ICH Q3C.docx

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