineconsidersmetalcatalystsandreagentsthatareactuallyusedinthesynthesisofpharmaceuticalsubstances;thatisthedrugsubstance(s)andexcipient(s).However,astheoriginofthemetalresiduesisirrelevantregardingtheirpotentialtoxiceffects,thesafetydatainthisguidelinecanalsobeusedforspecificmetalresiduesinpharmaceuticalproductswhichareresiduesfromothersources.Theguidelinedoesnotapplytometalsthataredeliberatecomponentsofthedrugsubstance(suchasacounterionofasalt)orareanexcipientinthedrugproduct(e.g.anironoxidepigment).ThemetalsincludedinthisguidelinearelistedinTable1.Generalconsiderationswithrespecttotheproposedpermitteddailyexposure(PDE)settingarediscussedinAppendix1.ForeachoftheincludedmetalsindividualmonographsareincludedinAppendix2.Inthereviewsthefollowingassumptionsand/ordefaultvaluesareused:•Bodyweight(bw)ofanadult:50kg.•Breathingvolumeofanadult:20m3perday(24h).•Occupational(workplace)inhalationexposure:8hperday(24h).•Exposurelimitswereestablishedusinguncertaintyfactorsasdescribedinappendix3oftheICHQ3Cguidance.•ForpragmaticreasonsanumberofuncertaintyfactorswereadaptedtoarriveatafinalsafeandpracticalPDEsetting-Q3Cmethodforuncertaintyfactor(UF)calculationplusadditionalpragmaticfactorforPDEcalculation.Acceptableadditionallifetimecancerrisk:anincreasedcancerriskof1in100,000wasidentifiedasacceptableforgenotoxicimpuritiesinpharmaceuticalsbytheCHMPLimitssetbasedonsafetycriteriamaythereforebehigherthanlimitssetonthebasisofGMP,processcapabilities,orothersuitablequalitycriteriaTheguidelinemaybeupdatedtoincludeothersourcesofmetalresiduesandadditionalelementsinduecourse.Anyinterestedpartycanmakearequestandsubmitrelevantsafetydata.Classificationandlimitsmaychangeasnewsafetydatabecomesavailable.©EMEA20077Page3/322.SCOPEMetalcatalystsandmetalreagentsaredefinedhereaschemicalsubstancesthatareusedtochangetherateofchemicalreactionsorwhichactonotherchemicalsubstancesinchemicalreactions.Forthepurposesofthisguideline,theyaresubstancesusedinthesynthesisofthedrugsubstanceoranexcipientusedinamedicinalproduct.Residuesofmetalscaneitherbepresentastheoriginalformofthemetalorasaformofthemetallicelementalteredbydownstreamchemicalprocessing.ExcludedfromthisdocumentareextraneousmetalcontaminantsthatshouldnotoccurindrugsubstancesorexcipientsandaremoreappropriatelyaddressedasGoodManufacturingPractice(GMP)issues.Thisguidelineappliestonewandexistingmarketeddrugproducts.Howeverforexistingmarketeddrugproductsatimelimitof5yearsissetfortheimplementationoftheguidelineincasesanearlierimplementationisnotfeasible.Thisguidelinedoesnotapplytopotentialnewdrugsubstances,orexcipients,usedduringtheclinicalresearchstagesofdevelopmentofamedicinalproduct.Differentlimitsareappliedtooralandparenteralroutesofadministrationduetolimitedoralbioavailabilityofmanymetals.Asdifferentroutesofexposuremayhavedifferenttoxicologicalproperties,specificlimitshavebeensetforinhalationexposuretosomemetals,seesection4.4.WhentheexposureisshortthePDE´smentionedinthisguidelinemaybeadaptedasindicatedinsection4.5.3.LEGALBASISThisguidelinehastobereadinconjunctionwithDirective2001/83/EC(asamended)andallrelevantCHMPGuidancedocumentswithspecialemphasison:NoteforGuidanceonImpuritiesinNewDrugProducts(CPMP/ICH/2738/99,ICHQ3B(R))ImpuritiesTestingGuideline:ImpuritiesinNewDrugSubstances(CPMP/ICH/2737/99,ICHQ3A)NoteforGuidanceonImpurities:ResidualSolvents(CPMP/ICH/283/95inconjunctionwithCPMP/ICH/1507/02)GuidelineontheLimitsofGenotoxicImpurities(CPMP/SWP/5199/02)4.MAINGUIDELINETEXT4.1ClassificationofmetalsThetermtolerabledailyintake(TDI)isusedbytheInternationalProgramonChemicalSafety(IPCS)todescribeexposurelimitsoftoxicchemicalsandthetermacceptabledailyintake(ADI)isusedbytheWorldHealthOrganization(WHO)andothernationalandinternationalhealthauthoritiesandinstitutes.ToavoidconfusionofdifferingvaluesforADI’softhesamesubstanceandsimilartotheICHQ3Cguidelineforresidualsolvents,thepermitteddailyexposure(PDE)foreachoftheevaluatedmetalswasdefined.InthepresentguidancethePDEisthepharmaceuticallymaximumacceptableexposuretoresidualmetalsonachronicbasisthatisunlikelytoproduceanyadversehealtheffects.PDEappliestoeachpharmaceuticalsubstance.Metalswereevaluatedfortheirpotentialrisktohumanhealthandplacedintooneofthreeclassesasfollows:Class1Metals:Metalsofsignificantsafetyconcern©EMEA20077Page4/32Knownorsuspecthumancarcinogens,orpossiblecausativeagentsofothersignificanttoxicity.Class2metals:MetalswithlowsafetyconcernMetalswithlowertoxicpotentialtoman.Theyaregenerallywelltolerateduptoexposuresthatarerelevanttothecontextofthisguideline.Theymaybetracemetalsrequiredfornutritionalpurposesortheyareoftenpresentinfoodstuffsorreadilyavailablenutritionalsupplements.Class3metals:MetalswithminimalsafetyconcernMetalswithnosignificanttoxicity.Theirsafetyprofileiswellestablished.Theyaregenerallywelltolerateduptodosesthatarewellbeyonddosesrelevanttothecontextofthisguideline.Typicallytheyareubiquitousintheenvironmentortheplantandanimalkingdoms.Foreachoftheseclassesexposure/concentrationlimitsweredefinedasdescribedinsection4.2.4.2ExposureLimitsBasedonPDEsestablishedforeachindividualmetal(Appendix2)inaparticularclassageneralsetofsafetybasedlimitsisdefinedtakingintoaccounttherouteofadministration.Class1issubdividedinto3subclasses.Platinoidsareinclass1Aandclass1B.Fortheplatinoidsinsubclass1Baconservativeapproachhasbeenadopted,becausethereareverylimitedtoxicitydata.ThustheindicatedlimitforClass1Bisthelimitforthetotalamountofthoseplatinoidsthat,basedontheusedsynthesisprocedures,areanticipatedtobepresent.Oralandparenteralexposure/concentrationlimitspermetalforthedifferentmetalclassesandalistingofthemetalsincludedineachclassarepresentedintable1.©EMEA20077Page5/32Table1:ClassExposureandConcentrationLimitsforIndividualMetalCatalystsandMetalReagentsOralExposureParenteralExposureClassificationPDE(µg/day)Concentration(ppm)PDE(µg/day)Concentration(ppm)Class1A:Pt,PdClass1B:Ir,Rh,Ru,OsClass1C:Mo,Ni,Cr,VMetalsofsignificantsafetyconcern100100**3001010**3010*10**30*1*1**3*Class2:Cu,MnMetalswithlowsafetyconcern250025025025Class3:Fe,ZnMetalswithminimalsafetyconcern1300013001300130*SpecificlimitshavebeensetforinhalationexposuretoPlatinum,ChromiumVIandNickel(seesection4.4andtherespectivemonographs**Subclasslimit:thetotalamountoflistedmetalsshouldnotexceedtheindicatedlimit4.3SettingConcentrationLimitsofMetals:OralandParenteralRoutesTwooptionsareavailablewhensettinglimits/definingacceptancecriteriaformetalresidues.Option1:Perindividualmetaltheconcentrationlimitsinpartspermillion(ppm)statedinTable1canbeused.Theywerecalculatedusingequation(1)belowbyassumingamaximumdailydose(MDD)of10grams(g)administereddaily.(1)Concentration(ppm)=PDEMDDThePDEisgivenintermsofμg/dayandMDDisgivening/day.Theselimitsareconsideredacceptableforalllistedmetalresiduespresentindrugsubstances,excipients,orproductsandcanbeappliedforeachindividualmetal.Thisoptionmaybeappliedifthedailydoseisnotknownorfixed.Nofurthercalculationisnecessaryprovidedthedailydosedoesnotexceed10g.Productsthatareadministeredindosesgreaterthan10gperdayshouldbeconsideredunderOption2.Option2:WhenamaximumdailydoseisknownthismaybeusedtogetherwiththePDEintermsofµg/dayasstatedintable1andequation(1)abovetodeterminetheconcentrationofresidualmetalallowedinthedrugproduct.Alternatively,itmaybethattheanalyticalprocedureforthemetaltobelimiteddoesnothavetherequiredsensitivityforroutineuse(e.g.tosupporttheClass1limitforparenteralroute).Inthiscase,applicationofOption2canbeappropriate.Thelimitsshouldberealistic©EMEA20077Page6/32inrelationtoanalyticalprecision,manufacturingcapability,andreasonablevariationinthemanufacturingprocess.4.4OtherAdministrationRoutesParenterallimitsshouldbeusedforpharmaceuticalsubstancesthatareadministeredbyotherroutesofadministration,includinginhalation.However,orallimitsmaybeappliediftheabsorptionbytheotherrouteisnotlikelytoexceedtheabsorptionfollowingoraladministration.Forexample,oralconcentrationlimitsshouldbeappliedforcutaneousadministration.Aconcentrationof<5ppmofanyoneofthelistedelementsinthefinalproductisunlikelytocausecontactallergyeveninhighlysensitivepatients(Uteretal.1995).Thelowestapplicablelimitshouldbeusedforapharmaceuticalsubstancethatmaybeadministeredbyseveralroutes.Platinumsaltshavebeenshowntobeallergenic,hexachloroplatinicacidbeingclearlythemostallergenic(Malo,J-L,2005).Consequentlyaspecificlimitforinhalationexposureforthismoleculehasbeensetat70ng/day(seemonograph).ChromiumVIandnickel,wheninhaled,havebeenassociatedwithcarcinogenicity.ThereforespecificlimitsforinhalationexposurehavebeensetforChromiumVIat10ng/dayandforNickelat100ng/day(seerespectivemonographs).4.5ActivesubstancesUsedforShort-termOnlyAsthePDEsandlimitsmentionedinthisguidelinearebasedonchronicuse,higherconcentrationlimitsmaybeacceptableincasesofshort-termuse(30daysorless).ThismaybethecaseifneitheranOption1noranOption2limitisfeasible.Forinstanceinpracticethismayapplyforacontrastingagent,anantidote,orproductsfordiagnosticuse.Iftheparticularsubstanceisusedonlyasasingledoseorforaverylimitedduration,itmaybetoxicologicallyjustifiedtosetalimithigherthantheOption1orthecalculatedOption2limit.Specificrisk-benefitconsiderationssuchasforcompoundsusedforlife-savingindicationsmayalsowarranttheuseofhigherlimits.Justificationsshouldbemadeonacase-by-casebasis.4.6TestingStrategyIfsyntheticprocessesareknownorsuspectedtoleadtothepresenceofresidueswhenapplyingaspecificmetalcatalystorreagentfortheproductionofapharmaceuticalsubstance:•Element-specificassaysshouldbeundertakentodeterminetheactualamountofresidues,particularlyduringthedevelopmentofthesyntheticprocess.Ifthesyntheticprocessesareshowntoresultintheremovalofpotentialresidues1)ofthisparticularmetal:•Routinetestingmaybereplacedbyskiptesting.Ifthesyntheticprocessesdoleadtopotentialresidues:•Routinetestingwithasuitable,validatedmethodisnecessary2).1)Acatalystcanbeconsideredadequatelyremovedif,inanappropriatenumber(minimum3)ofrepresentativebatchesofthefinalsubstanceoranintermediatelessthan30%oftheoption1limitcouldbefound.©EMEA20077Page7/322)ThistestingcannotreplacetherequirementsofrelevantmonographsoftheEuropeanPharmacopoeia(Ph.Eur.)thatmay,forinstance,describeageneraltestforheavymetals.Thisgeneralheavymetaltestisindicative4.7AnalyticalProceduresIfapharmaceuticalsubstancemaycontainresiduesofmetalelements,usedascatalyst(s)orreagent(s)inthesynthesis,foreachoftheseresidualelementsanacceptancecriterionshouldbeset(notethatagrouplimitissetforclass1Bmetals).Forthedeterminationofeachofthespecifiedelementsanappropriateandvalidatedmethodshouldbeusedinrelationtothelimittobeapplied.Attentionshouldbepaidtothefactthattheresidualelementmaybepresentinadifferentformthantheformoftheelementintheoriginalcatalystorreagent.Wheresufficientjustificationcanbederived,amoregeneralmethodencompassingoneormoremetalswithagenerallimitcanbeappropriateifitcanbeshownthatthelevelfornoneofthespecifiedmetalswouldbeexceeded.MetallicresiduesaretypicallydeterminedusingtechniquessuchasatomicabsorptionorICP.Anyharmonizedproceduresfordetermininglevelsofmetallicresiduesasdescribedinthepharmacopoeiasshouldbeused,iffeasible.Otherwise,manufacturersarefreetoselectthemostappropriatevalidatedanalyticalprocedureforaparticularapplication.IfonlyClass2orClass3metalsarepresent,anon-specificmethodsuchasacolorimetricproceduremaybeused.SpecificallywithrespecttoplatinoidClass1Bwhereagrouplimitsapplies,itisacceptedthatduetotechnicallimitations,thelowerlimitofdetectionwillnotbelowerthen0.5ppmforindividualplatinoids.Generalsemi-quantitativeheavymetallimittestsbasedontheprecipitationatpH3.5ofcolouredmetalsulfidesaredescribedinseveralpublications(e.g.Ph.Eur.).Suchatestisnotsuitabletoquantitativelydeterminetheactuallevelsofaspecificmetalresidueinanactivesubstanceorexcipient.Ifadjusted(e.g.byusingstandardadditionmethods)andproperlyvalidated(includingcross-validationwithanelement-specifictest),atestbasedontheprincipleofsulfideprecipitation,maybesuitableforroutinetestinginsomecases.ValidationofmethodsformetallicresiduesshouldconformtoICHguidances,Q2ATextonValidationofAnalyticalProcedures(March1995)andQ2BValidationofAnalyticalProcedures:Methodology(November1996).4.8ReportingLevelsofMetallicresiduesManufacturersofpharmaceuticalproductsneedcertaininformationaboutthecontentofmetallicresiduesinexcipientsanddrugsubstancesinordertomeetthecriteriaofthisguidance.Thefollowingstatementsaregivenasacceptableexamplesoftheinformationthatcouldbeprovidedfromasupplierofexcipientsordrugsubstancestoapharmaceuticalmanufacturer.Thesuppliermightchooseoneofthefollowingasappropriate:OnlyClass3metalsarelikelytobepresent.OnlyClass2metalsX,Y,...arelikelytobepresent.AllarebelowtheOption1limit(herethesupplierwouldnametheClass2metalsrepresentedbyX,Y,....).IfClass1metalsarelikelytobepresent,theyshouldbeidentifiedandquantified."Likelytobepresent"referstothemetalusedinthefinalmanufacturingstepandtometalsthatareusedinearliermanufacturingstepsandnotremovedconsistentlybythemanufacturingprocess.5.GLOSSARYATSDR–AgencyforToxicSubstancesandDiseaseRegistryfortheoverallqualityofproduction,whichincludessourcesofmetalcontaminationthatareoutsidethescopeofthisguideline,suchasmanufacturingequipmentandenvironment.However,ifthePh.Eur.testisshowntobesuitableforthecontrolofthespecificelementsthatcouldbepresent,thenthisgeneralmethodmaybeappropriateforthecontroloftheknownresidues.©EMEA20077Page8/32FSD–FoodStandardAgencyRfD–ReferenceDoseUSEPA–UnitedStatesEnvir