3StepstoaSuccessfulAnalyticalMethodTransferofYourSolidOralDosageFormJohnFrankonis—LaboratoryDirector,RopackPharmaSolutions

Theanalyticaltestingofintermediateandfinisheddrugproductsisacriticalpartofthedrug

developmentprocess,asitisessentialtoensuringthesafetyandefficacyofthefinalproduct.

Oftenthelocationofthetestingneedstoshifttoanothersitewithinthecompany(tosupport

scale-upandcommercialactivities)oroutsidethecompanytoaCMO(forschedulingorcost-

cuttingpurposes).Iftheproductsneedtobetestedandreleasedatanotherfacility,FDA

guidancestatesthemethodneedstobeofficiallytransferredtothenewlocation,wheresimilar

analyticalresultsneedtobegenerated.Theoriginatorlaboratorycanavoidlengthydelaysby

draftingananalyticalmethodtransferthatensuresthereceivinglaboratorypossessesand

demonstratesthecapability,knowledge,andconsistencytotestthematerialasintended.

Whetherthetransferoccurswithinthesameorganizationorbetweendifferentorganizations,

thereareseveralchallengesacompanycanfaceduringthisprocess.Oneofthebiggest

challengesofananalyticalmethodtransferisensuringend-to-endconsistencyofthetesting

processfromonelabtoanother.Thiscanbeensuredbydraftinganeffectivemethodtransfer

protocol.Doingthisrequiresestablishingcommunicationearlyintheprocessandmaintainingit

throughcompletionofthetransfer.Withoutproperpreparationandearlycommunication,

boththeoriginatingandreceivinglaboratoriesruntheriskofmethodinconsistenciesthatcould

affectboththeaccuracyandefficiencyofthetesting.

Thefollowingstepswillhelpguidetheprocessofcompletingasuccessfulanalyticalmethod

transfer.Byadheringtothem,bothlaboratoriescanavoidcommonmissteps,therebyremoving

anybarrierstoprogressingthedrugtothenextphaseinitsdevelopmentand

commercialization.

1.OpentheLinesofCommunication…andNeverCloseThem

Inordertohavetheprotocolreadyatthetimeofthetransfer,

conversationsbetweenallpartiesinvolvedshouldbeginatleast

twomonthspriortotheexecutionofthetransfer.Thiswilllikely

involvearepresentativefromeachoftheorganizations’qualityassuranceteamsandthe

managementfromeachlaboratory.Theoriginatorlaboratoryshouldscheduleaninitial

meetingwiththereceivinglaboratoryandprovideacopyofitstestingmethods.Thereceiving

laboratorycanthenreviewthemethod(s)anddeterminewhatquestionsitmayhaveregarding

thespecificproceduresinvolved.Thisalsogivesitanopportunitytodeterminewhatsupplies,

chemicals,reagents,etc.itmightneedtopurchaseinordertosuccessfullyruneachmethod.

Areasthatmayneedtobediscussedorquestionedarethesmallmethod-specifictechniques

thatmaynotbehandledintheexactsamewaybetweentwodifferentlaboratories.

Forexample,thiscouldbeanythingfromweighingablendsampleaspecificway(e.g.,rinsing

contentsandthenweighingthedriedcontainer,ordrytransferringthepowderandgettinga

tareweight)todetailinginstructionsonhowtoshakeasamplepreparation.Becauseany

discrepancyinpracticecanhavenegativeeffectsonthetransfer,andthustheoverallproject

timelines,nothingcanbeassumedduringtheprocess.Thisiswhyeverydetail,especiallyany

grayareas,needstobereviewedanddiscussed.Thiscanalsoincludedetailswhenreviewing

therequiredinstrumentation.Toavoidapossiblevariationintheanalyticalresults,instrument

equivalencyshouldbediscussedandverified.Overall,theoriginatorlaboratorycouldhave

specifictechniquesorequipmentthatarepreferredoverothers,andnotusingthesecould

haveasignificantimpactontheacquiredtransferdata.Withouttheseearlyconversations,

costlymistakescanoccur,resultingintime-consuminginvestigations,corrective

actions/preventiveactions(CAPAs),andlowlaboratoryconfidence.

Partofearlypreparationalsoincludescreatingatimelineforcompletionofthetransfer,taking

intoconsiderationanytimeneededforadditionaltraining,orderingofequipment(ifthe

receivinglabdoesnothavethesameinstrumentsonhandasthosebeingusedbythe

originator),aswellasreviewsandapprovals.Thistimelinemustbemanagedbyboth

laboratoriesthroughouttheprocess.

Oncetherehasbeenaninitialmeetingtoaddressanyquestionsorconcernsaswellasto

establishatimelineforcompletion,theoriginatorlaboratorycanbegindraftingitsmethod

transferprotocol.

2.DraftaClearandEffectiveProtocol

Arobustmethodtransferprotocolshouldincludethefollowing

sections(furtherrecommendationscanbefoundincurrentFDA

guidanceaswellasUSPchapter<1224>):

• Introduction–thisincludesthenameoftheoriginatorlaboratory,

receivinglaboratory,thedrugbeingtransferred,anditsdosageform.

• Objective–thisdetailsthegoaloftheprotocol,whichistocompleteatestateachofthe

laboratoriesusingthemethodsoutlinedintheprotocol.Theobjectivealsoincludeswhat

dosagesshouldbetested.

• MethodsandMaterials–thisincludesthedetailsassociatedwiththespecificmethodstobe

transferred(includingtheirnameandnomenclature)andtheirspecificmaterialrequirements.

• ExperimentalDesign–thisprovidesthedetailsofeachtest,includingwhatsamplesshouldbe

tested(fromwhichlot,ofwhatpotency,etc.),theconditionsunderwhichtheyshouldbe

tested(duration,temperature,etc.),andwhatprocedureintheprotocolshouldbeused.If

therearemultiplepotencies,abracketing,risk-basedapproachcanbeusedtosavetimeand

increaseefficiency.

• QualificationCriteria–theacceptancecriteriaforeachtestisprovidedinthissection.The

resultsfrombothlabsshouldmeetthespecifiedcriteriafortheproduct.Theacceptance

criteria(thelimitsaroundthetesting)areusuallydefinedbytheoriginatorlaboratory/company

andwhatitbelievesisapractical,yetrobust,limitthatwelldefinesthecharacteristicsofthe

methods.Thisshouldbebasedontheanalyticalhistoryofthedrugandtheknown

performanceofthemethods.

• ManagementofResults–thisincludeswhoisresponsibleforreviewingandevaluatingthe

results,aswellaswhatshouldoccuriftheresultsdonotmeetthequalificationcriteria.

• Documentation–thisoutlinesthedocumentationpracticesofrawdatageneration,changesto

theprotocol,andhowthefinalreportshouldbewritten,reviewed,andapproved.

• StorageofRecordsandRawData–asitimplies,thissectionindicateswheretherecords,

protocols,finalreport,andrawdataofthetransferwillbestored.Eachsiteshouldstorethese

documentspertheirownarchivingprocedures.

Communicationbetweenbothpartiesshouldcontinuethroughouttheprocessofwritingthe

protocol.Typically,thelabdirectorfromeachlaboratorydraftstheprotocol,anditwillbe

exchangedbackandforthuntilfinalapprovalisreceivedfromthequalityassurance

representativeandlaboratoryrepresentativeateachsite.

3.EstablishFamiliaritywiththeDosageFormandMethodology

Oncethemethodtransferprotocoliscomplete,itisagoodideafor

thereceivinglabtobecomefamiliarwiththemethodsandhowthe

dosageforminquestionperformsanalytically.Thiscanbedonebycompletingaseriesof

experimental“testruns”ofthemethodormethodsbeingconsideredfortransfer.Doingso

ensuresfamiliaritywiththedosageformandmethodologypriortothetransfer.Thiscanhelp

avoidfuturedelaysandissuesafterthemethodisimplemented.Timeshouldbeallowedto

includethesetestsinthebuild-uptotherunningoftheofficialprotocol.

Theamountoftimethatshouldbebudgetedforthisisbasedonthecomplexityofthemethods

andthenumberofmethodstobetransferred.Thenumberoftestrunscompletedis

determinedbylaboratorymanagement,whowillusetheteststodeterminethecompetenceof

theirstaffwiththenewmethods.Somemayneedmanytestsandsomemayneedonlyone(or

none).Again,opendiscussioniskeytoironingoutanyobserveddiscrepanciesortechnical

observationsfoundduringthetestrun(s).

Asstatedinitsguidanceonanalyticalmethodtransfers,theFDArequirestheanalyticalmethod

transferprotocoltobesubmittedaspartofawell-writtenregulatoryfiling.Itisnotsubmitted

onitsownbutistypicallyaddedtoanNDAorANDAonfilewiththeFDAaseitherpartofa

yearlyupdateorapriorapprovalsupplement,ifdeemednecessary.

Conclusion

Overall,executingasuccessfulmethodtransferprotocolrequiresaconsiderableamountof

timeandcommunicationfromallpartiesinvolved.Byestablishingareasonabletimelineand

clearexpectationsfromthebeginning,bothteamsarebuildingnotjustconfidenceinthe

laboratoryresultsbutalsoasolidfoundationforthefutureofadrug’sdevelopmentalprocess.

Awell-transferredmethodensurescomplianceandreproducibleresultsandprovidesthe

evidencethattheinitialexpectationofqualitycarriesonbetweenthevarioussitesinvolvedin

bringingthefinaldosageformtothepatient.

JohnFrankonisisLaboratoryDirectorforRopackPharmaSolutions,whichsupportssolidoraldosageprojectsfromearly-stagedevelopmentthroughclinicalmanufacturing,packaging,distributionandcommercialmanufacturingandpackaging.Hehasspentmorethan20yearsinthedrugdevelopmentsector,withaparticularfocusonanalyticaldevelopmentandprojectmanagement.

JOHNFRANKONISLaboratoryDirector,RopackPharmaSolutionsjohn.frankonis@ropack.com