Home>GettingScientificAboutCleaningValidation

GettingScientificAboutCleaningValidation
Jul01,2015
ByAgnesShanley[1]
PharmaceuticalTechnology
Volume39,Issue7,pg4445,50

4Ximage/GettyImagesleaningis
sucha
basic
concept
thatitmay
bedifficult
toview

scientifically,butgettingitright,andvalidatingtheapproachtaken,iscriticalto
patientsafetyanddrugquality.Somepharmaceuticalmanufacturersmaystill
approachcleaningvalidationinasomewhatrandomway,usingimpreciseand
outdatedmethods.
AndrewWalsh,principalandownerofthePharmaCleanGroup,LLCandanindustry
professorinStevensInstituteofTechnologysPharmaceuticalManufacturingand
Engineeringprogram,hasbeenanoutspokenadvocateofchangingthestatusquo.
Heurgespharmaceuticalindustryprofessionalstoapplyriskbasedprinciplesand
science,andconceptssuchasLeanSixSigmaandProcessAnalyticalTechnology
(PAT)totheircleaningvalidationprograms.
Walshledtheglobalmultidisciplinaryteamthatdraftedthescience,riskand
statisticsbasedCleaningProcessDevelopmentandValidationforISPE(1).
PharmaceuticalTechnologyspokewithWalshabouttheguidance,whichis
expectedtobepublishedin2015.
Cleaningvalidationlimits
PharmTech:Whatswrongwiththeideaoflimits,astheyrecurrentlydefinedand
usedbypharmaceuticalmanufacturers?
Walsh:First,companiesareapplyingtheminconsistently.Backin1992,the
PharmaceuticalManufacturersAssociation(nowPhRMA)surveyedindustry
professionalsandfoundthattheywereusing44differentcriteria,basedeitheron
dose(e.g.,1/10thofatherapeuticdoseor1/1000thofthelowestdose,or1/50thof
themaximumtherapeuticdose),orondefaultlimits(e.g.,nogreaterthan1ppmor3
ppm)(2).
Fourteenyearslater,theParenteralDrugAssociation(PDA)surveyeditsmembers
andfoundthesamedisparityinpractice,withrespondentsusingdosebasedonly,or
acombinationofdosebasedanddefault.Mostused1/1000thasthedoselimitanda
majorityused10ppmasthedefaultlimit.
Butthelimitsthemselvesareinconsistent.Insomecases(forsomecompoundsand
atsomefacilities),theselimitswillleavelargeamountsofAPIresidue,andinothers,
smallamountsnearlyimpossibletomeasure.The10ppmdefaultwasaddedto
accountforthisproblem,butthisvalueisarbitraryandsomecompaniesevenhave
troublemeetingit.
PharmTech:Dodosebasedanddefaultcleaningvalidationlimitsdifferentiate
betweencompounds,basedonpotentialrisktothepatientoroperator?
Walsh:Thecurrentmethodoflimitsettingisnotsciencebased.Somemanufacturers
willtakethelowestdoseofanygivenAPIordrug,dividebyathousand,andset
limitsbasedontheresults,eventhoughtheymaynotreallybesafe.
Mostofthetime,however,thelimitsaresettoolow,sothatcleaningvalidationruns
failwhentherereallyisnoneedandtheresiduelevelspresentabsolutelynoriskto
thepatient.
Butsettingcleaningvalidationlimitsisabigdeal.Theindustryhassetthem
incorrectlyforyears,usingreverselogic.ThatswhytheISPEpublicationisso
important,especiallythesectionsdealingwithstatisticalanalysis.Alsoimportantare
theconceptofmeasuringthelevelofriskthroughprocesscapability.
Today,manymanufacturersuseanacceptabledailyexposurelimitof1/1000thbut
thatfailstotakeintoaccountpotentialproductrisk.Asaresult,a1/1000thlimitsetfor
lowdoseaspirinismuchlowerthanthelimitsthathavebeensetforsomedrugswith
potentiallyteratogenicorimmunogeniceffects.
Thepharmaceuticalindustryisuniqueinthatithasanenormousamountofdataon
itscompoundsavailablefromtoxicologicalandclinicalstudiesandthesecanbe
usedtosetappropriatelimitsforpatientexposure.Soitsimportanttohavea
toxicologistandpharmamanufacturingprofessionalsworktogetheronsettinglimits
basedonrealrisksandplantfloorrealities,andnotjustbysimplytakingadoseand
dividingitbyanumber.
ConceptsfromICHQ9andISPEsRiskMaPPguidewillalsobeveryimportantin
settingsciencebasedlimitsforAPIanddetergentresidue.
Workingwithtoxicologists

PharmTech:Shouldtoxicologistsbeworkingmorecloselywithmanufacturingand
qualityteamsatpharmacompanies?
Walsh:Atsomecompanies,theyalreadyare,butothermanufacturersarenotusing
theirexpertiseenough.IwouldliketoseeacloserconnectionbetweenToxicology
departmentsandQAandvalidation.
PharmaceuticaltoxicologistsaremainlyPhDs,andtendtobeatightlyknitgroup.
Manyhaveknowneachotherfordecades.Theyactuallyallmeetonceayear,and
havedonealotofworkonhowtosetlimits,buttheytendtopublishintheirown
specializedjournals,whichdoesnotgetthemessageouttotherestoftheindustry.
Generally,toxicologistsaregettingmorecloselyinvolvedinGMPissuestoday,but
moreofthemneedtobegiventheGMPperspective,andsomebetterunderstanding
ofhowtheGMPworldworks,frompeopleinthatworld.Acrossfunctional
perspectivewillbeveryimportantinmanysituations,forexample,insettinglimitsfor
earlydiscoverycompounds.
Scientificapproachtocleaningvalidation
PharmTech:Aremorecompaniesembracingthemorescientificapproachto
cleaningvalidation?
Walsh:Iseeitstartingtohappen.Ialsoseeamovetoriskbasedtoolsusing
statistics,anddrawingfromtheFDAsrevisedprocessvalidationguidance.ButIalso
feelthatmanyworkersdonthaveastrongmasteryofstatisticsoraclear
understandingofriskandhowtomeasureit,andarereluctanttorevisetheir
standardoperatingprocedures(SOPs).
Leanmanufacturing
PharmTech:WhatroledoyouseeLeanSixSigmaplayingincleaningvalidation
andcleaning?
Walsh:LeanSixSigmaconceptsareveryapplicabletocleaningvalidationso
applicablethattheoriginalnameformycompanywasClean6Sigmaandweeven
trademarkedandusetheterm.
ThekeygoalsforLeanSixSigmaareeliminatingwasteandreducingvariability,and
thatcanapplytocleaningvalidationandcleaning,too.Moremanufacturersneedto
askthemselvessuchquestionsasWhyarewerinsingfor15minutes?
IhavemadeValueStreamMapsofcleaningprocesses,andthereisclearlyalotof
wastedtimeandwaterinmostcleaningprocesses.Forexample,whyshoulda
proceduretakeanhourwhenitcouldeasilybedoneintwominutes?Many
companiesarediscoveringthatcapacityissuesarecloselytiedtocleaning,sothere
isarealneedtoshortencycletimes,butitcanbechallenging,sinceitrequires
revalidation.
Processanalyticaltechnology
PharmTech:Whatrolecouldprocessanalyticaltechnology(PAT)playincleaning
validation,andcleaningingeneral?
Walsh:PAThasalotofpotential.WehavebeendoingsomeworkwithGE
AnalyticalInstruments(Sievers)intheareaoftotalorganiccarbon(TOC)
measurement,usingtheirportablesystem.Thisway,insteadoftakingswabsamples
tothelab,youtakethelabtotheline.Withtheirinstrument,thereisarealpromiseof
parametricreleaseofequipmentaftercleaning,andthisisoneofthegoalsofthe
ISPEguide.
PharmTech:Whatotheranalyticaltechniquesshouldbeusedtoimprovecleaning
validation?
Walsh:Highpressureliquidchromatographyiscommonlyusedandalsoagood
tool,butsoissimplevisualinspectioninlowtomoderaterisksituations.Weare
workingwithcompaniesrightnowonasimple,costeffectiveprogramusingstandard
couponsforqualifyingoperatorstoreleaseequipmentvisually.TOC,conductivity,
andvisualinspectionusedtogetherinacomprehensiveprogramcouldsave
pharmaceuticalmanufacturersalotoftime.
Thereisadefiniteneedtomoveawayfromtheoldthreebatchesanddosebased
approach,towardscontinuousmonitoringwherenecessary.TOC,conductivity,and
visualinspectionwillhelpleadtheway.
Inaddition,manufacturersshouldpaycloseattentiontoequipmentdesignandinvest
inequipmentthatcanbethoroughlyandeasilycleaned.Theyshouldalsobe
subjectingtheircurrentandnewSOPstoriskassessments,toeliminateany
problemsbeforetheycanoccur.
References
1.A.Walsh,Pharm.Engineer,31(6)(November/December,2011).
2.A.Walsh,Pharm.Engineer.31(4),(July/August,2011).
ArticleDetails
PharmaceuticalTechnology
Vol.39,No.7
Pages:4445,50
Citation:
Whenreferringtothisarticle,pleaseciteitasA.Shanley,"GettingScientificAbout
CleaningValidation,"PharmaceuticalTechnology39(7)2015.

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