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RegulatoryCompliance|CAPAandRootCauseAnalysis|PharmaceuticalManufacturing

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CAPA and Root Cause Analysis

RecentFDAWarningLettershavecitedinsufficientcorrectiveandpreventiveaction(CAPA)programs

asmajorcomplianceweaknesses.HowdoesoneensureonesCAPAisontherighttrack?Doug

BartholomewinterviewsindustryQAprofessionalsandleadingconsultantsfortheanswers.

ByDougBartholomew,ContributingEditor

Jul20,2006

Investigatingthecauseofaqualityfailureorotherproductionproblemissomethingthatallpharmaceutical companiesmustdo somemorefrequentlythanothers.Themorecomprehensiveandstructuredthe investigationprocessis,themoreeffectiveitwillbe.

Thatstheconsensusofconsultantsandotherexpertsinthecorrectiveandpreventiveaction(CAPA)field.While

CAPAishandleddifferentlyatmanypharmaceuticalmanufacturers,bestpracticesforhandlingcomplaintsand

investigationsrevolvearoundcertaincoreactivities,abasicprocessand,moreoftenthannot,someenabling

technology.

TheCAPAcomplaintrootcauseinvestigationprocessisparamount.HavingasuccessfulCAPAismoreacultural

thingforacompanythanmerelyhavingthetechnologyforCAPA,saysSimonJacobson,researchanalystfor

manufacturingoperationsatAMRResearchinBoston.

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RegulatoryCompliance|CAPAandRootCauseAnalysis|PharmaceuticalManufacturing

InJacobsonsview,mostlargepharmaceuticalcompanieshavemoretroublebreakingdownthesilos inwhich theymighthaveseveraldifferentCAPAprocessesandtechnologiesbeingusedindifferentdepartmentsand plants toachieveasinglemanagedviewoftheprocess.Manypharmaceuticalcompanieshaveinstalledseveral CAPAsolutions,butthereisnocommonwayforthemtodotrendingandputpreventiveactioninplaceacrossthe company,hesays.

Surprisingly,smallerpharmaceuticalfirmsoftentakeamoresystematicapproachtohandlingCAPAcomplaints

thanlargercompanies.Atsingle­siteoperations,peoplearemoreinclinedtoworktogether,sothat,forinstance,

theR&Dchiefknowsthemanufacturingguy,Jacobsonobserves.Butwiththebiggercompanies,therearemore

silosandthereisagreaterneedforacommon,systematicapproachtoCAPA.

Often,CAPAproblemscanbetracedtothelackofconsistentprocessrequirementsandwrittenprocedures.

Becauseoftheseinconsistenciesacrosssites,companiesmayhavetochasethesamecomplaintatmultiple

facilities.Thisispreventingorganizationsfromhaltingwhatcouldbesystemicinefficiencies,Jacobsonsays.In

addition,hesays,Thelackofanorganization­widesystemicmanagementprocesspreventsacompanyfrom

successfullyauditingtheirprocessesandtakingeffectivepreventiveactions,suchastrendingacrossmultiple

sites.

The four-step method Inmostcases,aCAPAinvestigationissetinmotionbyanevent eitheralaboratoryinvestigation,a manufacturinginconsistency,aregulatoryorinternalaudit,oracustomercomplaint.Anyoftheseinvestigation recordsareenteredintoaCAPAsystem,whichcanspawnarelatedCAPAinvestigation,explainsRobert Fetterman,presidentofTechnicalBusinessSolutions(RoyersFord,Pa.).

ThemajorityofcompaniesinitiatetheirCAPAprocessesonceacomplaintorfieldfailureisdiscovered,says

AMRsJacobson.Thisisnotonlytoolatebecausethepatientisalreadyatrisk,butcompaniesarehardpressed

tocomplywiththeFDAsCAPArequirementsbecausetheylackinsightintotherootcauseofthedevice

malfunction.

TheCAPAprocess,ofcourse,isbroaderthanjusttheinvestigationofcomplaints.Butinvestigationoftheroot

causeofproblemsliesatitscore.AsJacobsonsays,AttheheartofasuccessfulCAPAisadefinitionofthe

problemandanassessmentofwho,whatandwhereisatrisk,aswellasthepotentialimpactontheorganization

shouldtheproblemgrow.

Ingeneral,CAPAexpertsrecommendthatrootcauseinvestigationsfollowafour­stepprocess:

1.Identify

theproblem.

1.Evaluate

itsmagnitude,whichincludesassessingrisk.

1.Investigate

andassignresponsibility.

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RegulatoryCompliance|CAPAandRootCauseAnalysis|PharmaceuticalManufacturing

1.Analyze

anddocumenttherootcauseoftheproblem.

Tracking best practices FettermanisnearlycompletionofaprojecttoinstallaCAPAsolutiongloballyatamajorpharmaceuticalfirm.

Weredevelopingthesystemandrollingitouttoalltheir30sitesworldwide,hesays.ThefirmisusingSparta

Systems(Holmdel,N.J.)TrackWisequalitymanagementsoftwarepackagebecauseitiseasilycustomized,

Fettermansays.Itlendsitselftoquickconfigurationofworkflowsandmodificationstomeetthebusinessneeds.It

alsorunsontheOraclesystemsthatareinuseatmanypharmaceuticalcompanies,hesays.

WithanyCAPAinvestigation,havingaprescribedworkfloworsetofactivitieswithdesignatedpeopleassignedto

carrythemoutisessential.YoucantrackaCAPAeventandthemultipleactivitiesrequiredthroughoutthe

workflowprocess,Fettermansays.EachCAPArecordislinkedtotheoriginalparentqualityevent,sothata

supervisorormanagercancheckthesystemandquicklyseethattheeventhasbeentrackedthroughtoclosure,

orifnot,exactlywhereitisstalledorheldup.

ThisisimportanttoCAPAcomplaintinvestigation,thattherebeasystemtomakesurethattheseproblemsare

trackedallthewaythroughtocompletion,Fettermansays.Thisway,theplantmanagerknowsthatappropriate

actionsweretaken

andthatthecorrectiveactionstakenare,infact,solvingtheproblem.

Thesoftwaresworkflowcapabilityhelpstoensurethateachstepistakeninatimelyfashion.Thesystemassigns

investigationtaskstoteammembers,trackingeachtaskthroughtocompletion.Eachinvestigatordocumentshis

orherfindingsinthesystem,withresultsandattachmentselectronicallyincluded.Theleadinvestigatorisnotified

aseachstepiscompletedor,conversely,undulydelayed.

Unfortunately,manycompanieshaveyettocomputerizetheirCAPAcomplaintsandinvestigations.Thedangerof

manuallydocumentingCAPAprobleminvestigationsisthatithasproventobeunreliable,Jacobsonpointsout.

TheFDAhasaddressedCAPAasthenumberonegoodmanufacturingpractice(GMP)deficiency,hesays.And

theFDAismoreinsistentthaneverthatmanufacturersmaintainconsistentfilesandproceduresacrosstheir

organizationsandembedFDAregulationsintocompanystandardoperatingproceduresregardingtheCAPA

process.

SomecompanieshaveimplementedelectronicsolutionsforpiecesoftheCAPAprocess.Butveryfew

pharmaceuticalfirmshaveimplementedacomprehensiveprocessliketheoneFettermanisinstallingforhis

currentclient,hesays.Theyhadatotallymanualprocessbefore,headds.

People issues InFettermansexperience,itisextremelydifficulttogetpeopleacrossallsitestofollowtheCAPAcomplaintand investigationprocessinthesameway.Thebiggestchallengewehadwiththisglobalrolloutwascomingupwitha consistentandreliableapproachtohandlingCAPAcomplaintsandinvestigationsworldwide,hesays.

Toestablishconsistency,companiesmusthaveastrongdirectivefromseniormanagementfortheproject,anda

commitmentbytheorganizationthatthisisthewaywearegoingtohandleit,hesays.Youjustdontwanttohave

separateworkflowsfordifferentsites.

Ofcourse,eventhebesttechnologiesandprocessesareonlypartofthesolution.Theculturalissueofgetting

peopleintheorganizationtoperformtheirCAPAresponsibilitiesisthekeytoanysuccessfulprogramfordealing

withCAPAcomplaintsandinvestigations.Howtoincentemployeestoworkonthesamepageisimportant,says

AMRsJacobson.Thetechnologyistheenablingcomponent,butsomeonehastoownresponsibilityforthe

process.Alotofcompanieshaveputtogethercross­functionalteams.

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RegulatoryCompliance|CAPAandRootCauseAnalysis|PharmaceuticalManufacturing

FDA­certifiedconsultantswhospecializeinCAPAcanfacilitateitsacceptance,Jacobsonsays.Havingacredible

outsidevoicetocomeinishelpful,hepointsout.

ThisisespeciallytrueforpharmaceuticalcompaniesthatplantoinstallaspecificsoftwarepackageforCAPA.For

asystemlikeTrackWise,youdoneedspecificexpertiseonhowtoconfigureit,Fettermansays.

ButCAPAtechnologyandconsultantswilltakeacompanyonlysofar,saysWadeSpeir,seniorconsultantinthe

lifesciencespracticeatKepner­Tregoe,Inc.,aPrinceton,N.J.consultingfirm.Thesoftwareisonlyapartofthe

solution,hesays.Therearetheprocessissues,whichoftenrequirechangingpeoplesbehaviors.

The bearer of bad news ThemostdifficultaspectofCAPAproblemsolvingisgettingasharpfixonexactlywhatconstitutestheproblemat issue,Speirsays.Byfarthehardestpartofproblemsolvingisgettingaclearconsensusofwhattheproblemis, hesays.Youneedtoidentifywhatsactuallyhappeningaswellaswhatisexpectedtohappen.

Forexample,pillsoftenshowsiliconecontaminationfromtheproductionprocess.Themanufacturerneedsto knowexactlyhowmuch,ifany,siliconewasexpectedtoappearinthepillunderoptimalcircumstances.Though drugcompaniesmaynotadmitit,Theresalwayssomecontaminationfromallthevalvesandmachinery,Speir says.Knowingtheproperbaseline whetherthereiszeroorthemostminuteamountofcontamination is essentialtodetermininghowmuchactualdeviationexists.

ToidentifytherootcauseofaCAPAproblem,themanufacturermustfirstspecifywhattheproblemis,whereit

occurs,howoften,andhowbigtheproblemis.Itmustalsotestpossiblecausesagainstthefactsofthe

occurrence.Theideaistoseewhichcauseexplainstheproblem.Atthesametime,thisprocessalsoshould

pointoutthepossibleproblemsthatcouldoccurandwhytheyarenot.

Theideaistobeabletoexplainwhythisbatchwasbad,aswellaswhytheprecedinglotandtheoneafterthe badonewereokay,Speirsays.Oncethecompanyhasahypothesisforwhatcausedtheproblem,thenextstep istotestit eitherbyexperimentation,orbyfixingitandseeingifthissolutionworks.

CompaniesneedtobesurethattheirCAPArootcauseanalysisinvestigatesallpossiblecausesandteststhe

suspectedonetomakesureitis,infact,therealcauseoftheproblem.Itsimportanttodistinguishbetweenthe

observedsymptomsofaproblemandthefundamentalorrootcause.Youwanttobesurepeoplearefixingthe

rightissueandaddressingtherightcause,saysJohnMcLaughlin,principalconsultantatTaratecDevelopment

(Bridgewater,N.J.).Youdontwantanengineerputtingafixonaproblemwithoutaddressingtheunderlying

issues.

Therootcauseanalysisinvolvesansweringabatteryofquestionsthataskwhywiththegoalofdiggingdeepuntil

thereasonfortheproblemisidentified.Sometimesthecauseoftheproblemmayonlybeasymptomofamore

pervasiveissue.Forexample,ifapoorlytrainedoperatorwastheimmediatereasonfortheproductionofabad

batch,therootcauseanalysisshoulddelvedeepertodetermineiftheplantstrainingprogramitselfisatfault.The

questionshouldbeasked,couldotheroperatorsbepoorlytrainedinthefuture?

Pharmaceuticalfirmsshouldbelookingacrosstheorganizationtoseeifalargerproblemexists,adds

McLaughlin.Thegoodnewsisalwaysgreattohear,butthebadnewsiswhatyoureallywanttohear.Companies

shouldrememberthat,attheendoftheday,theCAPAprocessissupposedtohelpthem.

AllthisactivitymustbedocumentedtoprepareafullinvestigationreportfortheFDA.Muchofthisinformationcan

bedrawnfromthebatchrecord,whichinmanyinstances,canbefoundinbindersofinformation.Formany

companiesthisisquiteachallengingeffort,Speiradds.Andusuallythepeopledoingitarenotthehighestpaidin

theorganization.

IdentifyingtherootcauseofaCAPAeventisonlypartoftheoverallCAPAactiontobetaken.Theotherhalfof

SHOWMORECONTENT

theprocessisdeterminingwhatactionscanbetakenbothtocorrectandpreventsuchoccurrences.

18/10/2016

RegulatoryCompliance|CAPAandRootCauseAnalysis|PharmaceuticalManufacturing

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