2017522 ChangeControlforFunctionallyEquivalentLikeForLikeChanges

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ChangeControlforFunctionallyEquivalentLikeForLikeChanges

By PaulL.PlutaJan22,201312:51pmPST

INTRODUCTION

Changecontrolisacriticalcomponentinregulatedpharmaceutical
manufacturingandqualitysystems.Changestomanufacturing
processes,formulations,equipment,cleaningprocedures,analytical
methods,andothersystemsareevaluatedonriskorimpact.
Complicatingthesejudgmentsareemergencysituationswhenchanges
mustbemadetomaintainoperationswithoutproactivethorough
evaluationofriskorimpact.

Riskevaluationofchangeisacriticaldetermination.Atoneextreme,
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changesmaybesignificant,representingahighrisktoprocessingor
otheroperations.Suchchangesrequirefullvalidationandqualification.
Attheotherextreme,changesmaybecompletelyinsignificantwithminimalrisktopatient,product,process,or
equipment.Functionallyequivalent(i.e.,likeforlike)changesareoftenjudgedtobechangesinthislatter
category.

Likeforlikechangesareminimalchangesmadetoprocesses,equipment,utilities,facilities,computers,orother
systems.Likeforlikechangesareusuallyjudgedtobeequivalentreplacements.Oftenthesechangesare
identicalreplacementsofparts,components,andotheritemsofinterest.Somemaynotconsiderlikeforlike
changestobeanactualchange.Areplacementmotor,replacementscreen,replacementfilterbag,replacement
piping,andsoonareoftenroutinemaintenanceonvalidatedandqualifiedequipmentandnotperceivedtobean
actualchange.Likeforlikechangesaretypicallythoughttonotrequireanysubsequenttesting.Logicisthat
becausetheoriginalequipmentorsystemhasalreadybeenvalidated,andbecausenothinghasreallychanged,
whytheneedtodonewvalidationwork?Whywastetimeoreffortwhennothinghaschanged?Isntthatthe
problemwithvalidationdoingtoomuchunnecessarywork,addingcost,delayingmanufacturing,andother
undesirableeffects?

Thisdiscussionaddressessituationsinwhichlikeforlikechangesdidnotperformasexpected.Oftenthese
changesareemergencychangesdoneduringthirdshiftoperationorduringweekendstomaintainmanufacturing
operations.Examplespresentedweredescribedbypharmaceuticalmanufacturingmanagersatinternational
conferences.Theoccurrencesdescribedareactualincidentsthatdemonstratethebroadscopeandsignificant
magnitudeofpotentialproblemswithlikeforlikechanges.

BACKGROUND

Theprocessofvalidationandqualificationtypicallycomprisesthefollowingsequenceofactivities:

1.Changedesired.Anewproductorprocessoraprocesschangeorequipmentchangeisneededor
required.Thismaybeanecessarychange,adesirableimprovement,emergencywork,orroutine
maintenance.
2.Supportprework.Appropriatepreworkiscompletedinadvanceandsupportingthechange.Thiswork
mayrangefromhighlycomplexandfarreaching(e.g.,newprocessdevelopment,newequipment
purchase,factoryacceptancetesting[FAT])toveryminimal(e.g.,selectingandorderingaminor
replacementpartforequipment).
3.Validationandchangerequest.Aformalrequesttoinitiatethevalidationprocessissubmittedtothe
validationapprovalcommittee(VAC).Supportworkreportsmaybeincludedintherequesttojustifythe

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2017522 ChangeControlforFunctionallyEquivalentLikeForLikeChanges

change.Thechangerequestmayincludeaproposedlevelofworktoconfirmtheacceptabilityofthe
change.Thelevelofworkisbasedonrisktothepatientandtotheorganization.TheVACapprovesthe
validationrequest.
4.Validationplan.Dependingonthescopeandmagnitudeofthevalidationrequest,avalidationplanmay
besubmitted.Thisplandescribesthevalidationworkrequiredingreaterdetail,appropriatetestingand
samplingproposedtodemonstrateasuccessfulchange,andacceptancecriteriafortherecommended
testing.TheVACapprovesthevalidationplan.
5.Validationprotocol.Aprotocoliswrittenspecifyingdetailedsamplingandtestingtoconfirmthe
acceptabilityofthechange.TheVACapprovesthevalidationprotocol.
6.Validationwork.Validationworkisperformedaccordingtotheprotocol.Samplingandtestingare
completed.Dataandotherresultsaregeneratedandrecorded.
7.Validationresultsandreport.Areportcontainingalltestresultswithdiscussionandconclusionsis
preparedandsubmittedtotheVACforapproval.Thereportisapproved,andtheprocessorequipment
changeisimplemented.Anappropriatelevelofpostvalidationmonitoringisproposedinthereport.
8.Validationclosure.Ifnootherworkisneeded,thevalidationprojectinitiatedbythechangerequestis
closed.
9.Emergencychanges.Incasesofemergencychanges,managementmayauthorizechangestobe
completedasneededapartfromtheabovedescribedprocess.Emergencychangesshouldbeevaluated
bytheQAandtheVACassoonaspossible.Supportingdocumentationisthencompletedtoconfirmthe
acceptabilityofthechangeandsubmittedtotheVACforapproval.
10.Documentation.Allrelevantdocumentationdescribedinsteps29includingsupportingpreworkshould
bestoredinthevalidationlibraryorreadilyaccessiblethroughaknowledgemanagementsystem.
11.Continuedverification.Postvalidationmonitoringconfirmingacceptabilityofthechangecontinues
throughoutthelifecycle.

Theissueaddressedinthiscasestudyoccurredinstep3,thevalidationandchangerequest,whichinitiatesthe
formaldocumentedvalidationprocess.Emergencychanges(step9)alsohaveapplicationinthisdiscussionand
wereoftenanimportantcontributingfactor.Specifically,changesrequestedwerejudgedtobelikeforlike
changesthatshouldhavehadnoimpactontheprocessorequipment.Becausenoimpactwasexpected,no
testingorotherworkwasrecommendedaspartofthechange.Likeforlikereplacementworkwasauthorizedand
completed.Workwasdocumentedonequipmenthistorylogs,maintenancerecords,orothersystemsin
accordancewithsiteprocedures.

VALIDATIONEVENTS

Discussionswithseveralmanagersfrompharmacompaniesregardingproblemstheyhaveexperienced
indicatedthatlikeforlikechangeswerearecurringproblem.Ingeneral,changesaredefinedaslikeforliketo
eliminateadditionalvalidationwork.Thedefinitionoflikeforlikemaybebroadlyinterpretedinthesecases,and
insomecasesweretoobroadlyinterpreted.Occasionallythesejudgmentsandensuingproblemshave
significantconsequences.Severalactualexamplesdescribedhereindemonstratesuchevents.Personnel
responsiblefortheselikeforlikejudgmentsdidnotrealizethepotentialproblemscausedbytheirjudgments.

LaminarAirFlowinAsepticProcessingFacility

Onemanagerdescribedanincidentinwhichroutinerevalidationofanasepticfillinglinewasbeingperformed.
Allactivitiesandtestswereperformedaccordingtoprocedure,includingsterilizerrevalidation,mediaruns,and
interventions.Allresultswereacceptableandasexpecteduntilthefillinglinesmoketestwasconducted.The
smoketestwasperformedtoconfirmthelaminarairflowdirectionintheasepticsuite.Allinvolvedwereshocked
whentheairflowwasshowntobeupwardtowardtheHEPAfilterinsteadofdownwardthroughthefiltertoward
openproduct.
Roomandequipmenthistoryrecordswerechecked.Theonlyactivityperformedintheareathatcouldhave
causedthiseventwastheinstallationofalikeforlikereplacementblowermotorbythesitemaintenanceshop
severalmonthspreviously.HEPAfiltrationofroomairhadthusbeencompromisedforseveralmonthsduring
whichtimemultipleproductlotsweremanufactured.Theselotshadpassedallproducttestingandwerereleased
tocommercialdistribution.

TheUSFoodandDrugAdministrationwasnotified.Alllotsmanufacturedduringthetimeperiodwhentheblower
motorwasoperatingincorrectlywererecalled.Thisincidentwashighlyembarrassingtotheorganizationwith
seriousnegativeimpressionsonregulatorypersonnel,healthprofessionals,patients,andthegeneralpublic.
Recallcostsweresignificant.
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MillingSolidsforTabletProducts

Anothermanagerdescribedanincidentinwhichmajorprocessingproblemswithseveraltabletproducts
occurred.Thiseventoccurredinalargemanufacturingfacilitythatproducedmultiplesoliddosageforms(e.g.,
tablets,capsules,granules,powders).Occasionalproductprocessingproblemswereobservedwithseveral
products.Astheseindividualincidentsbecamemorefrequent,investigationswereinitiated.Theproblemwas
eventuallyassociatedwithparticlesizedistributionchanges.Blendedgranulationshadsmallerparticlesize
distributionsthanexpectedwhencomparedtohistoricaldata.Eventually,theseproblemswereassociatedwith
processingusingaspecificimpactmill.Whenoperationofthemillwasinvestigated,itwasfoundthatthemillrotor
wasrunninginthereversedirectioncomparedtoothermillsatthesite.Thiscausedincorrectmillingofsolidsand
improperparticlesizedistributions.

Equipmenthistoryrecordswerereviewed.Theonlyactivityperformedthatcouldhavecausedthiseventwasthe
installationofalikeforlikereplacementmotor.Themotorchangewascorrelatedtothefirstreportofprocess
problemsatthesite.Problemswereassociatedwithmillingofactivedrugsandinactiveingredientsforrespective
lots.

CellCultureAgitation

Avalidationmanagerdescribedaneventinwhichthecellgrowthinabiotechnologyprocesswassignificantly
lowerthanthehistoricalaveragewhenculturesweregrowninaspecificmanufacturingtank.Becausethis
productwasahighvolumeproductthatwasmadeinmultipletanksandmanufacturinghadreasonablevariation,
thelowergrowthwasnotimmediatelyobvious.Asmorelowgrowthbatchesweremanufactured,itbecame
apparentthatlowyieldswerebeingconsistentlyproducedfromaspecificindividualprocessingtank.

Equipmenthistoryrecordsforthesuspecttankwerereviewed.Theonlyworkperformedonthetankdocumented
intheequipmenthistorylogwastheinstallationofareplacementmotoronthemixer.Themotorchangewas
correlatedtothefirstreportofloweredgrowthandsubsequentbatchesthereafter.Whenoperationofthetankwas
thoroughlyinvestigated,itwasfoundthattheimpellerwasrunninginthereversedirectioncomparedtothe
originalinstallationandcomparedtoothertanksatthesite.Thiseffectsignificantlyalteredthemixingprofileofthe
cellculture,resultinginreducedcellgrowthandAPIyield.

MixingProcessesforSmallMoleculeSolutionProducts

Amanufacturingmanagerdescribedaneventinwhichthemixingofasmallmoleculesolutionproductwas
significantlyaffected.Themanufacturingprocessfromtheproductrequiredmixingforaspecifiedmixingtime.The
productinvolvedhadalonghistoryofsuccessfulmanufacturing.Occasionaloccurrencesofcloudysolutions
wereobserved.Whenthisoccurred,adeviationtomixforadditionaltimewasissued,andtheresultingproduct
wasacceptable.Aftermultipledeviationshadbeenissued,aninvestigationwasinitiated.Itwasdeterminedthat
themixerwasrunninginthereversedirectioncomparedtopreviousprocessing.Thiscausedmixingtobemuch
lessefficientthanexpected.Thechangeindirectionwascorrelatedtoamotorreplacementperformedby
maintenancepersonnel.Thisevenpromptedareviewofallothermixersatthesite.Severalotherinstancesof
reversedmotordirectionswereidentified.

WHATARETHEISSUES?

Ineachoftheeventspresentedherein,alikeforlikechangewasperformedwithouttheapparentneedforany
confirmatorytesting.Identicalreplacementequipmentwasavailableforeachofthedescribedchanges.All
personnelinvolvedbelievedthatinstallationofreplacementequipmentwasinconsequentialandwouldbedone
correctly.Theproblemsobservedwerecompletelyunexpected.Ineachcase,thelikeforlikechangewas
consideredtobeinsignificant.Additionaltestingwasnotprescribed.Althoughthelikeforlikeequipment
selectionwasaccurateandacceptable,installationoftheequipmentwasnot.Faultyinstallationresultedin
seriousconsequencesforthemanufacturingsiteandtheorganization.IntheasepticHEPAfilterincident,a
significantrecallofproductreleasedtothemarketplacewasrequired.

TechnicalEvaluation

Ineachoftheevents,maintenancepersonnelperformedalikeforlikemotorchange.Themotorsinallofthe
eventswerelikelythreephasemotors.Thesemotorsrequirespecificconnectionstobeproperlyinstalled.If
connectionsareoutofsequence,directionofthemotorcanbereversed,resultinginmuchlessefficientoperation
ofthedrivendevice.Theerrorineachexamplehadthefollowingprobableunintendedconsequences:

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FilllineHEPAfilterfan:acentrifugalfanwasmostlikelydeliveringtheairtothefilterbankabovethefill
line.Whenrunbackwards,thistypeoffanperformsat10%30%ofitsproperlyrotatingairflow.Thisis
enoughairmovementtogivethefalseimpressionthatthesystemisoperatingproperly.
Millingmachine:theequipmentrequiresacam/followerorsimilarcontrolmechanismthathasdesigned
approachanddwelltimesrotatinginthedesignspecifieddirection.Rotatingintheoppositedirection
couldexposetheproducttoalteredimpactcyclesordifferentcomminutionmechanisms.
Cellcultureagitationandmixingprocesses:inthelasttwoexamplesthekineticenergybeingimparted
intothematerialsinthetanksmaynotbedirectedintothetankforoptimalvesselcirculation.Blade
rotationisacriticaloperatingparameterinthemixingprocess.

CORRECTIVEANDPREVENTIVEACTIONS

Theincidentsdescribedhereincausedchangesintherespectivechangecontrolprogramsandassociated
reviewprocesses.Somecommentsandsuggestedapproachesaredescribedbelow.

ReviewandApprovalofChanges

Allchangesinitiatedinafacilitymusthaveappropriatereviewbymeansofthesitechangecontrolprogram.The
respectivebusinessprocessesforchangecontrolintheorganizationareoftendifferent.Atoneextremeare
changesthatrequirewidespreadorganizationalinvolvement,regulatorysubmissions,approvalbyregulatory
agenciesbeforeimplementation,andanextendedtimelineforsuchchanges(e.g.,aregulatedproduct
formulationchange).Thesechangesareusuallyvisibleandeasilymanaged.

Attheotherextremeareminorchangessuchasrelativelysimplepartsreplacementsthatarequickly
accomplishedoftenwithoutmuchnotice(e.g.,themotorchangesdescribedabove).Therisksandconsequences
ofsuchchangesmustbeidentifiedandappropriatesubsequentactionstaken.Significantchangesmusthave
sufficientoversightandinvolvementofappropriatepersonnel.

Technicalevaluation.Technicalexpertsmustevaluatechangesasneeded.Complianceprofessionalsshould
developworkingrelationshipswiththeirtechnicalcolleaguestofacilitatetechnicalevaluationofchanges,
especiallywhentheyarebeyondtheexpertiseofthecomplianceorganization.Technicalorganizationsmust
understandthattheirinputisneededforchangeevaluations.Thisinputmustbeclearlydocumented.Technical
personnelmustbeawarethatsuchdocumentationmaybesubjectedtoregulatoryreviewinanaudit.

VACreviewandapproval.TheVACshould,ultimately,evaluateallchanges,includinglikeforlikechanges.
HavingallchangesreviewedbytheVACstandardizesevaluationanddecisionprocesses.Considerationforrisk
topatientandorganizationandensuingjudgmentswillbeuniformlyconductedbytheVAC.Appropriate
confirmationthatlikeforlikeequipmentisproperlyinstalledwouldthenbebasedonVACjudgment.Inmany
cases,additionalconfirmatoryworkwillnotberequired.Forexample,verificationofacorrectlyinstalled
replacementconveyorbeltmotorisnotnecessaryifthemotorwasinstalledincorrectlyandtheconveyorisgoing
backwards,theproblemwouldbeeasilyobserved.Theonlylikeforlikechangesrequiringverificationarethose
inwhichinstallationerrorswouldnotbeobviousduringoperation(e.g.,reversedlaminarairflow).

TheQAteammustalsoapprovelikeforlikechanges.ThequalityfunctionisusuallypartofthesiteVAC.
TheremaybeotherchangecontrolprocessesinvolvingVACorqualityapprovaldependingonorganizational
structureandpreferences.Whatevertheprocess,thekeypointisthattheremustbeacompetentdocumented
technicalevaluationofthechangethatisultimatelyapprovedbythevalidationandqualitydepartments.

Maintenancemanagementrole.Insomeorganizations,maintenancemanagementhasthefinalandcomplete
authoritytojudgewhetherornotvalidationofachangeundertheirauspicesisrequired.Thispracticeshouldbe
limitedonlytoinitiationnoteinitiationonlyofemergencychangesonly.Ifachangeislikeforlikeinthe
judgmentofmaintenancemanagement,theemergencyworkshouldbeinitiatedassoonaspossible.Work
shouldthenbedocumentedinequipmenthistorylogsorothersitedocumentationsystems.Completed
emergencychangesshouldthenbeevaluatedbythesiteVACincludingthequalitydepartment.Completed
changesarethenevaluatedbasedonworkdoneandrisktopatientandorganization.Appropriateconfirmatory
workwouldthenbeprescribed.Maintenancemanagementshouldbepermittedtoauthorizeemergency
changes.Allchangesultimatelyshouldbereviewed,evaluated,andjudgedbythesiteVACincludingQA.The
VACjudgmentsaredocumentedintheusualmanner.AcceptabilityofchangesistheultimateresponsibilityofQA.

ValidationDocumentationRequirements

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Protocolsshouldnotalwaysberequiredtoconfirmacceptabilityofalikeforlikeinstallation.Asimplewritten
memowithappropriatereviewandapprovalattestingtocorrectinstallationofreplacementequipmentshouldbe
sufficienttocompletethework.Thememoshouldincludeastatementthatcorrectequipmentoperationhadbeen
confirmedbyasecondindividual.Managementoftheresponsiblegroup(e.g.,maintenance,engineering,others)
andsiteQAshouldapprovethememo.Theapprovedmemowouldthenbefiledwiththevalidationrequestto
closethelikeforlikeactivity.Thisdocumentationapproachaccomplishestheneedtoverifyhighriskinstallation
withouttheencumbranceofvalidationprotocols,excessiveapprovals,andotherburdens.Somemanagershave
successfullyimplementedthisapproachforcertainchanges.Noadditionalverificationdocumentation(otherthan
equipmenthistory,etc.)wouldberequiredforinsignificantlikeforlikechangesorforchangesinwhichcorrect
installationwasapparentbyobviousfaultyequipmentoperation.

Technicalevaluationdocumentation.Evaluationofthechangebythetechnicalgroup(e.g.,shortmemo
discussingthechangeandrecommendingappropriateaction)shouldbeincludedintheabovevalidation
documentation.Forexample,inthecaseofanequipmentchange,theresponsibleengineeringgroupshould
providearecommendation.

ProceduresandTraining

Theaboveapproachtodocumentationshouldbespecifiedinapprovedprocedure.Specifyingtheacceptabilityof
suchconfirmatorydocumentationprovidesflexibilitytoaccomplishverificationwithouttheburdenofexcessive
protocolrequirements.Allassociatedindividualsintechnicalfunctions,validationpersonnel,maintenance
management,VACmembers,andQApersonnelshouldbetrainedonthenewprocedure.

EquipmentInstallationandMaintenanceProcedures

Validationmanagerscommentedthatengineeringandmaintenanceareasmusthaveclearproceduresforlike
forlikeequipmentreplacement.Proceduresmustbemaintainedandstrengthenedasneededwhenincidents
suchastheaboveoccur.Newpersonnelshouldbemadeawareofeventssuchastheaboveandbecautioned
aboutcuttingcorners.Businessandoperationspressuresoftendemandrapidworkfromthesegroups.
Personnelmustunderstandthatproperequipmentinstallationmustneverbepotentiallycompromised.

SeniorManagementSupport

Validationmanagersreportedthattheirrespectivesiteseniormanagementwassupportiveoftheabove
approaches.Managersreportednosimilarfaultyinstallationincidentsafterimplementationofthenewverification
procedure.

CONCLUSIONS

Thiscasestudydescribedseveralexamplesofimproperinstallationoffunctionallyequivalentlikeforlike
equipmentthatcausedsignificantproblemsforthemanufacturingsite.Emergencychanges(i.e.,changesdone
duringthirdshiftoroverweekendstomaintainproductivity)oftencontributedtotheseproblems.Likeforlike
changesaregenerallyassumedtobeofnoconsequence.However,improperinstallationofsuchequipmentcan
haveseriousramificationsincludingproductrecalls.Managersagreedthatallchanges,includinglikeforlike
changes,musthavetechnicalgroupinvolvementandultimatelyshouldbeevaluatedbythesiteVACincluding
theQAfunctiontostandardizeevaluationanddecisionprocesses.Documentationrequirementsattestingto
correctinstallationofhighrisklikeforlikeequipmentcanbeaccomplishedbyasimpleapprovedmemothatis
filedwiththedocumentationrequest.Thisapproachprovidescertaintyofsuccessfulinstallationwithoutundue
documentationburden.Engineeringandmaintenanceproceduresforlikeforlikeequipmentreplacementmust
beclear.Compliancepersonnelshouldbewaryofsupposedinconsequentiallikeforlikechangesandensure
thatsuchequipmentinhighriskapplicationsisproperlyinstalled.Simplyreplacingsamecomponentsisoften
notenoughtoensureacceptableoperation.GXP

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