8/18/2016 AirborneParticleMonitoring:SatisfyingTheChangingDemandsinRegulationsandMethods

Airborne Particle Monitoring:

Satisfying The Changing
Demands in Regulations and
Methods
Tue, 09/01/2009 - 12:00am by Joe Gecsey

Todaysuserisoftenfacedwiththe
challengeofmeetingseveralinternational
standardsandregulatoryguidancesaswell
asperformingsamplingforairborne
particlesinaconsistentandreproducible
manner.

Internationalstandardsforthemonitoringof
airborneparticlesareusedbyallindustriesthat
employcleanroomsorcleanzones.Someform
ofairbornesamplingforparticlesisneededfor
thesecontrolledenvironmentsinordertoassure
thequalityoftheproductbeingmanufacturedor
thesuccessoftheprocessthatisbeing
conductedinthiscontrolledorcritical
environment.Manyvariableswillaffectthe
successoftheoperationsintheseareasbutthe
particulatelevelsintheairareoftena
significantelementinthecontrolofrisk,or,
inversely,thelikelihoodofsuccessforthe
controlledoperation.
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Theinitialstandardforcleanroomsandclean
zonesfromtheUnitedStates,knownasFederal
Standard209E,hadaglobalimpactformany
yearsbutwasofficiallyreplacedin1999bya
newglobalstandard,ISO146441.However,
FederalStandard209Eleftalegacyofsampling
techniquesandsamplevolumesthatremainin
placetodayinmanyapplications,suchasthe
focusonsamplevolumesof1cubicfoot,sample
timesof1minuteindurationandthe
designationofareasasClass100,Class10K,
etc.Althoughsomeofthesemethodsarestill
appropriatetoday,itcanbeusefultoconsider
someofthechangesinstandards,regulatory
guidancesandrecommendedpracticesthat
haveoccurredsince1999.Someofthese
addressthespecifictechniquesofexecutinga
roomclassification[ISO146441,EUGMP
Annex1]whileotherslookattheissuesof
gainingconsistencyofsamplingacrossthe
inventoryofvariousparticlecountersatausers
sitethroughenhancedonsitecalibration
techniques[ISO215014,IESTRP14].

CLASSIFICATIONVERSUSMONITORING
Oneofthemostimportantfactorsinchoosing
therightmethods,standard,orguidanceforan
applicationistheunderstandingthatasampling
methodisintendedtoeithera)provideaformal
roomclassificationatamomentintime,orb)
provideawindowthroughoutaprocessor
procedureinordertocontainthemomentto
momentriskthatairbornecontaminantswill
causefailureoradulterationofthatprocessor
procedure.

Formalroomclassificationsexecutedunderthe
earlierFederalStandard209EorthecurrentISO
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146441areperformedona6monthor12
monthbasisandgiveadetailedsnapshotof
theareabasedontheuseofstatisticalmethods.
Thisisinordertogainconfidencethatthearea
meetstheinitialrequirementsfortheprocessto
beperformedintheareaorzone.Statistics
comeintoplayherebecausetheairborne
samplingisarepresentativesamplingtechnique
thatis,onlyaportionofthetotalairofthe
roomorzoneairisextractedfromthezoneor
areasmallandtheconcernisthatthesampled
airwillrepresentthetotalpotentiallevelof
suspendedairborneparticles.

Buttheneedisoftentoknowmomentto
momentthattheareaorzoneisunder
controlduringaprocess.Thisneedoften
requiresdifferentmethodsandalarmsettingsin
ordertounderstandandcontroltherisktothe
successofaprocess.Thepharmaceuticaland
biotechnologyindustrieshaveauniqueand
importantinterestincontrollingriskduring
asepticprocessesusedtoproducesterile
products.Theseconcernsareduetothehealth
risksandensuingfinancialrisksthatan
injectablemedicinecouldcontainunacceptable
levelsofcontaminantsduetoexposureto
airbornecontaminantsduringtheirmanufacture.
Currently,itisthisasepticfillingapplicationthat
representsthemostcriticalmonitoringand
classificationchallengesforairbornemonitoring
thisarticlewillcoverclassificationand
monitoringingeneralaswellasprovideamore
detaileddiscussionofthecurrentsampling
requirementsinasepticfilling.

CLASSIFICATIONISO146441,2
Manyoftheaspectsoftheclassificationeffort
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havebeencoveredinarticlesinthismagazine
sothedetailsofexecutionwillnotbecovered
here.Theclassificationexerciseisbasedon
thesekeypoints:

a)Frequency:Iftheareaorzoneistobe
classifiedasISOClass1through5,thenthe
classificationmustberepeatedat6month
intervals.IfISOClass6through9,thenthe
frequencyisevery12months.
b)Physicalareainsquaremeters:The
surfaceareamustbedeterminedinorderto
calculatetheminimumnumberofsample
points.
c)Distributionofsamplepoints:Ideally,the
samplepointsarespreadthroughoutthe
roominanevenlydistributedpatternbut
thismayhavetobealteredduetoroom
designandequipmentpositions.
d)Minimumsamplevolumeandsample
time:Withtheintentiontomakeeachair
samplestatisticallyrepresentativeofthe
qualityoftheairatthatpoint,thereisa
requirementofaminimumsampletimeof1
minuteateachpointandarequirementthat
thecalculatedminimumsamplevolume
mustbeobtained.Oftensamplingforthe1
minuteminimumtimeperiodwillalso
satisfytheminimumsamplevolume,but
thisisdependentontheflowrateofthe
instrumentandthetargetedISOClassfor
theclassificationexercise.

NotethatISO146441doesnotspecifyany
specificorminimum/maximumsamplingflow
ratefromaninstrument.

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CLASSIFICATIONANDMONITORINGIN
GUIDANCESFROMTHEFDAANDEMEA
Forthespecificapplicationofasepticprocessing
areas,theregulatorybodieshaveprovided
guidancedocuments.Thesedocumentsaddress
manyaspectsoftheasepticprocessingeffort,
includingspecifyingairborneparticlecountsin
keyareasofmanufactureandsupport.TheFDA
guidancetiesthecriticalareatotheISOClass
5andthecontrolledareatoISOClass7or
ISOClass8.TheFDArequiressamplingduring
processesatthesizerangeof0.5micronsand
largerbutdoesnotspecifyanyspecific
monitoringmethodorflowratenordoesit
discussanyclassificationmethodotherthan
inferringuseoftheISO146441methodology
throughitsuseoftheISOClassdesignationsin
thetext.

TheEuropeanGMPAnnex1providesmore
specificcountlimitsforthecriticaland
controlledareas,designatedasGradesA,B,C
andD(Table1),andalsorequestssampling
bothsizerangesof0.5micronsandlargerand
5.0micronsandlarger.Inparticular,the
Annex1callsforaclassificationfortheseareas
basedonISO146441withtheimportant
exceptionfortheGradeAareas:classificationof
theGradeAareasfollowsISO146441for
establishingtheminimumnumberofpointsbut
requiresamoreextensiveminimumsample
volumeof1cubicmeterateachsamplepoint
fortheGradeA[ISOClass4.8]areas.Although
thepurposeforthislargervolumeisnot
explicitlystated,itcanbeassumedthattheEU
authoritiesfeltthatalargervolumeinthesekey
areasforsterileproductswouldgivestronger
statisticalsupportinthedeterminationoftheair

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quality,especiallygiventhenormallyextremely
lowquantityofparticlesintherangeof5.0
micronsandlarger.

ThereisnospecificationwithinAnnex1
[Sections8through20]concerningthesample
volumeorflowratesrequiredduringprocess
monitoringonlythatcontinuousmonitoringof
airborneparticlesshouldbeemployedduring
setupandbatchprocessingforsterileproducts
filledbyasepticprocess.

Althoughcompaniesarefreetosetmore
stringentclassificationschedules,thecurrent
ISO146441requiresthatISOClass5areasbe
reclassifiedona6monthbasis.Thisfrequency
islikelytobeadjustedto12monthsforall
classesinthenextversionofISO146441due
tobereleasedinmidtolate2010.

IMPACTOFISOANDRPMETHODSFOR
INSTRUMENTCALIBRATION

AlsointhenextrevisionofISO146441,the
newISO215014standardfortheenhanced
calibrationofairbornecounterswilllikelybe
mentioned.Thisnewinstrumentcalibration
standardisbasedontheearlierJapanese

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standardJIS9921thatwasoftenemployedto
controltheperformanceofaninstrumentatthe
timeofmanufactureISO215014expandsthe
morerigorouscalibrationmethodstotheseries
ofcalibrationsthatoccurthroughoutthelifetime
oftheinstrument.Theintentionistoprovide
betterconsistencyacrossafleetofinstruments
atonesiteaswellasconsistentperformance
fromasingleinstrumentyearuponyear.The
testmethodscanshowupcertainperformance
shortcomingsininstrumentdesign,duetoaging
orduetocomponentdegradation.Inparticular,
someofthemorerecenthigherflowdesigns
performpoorlyduetolowcapacityvacuum
pumpsthatcannottoleratemuchrestrictionin
theflowpath.Thedecisiontoincreasethe
diameteroftheinletnozzletoreducethe
demandonthepumpcanresultindegraded
performanceintermsofresolutiondueto
increasedturbulenceortostrongervariationsin
thelightintensityinthedetectionzone.Ideally
thisilluminationfieldisperfectlyuniformbuta
smallamountofvariationusuallyoccursin
todayslaserdiodedesigns.Thedifficultywith
opticaluniformityisusuallyexacerbatedbythe
designchoicetowidentheinletnozzleto
achieveareductioninpressuresothatimpeller
typepumpscanobtaintheflowratedesired
(Figure1).

Particlecounterdesignscanhavehigherflow
ratesandalsostillmeetISO215014tests
whenwelldesigned,althoughsomesuppliers
havechosennottomeetalltestsespecially
resolution.Inmanycases,alowerflowdesign
of28.3LPM[1CFM]or50LPM[1.77LPM]can
provideamorerobustsolutiontothechallenges
oftodaysparticlecountingwhileassuring

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compliancetothenewestcalibrationstandard,
ISO215014.Itmaybechallengingtofind
globalfieldsupportforISO215014fromall
vendorsbut,whenavailable,theaccuracy,
repeatability,andreproducibilityofairborne
samplingfromaninstrumentcalibrated
accordingtoISO215014willprovide
confidencethatthecontrolofairborneparticles
intheenvironmentisaknownquantity.

Furthersupportforthisnewandmore
comprehensivefieldcalibrationstandardcomes
fromtheIESTorganizationintheU.S.wherea
revisedRecommendedPractice,RP14,willsoon
bereleasedinsupportoftheISO215014
standard.RP14providesfurtherinformation
andinstructiontotechnicianswhoneedto
executeacalibrationofanairbornecounter
accordingtoISO215014.

USEOFTHESEQUENTIALSAMPLINGMETHOD
FROMISO146441ANNEXF
Insteadofadheringstrictlytotheminimum
samplevolumetoobtaintheconfidencelevelin
theresults,userswhoaredoing5microntests
tocertifytheircleanroomcanusetheSequential
Samplingmethodtolimitthelengthoftimefor

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thesamplingprocess.Inreading146441,
AppendixF,thereisatableoftimefragments
(TableF.1)thatstatesifobservedcounts(C)are
lessthanagivenlimitwithincertaintime
fragmentsofthesampleperiod,thenthe
samplepointcanbepresumedtomeetthe
Classlimits.Forexample,iftheobservedcounts
arestill0aftertheFractionalTime(t)of0.1922
haspassed,thenthesamplepointpasses.The
time(t)isbasedonthetimeneededtocount20
particlesiftherewerepreciselythatnumberof
particlesofthatsizeinthesampleareatomeet
theclasslimit.

IfthewishistoclassifyaGradeB(ISOClass5)
areaatrest,thelimitis(29)5micronparticles
inacubicmeter.Togather(20)particleswould
require0.69cubicmetersor24.3cubicfeet.For
aparticlecounterrunningat1CFM,thiswould
meanaminimumsampletime(t)of24.3
minutes.

Thus,ifnocountswereobservedat5microns
after4minutesand41seconds,thesampling
processcouldbestoppedandthesamplepoint
declaredtohavepassedatthe5micronlimitfor
ISOClass5.

Orif(1)countwasrecorded,thenifnomore
countswererecordedwithin5.85minutes,
againyoucouldrecordaPASS.

Foraflowrateof1.77CFM[50LPM],thechart
wouldthenshowthesetimesfort=24.3/1.77
=13.73minutes:

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However,innocasecanthesampleperiodata
locationbelessthan1minute.[ISO146441,
AnnexB4.2.2]

SAMPLINGMETHODS
Itisanimportantbeginningtoknowboththe
regulationsaffectingsamplingandalsotoknow
thattheinstrumentemployedcanmeet
internationalstandardsforcalibration.Butitis
alsousefultorealizethattherearesome
practicalmethodsinthesetupanduseofthese
instrumentsthatcanhaveapositiveeffecton
thequalityandconsistencyofparticlecount
dataobtained.

Acommonpointofconfusionistheorientation
forthefunnelshapedisokineticprobesupplied
withmostunits.Theneedistopositionthis

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probesothattheopeningintersectsthelinesof
flowinthesamplearea.Thismeansthata
probesamplinginaverticalflowstreamwillbe
positionedwithitsopeningup(Figure2)a
probesamplingahorizontalflowstreamwillbe
tiltedinparallelwiththeearthssurfaceinorder
tobestreceiveanyairborneparticlesthatmight
befoundinthesampleair.

Anothercommonconcern,especiallyinthelife
sciencesindustries,istherequiredorpreferred
lengthofinlettubing.Althoughthereisno
specificstatementinthestandardsorinthe
guidances,theindustrybestpracticeisto
keepthetubinglengthasshortaspossible,and
generallyisassumedtobeamaximumof3
meters(approximately10feet)whenthereisa
significantconcernforthemeasurementof
largerparticles[suchas5micronsandlarger]
aswellasthemorecommon0.5micronsand
largersizerange.

Especiallywhenusingahighflowunit,aserious
concernisthattheexhaustofthesampledair
willalterorevenlyseverelydeflectordistortthe
airflowpatternfoundinmostISOClass5areas.
Sampledairmustbeexhaustedsomewhere
75litersinmustalsomean75litersoutand
iftheexhaustairflowpatternsarenotaccounted
for,eddycurrentscouldbecreatedinand
aroundkeyhighriskareas.Thehighertheflow
rateemployed,themoretheeffectofthe
dischargedsampleairmustbeconsidered.

Dynamicsmokestudies(Figure3)canhelp
revealchangesinthedesiredflowpatternsand
instructtheoperatorsintheproperpositioning
anduseofaparticlecounterinordertoprevent
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unintendedcirculations.Astherateofsampled
airincreases,theriskofunintentionalalteration
oftheflowpatternsincriticalareasbecomes
higherandperhapsunacceptable.Intandem
withthisgoestheneedforassurancethatthe
exhaustairisfilteredtoatleast0.2microns,
preferablyata100%captureratefortherange
of0.2micronsandlarger.Somenewerhighflow
designscannotaccepttherestrictionofflow
causedbyabsolutefiltersandchoosetofilter
withHEPAfiltersratedat95%efficiencyat0.3
microns.Forcertainkeyorcriticalareas,this
limitedqualityofexhaustairfiltrationusingonly
95%efficientfiltersmightprovetobe
unacceptable.

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CONCLUSIONS
Todaysenvironmentsespeciallyasepticfilling
operationsbutalsominienvironmentsandother
specialtyprocessesinelectronicsandaerospace
requireconsistentandreproducibleresults.
Thenewcalibrationstandardsand
recommendedpracticeshelpwithassuringthe
functionalityoftheparticlecounterbutthere
needstobeasignificantfocusonthesampling
methodsandpracticessothathighqualitydata
isobtained,andalsosothattheactofobtaining
thesampledoesnotcompromisetheprocessor
productinthekeyareas.

Dynamicsmokestudiescanbeextremely
valuabletodetermineifthecombinationof
airflowandactivitywillresultinriskypatternsof
flowthatcoulddrawcontaminationintothe
criticalzones.Thepotentialvalueofhighflow
particlecountersneedstobecarefullyweighed
againsttheheightenedriskofinfluencingairflow
patterns.Perhapsnewproceduresneedtobe
designedandimplementedinyourfacilityafter
reviewingsmokestudiesinordertomaintain

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thequalityandconsistencyoftheair
environmentduringactivity.

References

FederalStandard209E
ISO146441
EUGMPAnnex1
FDAGuidanceforthemanufactureof
SterileProductsbyAsepticProcesses
IESTRP14
ISO215014
JIS9921
Whyte,Bill,editor,CleanroomDesign,
2ndEdition

Acknowledgments
UseofDIwaterbasedsmokegeneratorfor
flowvisualization:Dr.JackMenear,JackMenear
Associates,SantaCruz,CA
www.jackmenear.com

JoeGecseyistheLifeSciencesApplication
ManageratHACHinGrantsPass,Oregon,USA.
Heisresponsiblefortrackingregulatory
changesregardingparticulatecountinginthe
LifeScienceindustryandisoneoftwoUS
representativesontheTC209WorkingGroup
(WG1)taskedwithfinalizingtherevisionstoISO
146441and146442.Hehasconducted
seminarsthroughouttheworldonparticle
counterdesignandapplications.Hecanbe
reachedbytelephoneat:(541)4726526orat
jgecsey@hach.com.HACH,481California
Avenue,GrantsPass,Oregon97526USA

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