ICH Q3C.docx
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ICH Q3C.docx
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ICHQ3C
ICH
GuidelineforResidualSolvents
Q3C
Rapporteur:
Dr.ShigeoKojima
Date:
16July1997
Step4Document
1.INTRODUCTION
2.SCOPEOFTHEGUIDELINE
3.GENERALPRINCIPLES
3.1CLASSIFICATIONOFRESIDUALSOLVENTSBYRISKASSESSMENT
3.2METHODSFORESTABLISHINGEXPOSURELIMITS
3.3OPTIONSFORDESCRIBINGLIMITSOFCLASS2SOLVENTS
3.4ANALYTICALPROCEDURES
3.5REPORTINGLEVELSOFRESIDUALSOLVENTS
4.LIMITSOFRESIDUALSOLVENTS
4.1SOLVENTSTOBEAVOIDED
4.2SOLVENTSTOBELIMITED
4.3SOLVENTSWITHLOWTOXICPOTENTIAL
4.4SOLVENTSFORWHICHNOADEQUATETOXICOLOGICALDATAWASFOUND
GLOSSARY
APPENDIX1.LISTOFSOLVENTSINCLUDEDINTHEGUIDELINE
APPENDIX2.ADDITIONALBACKGROUND
A2.1ENVIRONMENTALREGULATIONOFORGANICVOLATILESOLVENTS
A2.2RESIDUALSOLVENTSINPHARMACEUTICALS
APPENDIX3.METHODSFORESTABLISHINGEXPOSURELIMITS
1.INTRODUCTION
Theobjectiveofthisguidelineistorecommendacceptableamountsforresidualsolventsinpharmaceuticalsforthesafetyofthepatient.Theguidelinerecommendsuseoflesstoxicsolventsanddescribeslevelsconsideredtobetoxicologicallyacceptableforsomeresidualsolvents.
Residualsolventsinpharmaceuticalsaredefinedhereasorganicvolatilechemicalsthatareusedorproducedinthemanufactureofdrugsubstancesorexcipients,orinthepreparationofdrugproducts.Thesolventsarenotcompletelyremovedbypracticalmanufacturingtechniques.Appropriateselectionofthesolventforthesynthesisofdrugsubstancemayenhancetheyield,ordeterminecharacteristicssuchascrystalform,purity,andsolubility.Therefore,thesolventmaysometimesbeacriticalparameterinthesyntheticprocess.Thisguidelinedoesnotaddresssolventsdeliberatelyusedasexcipientsnordoesitaddresssolvates.However,thecontentofsolventsinsuchproductsshouldbeevaluatedandjustified.
Sincethereisnotherapeuticbenefitfromresidualsolvents,allresidualsolventsshouldberemovedtotheextentpossibletomeetproductspecifications,goodmanufacturingpractices,orotherquality-basedrequirements.Drugproductsshouldcontainnohigherlevelsofresidualsolventsthancanbesupportedbysafetydata.Somesolventsthatareknowntocauseunacceptabletoxicities(Class1,Table1)shouldbeavoidedintheproductionofdrugsubstances,excipients,ordrugproductsunlesstheirusecanbestronglyjustifiedinarisk-benefitassessment.Somesolventsassociatedwithlessseveretoxicity(Class2,Table2)shouldbelimitedinordertoprotectpatientsfrompotentialadverseeffects.Ideally,lesstoxicsolvents(Class3,Table3)shouldbeusedwherepractical.ThecompletelistofsolventsincludedinthisguidelineisgiveninAppendix1.
Thelistsarenotexhaustiveandothersolventscanbeusedandlateraddedtothelists.RecommendedlimitsofClass1and2solventsorclassificationofsolventsmaychangeasnewsafetydatabecomesavailable.Supportingsafetydatainamarketingapplicationforanewdrugproductcontaininganewsolventmaybebasedonconceptsinthisguidelineortheconceptofqualificationofimpuritiesasexpressedintheguidelinefordrugsubstance(Q3A,ImpuritiesinNewDrugSubstances)ordrugproduct(Q3B,ImpuritiesinNewDrugProducts),orallthreeguidelines.
2.SCOPEOFTHEGUIDELINE
Residualsolventsindrugsubstances,excipients,andindrugproductsarewithinthescopeofthisguideline.Therefore,testingshouldbeperformedforresidualsolventswhenproductionorpurificationprocessesareknowntoresultinthepresenceofsuchsolvents.Itisonlynecessarytotestforsolventsthatareusedorproducedinthemanufactureorpurificationofdrugsubstances,excipients,ordrugproduct.Althoughmanufacturersmaychoosetotestthedrugproduct,acumulativemethodmaybeusedtocalculatetheresidualsolventlevelsinthedrugproductfromthelevelsintheingredientsusedtoproducethedrugproduct.Ifthecalculationresultsinalevelequaltoorbelowthatrecommendedinthisguideline,notestingofthedrugproductforresidualsolventsneedbeconsidered.If,however,thecalculatedlevelisabovetherecommendedlevel,thedrugproductshouldbetestedtoascertainwhethertheformulationprocesshasreducedtherelevantsolventleveltowithintheacceptableamount.Drugproductshouldalsobetestedifasolventisusedduringitsmanufacture.
Thisguidelinedoesnotapplytopotentialnewdrugsubstances,excipients,ordrugproductsusedduringtheclinicalresearchstagesofdevelopment,nordoesitapplytoexistingmarketeddrugproducts.
Theguidelineappliestoalldosageformsandroutesofadministration.Higherlevelsofresidualsolventsmaybeacceptableincertaincasessuchasshortterm(30daysorless)ortopicalapplication.Justificationfortheselevelsshouldbemadeonacasebycasebasis.
SeeAppendix2foradditionalbackgroundinformationrelatedtoresidualsolvents.
3.GENERALPRINCIPLES
3.1CLASSIFICATIONOFRESIDUALSOLVENTSBYRISKASSESSMENT
Theterm"tolerabledailyintake"(TDI)isusedbytheInternationalProgramonChemicalSafety(IPCS)todescribeexposurelimitsoftoxicchemicalsand"acceptabledailyintake"(ADI)isusedbytheWorldHealthOrganization(WHO)andothernationalandinternationalhealthauthoritiesandinstitutes.Thenewterm"permitteddailyexposure"(PDE)isdefinedinthepresentguidelineasapharmaceuticallyacceptableintakeofresidualsolventstoavoidconfusionofdifferingvaluesforADI'softhesamesubstance.
ResidualsolventsassessedinthisguidelinearelistedinAppendix1bycommonnamesandstructures.Theywereevaluatedfortheirpossiblerisktohumanhealthandplacedintooneofthreeclassesasfollows:
Class1solvents:
Solventstobeavoided
Knownhumancarcinogens,stronglysuspectedhumancarcinogens,andenvironmentalhazards.
Class2solvents:
Solventstobelimited
Non-genotoxicanimalcarcinogensorpossiblecausativeagentsofotherirreversibletoxicitysuchasneurotoxicityorteratogenicity.
Solventssuspectedofothersignificantbutreversibletoxicities.
Class3solvents:
Solventswithlowtoxicpotential
Solventswithlowtoxicpotentialtoman;nohealth-basedexposurelimitisneeded.Class3solventshavePDEsof50mgormoreperday.
3.2METHODSFORESTABLISHINGEXPOSURELIMITS
ThemethodusedtoestablishpermitteddailyexposuresforresidualsolventsispresentedinAppendix3.SummariesofthetoxicitydatathatwereusedtoestablishlimitsarepublishedinPharmeuropa,Vol.9,No.1,Supplement,April1997.
3.3OPTIONSFORDESCRIBINGLIMITSOFCLASS2SOLVENTS
TwooptionsareavailablewhensettinglimitsforClass2solvents.
Option1:
TheconcentrationlimitsinppmstatedinTable2canbeused.Theywerecalculatedusingequation
(1)belowbyassumingaproductmassof10gadministereddaily.
(1)
Here,PDEisgivenintermsofmg/dayanddoseisgivening/day.
Theselimitsareconsideredacceptableforallsubstances,excipients,orproducts.Thereforethisoptionmaybeappliedifthedailydoseisnotknownorfixed.IfallexcipientsanddrugsubstancesinaformulationmeetthelimitsgiveninOption 1,thenthesecomponentsmaybeusedinanyproportion.Nofurthercalculationisnecessaryprovidedthedailydosedoesnotexceed10g.Productsthatareadministeredindosesgreaterthan10gperdayshouldbeconsideredunderOption2.
Option2:
ItisnotconsiderednecessaryforeachcomponentofthedrugproducttocomplywiththelimitsgiveninOption 1.ThePDEintermsofmg/dayasstatedinTable2canbeusedwiththeknownmaximumdailydoseandequation
(1)abovetodeterminetheconcentrationofresidualsolventallowedindrugproduct.Suchlimitsareconsideredacceptableprovidedthatithasbeendemonstratedthattheresidualsolventhasbeenreducedtothepracticalminimum.Thelimitsshouldberealisticinrelationtoanalyticalprecision,manufacturingcapability,reasonablevariationinthemanufacturingprocess,andthelimitsshouldreflectcontemporarymanufacturingstandards.
Option2maybeappliedbyaddingtheamountsofaresidualsolventpresentineachofthecomponentsofthedrugproduct.ThesumoftheamountsofsolventperdayshouldbelessthanthatgivenbythePDE.
ConsideranexampleoftheuseofOption1andOption2appliedtoacetonitrileinadrugproduct.Thepermitteddailyexposuretoacetonitrileis4.1mgperday;thus,theOption1limitis410ppm.Themaximumadministereddailymassofadrugproductis5.0g,andthedrugproductcontainstwoexcipients.Thecompositionofthedrugproductandthecalculatedmaximumcontentofresidualacetonitrilearegiveninthefollowingtable.
Component
Amountinformulation
Acetonitrilecontent
Dailyexposure
Drugsubstance
0.3g
800ppm
0.24mg
Excipient1
0.9g
400ppm
0.36mg
Excipient2
3.8g
800ppm
3.04mg
DrugProduct
5.0g
728ppm
3.64mg
Excipient1meetstheOption1limit,butthedrugsubstance,excipient2,anddrugproductdonotmeettheOption1limit.Nevertheless,theproductmeetstheOption2limitof4.1mgperdayandthusconformstotherecommendationsinthisguideline.
Consideranotherexampleusingacetonitrileasresidualsolvent.Themaximumadministereddailymassofadrugproductis5.0g,andthedrugproductcontainstwoexcipients.Thecompositionofthedrugproductandthecalculatedmaximumcontentofresidualacetonitrileisgiveninthefollowingtable.
Component
Amountinformulation
Acetonitrilecontent
Dailyexposure
Drugsubstance
0.3g
800ppm
0.24mg
Excipient1
0.9g
2000ppm
1.80mg
Excipient2
3.8g
800ppm
3.04mg
DrugProduct
5.0g
1016ppm
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