17/3/2017 CleanroomMonitoringBasics

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Cleanroom Monitoring Basics

Cleanroomclassificationsasspecifiedbydifferentstandardsareshown
belowinTable1.

SterileproductsarerequiredtobefilledandstopperedinanISOClass5
orEUGMPClassAenvironment.Nonsterileproductsaretypically
producedinanISOClass8orEUGMPClassDenvironment.

MostBiopharmaceuticalQualityManagerscreatetheirriskassessment
usingaconflationofthemostconservativestandardrequirements
(showninTable1).
TABLE1.
Max.ConcentrationLimits
(particles/m3 ofair)
Obsolete ISO EUGMP, forparticlesequaltoandlargerthan
FedStd209E 146441 Annex1 thesizeslistedbelow
0.3m 0.5m(1) 1m 5m(2)
ISOClass4.8 GradeA notdefined 3,520 notdefined 20
100 ISOClass5 GradeB 10,200 3,520 832 29
1,000 ISOClass6 102,000 35,200 8,320 290
10,000 ISOClass7 GradeC notdefined 352,000 83,200 2,900
100,000 ISOClass8 GradeD notdefined 3,520,000 832,000 29,000

(1)EUGMPAnnex1andISO146441:2015limitsareidenticalonthe0.5
mparticlesize"atrest".

(2)EUGMP,Annex1requirementsfor5m.Virtuallyevery
pharmaceuticalmonitors5mparticlesinClass5areasasakeyindicator
ofbiocontaminationriskassessment.

TABLE2.
Max.MicrobiologicalActiveAirActionLevel
ColonyFormingUnits(cfu)percubicmeter(averagevalues)
ISO146441 FDA WHO,Tech
EUGMP,Annex
Class Pharmaceutical ReportSeries,No.
1
(GMPGrade) CGMP:2004 902,2002
4.8(A) NotDefined <1 <3
5(B) 1 10 10
6 7 NotDefined NotDefined
7(C) 10 100 100
8(D) 100 200 200

WiththereleaseofEUGMP:2008andISO14644,andwiththeincreaseimportanceof5
micronparticletotheLifeScienceIndustry,cubicmetersamplingbecamearequirement
forISOClass5(EUClassA)environments.

SampleTimes
WhensamplingaonecubicmeterofairinanISOClass35Cleanroom,thesampletime
isafunctionoftheparticlecounter'sflowrate,asGMPrequiresacubicmetersamplefor
GradeA/Bzones(regulatoryminimum).Asabestpractice,thelifescienceindustry
typicallyusefullcubicmetersamplingforISOClass5.

0.1CFMequals2.83LPMflowrate,andtakes5hours53minutespersample.
1CFMequals28.3LPMflowrate,andtakes35.3minutespersample.
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50LPMflowratetakes20minutespersample.

75LPMflowratetakes13.3minutespersample.

100LPMflowratetakes10minutespersample.(recommendedwithspotor
sequentialmonitoring)

**FillStationsorothercontinuousmonitoringapplications(aka"Critical
Areas")shouldusea1CFMparticlecounter.

WhensamplingairinanISOClass6cleanroom:

0.1CFMequals2.83LPMflowrate,andtakes24minutes6secondspersample.
1CFMequals28.3LPMflowrate,andtakes2minutes25secondspersample.
50LPMflowratetakes1minuteand22secondspersample.
75LPMflowratetakes1minutepersample(regulatoryminimum)
100LPMflowratetakes1minutepersample(regulatoryminimum)

Asyoucansee,ifyouhaveanISOClass5cleanroom,laborefficienciescanbeattainedby
usinghigherflowrateparticlecounterswhen5misasizeofinterest(e.g.,lifescience
industry).Theadditionalcostforahigherflowrateinstrumentcangenerallyberecovered
fromlesslaborhoursrequiredtodosampling/monitoring.Ifdoingsequentialmonitoring,
youcanusethethesamehighflowrateparticlecounterinhigherISO/GMPclassifications.

GoodMonitoringTechniques
Thereisadifferencebetweencleanroommonitoringandcertification/validation.

Thenumberofsamplelocationswhencertifyingorvalidatingacleanroomisdetermined
byachartprovidedintheISO14644standard.

However,whendoingdaytodaymonitoringoftheroom,youareonlytryingtoverifythat
theairenvelopingtheprocessisadequatelycleanenoughto"wellexceed"regulatory
standards.Processeswhichgeneratesubmicronparticlesinclude:

Processandmachinery.Basically,anythingthatcreatesfrictioniscreating
particles.
People:skinflakesandoil,cosmeticsandperfume,spittle,clothingdebris(lint,
fibers,etc.),andhair.Peopleareamajorsourcesofparticles.
Fluids:Particlesfloatinginair,bacteria,organicsandmoisture,floorfinishesor
coatings,cleaningchemicals,plasticizers(outgasses),anddeionizedwater.

Simply,anykindofprocess,machinery,andespeciallypeopleaddtotheparticleburdenof
theroom.

BestPractices

ZeroCountTest(alsocalledthePurgeTest):Beforeyoubeginyourdailyroundof
sampling,itisgoodpracticetoinstallapurgefilterontotheinlet,andperformaone
minuteFalseCountTest(alsoknownasaZeroCountTest)toensuretheparticle
counterdoesnothaveafundamentalorcatastrophicfailure.MoreInformationHere

SampleAveraging:Inaparticularlocation,takethreesamples,thenaveragethe
counts.Ifyoubeginmonitoringimmediately,andyoutake(forexample)threeone
minutesamplestoaverageyouwilllikelyseethatthe5microncountoneachsample
decreaseswhilethe0.5microncountdoesnotchangesignificantly.Thisisbecause5
micronparticlesfalloutmorequicklythan0.5micronparticles.

AirSettlement:
Whenmonitoringacleanroomitisgoodpracticetolettheairsettlepriortotakinga
sample.Manyofourcustomersprogramaminuteortwodelayintotheirparticle
countersothatthesamplingbeginsaftertheairinthesampleareaisallowedto
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settle.Again,thisallowsthepersontakingthesampleanopportunitytoatleaststep
back610feettoallowtheairtosettle(remember,peopleareasourceofparticles).
Youarealsomonitoringaprocess,andthereforeevacuatinganentirecleanroomto
domonitoringisnotrecommended.

SampleHeight:
Itisgoodpracticetotakethesamplefromaheightofaboutonemeteror"atwork
height"abovethefloor.Thiswouldbefromacountertoporoftenfromacart.With
regardstomonitoringfilters,unlessyouaredoingafilterscanyouarenotlikelyto
pickupanyleaks...simply,itisawastedeffort.

TrendAnalysis:
Particlecountsshouldbeuploadedintoadatabasetoallowfortrendanalysis.The
wholeideaoftrendanalysisistoidentifyworseningtrendsbeforeitbecomesa
deviation,whichrequiresaconsiderableamountofpaperwork.Byidentifyingan
earlytrend,youcanstartyourinvestigationandtakeearlycorrectiveactionsbeforea
problemoccurs.Increasingcountsmayoccurslowlyoverthecourseofmonths,and
thoseperformingthemonitoringshouldknowthenormalparticleburdenofthe
cleanroomaswellasanytrends.TherearecertainlyLIMSsolutionsthatlarge
pharmaceuticalsutilize.Forthesmallerbiotechorpharmaceuticalfirms,Climet
offersaproprietarysoftwaresolutionthat'safractionthecostofaLIMSsystem.

SampleLocation:
Generally,youwanttosampleincloseproximitytotheprocess,sothatyouare
samplingtheairthatenvelopestheprocessbutnottooclosetoaprocessthat
inherentlygeneratesparticles.Beingtooclosemayskewthesampledata,andmay
contaminatetheparticlecountersensor.Thiscanbeespeciallytrickywhenyouare
involvedinafillprocess,whereapowderorliquidspraymaybesuckedintothe
sampleprobe.Fortheseapplications,testingthepositionoftheprobeshouldbepart
ofthevalidationprocess.Pleasenote,1CFMparticlecountersarebestsuitedfor
fillprocessesorcontinuousmonitoringapplications.Fillprocessesrequire
continuousmonitoring(before,duringandafter).Highflowratesmayhavean
adverseimpactastheypullairinfromawiderradius.

MicrobialMonitoringintheLifeScienceIndustry(SterileEnvironments):
InLifeScienceindustriestheseorganizationsshouldbemeasuringbothparticle
concentration,andforsterility.Theparticleconcentrationismonitoredwitha
particlecounterandsterilityismonitoredthroughamicrobialairsampler.The
particlecounter'sfunctionistoprovideearlywarningtoaseriouseventinorderto
allowuserstostoptheprocessbeforeexpensivematerialsarewasted.Themicrobial
samplerdemonstratesthattheareawassterileandthatproductcanbereleased.
AccordingtoEUGMP(Annex1,#18,#19),"Whereasepticoperationsare
performedmonitoringshouldbefrequent."Microbialsamplingmustbepartofyour
normalmonitoringprotocol.

ConservativeInterpretation
ItisgoodpracticetoconservativelyinterprettheISOandEUGMPstandards,andto
alwaysputqualityaboveprice.Failingtofollowthisadvisenotonlyputsexpensive
productionatrisk,butthosewhoselfinterpretmayalsoriskheavyfinesleviedby
theFDAorGMP,andevenplantclosures.Itisrecommendedthattermsinthe
standardssuchas'should'or'recommended'beinterpretedas'shall'and'must'

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ClimetInstrumentsCompany
ADivisionofVenturedyne,Ltd.

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