06/01/2016

DissoultionProfileComparison

dx.doi.org/10.14227/DT060399P15

DissolutionProfileComparisonUsing
SimilarityFactor,f2
VinodP.Shah,YiTsong,PradeepSatheandRogerL.Williams
OfficeofPharmaceuticalScience,CenterforDrugEvaluationandResearch
FoodandDrugAdministration,Rockville,MD

Whatisadissolutionprofilecomparisonandwhatisitsimpact?
Inrecentyears,FDAhasplacedmoreemphasisonadissolutionprofilecomparisonintheareaofpost
approvalchangesandbiowaivers.Underappropriatetestconditions,adissolutionprofilecan
characterizetheproductmorepreciselythanasinglepointdissolutiontest.Adissolutionprofile
comparisonbetweenprechangeandpostchangeproductsforSUPACrelatedchanges,orwithdifferent
strengths,helpsassuresimilarityinproductperformanceandsignalsbioinequivalence.
Amongseveralmethodsinvestigatedfordissolutionprofilecomparison,f2isthesimplest.Mooreand
Flannerproposedamodelindependentmathematicalapproachtocomparethedissolutionprofileusing
twofactors,f1andf2(1).

whereRtandTtarethecumulativepercentagedissolvedateachoftheselectedntimepointsofthe
referenceandtestproductrespectively.Thefactorf1isproportionaltotheaveragedifferencebetween
thetwoprofiles,whereasfactorf2isinverselyproportionaltotheaveragesquareddifferencebetween
thetwoprofiles,withemphasisonthelargerdifferenceamongallthetimepoints.Thefactorf2
measurestheclosenessbetweenthetwoprofiles.Becauseofthenatureofmeasurement,f1was
describedasdifferencefactor,andf2assimilarityfactor(2).Indissolutionprofilecomparisons,
especiallytoassuresimilarityinproductperformance,regulatoryinterestisinknowinghowsimilarthe
twocurvesare,andtohaveameasurewhichismoresensitivetolargedifferencesatanyparticulartime
point.Forthisreason,thef2comparisonhasbeenthefocusinAgencyguidances.
Whenthetwoprofilesareidentical,f2=100.Anaveragedifferenceof10%atallmeasuredtimepoints
resultsinaf2valueof50.FDAhassetapublicstandardoff2valuebetween50100toindicate
similaritybetweentwodissolutionprofiles.
Foradissolutionprofilecomparison:
Atleast12unitsshouldbeusedforeachprofiledetermination.Meandissolutionvaluescanbe
usedtoestimatethesimilarityfactor,f2.Tousemeandata,the%coefficientofvariationatthe
earlierpointshouldnotbemorethan20%andatothertimepointsshouldnotbemorethan10%.
Forcircumstanceswherewidevariabilityisobserved,orastatisticalevaluationoff2metricis
desired,abootstrapapproachtocalculateaconfidenceintervalcanbeperformed.
Thedissolutionmeasurementsofthetwoproducts(testandreference,preandpostchange,two
strengths)shouldbemadeunderthesametestconditions.Thedissolutiontimepointsforboththe
profilesshouldbethesame,e.g.,forimmediatereleaseproducts15,30,45and60minutes,for
extendedreleaseproducts1,2,3,5and8hours.
Becausef2valuesaresensitivetothenumberofdissolutiontimepoints,onlyonemeasurement
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DissoultionProfileComparison

shouldbeconsideredafter85%dissolutionoftheproduct.
Forproductswhicharerapidlydissolving,i.e.,morethan85%in15minutesorless,aprofile
comparisonisnotnecessary.
Af2valueof50orgreater(50100)ensuressamenessorequivalenceofthetwo
curvesand,thus,theperformanceofthe
twoproducts.
Ageneralquestionishowlargecanthedifferencebetweenthemeandissolutionprofilesbebeforethe
differenceislikelytoimpactoninvivoperformance.Fromapublichealthpointofview,andasa
regulatoryconsideration,aconservativeapproachisappropriate.Thef2comparisonmetricwithavalue
of50orgreaterisaconservative,butareliableestimatetoassureproductsamenessandproduct
performance.
References:
1.J.W.MooreandH.H.Flanner,MathematicalComparisonofcurveswithanemphasisoninvitro
dissolutionprofiles.Pharm.Tech.20(6),:6474,1996.
2.V.P.Shah,Y.TsongandP.Sathe,Invitrodissolutionprofilecomparisonstatisticsandanalysisofthe
similarityfactor,f2.Pharm.Res.15:889896,1998.

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