8/3/2017 HowToEstablishSampleSizesForProcessValidationUsingStatisticalToleranceIntervals

GuestColumn|October27,2016

How To Establish Sample Sizes For Process Validation Using Statistical Tolerance
Intervals
ByMarkDurivage,ASQFellow

Thefirstarticleinthisseries,RiskBasedApproachesToEstablishingSampleSizesForProcess
Validation(June2016),establishedtherelationshipbetweenriskandsamplesize.Subsequent
articleshaveintroduceddifferentmethodsfordeterminingsamplesizestoensurevalidation
activitieswillyieldvalidresults.Thisinstallmentwilldemonstratehowtousestatisticaltolerance
limits,whichusetheconfidencelevel(howsureweare)andreliabilityvalue(populationvalue)to
determineappropriatestatisticallyvalidsamplesizesforprocessvalidation.

StartWithFMEA

Beforewebegin,wemustestablishourdefinitionsofriskandtheirassociatedconfidenceleveland
reliabilityvalue.Thesedefinitionscanandshouldvarybasedupontheorganizationalneeds.Agood
placetodeterminetherisklevelisfailuremodeandeffectsanalysis(FMEA),asystematicgroupof
activitiesdesignedtorecognize,document,andevaluatethepotentialfailureofaproductorprocessanditseffects.FMEAusesariskprioritynumber
(RPN),whichisbasedonthefrequency,detection,andseverityofapotentialfailuremode.ThehighertheRPN,thehighertherisk.However,alow
probabilityofoccurrenceinconjunctionwithhighseverityandhighprobabilityofdetectionmaystillnecessitatetheappropriatecontrolsforhighrisk.

Table1depictsanexampleFMEAwiththeassociatedrisklevels.Oncetherisklevelhasbeendetermined(low,medium,high),theappropriate
confidencelevelandreliabilitycanbeselectedusingTable3.Figure1depictsthelinkagebetweenFMEA,risk,andconfidencelevelandreliability.

Table1:ExampleFMEA

Figure1:Riskprocessfordeterminingtheappropriateconfidencelevelandreliability

Table2showsanexampleofriskleveldefinitionswithaccompanyingdefectclassifications.Thesedefinitionscanandwillvarybaseduponthe
product(s)producedanditsintendedandunintendeduses.

Table2:ExampleofRiskLevelDefinitions

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Table3depictsexampleconfidencelevelsandreliabilityvaluesbaseduponrisk.Ofcourse,differentconfidenceandreliabilitylevelscanandshouldbe
utilizedbaseduponanorganizationsriskacceptancedeterminationthreshold,industrypractice,guidancedocuments,andregulatoryrequirements.

Table3:ExampleConfidenceandReliabilityLevelsBaseduponRiskAcceptance

StatisticalToleranceIntervals

Whenusingstatisticaltoleranceintervals,thereisanassumptionandexpectationthatthedataisnormallydistributed.Therearemanywaysto
determineifdataisnormallydistributed,includingcomputerprogramsandspreadsheets.However,forsmallsamples(15orfewer)normalprobability
plotscanbeusedtoassessnormality.

Normalprobabilityplotscanbeconstructedtolookforlinearitywhenusingonevariable.Normalprobabilityplotsprovideavisualwaytodetermineifa
distributionisapproximatelynormal.Ifthedistributionisclosetonormal,theplottedpointswilllieclosetoaline.Normalprobabilityplotsare
constructedbydoingthefollowing:

1.Arrangethedatafromsmallesttolargest.
2.Determinethepercentileofeachdatavalue.
3.Fromthesepercentiles,donormalcalculationstodeterminetheircorrespondingzscores.
4.Ploteachzscoreagainstitscorrespondingdatavalue.
5.Performagraphicalreviewofthenormalprobabilityplotforthedatapointstoverifyiftheygenerallyfallonthelineofbestfitsometimes
referredtoasthepenciltest.Ifthedataisnotnormallydistributed,itisbesttouseanalternativemethod.

(Foranexampleofhowtocreateandanalyzenormalprobabilityplots,refertoChapter4ofPracticalEngineering,Process,andReliabilityStatistics,
ASQQualityPress,2014.)

Statisticaltoleranceintervalscanbeonesidedortwosided,dependingifthespecificationrequiresaminimumormaximumvalueorifthespecification
hasanallowablerange.However,itisgenerallybestpracticetouseonesidedtoleranceintervalsthismethodwillprovideamoreconservative
approach,becausetheriskisplacedononesideratherthanbeingsplit.Ifthespecificationisbilateral,usethespecificationthatisclosesttothesample
mean,whichiscalculatedfromtheinitialsample.

Thefirststepinusingstatisticaltoleranceintervalstodeterminesamplesizesforprocessvalidationistocalculatethemeanandstandarddeviationfrom
asmallsample,whichshouldcapturetheexpectedrangeofvariationthatcanreasonablybeexpectedfromtheprocess(differentbatchesofmaterials,
operators,etc.).Todeterminethisminimuminitialsampleforaonesidedtest:

Andforatwosidedtest:

Where:

z=normaldistributionvalue

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=confidence

=reliability

=thedifferenceorshiftwewanttodetect

Table4providesthenumberofsamplesrequiredtodetecteithera1.0shiftora1.5shift.Ifthetestingtobeperformedisdestructive,expensive,oron
highvalueparts,usinga1.5shiftissuggestedotherwiseusea1.0shift.Pleasenotethatthesearetheminimumnumberofsamplestoestablishthe
samplemeanandstandarddeviation.

Table4:InitialSampleTable

SingleSidedSpecificationExample

ApouchsealingoperationisconsideredhighriskaccordingtheFMEAinTable1.Highriskrequires95%confidence(0.05)and99%reliability(0.01),
asshowninTable3.Thevalidationteamdecidedtouseaof1.0.Table4requiresaninitialsampleof16.The16sampleswerefoundtobenormally
distributed,withameanof3.2lbsandsigmaof0.23.Thepouchsealingprocessspecificationrequiresaminimumpullstrengthof2.5lbs.

Forasinglesidedspecification:

Table5:95%OneSidedTolerancekFactors(Partial)

Thecalculatedkvalueis3.043.(Thekvalueselectedshouldbeequaltoorlessthanthecalculatedvalue.)Highriskrequires95%confidence(0.05)
and99%reliability(0.01),forwhichTable5indicatesaminimumof35samples.Aminimumof35samplesmustbeusedforthevalidation.Because
thecompanytypicallyusesthreebatchesforprocessvalidation,12sampleswillberandomlydrawnfromeachofthreebatchesforatotalof36samples.

Threevalidationlotsweremanufactured.The36sampleswerefoundtobenormallydistributedwithameanof3.1lbsandsigmaof0.21.

Foraonesidedtolerance:

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Sincethecalculatedtoleranceinterval(3.037lbs)isgreaterthantheminimumpullstrengthof2.5lbs,thevalidationpassed.Wecanstatethatweare
95%confidentthattheprocessis99%reliable.Inotherwords,wecanclaimthat95%ofthetime,99%oftheproductsproducedwillexceedthe
minimumpullstrengthof2.5lbs.

Sample size does matter! Let Mark Durivage show you which method for determining sample size is best for your process validation efforts:

RiskBased Approaches To Establishing Sample Sizes For Process Validation

February 16, 2017 | 1:002:30PM EST

DoubleSidedSpecificationExample

AfillingoperationisconsideredtobemediumriskaccordingtheFMEAinTable1.Mediumriskrequires95%confidence(0.05)and95%reliability
(0.05),asshowninTable3.Thevalidationteamdecidedtouseaof1.0.Table4requiresaninitialsampleof13.The13sampleswerefoundtobe
normallydistributed,withamean995gandsigmaof4.3.Fillingprocessspecificationis1000g5g.

Foradoublesidedspecification:

Thecalculatedkvalueis2.326.(Thekvalueselectedshouldbeequaltoorlessthanthecalculatedvalue.)Mediumriskrequires95%confidence(0.05)
and95%reliability(0.05),whichTable6indicatesaminimumof80samples.Aminimumof80samplesmustbeusedforthevalidation.Becausethe
companytypicallyusesthreebatchesforprocessvalidation,27sampleswillberandomlydrawnfromeachofthreebatchesforatotalof81samples.

Threevalidationlotsweremanufactured.The81sampleswerefoundtobenormallywithasamplemeanof994gandsamplestandarddeviationof4.2.

Table6:95%TwoSidedTolerancekFactors(Partial)

Foratwosidedtolerance:

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Recallthetoleranceis1000g5g(995gto1005g).Sincethelowertoleranceinterval(984.5g)isbelowthelowerspecificationof995g,thevalidation
hasfailed.Itshouldbeapparentthattherearetwoissueswiththeprocess.Thefirstisthattheprocessisnotcentered,andsecondisthatthereis
excessivevariation.Thevalidationteammustfirstcentertheprocessandthendeterminethebestmethod(s)toreducethevariationwithintheprocess.

ChoosingTheRightMethodForYourProcess

Althoughtheexamplesprovidedusesinglesidedanddoublesidedspecifications,inpracticeIprefertousethesinglesidedmethod,toaccountforan
offcenterprocess(sameprincipleasCpk).Remember,thecriteriausedshouldbebaseduponriskandshouldbedocumentedandproceduralized.When
avalidationfails,therearethreedistinctoptionsavailable:

Centertheprocess
Reducethevariation
Changethespecification(tolerance)

Iwanttoreinforcethatdifferentconfidencelevelsandreliabilityvaluescanandshouldbeutilizedbaseduponanorganizationsriskacceptance
determinationthreshold,industrypractice,guidancedocuments,andregulatoryrequirements.Usingstatisticaltoleranceintervalstoestablishsample
sizesforprocessvalidationactivitiesisawidelyusedandacceptedpracticeinFDAregulatedindustries.

Themethodspresentedherehavebeenusedandsuccessfullydefendedduringauditsandinspections.Icannotemphasizeenoughtheimportanceof
proceduralizing(documenting)thestatisticalmethodsandrationaleyourorganizationmayuseforprocessvalidationactivities.Table2providesan
exampleofdocumentingandstandardizingrisklevels,defectclassifications,anddefectdefinitions.Table3providesanexamplefordocumentingthe
confidencelevelandreliabilityrequirementsforprocessvalidationactivities.Ialsorecommendthatvalidationandstatisticaltechniqueprocedures
includetheformulasaswellasfullyworkedexamples,likethosedemonstratedabove,toprovideclarityandguidanceforthoseindividualswriting,
performing,executing,andapprovingprocessvalidationactivities.

Subsequentarticlesinthisserieswillprovideadditionalhowtoexamplesforapplyingriskbasedsamplesizetechniquestoprocessvalidationsin
yourorganization.Previousarticlesinclude:

RiskBasedApproachesToEstablishingSampleSizesForProcessValidation
HowToEstablishSampleSizesForProcessValidationUsingTheSuccessRunTheorem
HowToUseReliabilityBasedLifeTestingSamplingForProcessValidation
HowToEstablishSampleSizesForProcessValidationUsingC=0SamplingPlans

AbouttheAuthor

MarkAllenDurivageisthemanagingprincipalconsultantatQualitySystemsComplianceLLCandanauthorofseveralquality
relatedbooks.HeearnedaB.A.SincomputeraidedmachiningfromSienaHeightsUniversityandanMSinqualitymanagementfrom
EasternMichiganUniversity.DurivageisanASQFellowandholdsseveralASQcertificationsincludingCQM/OE,CRE,CQE,CQA,
CHA,CBA,CPGP,andCSSBB.HealsoisaCertifiedTissueBankSpecialist(CTBS)andholdsaGlobalRegulatoryAffairsCertification
(RAC).DurivageresidesinLambertville,Michigan.Pleasefeelfreetoemailhimatmark.durivage@qscompliance.comwithany
questionsorcomments,orconnectwithhimonLinkedIn.

References:

1.Durivage,M.A.,PracticalEngineering,Process,andReliabilityStatistics,Milwaukee,ASQQualityPress,2014.
2.Durivage,M.A.andMehtaB.,PracticalProcessValidation,Milwaukee,ASQQualityPress,2016.
3.Durivage,M.A.,RiskBasedApproachesToEstablishingSampleSizesForProcessValidation,LifeScienceConnect,2016.
4.InternationalOrganizationforStandardization,ISO162696:2013StatisticalinterpretationofdataPart6:Determinationofstatistical
toleranceintervals,2014.

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