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U.S.FoodandDrugAdministration
ProtectingandPromotingYourHealth

ValidationofCleaningProcesses
(7/93)
GUIDETOINSPECTIONSVALIDATIONOFCLEANINGPROCESSES
Note:ThisdocumentisreferencematerialforinvestigatorsandotherFDApersonnel.
ThedocumentdoesnotbindFDA,anddoesnoconferanyrights,privileges,benefits,or
immunitiesfororonanyperson(s).
I. INTRODUCTION
Validationofcleaningprocedureshasgeneratedconsiderablediscussionsinceagency
documents,includingtheInspectionGuideforBulkPharmaceuticalChemicalsandthe
BiotechnologyInspectionGuide,havebrieflyaddressedthisissue.TheseAgency
documentsclearlyestablishtheexpectationthatcleaningprocedures(processes)be
validated.
Thisguideisdesignedtoestablishinspectionconsistencyanduniformitybydiscussing
practicesthathavebeenfoundacceptable(orunacceptable).Simultaneously,onemust
recognizethatforcleaningvalidation,aswithvalidationofotherprocesses,theremaybe
morethanonewaytovalidateaprocess.Intheend,thetestofanyvalidationprocessis
whetherscientificdatashowsthatthesystemconsistentlydoesasexpectedandproduces
aresultthatconsistentlymeetspredeterminedspecifications.
Thisguideisintendedtocoverequipmentcleaningforchemicalresiduesonly.
II. BACKGROUND
ForFDAtorequirethatequipmentbecleanpriortouseisnothingnew,the1963GMP
Regulations(Part133.4)statedasfollows"Equipment***shallbemaintainedinaclean
andorderlymanner***."Averysimilarsectiononequipmentcleaning(211.67)was
includedinthe1978CGMPregulations.Ofcourse,themainrationaleforrequiringclean
equipmentistopreventcontaminationoradulterationofdrugproducts.Historically,FDA
investigatorshavelookedforgrossinsanitationduetoinadequatecleaningand
maintenanceofequipmentand/orpoordustcontrolsystems.Also,historicallyspeaking,
FDAwasmoreconcernedaboutthecontaminationofnonpenicillindrugproductswith
penicillinsorthecrosscontaminationofdrugproductswithpotentsteroidsorhormones.A
numberofproductshavebeenrecalledoverthepastdecadeduetoactualorpotential
penicillincrosscontamination.

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OneeventwhichincreasedFDAawarenessofthepotentialforcrosscontaminationdueto
inadequateprocedureswasthe1988recallofafinisheddrugproduct,Cholestyramine
ResinUSP.Thebulkpharmaceuticalchemicalusedtoproducetheproducthadbecome
contaminatedwithlowlevelsofintermediatesanddegradantsfromtheproductionof
agriculturalpesticides.Thecrosscontaminationinthatcaseisbelievedtohavebeendue
tothereuseofrecoveredsolvents.Therecoveredsolventshadbeencontaminated
becauseofalackofcontroloverthereuseofsolventdrums.Drumsthathadbeenusedto
storerecoveredsolventsfromapesticideproductionprocesswerelaterusedtostore
recoveredsolventsusedfortheresinmanufacturingprocess.Thefirmdidnothave
adequatecontrolsoverthesesolventdrums,didnotdoadequatetestingofdrummed
solvents,anddidnothavevalidatedcleaningproceduresforthedrums.
Someshipmentsofthispesticidecontaminatedbulkpharmaceuticalweresuppliedtoa
secondfacilityatadifferentlocationforfinishing.Thisresultedinthecontaminationofthe
bagsusedinthatfacility'sfluidbeddryerswithpesticidecontamination.Thisinturnledto
crosscontaminationoflotsproducedatthatsite,asitewherenopesticideswerenormally
produced.
FDAinstitutedanimportalertin1992onaforeignbulkpharmaceuticalmanufacturerwhich
manufacturedpotentsteroidproductsaswellasnonsteroidalproductsusingcommon
equipment.Thisfirmwasamultiusebulkpharmaceuticalfacility.FDAconsideredthe
potentialforcrosscontaminationtobesignificantandtoposeaserioushealthrisktothe
public.Thefirmhadonlyrecentlystartedacleaningvalidationprogramatthetimeofthe
inspectionanditwasconsideredinadequatebyFDA.Oneofthereasonsitwasconsidered
inadequatewasthatthefirmwasonlylookingforevidenceoftheabsenceoftheprevious
compound.Thefirmhadevidence,fromTLCtestsontherinsewater,ofthepresenceof
residuesofreactionbyproductsanddegradantsfromthepreviousprocess.
III. GENERALREQUIREMENTS
FDAexpectsfirmstohavewrittenprocedures(SOP's)detailingthecleaningprocesses
usedforvariouspiecesofequipment.Iffirmshaveonecleaningprocessforcleaning
betweendifferentbatchesofthesameproductanduseadifferentprocessforcleaning
betweenproductchanges,weexpectthewrittenprocedurestoaddressthesedifferent
scenario.Similarly,iffirmshaveoneprocessforremovingwatersolubleresiduesand
anotherprocessfornonwatersolubleresidues,thewrittenprocedureshouldaddressboth
scenariosandmakeitclearwhenagivenprocedureistobefollowed.Bulkpharmaceutical
firmsmaydecidetodedicatecertainequipmentforcertainchemicalmanufacturingprocess
stepsthatproducetarryorgummyresiduesthataredifficulttoremovefromtheequipment.
Fluidbeddryerbagsareanotherexampleofequipmentthatisdifficulttocleanandisoften
dedicatedtoaspecificproduct.Anyresiduesfromthecleaningprocessitself(detergents,
solvents,etc.)alsohavetoberemovedfromtheequipment.

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FDAexpectsfirmstohavewrittengeneralproceduresonhowcleaningprocesseswillbe
validated.
FDAexpectsthegeneralvalidationprocedurestoaddresswhoisresponsiblefor
performingandapprovingthevalidationstudy,theacceptancecriteria,andwhen
revalidationwillberequired.
FDAexpectsfirmstopreparespecificwrittenvalidationprotocolsinadvanceforthestudies
tobeperformedoneachmanufacturingsystemorpieceofequipmentwhichshould
addresssuchissuesassamplingprocedures,andanalyticalmethodstobeusedincluding
thesensitivityofthosemethods.
FDAexpectsfirmstoconductthevalidationstudiesinaccordancewiththeprotocolsandto
documenttheresultsofstudies.
FDAexpectsafinalvalidationreportwhichisapprovedbymanagementandwhichstates
whetherornotthecleaningprocessisvalid.Thedatashouldsupportaconclusionthat
residueshavebeenreducedtoan"acceptablelevel."
IV. EVALUATIONOFCLEANINGVALIDATION
Thefirststepistofocusontheobjectiveofthevalidationprocess,andwehaveseenthat
somecompanieshavefailedtodevelopsuchobjectives.Itisnotunusualtosee
manufacturersuseextensivesamplingandtestingprogramsfollowingthecleaningprocess
withouteverreallyevaluatingtheeffectivenessofthestepsusedtocleantheequipment.
Severalquestionsneedtobeaddressedwhenevaluatingthecleaningprocess.For
example,atwhatpointdoesapieceofequipmentorsystembecomeclean?Doesithave
tobescrubbedbyhand?Whatisaccomplishedbyhandscrubbingratherthanjusta
solventwash?Howvariablearemanualcleaningprocessesfrombatchtobatchand
producttoproduct?Theanswerstothesequestionsareobviouslyimportanttothe
inspectionandevaluationofthecleaningprocesssinceonemustdeterminetheoverall
effectivenessoftheprocess.Answerstothesequestionsmayalsoidentifystepsthatcan
beeliminatedformoreeffectivemeasuresandresultinresourcesavingsforthecompany.
Determinethenumberofcleaningprocessesforeachpieceofequipment.Ideally,apiece
ofequipmentorsystemwillhaveoneprocessforcleaning,howeverthiswilldependonthe
productsbeingproducedandwhetherthecleanupoccursbetweenbatchesofthesame
product(asinalargecampaign)orbetweenbatchesofdifferentproducts.Whenthe
cleaningprocessisusedonlybetweenbatchesofthesameproduct(ordifferentlotsofthe
sameintermediateinabulkprocess)thefirmneedonlymeetacriteriaof,"visiblyclean"for
theequipment.Suchbetweenbatchcleaningprocessesdonotrequirevalidation.
1. EquipmentDesign

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Examinethedesignofequipment,particularlyinthoselargesystemsthatmayemploy
semiautomaticorfullyautomaticcleaninplace(CIP)systemssincetheyrepresent
significantconcern.Forexample,sanitarytypepipingwithoutballvalvesshouldbe
used.Whensuchnonsanitaryballvalvesareused,asiscommoninthebulkdrug
industry,thecleaningprocessismoredifficult.
Whensuchsystemsareidentified,itisimportantthatoperatorsperformingcleaning
operationsbeawareofproblemsandhavespecialtrainingincleaningthesesystems
andvalves.Determinewhetherthecleaningoperatorshaveknowledgeofthese
systemsandtheleveloftrainingandexperienceincleaningthesesystems.Alsocheck
thewrittenandvalidatedcleaningprocesstodetermineifthesesystemshavebeen
properlyidentifiedandvalidated.
Inlargersystems,suchasthoseemployinglongtransferlinesorpiping,checktheflow
chartsandpipingdiagramsfortheidentificationofvalvesandwrittencleaning
procedures.Pipingandvalvesshouldbetaggedandeasilyidentifiablebytheoperator
performingthecleaningfunction.Sometimes,inadequatelyidentifiedvalves,bothon
printsandphysically,haveledtoincorrectcleaningpractices.
Alwayscheckforthepresenceofanoftencriticalelementinthedocumentationofthe
cleaningprocessesidentifyingandcontrollingthelengthoftimebetweentheendof
processingandeachcleaningstep.Thisisespeciallyimportantfortopicals,
suspensions,andbulkdrugoperations.Insuchoperations,thedryingofresidueswill
directlyaffecttheefficiencyofacleaningprocess.
WhetherornotCIPsystemsareusedforcleaningofprocessingequipment,
microbiologicalaspectsofequipmentcleaningshouldbeconsidered.Thisconsists
largelyofpreventivemeasuresratherthanremovalofcontaminationonceithas
occurred.Thereshouldbesomeevidencethatroutinecleaningandstorageof
equipmentdoesnotallowmicrobialproliferation.Forexample,equipmentshouldbe
driedbeforestorage,andundernocircumstancesshouldstagnantwaterbeallowedto
remaininequipmentsubsequenttocleaningoperations.
Subsequenttothecleaningprocess,equipmentmaybesubjectedtosterilizationor
sanitizationprocedureswheresuchequipmentisusedforsterileprocessing,orfor
nonsterileprocessingwheretheproductsmaysupportmicrobialgrowth.Whilesuch
sterilizationorsanitizationproceduresarebeyondthescopeofthisguide,itis
importanttonotethatcontrolofthebioburdenthroughadequatecleaningandstorage
ofequipmentisimportanttoensurethatsubsequentsterilizationorsanitization
proceduresachievethenecessaryassuranceofsterility.Thisisalsoparticularly

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importantfromthestandpointofthecontrolofpyrogensinsterileprocessingsince
equipmentsterilizationprocessesmaynotbeadequatetoachievesignificant
inactivationorremovalofpyrogens.
2. CleaningProcessWritten
ProcedureandDocumentation
Examinethedetailandspecificityoftheprocedureforthe(cleaning)processbeing
validated,andtheamountofdocumentationrequired.WehaveseengeneralSOPs,
whileothersuseabatchrecordorlogsheetsystemthatrequiressometypeofspecific
documentationforperformingeachstep.Dependinguponthecomplexityofthesystem
andcleaningprocessandtheabilityandtrainingofoperators,theamountof
documentationnecessaryforexecutingvariouscleaningstepsorprocedureswillvary.
Whenmorecomplexcleaningproceduresarerequired,itisimportanttodocumentthe
criticalcleaningsteps(forexamplecertainbulkdrugsynthesisprocesses).Inthis
regard,specificdocumentationontheequipmentitselfwhichincludesinformation
aboutwhocleaneditandwhenisvaluable.However,forrelativelysimplecleaning
operations,themeredocumentationthattheoverallcleaningprocesswasperformed
mightbesufficient.
Otherfactorssuchashistoryofcleaning,residuelevelsfoundaftercleaning,and
variabilityoftestresultsmayalsodictatetheamountofdocumentationrequired.For
example,whenvariableresiduelevelsaredetectedfollowingcleaning,particularlyfor
aprocessthatisbelievedtobeacceptable,onemustestablishtheeffectivenessofthe
processandoperatorperformance.Appropriateevaluationsmustbemadeandwhen
operatorperformanceisdeemedaproblem,moreextensivedocumentation(guidance)
andtrainingmayberequired.
3. AnalyticalMethods
Determinethespecificityandsensitivityoftheanalyticalmethodusedtodetect
residualsorcontaminants.Withadvancesinanalyticaltechnology,residuesfromthe
manufacturingandcleaningprocessescanbedetectedatverylowlevels.Iflevelsof
contaminationorresidualarenotdetected,itdoesnotmeanthatthereisnoresidual
contaminantpresentaftercleaning.Itonlymeansthatlevelsofcontaminantgreater
thanthesensitivityordetectionlimitoftheanalyticalmethodarenotpresentinthe
sample.Thefirmshouldchallengetheanalyticalmethodincombinationwiththe
samplingmethod(s)usedtoshowthatcontaminantscanberecoveredfromthe
equipmentsurfaceandatwhatlevel,i.e.50%recovery,90%,etc.Thisisnecessary
beforeanyconclusionscanbemadebasedonthesampleresults.Anegativetestmay
alsobetheresultofpoorsamplingtechnique(seebelow).

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4. Sampling
Therearetwogeneraltypesofsamplingthathavebeenfoundacceptable.Themost
desirableisthedirectmethodofsamplingthesurfaceoftheequipment.Another
methodistheuseofrinsesolutions.
a. DirectSurfaceSamplingDeterminethetypeofsamplingmaterialusedandits
impactonthetestdatasincethesamplingmaterialmayinterferewiththetest.For
example,theadhesiveusedinswabshasbeenfoundtointerferewiththeanalysis
ofsamples.Therefore,earlyinthevalidationprogram,itisimportanttoassurethat
thesamplingmediumandsolvent(usedforextractionfromthemedium)are
satisfactoryandcanbereadilyused.

Advantagesofdirectsamplingarethatareashardesttocleanandwhichare
reasonablyaccessiblecanbeevaluated,leadingtoestablishingalevelof
contaminationorresiduepergivensurfacearea.Additionally,residuesthatare
"driedout"orareinsolublecanbesampledbyphysicalremoval.

b. RinseSamplesTwoadvantagesofusingrinsesamplesarethatalargersurface
areamaybesampled,andinaccessiblesystemsoronesthatcannotberoutinely
disassembledcanbesampledandevaluated.

Adisadvantageofrinsesamplesisthattheresidueorcontaminantmaynotbe
solubleormaybephysicallyoccludedintheequipment.Ananalogythatcanbe
usedisthe"dirtypot."Intheevaluationofcleaningofadirtypot,particularlywith
driedoutresidue,onedoesnotlookattherinsewatertoseethatitiscleanone
looksatthepot.
Checktoseethatadirectmeasurementoftheresidueorcontaminanthasbeen
madefortherinsewaterwhenitisusedtovalidatethecleaningprocess.For
example,itisnotacceptabletosimplytestrinsewaterforwaterquality(doesit
meetthecompendiatests)ratherthantestitforpotentialcontaminates.
c. RoutineProductionInProcessControl
MonitoringIndirecttesting,suchasconductivitytesting,maybeofsomevalue
forroutinemonitoringonceacleaningprocesshasbeenvalidated.Thiswouldbe
particularlytrueforthebulkdrugsubstancemanufacturerwherereactorsand
centrifugesandpipingbetweensuchlargeequipmentcanbesampledonlyusing
rinsesolutionsamples.Anyindirecttestmethodmusthavebeenshownto
correlatewiththeconditionoftheequipment.Duringvalidation,thefirmshould
documentthattestingtheuncleanedequipmentgivesanotacceptableresultfor
theindirecttest.

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V. ESTABLISHMENTOFLIMITS
FDAdoesnotintendtosetacceptancespecificationsormethodsfordeterminingwhethera
cleaningprocessisvalidated.ItisimpracticalforFDAtodosoduetothewidevariationin
equipmentandproductsusedthroughoutthebulkandfinisheddosageformindustries.The
firm'srationalefortheresiduelimitsestablishedshouldbelogicalbasedonthe
manufacturer'sknowledgeofthematerialsinvolvedandbepractical,achievable,and
verifiable.Itisimportanttodefinethesensitivityoftheanalyticalmethodsinordertoset
reasonablelimits.Somelimitsthathavebeenmentionedbyindustryrepresentativesinthe
literatureorinpresentationsincludeanalyticaldetectionlevelssuchas10PPM,biological
activitylevelssuchas1/1000ofthenormaltherapeuticdose,andorganolepticlevelssuch
asnovisibleresidue.
Checkthemannerinwhichlimitsareestablished.Unlikefinishedpharmaceuticalswhere
thechemicalidentityofresidualsareknown(i.e.,fromactives,inactives,detergents)bulk
processesmayhavepartialreactantsandunwantedbyproductswhichmayneverhave
beenchemicallyidentified.Inestablishingresiduallimits,itmaynotbeadequatetofocus
onlyontheprincipalreactantsinceotherchemicalvariationsmaybemoredifficultto
remove.TherearecircumstanceswhereTLCscreening,inadditiontochemicalanalyses,
maybeneeded.Inabulkprocess,particularlyforverypotentchemicalssuchassome
steroids,theissueofbyproductsneedstobeconsideredifequipmentisnotdedicated.
Theobjectiveoftheinspectionistoensurethatthebasisforanylimitsisscientifically
justifiable.
VI. OTHERISSUES
a. PlaceboProduct
Inordertoevaluateandvalidatecleaningprocessessomemanufacturershave
processedaplacebobatchintheequipmentunderessentiallythesameoperating
parametersusedforprocessingproduct.Asampleoftheplacebobatchisthentested
forresidualcontamination.However,wehavedocumentedseveralsignificantissues
thatneedtobeaddressedwhenusingplaceboproducttovalidatecleaningprocesses.
Onecannotassurethatthecontaminatewillbeuniformlydistributedthroughoutthe
system.Forexample,ifthedischargevalveorchuteofablenderarecontaminated,
thecontaminantwouldprobablynotbeuniformlydispersedintheplaceboitwould
mostlikelybeconcentratedintheinitialdischargeportionofthebatch.Additionally,if
thecontaminantorresidueisofalargerparticlesize,itmaynotbeuniformlydispersed
intheplacebo.
Somefirmshavemadetheassumptionthataresidualcontaminantwouldbewornoff
theequipmentsurfaceuniformlythisisalsoaninvalidconclusion.Finally,the
analyticalpowermaybegreatlyreducedbydilutionofthecontaminate.Becauseof

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suchproblems,rinseand/orswabsamplesshouldbeusedinconjunctionwiththe
placebomethod.
b. Detergent
Ifadetergentorsoapisusedforcleaning,determineandconsiderthedifficultythat
mayarisewhenattemptingtotestforresidues.Acommonproblemassociatedwith
detergentuseisitscomposition.Manydetergentsupplierswillnotprovidespecific
composition,whichmakesitdifficultfortheusertoevaluateresidues.Aswithproduct
residues,itisimportantanditisexpectedthatthemanufacturerevaluatetheefficiency
ofthecleaningprocessfortheremovalofresidues.However,unlikeproductresidues,
itisexpectedthatno(orforultrasensitiveanalyticaltestmethodsverylow)detergent
levelsremainaftercleaning.Detergentsarenotpartofthemanufacturingprocessand
areonlyaddedtofacilitatecleaningduringthecleaningprocess.Thus,theyshouldbe
easilyremovable.Otherwise,adifferentdetergentshouldbeselected.

c. TestUntilClean
Examineandevaluatetheleveloftestingandtheretestresultssincetestinguntilclean
isaconceptutilizedbysomemanufacturers.Theytest,resample,andretest
equipmentorsystemsuntilan"acceptable"residuelevelisattained.Forthesystemor
equipmentwithavalidatedcleaningprocess,thispracticeofresamplingshouldnotbe
utilizedandisacceptableonlyinrarecases.Constantretestingandresamplingcan
showthatthecleaningprocessisnotvalidatedsincetheseretestsactuallydocument
thepresenceofunacceptableresidueandcontaminantsfromanineffectivecleaning
process.

VII. REFERENCES
1. J.Rodehamel,"CleaningandMaintenance,"Pgs8287,UniversityofWisconsin's
ControlProceduresinDrugProductionSeminar,July1722,1966,WilliamBlockstein,
Editor,PublishedbytheUniversityofWisconsin,L.O.C.#6664234.
2. J.A.Constance,"WhySomeDustControlExhaustSystemsDon'tWork,"Pharm.Eng.,
JanuaryFebruary,2426(1983).
3. S.W.Harder,"TheValidationofCleaningProcedures,"Pharm.Technol.8(5),2934
(1984)
4. W.J.Mead,"Maintenance:ItsInterrelationshipwithDrugQuality,"Pharm.Eng.7(3),
2933(1987).
5. J.A.Smith,"AModifiedSwabbingTechniqueforValidationofDetergentResiduesin
CleaninPlaceSystems,"Pharm.Technol.16(1),6066(1992).
6. Fourman,G.L.andMullen,M.V.,"DeterminingCleaningValidationAcceptanceLimits
forPharmaceuticalManufacturingOperations,"Pharm.Technol.17(4),5460(1993).

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7. McCormick,P.Y.andCullen,L.F.,inPharmaceuticalProcessValidation,2ndEd.,
editedbyI.R.BerryandR.A.Nash,319349(1993)

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