Home>CleanabilityofPharmaceuticalSoilsfromDifferentMaterialsofConstruction

CleanabilityofPharmaceuticalSoilsfromDifferent
MaterialsofConstruction
Theauthorslookatthecleanabilityofpharmaceuticalsoilsfromavarietyofmaterials
ofconstructiontodeterminetherelativeeaseofcleaningandexplorepotential
groupingstrategiesaspartofacomprehensivecleaningvalidationprogram.
Jul02,2014
ByKellyJordan[1] ,KeithBader[2] ,RichardJ.Forsyth[3]
PharmaceuticalTechnology
Volume38,Issue7
Acleaningprocedureisexpectedtoremovesoilfromproductcontactequipment
surfaces.Avalidatedcleaningprocedurehasbeenshowntoreliablyremovesoils
fromthesesurfaces.Oneoftheacceptedapproachestocleaningvalidationisto
identifyaworstcasesoilforvalidation.Aworstcasesoilisonethatisthemost
difficulttocleaninrelationtoallothersoilsmanufacturedinapharmaceuticalfacility.
Iftheworstcasesoilcanbecleanedtoanacceptablelevel,itcanbeconcludedthat
theothersoilsinthefacilitycanalsobecleanedtoanacceptablelevelusingthe
validatedcleaningprocedure.
Identificationofaworstcasesoilcanbeaccomplishedthroughequipmentwasher
andformulatorexperience.Thoseinvolvedinmanufacturingformulations,cleaning,
andmaintainingtheequipmentareinthebestpositiontoidentifythehardestto
cleansoil.Thisapproachisapracticalbutsubjectivedeterminationandwouldleave
afacilityopentoquestionuntilongoingdatasupportstheinitialconclusionsonthe
worstcasesoil.
Asecondapproachisacomparison
ofAPIsolubility.Solubilitydatafor
APIsaretypicallygeneratedinwater
andorganicsolventsaspartofthe
physicalandchemical
characterizationworkupfortheAPI.
ThoseAPIsthatareleastsolublein
thecleaningsolventareconsidered
thehardesttoclean.Thisapproach
neglectstheformulationexcipients,
whichareofteninsoluble,comprise
amuchgreaterpercentageofthe
formulation,andcanbemoredifficult
tocleanthantheAPI.

RELATEDCONTENT
QualifyingPersonneltoVisuallyInspect
CleanedEquipment[4]
UnderstandingtheCleaningValidation
Lifecycle[5]
MoreGMPs/ValidationTopics[6]

Amoreempiricalmethodtodetermineaworstcasesoilistospotcouponswiththe
soils,allowthemtodry,andcleanthemusingtheidenticalconditionsencounteredin
thecleaningcycle.Equipmentsurfaces,however,encounterdifferenttypesof
cleaningactiondependingontheirlocationinthemanufacturingequipment.Soils
couldbesubjectedtomanualscrubbing,impingementunderthecleaningsolvent,
turbulentflowfromapumpforcingcleaningsolventthroughpiping,oracascade
actionasthecleaningsolventmovesacrossequipmentsurfaces.
Cleanabilitystudiesaretypicallyconductedusingdriedresiduespottedonacoupon
dippedintoabeakercontainingwaterorthecleaningsolventorsolution.The
cleaningsolventisstirred,creatingalessrigorouscleaningactionthanencountered
duringactualcleaning,andwouldbeconsideredaworsecasecondition.The
experimentcanbeconductedatroomtemperatureoranelevatedtemperature.The
soilwiththelongestcleanabilitytimecanbeconsideredtheworstcasesoilfor
cleaningvalidationwithinthevariabilityofthetestparameters.Numerousstudies
havebeenconductedtodemonstratecleanability.Studiesrangefromapaperbased
evaluationofafacilityssoils(1)tobasiclaboratoryconditions,suchassuspending
thecouponsinabeakerofcleaningsolvent,allthewayuptoasophisticated
cleanabilitybath(2).Cleaningparametervariationshavebeencharacterizedusing
cleaningprocessdesignonbenchscalestudies(3),butforthisstudythecleaning
parameterswereheldconstant.Statisticalequivalencetestingforassessing
cleanability(4)canshowthatsoilsarecleanedtoanequivalentextent.Ifpotential
worstcasesoilsdemonstratecomparablecleanability,itwouldbeprudenttouse
morethanoneworstcasesoilforfurthertesting.
Awellexecutedcleanabilitystudyisonepartofacomprehensivecleaningvalidation
program.Theexperimentalcleanabilitycanbeprecededbyanevaluationofthe
formulationcomponentstonarrowthenumberofsoilstested.Theselectedsoilsand
materialsofconstructioncanbetestedusingamatrixapproachtodetermineaworst
casesoilandahardesttocleanmaterialofconstruction.
Complementarystudiescanincluderinserecoveriesandswabrecoveriesfor
analyticaltesting,andvisibleresiduelimits(5)forinspectionofcleanedequipment.

Thestudiescanbeconductedinparallel,oftenusingthesamecouponsamplesfor
multiplestudies.Allstudiesmightnotbenecessary,basedonthenumberof
formulationsoilsandthemanufacturingequipmentinvolved,butacomprehensive
pictureofthephysicalpropertiesofthesoilsduringcleaning,andtheabilitytotest
anddetectresidualsoilsaftercleaning,formasoundbasisforavalidatedcleaning
program.
Methods
Thecleanabilitystudywasconductedtodetermineeaseofcleaningforavarietyof
soilsonarangeofmaterialofconstructioncouponsusingthefollowingparameters.
TableIlists10materialofconstructioncoupontypes,whichareamongthe
commonlyusedmaterialsofconstructioninpharmaceuticalandbiopharmaceutical
manufacturing.All10materialsofconstructionweretestedduringthestudy.

Thecleanabilitystudytodeterminetheworstcasesoilswasconductedusingthree
buffersandthreemediaunderthefollowingparameters.Thecouponswereweighed
andsoilswerespottedintriplicateforeachofthematerialofconstructioncoupon
typeslistedinTableI.Eachindividualcouponwasspottedwith1mlofthesoil.The
soilwasallowedtodryforatleast4hours,oruntilvisuallydry,butnolongerthan3
days,whichwastheestablisheddirtyholdtime.Followingdrying,thecouponswere
reweighedandthecouponweightwassubtractedtodeterminetheweightofthe
residue.Thecouponswereimmersedina600mlbeakercontaining400mlofroom
temperaturepurifiedwater.The600mlbeakerwasthesmallestbeakerthatwould
holdthe2.5x2.5couponswithoutimpedingflowaroundthecouponsduring
testingand400mlwastheminimalvolumenecessarytocompletelycoverthe
coupons.Thewaterwasagitatedonamagneticstirreratafixedrotationanddidnot
generateavortexduringtesting.Thecleanabilityendpointwasdefinedasthetimeat
whichthesoilwasnolongervisibletotheobserverunderdefinedconditions:
distance18inches,optimalviewingangledependentonthematerialofconstruction
coupontype,and700luxlightintensity.Thecouponswereremovedfromthebeaker
immediatelyafterthevisualendpointwasdetermined.
Thevisualendpointwasconfirmedanalyticallythroughconductivity,totalorganic
carbon(TOC),andgravimetrictesting.Thecleaningsolutioninthebeakerwas
testedforconductivity.Asampleofthecleaningsolutionwastakenandtestedfor
TOC.PositivecontrolsweretestedforconductivityandTOCbypipetting1mlofsoil
directlyintoabeakerandtestingforconductivityandTOC.Afterdrying,thecoupons
wereagainweighedandtheweightwascomparedtotheinitialweighttodetermine
cleanabilityofthesoilsgravimetrically.
Resultsanddiscussion
Thematerialofconstructioncouponschosenforthestudywereseenas
representativeofawidevarietyofmaterials.Anumberofliquidsoilswerechosento
representasamplingofpharmaceuticalandbiopharmaceuticalsoils.
Implementationofthisapproachatasiteshouldaddressallsoilsonallmaterialsof
constructionemployedatthesiteunlessanabbreviatedapproachcanbejustified.
Instrumentswerecheckedwitheveryusetoensuretheywereoperatingproperlyand
withincalibrationdating.Thesoilsandthecleanabilityresultsalongwithsupporting
TOCandconductivitydataarepresentedinthefollowingsections.
Twobuffers(regenerationbufferandzincwashbuffer)werespottedandheldfor3
daystomatchtheproposeddirtyholdtimemaximum,butthesebuffersdidnotdry
duetohighethyleneglycolcontent.Itshouldbenotedthataproperlyexecuted
paperbasedevaluation(1)wouldhaveeliminatedthesetwosoilsfromthe
laboratorytestingandsaved2daysofwaitingforeachofthetrials.Theassaysfor
thesetwobufferson316finishstainlesssteelwererepresentativeforallofthe
materialsofconstruction.
ThevisualremovaldatageneratedforthesoilsasshowninTableIIdemonstrated
completeremovalofthesoilsfromallmaterialsofconstruction.ThedatainTablesII
Vareexpressedasanaverageofthethreeindividualdeterminations.Timesvary
widely,withthetwobuffersthatdidnotdryrinsingfromallcouponswithin10
seconds.The316finishstainlesssteelandnickelsteelalloy(Hastelloy)coupons
weretheonlymaterialsofconstructionthatdemonstratedretentionoftheotherfour
soils.Theyprovidedarepresentativerankingofthecleanabilityforallthesoilsand
comprisedthevastmajorityofmaterialofconstructionsurfaceareaforallautomated
cleaningcircuits.Ethylenepropylenedienemonomer(EPDM),silicone,
polytetrafluoroethylene(Teflon),andsyntheticfluoropolymerrubber(Viton)all
becamevisuallycleanquicklyforallsoils,makinganytypeofsoilrankingdifficulton
thosematerials.Oftheremainingfourmaterialofcontructioncoupontypes:acrylic,

glass,polypropylene,andpolyetheretherketone(PEEK),allretainedsomesoilsbut
notothers.Theseinconsistentresultswerecoupledwiththefactthesoilsretainedby
thesematerialswerealsoretainedstronglyby316finishstainlesssteelandnickel
steelalloy(Hastelloy).Visualendpointtestingissubjective,andtherefore,shouldbe
doneinmultiplesbyasmall,welltrainedpersonnelgrouptomaintainconsistency
fortheobservations.

TheconductivityresultsshowninTableIIIdemonstratedhighpercentageofremoval
fromallofthematerialsofcontructionforeachofthesoilsexceptfortheregeneration
bufferwith20%ethanol,whichevaporatedduringthecoupondrying.Removals
greaterthan100%canbeattributedtodaytodayvarianceincalibrationofthe
conductivitymeter.Conductivity,however,couldbemisleading.Theconductivity
readingsbegantoplateauwellbeforethecouponsbecamevisuallyclean.The
conductivitylevelsofthefullydissolvedsoilswererelativelylow(<60S/cm).Useof
conductivitymeasurementsshouldconfirmtheconductivityofthesoilsandshould
graphtherateofsoilremovalduringcleanabilitytestingandcomparedtovisual
endpointmeasurements.

ThegravimetricresultsinTableIVshowcompleteremovaloftheresidues.Other
than316finishstainlesssteel,glass,andnickelsteelalloy(Hastelloy),thematerial
ofconstructioncoupontypesdemonstratedsomeresultswherethefinalweightwas
lessthantheinitialweight,indicatingthatthecouponscontinueddryingovera
numberofdaysatambienttemperature.Thisobservationmakesallothermaterials
ofconstructionpoorcandidatesfortheinitialcleanabilityunlesstheyareovendried
andcouldaffectthespeedandaccuracyofastudy.Continueduseofgravimetric
measurementsforthe316finishstainlesssteelandglasscouponswouldprovide
dataoflimitedvalue,giventhatgravimetrictestingdemonstratedcompletesoil
removalbutdidnotprovideanendpointdetermination.Othertestingisnecessaryin
conjunctionwithgravimetricdeterminations.

TOCtestingresults,asshowninTableV,werereasonablyconsistentwiththe
conductivityandgravimetric.Onesoil,phosphatebufferedsaline,hadnoorganic
carbontomeasureandwas,therefore,notapplicableforthistest.Theresultsforthe
firstmediawereconsistentlyhigh,asweretheconductivityresults.Themostlikely
causewouldbealowpositivecontrol,butbecausethegravimetricresultswere
consistentlygood,arepeatoftheexperimentwasnotnecessary.Mostsoilsrequired
multipledilutionspriortoTOCtesting,andtestingwastimeconsumingcomparedto
conductivityandgravimetrictestingmakingTOCalessattractivesoilremoval
confirmationtest.
Theevaluationofthedatatoidentifytheworstcasesoilonthehardesttoclean
materialofconstructionshouldbedoneintandem.TableVIranksthefourretained
soilsoneachmaterialofconstructionfrom1to4,with1beingthehardesttoclean.
TherankingswerethenaveragedacrossthesoilsandMediaAwasdeterminedto
bethehardesttocleansoilbyasmallmarginoverthemediawithphenolred.
TableVIIranksretentiononthesixoutof10materialsofconstructionthat
demonstratedretentioncharacteristics.Thefoursoilswererankedfrom1to6,with1
beingthehardesttocleanmaterialofconstruction.Therankingswerethen
averagedacrossthematerialsofconstructionand316finishstainlesssteeland
nickelsteelalloy(Hastelloy)weredeterminedtobethehardesttocleanmaterialsof
constructionbyawidemargin.

TheworstcasecombinationofsoilandmaterialofconstructionwasMediaAon316
finishstainlesssteelornickelsteelalloy(Hastelloy)forthesoilsandmaterialsof
constructiontested.Thesoilandmaterialofconstructionmatrixatafacilitycanbe
combinedintogroupsbasedondataandidentificationofaworstcase.Asimilar
analysisforswabrecoveries(6,7)identifiedstainlesssteelasarepresentative
materialofconstructionformostequipmentandforalargemajorityofsoils.The
presentstudyindicatesasimilarconclusion,(i.e.,316finishstainlesssteelisa
representativematerialofconstructionforcleanability),butthedatasetistoosmallto
beconclusive.Thistypeofgroupingstrategyshouldbeexploredforeachfacilityto
streamlineexperimentationwhilestillpresentingacomprehensivepictureofthesoils
andmaterialsofconstructioninmanufacturingoperations.

Cleanabilitytestingofthematrixofsoilsandmaterialsofconstructionatagivensite
cancoverallsoilsonallmaterialsofconstructionorcanbefocusedbasedonan
evaluationofthecomponentsofthesoils(1),coupledwithpreliminarytestingover
therangeofmaterialsofconstruction.Thetestingplanshouldbedonewithinthe
overallcleaningevaluationincludingcleaningcycledevelopment,swabandrinse
recoveries,andvisibleresiduelimitdeterminations.

Conclusion
Cleanabilitystudiescanprovideobjectivedataonthehardesttocleansoilata
facility.Conclusionscoulddifferbasedonthesoilsandmaterialsofconstructionata
givenfacility.Asimilarsurveyofsoilsandmaterialsofconstructionshould,therefore,
beexecuted.Measuringthecleanabilityendpointshouldbedoneconsistently,
includingvisualobservationandatleastoneotherconfirmationtest.Theresulting
cleanabilitydatacanvaryfordifferentmaterialsofconstructiondependingonthe
soil,andanevaluationofthematrixofsoilsandmaterialsofconstructionwillprovide
apathforwardforcleaningvalidationexecution.
Forthisstudy,basedonthematerialsofconstructionandsoilstested,itcanbe
concludedthatperformingcleaningvalidationoftheworstcasesoilsfocusingonthe
316finishstainlesssteelornickelsteelalloy(Hastelloy)surfaceswithconductivity
resultstoconfirmvisualresultsisanapproachthatwillprovidethemostconclusive
results.Thesematerialshavetheaddedadvantageofbeingthemostfrequently
usedmaterialsofconstructionforallautomatedcleaningcircuits.
Althoughimportant,cleanabilityisonlyoneaspectofacomprehensivecleaning
validationprogram.Personnelcleaningexperience,rinserecoveries,swab
recoveries,visualresiduelimits,cleaningcycledevelopment,andcleaning
validationareallcrucialelementsofawelldefined,documented,anddefendable
cleaningprogram.
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AbouttheAuthor
RichardJ.ForsythisaseniorconsultantwithForsythPharmaceuticalConsulting,
907ShamrockCt,Royersford,PA19468,forsythpharmaconsulting@gmail.com
KeithBaderisseniordirectoroftechnologyandKellyJordanisanengineer,both
withHydeEngineering&Consulting,6260LookoutRoad,Suite120,Boulder,
Colorado80301.
2016AdvanstarCommunications,Inc.Allrightsreserved.Reproductioninwholeorinpartisprohibited.Pleasesendanytechnicalcommentsorquestionstoourwebmasters.

SourceURL:http://www.pharmtech.com/cleanabilitypharmaceuticalsoilsdifferentmaterialsconstruction
Links:
[1]http://www.pharmtech.com/kellyjordan
[2]http://www.pharmtech.com/keithbader
[3]http://www.pharmtech.com/richardjforsyth
[4]http://www.pharmtech.com/pharmtech/GMPs%2FValidation/QualifyingPersonneltoVisuallyInspectCleanedE/ArticleStandard/Article/detail/832220%20
[5]http://www.pharmtech.com/pharmtech/GMPs%2FValidation/UnderstandingtheCleaningValidationLifecycle/ArticleStandard/Article/detail/840315%20
[6]http://www.pharmtech.com/gmps_validation%20