26/02/2017 Statistical Tools for Development and Control of Pharmaceutical Processes: Statistics in the FDA Process Validation Guidance

PublishedonIVTNetwork(http://www.ivtnetwork.com)

StatisticalToolsforDevelopmentandControlofPharmaceutical
Processes:StatisticsintheFDAProcessValidationGuidance

By PaulL.Pluta,Ph.D.Mar17,201411:17amPDT

PeerReviewed:Statistics
WelcometoStatisticalTools.

Thisfeatureprovidesdiscussionandexamplesofstatisticalmethodsusefultopractitionersinvalidationand
compliance.Weintendtopresenttheseconceptsinameaningfulwaysoastoenabletheiruseindailywork
situations.Ourobjective:Usefulinformation.

TherecentlyissuedFDAProcessValidationGuidancerecommendedmultiplespecificapplicationsforstatisticsin
thelifecycleapproachtoprocessvalidation.TheseapplicationswereidentifiedinStage1ProcessDesign,Stage2
ProcessQualification(PQ),andStage3ContinuedProcessVerification.FDArecommendationswerequitespecific
fortheserespectivestages,indicatingAgencyfocusonstatisticalmethods.Theguidancedescribedseveral
specificdetailsofstatisticsapplications,includingdesignofexperiment(DOE)studiesinformulationandprocess
development,statisticalmetricsinPQ,andtrendingofmaterial,process,andproductdatainmonitoringand
maintainingvalidation.Theimportanceofstatisticalexpertisewasemphasizedthroughouttheguidance.

StatisticalToolswillproviderelevantpracticalexamplesofusingstatisticsinthevariousstagesofvalidation.The
contentofStatisticalToolswillprovidereaderswiththeoryandpracticeontopicsrelevanttovalidation.Reader
understandingofthisvitalsubjectinvalidationshouldbeenhancedthroughtheserespectivediscussions.

ThefirstpartofStatisticalToolsdiscussesgeneralareasidentifiedintheguidancethatrecommendapplicationsof
statisticsanintroductiontothefuturecontentinStatisticalTools.

Comments,questions,andsuggestionsfromreadersareneededtohelpusfulfillourobjectiveforthisseries.
Suggestionsforfuturediscussiontopicsorquestionstobeaddressedareinvited.Readersarealsoinvitedto
participateandcontributemanuscriptsforthiscolumn.Casestudiessharingusesofstatisticsinvalidationaremost
welcome.WeneedyourhelptomakeStatisticalToolsausefulresource.PleasecontactcolumncoordinatorPaul
Plutaatpaul.pluta@comcast.netorIVTCommunityManagerCaleRubensteinatcrubenstein@advanstar.comwith
comments,questions,suggestions,orcasestudiesforpublication.

Abstract
TherecentUSFoodandDrugAdministrationProcessValidationGuidancehasprovidedclearstatementsonthe
needforstatisticalproceduresinprocessvalidation.FDAhasredefinedvalidationtoincludeactivitiestakingplace
overthelifecycleofproductandprocessfromprocessdesignanddevelopmentthroughongoing
commercialization.Newapplicationshaveevolvedasresultofthisguidance.Statisticalapplicationsshouldbeused
inprocessvalidationandrelatedapplicationstoimprovedecisionmaking.Developmenteffortsshouldinclude
statisticallydesignedexperimentstodeterminerelationshipsandinteractionsbetweeninputsandoutputs.
Manufacturersshouldunderstandthesourcesofvariation,understanditsimpactonprocessandproduct,and
controlvariationcommensuratewiththerisk.Statisticalmethodsshouldbeusedtomonitorandquantifyvariation.
Statisticalmethodsshouldbeusedinsupportofsamplingandtestinginprocessqualification(PQ).Samplingplans
shouldreflectriskanddemonstratestatisticalconfidence.Validationprotocolsamplingplansshouldinclude
samplingpoints,numbersofsamples,samplingfrequency,andassociatedattributes.Acceptancecriteriashould

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26/02/2017 Statistical Tools for Development and Control of Pharmaceutical Processes: Statistics in the FDA Process Validation Guidance
includestatisticalmethodstoanalyzedata.Continuingprocessverificationdatashouldincludedatatoevaluate
processtrends,incomingmaterial,inprocessmaterials,andfinalproducts.Datashouldfocusonongoingcontrolof
criticalqualityattributes.FDArecommendsthatpersonnelwithadequateandappropriateeducationinstatistics
shouldbeusedfortheseactivities.

Introduction
FDAissuedProcessValidation:GeneralPrinciplesandPractices(1)inJanuary2011.Thisguidancetransformed
processvalidationfromanindividualandsingulareventtoanongoingcontinuumofactivitiesduringtheentire
lifecycle(i.e.,developmentthroughcommercialization)ofapharmaceuticalproduct.Theguidanceincorporates
qualitybydesign(QbD),processanalyticaltechnology(PAT),riskmanagement,andothermodernconceptsintoa
comprehensiveapproachtoprocessvalidation.Theapplicationofstatisticalmethodsisanimportantpartof
implementingtheguidanceinpharmaceuticalprocessvalidationprograms.FDAalsorecentlyissued(draft
guidance)AnalyticalProceduresandMethodsValidationforDrugsandBiologics(2).Thisdocumentdescribes
statisticalanalysisandmodelsappropriateforvalidationofanalyticalmethods.Theprinciplesandapproaches
describedabovearealsobeingappliedtootherprocesses(e.g.,cleaning,packaging),qualifications(e.g.,
equipment,facilities,utilities,controlsystems),hybridsystems(e.g.,water,heating,ventilation,andairconditioning
[HVAC]),andqualitysystems.Measurementisitselfaprocess.Statisticiansplayaroleinevaluatingcapabilityof
themeasurementprocess,withoutwhichnootherworkcanbedone.Pharmaceuticalprocessesoftencomprise
multiplesubprocessesinsideeachfurthersubsubprocessesarenested,andsoon.Atthebaseofalloftheseis
themeasurementprocessitself,withoutwhichitisimpossibletostudyanyofthehigherorderprocesses.Statistical
methodsaretoolstobeutilizedforbetterriskbaseddecisionmakinginthefaceofvariationanduncertainty.

GuidanceDefinition

Processvalidationisdefinedinthe2011guidanceasfollows(1):

Processvalidationisdefinedasthecollectionandevaluationofdata,fromtheprocessdesignstagethroughout
production,whichestablishesscientificevidencethataprocessiscapableofconsistentlydeliveringqualityproduct.
Processvalidationinvolvesaseriesofactivitiestakingplaceoverthelifecycleoftheproductandprocess.This
guidancedescribestheprocessvalidationactivitiesinthreestages:

Stage1ProcessDesign:Thecommercialprocessisdefinedduringthisstagebasedonknowledge
gainedthroughdevelopmentandscaleupactivities.
Stage2ProcessQualification:Duringthisstage,theprocessdesignisconfirmedasbeingcapableof
reproduciblecommercialmanufacturing.
Stage3ContinuedProcessVerification:Ongoingassuranceisgainedduringroutineproductionthatthe
processremainsinastateofcontrol.

Thelifecycleapproachtoprocessvalidationisbasedonthefollowingbasictenetsasstatedintheguidance(1):

Quality,safety,andefficacyaredesignedorbuiltintotheproduct.
Qualitycannotbeadequatelyassuredmerelybyinprocessandfinishedproductinspectionortesting.
Eachstepofamanufacturingprocessiscontrolledtoassurethatthefinishedproductmeetsalldesign
characteristicsandqualityattributesincludingspecifications.

TheaboveisproposedbyFDAforapplicationtohumandrugs,veterinarydrugs,biologicalandbiotechnology
products,activepharmaceuticalingredients,finishedproducts,andthedrugcomponentofcombinationdrugand
medicaldeviceproducts.Theabovedoesnotspecificallyapplytoprocessvalidationofmedicaldevices.However,
thesesamegeneralstagesandtheirrespectiveinclusionshavepreviouslybeenpublishedformedicaldevices(3).

FDAExpectationsVariation,Control,andStatistics

TheFDAguidancedocumentchangedandexpandedthescopeofprocessvalidation.Theguidancefurtherraised
expectationsregardingscopeandcontentofvalidationactivities.Applicationofstatisticalmethodshasbecomea
significantpartoftheseexpectations.

AbriefsectionintheopeningpagesoftheFDAguidanceclearlystatesexpectationsforindustryvalidation
programs.Thissectiondescribestheexpandedviewofvalidationfornewandlegacyproducts.Keyconceptsinthis
sectionincluderecognitionofvariationandassociatedcontrolofvariationthroughouttheentiretyoftheproduct
lifecycle.Collectionandanalysisofdataarecriticaltothiseffort.Specifically:

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Asuccessfulvalidationprogramdependsuponinformationandknowledgefromproductandprocess
development.Thisknowledgeandunderstandingisthebasisforestablishinganapproachtocontrolofthe
manufacturingprocessthatresultinproductswiththedesiredqualityattributes.Manufacturersshould:

Understandingsourcesofvariation
Detectthepresenceanddegreesofvariation
Understandtheimpactofvariationintheprocessandultimatelyonproductattributes
Controlthevariationinamannercommensuratewiththeriskitrepresentsintheprocessand
product.

Eachmanufacturershouldjudgewhetherithasgainedsufficientunderstandingtoprovideahighdegreeof
assuranceinthemanufacturingprocesstojustifycommercialdistributionoftheproduct.Focusingexclusively
onqualificationeffortswithalsounderstandingthemanufacturingprocessandassociatedvariationmaynot
leadtoadequateassuranceofquality.Afterestablishingandconfirmingtheprocess,manufacturersmust
maintaintheprocessinastateofcontroloverthelifeoftheprocess,evenasmaterials,equipment,
productionenvironment,personnel,andmanufacturingprocedureschange.

Manufacturersshoulduseongoingprogramstocollectandanalyzeproductandprocessdatatoevaluatethe
stateofcontroloftheprocess.Theseprogramsmayidentifyprocessorproductproblemsoropportunitiesfor
processimprovementsthatcanbeevaluatedandimplementedthroughsometheactivitiesdescribedin
Stages1and2.

Manufacturersoflegacyproductscantakeadvantageoftheknowledgegainedfromtheoriginalprocess
developmentandqualificationworkaswellasmanufacturingexperiencetocontinuallyimprovetheir
processes.Implementationoftherecommendationsinthisguidanceforlegacyproductandprocesseswould
likelybeginwiththeactivitiesdescribedinStage3.(1).

RegulatoryRequirementsandRecommendations

Processvalidationisalegallyenforceablerequirementinthepharmaceuticalgoodmanufacturingpractices
(GMPs).Theguidanceidentifiestwoareastoexemplifyemphasisonrecognitionofvariationandcontrol.Both
samplingandinprocessspecificationsarementionedasaspectsofprocessvalidation.Statisticalanalysesare
explicitlymentionedinboththeseareas.Samplingplansmustresultinstatisticalconfidencethatproductbatches
meetpredeterminedspecifications.Inprocesslimitsmustbedeterminedbyapplicationofstatisticalprocedures.
Theguidancealsoprovidesalistofrecommendationsthatfurtheremphasizerecognitionofvariationand
associatedcontrol.FDArecommendsateamapproachtoprocessvalidation,includingrepresentationofexpertise
instatistics.

Stage1ProcessDesign
TheStage1ProcessDesignstageofprocessvalidationcomprisesworkconductedtowardsprovidingfundamental
understandingoftheproductandprocess.Itincludeslaboratoryscaleexperimentalstudiesconductedtodetermine
basictechnicalrelationshipsbetweenformulationingredients,processparameters,andproductattributes.Italso
includesworkconductedatanincreasingscaleculminatingatthefullscalecommercialprocess.Good
understandingofthemanufacturingprocessmustbetechnicallyandscientificallybased.Criticalqualityattributes
andcriticalprocessparametersmustbeidentifiedandtheirrelationshipsunderstood.TheworkofStage1should
becommensuratewiththeidentifiedorexpectedriskfortheproductandprocess.

Stage1recommendationsaddressdevelopmentactivitiesthatwillultimatelybereflectedinthemasterproduction
recordandcontrolrecords.TheguidanceclearlystatesthegoalofStage1,Todesignaprocesssuitablefor
routinecommercialmanufacturingthatcanconsistentlydeliveraproductthatmeetsitsqualityattributes.(1).Two
generaltopicsarediscussedintheguidance:1)buildingandcapturingprocessknowledgeand2)understanding
andestablishingastrategyforprocesscontrol.

ApplicationofStatistics

Productandprocessscientistsandengineersworkingindevelopmentofpharmaceuticalproductsmustunderstand
andutilizestatisticalmethodswheneverpossible.Theirworkprovidesthebasesforfuturemanufacturingand
selectionofparametersinpharmaceuticalprocesses.Documentationoftheirworkwillbeutilizedinregulatory
submissions,regulatoryaudits,changecontrol,andotheractivitiessupportivetoproductsandprocesses.TheFDA
guidancespecificallycommentsontheuseofDOEstudiestodevelopprocessknowledgerevealrelationships,
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26/02/2017 Statistical Tools for Development and Control of Pharmaceutical Processes: Statistics in the FDA Process Validation Guidance
includingmultivariateinteractionsscreenvariablesandotherapplications.Theguidancementionsapplicationsof
DOEinestablishingrangesofincomingcomponentquality,equipmentparameters,andinprocessmaterialquality
attributes.Alsomentionedareexperimentsatlaboratoryorpilotscalethatmayassistinevaluationofconditions
andpredictionofprocessperformance.Applicationofstatisticalmethodsareusefulintheseandassociated
activities.

Stage2ProcessQualification
TheStage2ProcessQualificationstagecomprisesperformanceofthecommercialprocessbymeansof
conformancelots.ThisstageconfirmsworkofStage1ProcessDesignanddemonstratesthattheproposed
manufacturingprocessiscapableofreproduciblecommercialmanufacture.ProcessPerformanceQualification
(PPQ)conformancelotmanufacturingincludesincreasedtestingtodemonstrateacceptabilityofthedeveloped
formulationandprocess.ThetestingofStage2shouldbecommensuratewiththeriskidentifiedfortheproductand
process.

TheFDAguidancespecificallydiscussesdesignoffacility,utilities,andequipment,ProcessPerformance
Qualification(PPQ),thePPQprotocol,andPPQprotocolexecutionandreportinStage2,allofwhicharedirectly
connectedtospecificprocessvalidation.PPQisintendedtoconfirmtheprocessdesignanddevelopmentworkand
demonstratethatthecommercialmanufacturingprocessperformsasexpected.Thisstageisanimportant
milestoneintheproductlifecycle.PPQshouldbebasedonsoundscienceandexperienceasdevelopedinStage1
studiesandactivities.PPQshouldhaveahigherleveloftestingandsampling.ThegoalofPPQistodemonstrate
thattheprocessisreproducibleandwillconsistentlydeliverqualityproducts.

PPQProtocolandApplicationofStatistics

AwrittenprotocolisessentialforacceptablePPQ.SpecificrequirementsmentionedintheFDAguidance,manyof
whichrequiringstatisticalmethods,includethefollowing:

Manufacturingconditions,processparameters,processlimits,andrawmaterialinputs
Datacollectionandevaluation
Testingandacceptancecriteria
Samplingplan,includingsamplingpointsandnumberofsamples
Numberofsamples,whichdemonstratestatisticalconfidence
Confidencelevelbasedonriskanalysis
Criteriaforarationalconclusionofwhethertheprocessisacceptable
Statisticalmethodsthatareusedtoanalyzedata,includingstatisticalmetricsdefiningbothintrabatchand
interbatchvariability
Provisiontoaddressdeviationsandnonconformances
Designoffacilitiesandqualificationofequipmentandfacilities
Personneltrainingandqualification
Verificationofsourcesofmaterialsandcontainers/closures
Analyticalmethodvalidation
Reviewandapprovalbyappropriatedepartmentsandthequalityunit.

Stage3ContinuingProcessVerification
TheStage3ContinuedProcessVerificationstagecomprisestheongoingcommercialmanufacturingoftheproduct
underthesameorequivalentconditionsasdemonstratedinStage2ProcessQualification.Thisphasecontinues
throughouttheentirecommerciallifeoftheproduct/process.MaintenanceactivitiesofStage3shouldbe
commensuratewiththeriskidentifiedfortheproductandprocess.

Assuminggooddevelopmentoftheprocess,identificationofpotentialsourcesofvariation,andcontrolofthis
variation,themanufacturermustmaintaintheprocessundercontrolovertheproductlifetime(i.e.,theworkofStage
3).Thiscontrolmustaccommodateexpectedchangesinmaterials,equipment,personnel,andotherchanges
throughoutthecommerciallifeoftheproduct,anditmustdosobasedonriskanalysis.

ApplicationofStatistics

Specificitemsinthissectionoftheguidancerequiringstatisticalapplicationincludethefollowing:

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26/02/2017 Statistical Tools for Development and Control of Pharmaceutical Processes: Statistics in the FDA Process Validation Guidance
Ongoingprogramtocollectandanalyzeprocessdata,includingprocesstrends,incomingmaterials,in
processmaterial,andfinishedproducts
Statisticalanalysisofdatabytrainedpersonnel
Proceduresdefiningtrendingandcalculations
Evaluationofinterbatchandintrabatchvariation
EvaluationofparametersandattributesatPPQlevelsuntilvariabilityestimatescanbeestablished
Adjustmentofmonitoringlevelsbasedontheabove
Timelyassessmentofdefectcomplaints,outofspecification(OOS)findings,deviations,yieldvariations,
andotherinformation
Periodicdiscussionwithproductionandqualitystaffonprocessperformance
Processimprovementchanges
Maintenanceoffacilities,utilities,andequipmenttoensureprocesscontrol.

Continuingprocessverificationdatashouldincludedatatoevaluateprocesstrends,incomingmaterial,inprocess
materials,andfinalproducts.Datashouldfocusonongoingcontrolofcriticalqualityattributes.

ExpertiseinStatistics

Theguidanceclearlyshowsscope,objectives,andcriticalityofdataanalysisandstatisticaltreatmentofdatain
Stage3.SpecificFDArecommendationsregardingexpertiseinstatisticsarenoteworthy:

Anongoingprogramtocollectandanalyzeproductandprocessdatathatrelatetoproductqualitymustbe
established.Thedatacollectedshouldincluderelevantprocesstrendsandqualityofincomingmaterialsor
components,inprocessmaterials,andfinishedproducts.Thedatashouldbestatisticallytrendedand
reviewedbytrainedpersonnel.Theinformationcollectedshouldverifythatthequalityattributesarebeing
appropriatelycontrolledthroughouttheprocess.

Werecommendthatastatisticianwithadequatetraininginstatisticalprocesscontroltechniquesdevelopthe
datacollectionplanandstatisticalmethodsandprocedureusedinmeasuringandevaluatingprocessstability
andprocesscapability.Proceduresshoulddescribehowtrendingandcalculationsaretobeperformedand
shouldguardagainstoverreactiontoindividualeventsaswellasagainstfailuretodetectunintendedprocess
variability.Productiondatashouldbecollectedtoevaluateprocessstabilityandcapability.Thequalityunit
shouldreviewthisinformation.Ifproperlycarriedout,theseeffortscanidentifyvariabilityintheprocessand/or
signalpotentialprocessimprovements.(1).

Thefollowingparagraphfromtheguidanceprovidesanotherclearrecommendation:

Manytoolsandtechniques,somestatisticalandothersmorequalitative,canbeusedtodetectvariation,
characterizeit,anddeterminetherootcause.Werecommendthatthemanufacturerusequantitative
statisticalmethodswheneverfeasible.(1).

SeriesDiscussionTopics
Thetentativeplanforthecontentinthisserieswillbeginwithdiscussionofbasicprinciples.Fundamentaltopicsin
thisareawillincludetypesofdata,graphicalrepresentation,distributions,centraltendencies,dispersions,and
probability.Confidenceintervalsandtoleranceintervalswillbediscussed.Subsequenttopicswilladdressareas
particularlyapplicabletotherespectivelifecyclestagesofprocessvalidation.Thesewillincludetopicssuchas
experimentaldesign,includingscreeningstudiesandmultivariateexperimentalstudies.Discussionsonmetrology,
processcapability,controlcharts,trending,andotherrelatedtopicsareplanned.Examplecasestudiesand
calculationswillfurtherdescribetheabovetopics.ValidationbyDesignTheStatisticalHandbookfor
PharmaceuticalProcessValidationbyTorbeck(4)isrecommendedforacomprehensivesummaryofstatistics
topicsassociatedwithprocessvalidation.

Asmentionedabove,theobjectiveforthisseriesofdiscussionsonstatisticaltopicsisusefulinformation.Reader
inputthroughcomments,questions,andotherdiscussionisneeded.Suggestionsforfuturediscussiontopicsare
invited.Readersarealsoinvitedtoparticipateandcontributemanuscriptsreflectingactualexperiencesutilizing
statisticaltoolsfordevelopmentandcontrolofpharmaceuticalprocessesoranalyticalmethods.

References
1.FDA,ProcessValidation:GeneralPrinciplesandPractices(Rockville,MD,Jan.2011).
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26/02/2017 Statistical Tools for Development and Control of Pharmaceutical Processes: Statistics in the FDA Process Validation Guidance
2.FDA,AnalyticalProceduresandMethodsValidationforDrugsandBiologics(DraftGuidance)(Rockville,
MD,Feb.2014).
3.GHTF,QualityManagementSystemsProcessValidationGuidance,Edition2,January2004.
4.L.Torbeck,ValidationbyDesign.TheStatisticalHandbookforPharmaceuticalProcessValidation,PDA
andDHIPublishing,2010.

AlsoSee:

Blog: Statistical Tools for Process Qualification

GXP: FDAs 2011 Process Validation Guidance: A Blueprint for Modern Pharmaceutical
Manufacturing

SourceURL:http://www.ivtnetwork.com/article/statisticaltoolsdevelopmentandcontrolpharmaceutical
processesstatisticsfdaprocessva

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