MultifactorNonlinearModelingforAcceleratedStability

AnalysisandPrediction

Therightapproachcanprovideaclear,statisticallydefendablemethodfordeterminingdissolutionand
acceleratedstability.
Jul02,2014
PharmaceuticalTechnology
Volume38,Issue7
Acceleratedstabilityanalysisisastrategyusedtoquicklyevaluatealternativeformulations,packaging,and
processes.Acceleratedlinearstudiesarecommonlyperformedandmodeledhowever,accelerated
multiplefactornonlinearmodelinghasbeenagap,andstatisticalsoftwaretoolssuchasSAS/JMPdonot
directlyhaveanyprovisiontomodelmultiplefactornonlinearresponses.Thispaperoutlinesanapproachto
modelandpredictnonlinearmultiplefactorstability/tabletdissolutiondataunderacceleratedandnominal
storageconditions.

RELATEDCONTENT
Therearemanynonlinearstabilitycasessuchasdissolution,leachables,andmoisture.Beingableto
modelthesenonlinearprocessesiscrucialtoproperdrugdevelopment.Inadditiontogeneralnonlinear
modeling,therearemultiplefactorsthatmayinfluencethenonlinearcurve.Thefollowingisalistoffactors
thatmayimpacttheasymptotes,growthrate,andinflectionpointofacurve:

Stabilitystoragetemperatureandhumidity
Particlesize
pH
Amountofanexcipient
Processingconditionsand/orsetpoints
Packagingmaterials/method

Studydesign
Properdesignofexperimentsfordatacollectionandcurveisolationiscrucialforbuildingnonlinearmodels.
Figure1illustratesthefactorsthatshouldallbesquarerelativetoallotherfactorsandhavezerocorrelation
relativetoeachother.Forthistabletdissolutionexample,multipletimepoints(minutes),multiplestorage
conditions(temperature),multipledrugsubstanceparticlesizes,andmultipleweeksweremeasured.
Percentdissolutionwastheresponseofinterest.
Analysismethod
Thefollowingisastepbystepprocedurefornonlinearstabilitymodelingandexpirydetermination.

Stepone.Measurethedataatmultipletimeperiods,usingmultipleparticlesizesandatmultiple
temperatures.Generateaplotofthedatatovisualizetherelationshipofthecurvesovertime(25100:
25=Temperature,10=ParticleSize,and0=days)(see
Figure2).

Steptwo.Fiteachcurveindividually.Inthisexample,eachdissolutioncurvewasfitusingafourparameter
logistics(4PL)curve.Thefourparametersare:upperasymptote,lowerasymptote,inflectionpoint,and
slopeofthedissolutioncurve.RSquareshouldbehigh(typicallyabove0.95)andRMSEerrorshouldbe
lowforeachcurve.Outliersshouldbecheckedusingtheresiduals.Savetheparametersofthecurve.In
thisexample,therearefourparameters,upperasymptote,lowerasymptote,growthrate(slope),and
inflectionpoint(seeFigure3).

Stepthree.Savetheparametersfromthecurveandthefactorsthatinfluencethemintoatable.Forthis
example,thegrowthrateandinflectionpointarethecoefficientsthatmaychangethemostbasedonthe
factorsunderconsideration.Theupperandlowerasymptotesarenotofconcernforthisproblemasallof
thecurveshavesimilarlowerasymptotesandsimilarupperasymptotes,butupperandlowerasymptotes
couldbeimportantforotherproblems,sogenerallyitisbesttomodelallofthecurveparameters(see
Figure4).
Stepfour.Fitthecurveparameterswithaleastsquaresmultivariateregression.Growthrate,theslopeof
the4PLfit,andinflectionpointarethemostimportantasthedissolutionstartingpointandtheupper
asymptoteareessentiallythesameforallcurves.Maineffectsandinteractionmodelsgenerallyworkbest
andpvaluesandFtestscanbeusedtoevaluateeachmodelterm(seeFigure5).
Stepfive.Savetheequationfromthemultivariateparametermodel.Anexampleoftheinflectionpoint
modelisinEquation1.
[Eq.1]

Stepsix.Substitutethegrowthrate(slope)andinflectionpointcoefficientsfromthemultivariatemodelinto
thenonlinearprediction.TheredboxinFigure6showsthesubstitutionfortheinflectionpoint.
Stepseven.Checkthemodeltomakesureitmatchestheactualdata.Correctanymodelingerrorsby
addingormodifyingamultivariatemodelterm.AsimpleYXregressionplotofthemodelversusthe
measurementwillindicatemodelqualityandanysystematicerrors(seeFigure7).

Stepeight.Createaprofilerfromtheequationtopredictfuturedissolutionrates.Thiscanbedoneusinga
modernstatisticalpackagesuchasSAS/JMP(seeFigure8).
Stepnine.Predictdissolutionatanytime,temperature,orparticlesizecombinationusingtheprofiler.For
thisexample,particlesizewassetto5m,tempto25andtimeinweekstozero.Thedissolutiontimewas
fixedat100minwithaspecificationofnotlessthan90%(seeFigure9).

Stepten.Fromtheprofilerateachtimepoint(weeks),makesurethetime(min)andparticlesize(5um)
arefixed,determinedissolutionatthenominaltemperature(nonacceleratedcondition).Fittherateof
degradationusingeitheralinearornonlinearmodelfromtheprofilerpredicteddata.Inthiscase,therateof
dissolutionisnotlinearsoanonlinearcurveisfittothedataandtheexpiryisdeterminedbasedonthe
extrapolatedcurve(seeFigure10).
Thesamemethodisusedforpredictingboththenominalexpiryandthe95%CIexpiry.
Stepeleven.Finally,longtermstabilityevaluationatnominalstorageconditionswillbeusedtoconfirmthe
earlymodelpredictionandwillprovideanindependentsecondarydeterminationofstabilityandchangesin
dissolution.Understandingratesofchangeshouldfactorintoshelflifeandreleasespecificationlimits(1).

Summary
Nonlinearmultiplefactoranalysishaslongbeenaprobleminavarietyofprocessandproductmodeling
andprediction.Thenovelprocedurediscussedinthispaperforthecharacterizationofmultiplefactornon
linearproductperformanceprovidesaclear,statisticallydefendablemethodfordeterminingdissolutionand
acceleratedstability.Longtermverificationofacceleratedconditionsshouldalwaysfollowearly
determinationsofexpiry,accelerationrates,andratesofdegradation.

Reference
1.ICH,Q6ASpecifications:TestProceduresandAcceptanceCriteriaforNewDrugSubstancesandNew
DrugProducts:ChemicalSubstances(Oct.6,1999).

AbouttheAuthor
MarkAlasandro,PhD,isdirector,AllerganIrvine.ThomasA.LittlePhD,ispresident,ThomasA.Little
Consulting,drlittle@drtom.com.

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