usp311092 THE DISSOLUTION PROCEDURE DEVELOPMENT AND VALIDATION.docx
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usp311092 THE DISSOLUTION PROCEDURE DEVELOPMENT AND VALIDATION.docx
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usp311092THEDISSOLUTIONPROCEDUREDEVELOPMENTANDVALIDATION
1092THEDISSOLUTIONPROCEDURE:
DEVELOPMENTANDVALIDATION
TheUSPdissolutionprocedureisaperformancetestapplicabletomanydosageforms.Itisonetestinaseriesofteststhatconstitutethedosageform'spublicspecification(tests,proceduresforthetests,acceptancecriteria).Tosatisfytheperformancetest,USPprovidesthegeneraltestchaptersDisintegration701,Dissolution711,andDrugRelease724.Thesechaptersprovideinformationaboutconditionsoftheprocedure.Fordissolution,theseincludeinformationabout
(1)medium,
(2)apparatus/agitationrate,(3)studydesign,(4)assay,and(5)acceptancecriteria.Overallthedissolutionprocedureyieldsdatatoallowanaccept/rejectdecisionrelativetotheacceptancecriteria,whicharefrequentlybasedonaregulatorydecision.Thischapterprovidesrecommendationsonhowtodevelopandvalidateadissolutionprocedure.
GENERALCOMMENTS
Thedissolutionprocedurerequiresanapparatus,adissolutionmedium,andtestconditionsthatprovideamethodthatisdiscriminatingyetsufficientlyruggedandreproducibleforday-to-dayoperationandcapableofbeingtransferredbetweenlaboratories.
Theacceptancecriteriashouldberepresentativeofmultiplebatcheswiththesamenominalcompositionandmanufacturingprocess,typicallyincludingkeybatchesusedinpivotalstudies,andrepresentativeofperformanceinstabilitystudies.
Theprocedureshouldbeappropriatelydiscriminating,capableofdistinguishingsignificantchangesinacompositionormanufacturingprocessthatmightbeexpectedtoaffectinvivoperformance.Itisalsopossiblefortheproceduretoshowdifferencesbetweenbatcheswhennosignificantdifferenceisobservedinvivo.Thissituationrequirescarefulevaluationofwhethertheprocedureistoosensitiveorappropriatelydiscriminating.Assessingtheresultsfrommultiplebatchesthatrepresenttypicalvariabilityincompositionandmanufacturingparametersmayassistinthisevaluation.Itissometimesvaluabletointentionallyvarymanufacturingparameters,suchaslubrication,blendtime,compressionforce,ordryingparameters,tofurthercharacterizethediscriminatorypoweroftheprocedure.
Withregardtostability,thedissolutiontestshouldappropriatelyreflectrelevantchangesinthedrugproductovertimethatarecausedbytemperature,humidity,photosensitivity,andotherstresses.
Aproperlydesignedtestshouldresultindatathatarenothighlyvariableandshouldnotbeassociatedwithsignificantanalyticalsolutionstabilityproblems.Highvariabilityinresultscanmakeitdifficulttoidentifytrendsoreffectsofformulationchanges.Dissolutionresultsmaybeconsideredhighlyvariableiftherelativestandarddeviation(RSD)isgreaterthan20%attimepointsof10minutesorlessandgreaterthan10%RSDatlatertimepoints.1However,mostdissolutionresultsexhibitlessvariabilitythanthis.Thesourceofthevariabilityshouldbeinvestigatedwhenpractical,andattemptsshouldbemadetoreducevariabilitywheneverpossible.Thetwomostlikelycausesaretheformulationitself(e.g.,drugsubstance,excipients,ormanufacturingprocess)orartifactsassociatedwiththetestprocedure(e.g.,coning,tabletsstickingtothevesselwallorbasketscreen).Visualobservationsareoftenhelpfulforunderstandingthesourceofthevariabilityandwhetherthedissolutiontestitselfiscontributingtothevariability.Anytimethedosagecontentsdonotdispersefreelythroughoutthevesselinauniformfashion,aberrantresultscanoccur.Dependingontheproblem,theusualremediesincludechangingtheapparatustype,speedofagitation,ordeaeration;considerationand/orexaminationofsinkertype;andchangingthecompositionofthemedium.Modificationstotheapparatusmayalsobeuseful,withproperjustificationandvalidation.
Manycausesofvariabilitycanbefoundintheformulationandmanufacturingprocess.Forexample,poorcontentuniformity,processinconsistencies,areactiontakingplaceatdifferentratesduringdissolution,excipientinteractionsorinterference,filmcoating,capsuleshellaging,andhardeningorsofteningofthedosageformonstabilitymaybesourcesofvariabilityandinterferences.Duringroutinetestingoftheproduct,variabilityoutsidetheexpectedrangeshouldbeinvestigatedfromanalytical,formulation,andprocessingperspectives.
MEDIUM
Physicalandchemicaldataforthedrugsubstanceanddosageunitneedtobedeterminedbeforeselectingthedissolutionmedium.TwokeypropertiesofthedrugarethesolubilityandsolutionstatestabilityofthedrugasafunctionofthepHvalue.Whenselectingthecompositionofthemedium,theinfluenceofbuffers,pHvalue,andsurfactantsonthesolubilityandstabilityofthedrugneedtobeevaluated.Keypropertiesofthedosageunitthatmayaffectdissolutionincludereleasemechanism(immediate,delayed,ormodified)anddisintegrationrateasaffectedbyhardness,friability,presenceofsolubilityenhancers,andpresenceofotherexcipients.
Generally,whendevelopingadissolutionprocedure,onegoalistohavesinkconditions,definedasthevolumeofmediumatleastthreetimesthatrequiredinordertoformasaturatedsolutionofdrugsubstance.Whensinkconditionsarepresent,itismorelikelythatdissolutionresultswillreflectthepropertiesofthedosageform.Amediumthatfailstoprovidesinkconditionsmaybeacceptableifitisshowntobemorediscriminatingorotherwiseappropriatelyjustified.
Usinganaqueous–organicsolventmixtureasadissolutionmediumisdiscouraged;however,withproperjustificationthistypeofmediummaybeacceptable.
Purifiedwaterisoftenusedasthedissolutionmedium,butisnotidealforseveralreasons.First,thequalityofthewatercanvarydependingonthesourceofthewater,andthepHvalueofthewaterisnotcontrolled.Second,thepHvaluecanvaryfromdaytodayandcanalsochangeduringtherun,dependingontheactivesubstanceandexcipients.Despitetheselimitations,waterisinexpensive,readilyavailable,easilydisposedof,ecologicallyacceptable,andsuitableforproductswithareleaserateindependentofthepHvalueofthemedium.
ThedissolutioncharacteristicsofanoralformulationshouldbeevaluatedinthephysiologicpHrangeof1.2to6.8(1.2to7.5formodified-releaseformulations).Duringmethoddevelopment,itmaybeusefultomeasurethepHbeforeandafteraruntodiscoverwhetherthepHchangesduringthetest.Selectionofthemostappropriateconditionsforroutinetestingisthenbasedondiscriminatorycapability,ruggedness,stabilityoftheanalyteinthetestmedium,andrelevancetoinvivoperformance,wherepossible.
Typicalmediafordissolutionmayincludethefollowing(notlistedinorderofpreference):
dilutehydrochloricacid,buffersinthephysiologicpHrangeof1.2to7.5,simulatedgastricorintestinalfluid(withorwithoutenzymes),water,andsurfactants(withorwithoutacidsorbuffers)suchaspolysorbate80,sodiumlaurylsulfate,andbilesalts.
Themolarityofthebuffersandacidsusedcaninfluencethesolubilizingeffect,andthisfactormaybeevaluated.
Forcompoundswithhighsolubilityandhighpermeability(asdefinedbytheBiopharmaceuticsClassificationSystem),thechoiceofmediumandapparatusmaybeinfluencedbythereferencedFDAGuidance1.
Forverypoorlysolublecompounds,aqueoussolutionsmaycontainapercentageofasurfactant(e.g.,sodiumlaurylsulfate,polysorbate,orlauryldimethylamineoxide)thatisusedtoenhancedrugsolubility.Theneedforsurfactantsandtheconcentrationsusedcanbejustifiedbyshowingprofilesatseveraldifferentconcentrations.Surfactantscanbeusedeitheraswettingagentsortosolubilizethedrugsubstance.
Volume
Normally,forbasketandpaddleapparatus,thevolumeofthedissolutionmediumis500mLto1000mL,with900mLasthemostcommonvolume.Thevolumecanberaisedtobetween2and4L,usinglargervesselsanddependingontheconcentrationandsinkconditionsofthedrug;justificationforthisprocedureisexpected.
Deaeration
Thesignificanceofdeaerationofthemediumshouldbedetermined,becauseairbubblescaninterferewiththetestresults,actingasabarriertodissolutionifpresentonthedosageunitorbasketmesh.Further,bubblescancauseparticlestoclingtotheapparatusandvesselwalls.Ontheotherhand,bubblesonthedosageunitmayincreasebuoyancy,leadingtoanincreaseinthedissolutionrate,ormaydecreasetheavailablesurfacearea,leadingtoadecreaseinthedissolutionrate.AdearationmethodisdescribedasafootnoteintheProceduresectionunderDissolution711.Typicalstepsincludeheatingthemedium,filtering,anddrawingavacuumforashortperiodoftime.Othermethodsofdeaerationareavailableandinroutineusethroughouttheindustry.Mediacontainingsurfactantsarenotusuallydeaeratedbecausetheprocessresultsinexcessivefoaming.Todeterminewhetherdeaerationofthemediumisnecessary,resultsfromdissolutionsamplesruninnondeaeratedmediumanddeaeratedmediumshouldbecompared.
Enzymes
TheuseofenzymesinthedissolutionmediumispermittedinaccordancewithDissolution711whendissolutionfailuresoccurasaresultofcross-linkingwithgelatincapsulesorgelatin-coatedproducts.
InVitro–InVivoCorrelation(IVIVC)
Anin-depthdiscussiononIVIVCcanbefoundinInVitroandInVivoEvaluationofDosageForms1088.Abriefdiscussionfollows.
Biorelevantmediumisamediumthathassomerelevancetotheinvivoperformanceofthedosageunit.Choiceofabiorelevantmediumisbasedon
(1)amechanisticapproach
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