9/11/2016

MonitoringAirborneMicroorganismsinBlowFillSealTechnology

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MonitoringAirborneMicroorganismsinBlowFill
SealTechnology
Jun01,2004
ByElmarHerbig[1]
PharmaceuticalTechnologyEurope

Thearticledescribesthebasicprinciplesofblowfillseal(BFS)technologytogether
withtheadvantagesitoffers.AlthoughBFStechnologyisanidealprocessforaseptic
fillingofliquidpharmaceuticalproductsthereisstillariskofcontaminatingthe
productinsidethefillingarea.This,togetherwithregulatoryrequirementsforthe
microbiologicalcontrolofcriticalareasinpharmaceuticalproduction,makes
microbiologicalmonitoringanecessity.
Two
concepts
willbe

Figure1ThestagesinvolvedintheBFSprocess(courtesyofRommelag
AG).(Clicktoenlarge)
presentedinthisarticle,describinghowmicrobiologicalmonitoringofBFSmachines
canbecarriedoutinthecriticalfillingzoneduringproductionwithoutanyriskof
contaminationandcomplyingwiththerelevantguidelines.
Blowfillseal(BFS)technologyisbeingincreasinglyusedforasepticliquidfilling.
TheEuropeanUnion(EU)GuideforGoodManufacturingPractice(GMP)(revisionof
Annex1,ManufactureofSterileMedicalProducts)definesBFSmachinesas"...units
thatarepurposebuiltmachinesinwhich,inonecontinuousoperation,containers
areformedfromathermoplasticgranulate,filledandthensealed,allbyone
automaticmachine."1 Thus,BFSmachinesmanufacturethecontainerstobefilled,fill
themandthensealthemimmediately,withallstepsperformedrapidlyandwithina
smallspace.2 TheindividualstagesoftheBFSprocessareillustratedinFigure1.
BFStechnologyallowscontainerstobeunitdoses,multidoseampoules,vialsor
bottles.Comparedwithconventionalmethods,thetechnologyhastheadvantagesof
preservativefreeproducts(unitdoses)
minimizedtimeandspace
automation
increasedproductsafety(microbialfree).

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MonitoringAirborneMicroorganismsinBlowFillSealTechnology

Despitetheseadvantages,BFS
technologyalwaysentailsapotential
riskofcontaminatingtheproduct
withinitssmallspace.Forthis
reason,theliquidtobefilledandthe
containerareprotectedfromany
possiblecontaminationduringthe
fillingprocessbyastreamoffiltered
sterileair.Therelevantguidelines1
areincreasinglycallingfortesting
themicrobiologicalqualityofBFS
machines.EUguidelinesclassifythe
fillingareaofaBFSmachineasa
gradeAenvironmentthatis,the
concentrationofmicroorganisms
mustbe,<1cfu/m3 air(wherecfuis
colonyformingunits).Figure2
showsatypicalsetupfor
microbiologicalmonitoringofBFS
machines,suchasthatusedat
Holopack(Abtsgmund
Untergrgen,Germany).
ThemeasuringsystemMonitoring
airdirectlyatthepointoffilling
meansthatafewobstaclesmustbe
overcome:limitedspace,poor
accessibility,movablepartsanda
latentriskofcontamination.This
makesitnecessarytowithdrawthe
airsamplefromtheinteriorofthe
BFSmachinewhilsttheairsampler
remainsoutside.Themonitoring
system(asusedinFigure2)consists
ofanairsampler(pumpandflow
ratemeter),areusablemetalfilter
holderconnectedtotheairsampler
byahoseandaneasytoexchange
disposablegelatinfilter.

Figure2Bottlepackmachine(locatedat
Holopack)withthefilterholderattachednear
thefillingzoneandwiththeMD8airscan.
(Clicktoenlarge)

Thehoseconnectionenablessamplingtotakeplacewithinthefillingareawhilstthe
airsampleritselfremainsoutsidethecriticalarea.Duringsampling,theairsampler
drawsadefinedvolumeofairthroughthegelatinfilteraftersampling,thefilteris
placedonasuitableculturemediuminapetridishandincubated.Thecolonies
formedarecountedandevaluatedasthenumberofcfu/m3 ofair.
Watersolublegelatinfiltershaveaporesizeof3m.Theyaresterilizedbygamma
irradiationandarecapableofretaining99.9995%ofBacillussubtilisnigerspores(at
anairflowrateof0.25m/s)3 and99.94%ofcoliphagesT3(at80%relativehumidity
[RH]).4 Theairsamplercanbecalibratedonsiteandhasbeenoptimizedforusein
criticalareassuchasgradesAandB(class100)cleanrooms,isolatorsandBFS
machines.TwodifferentconceptsforairmonitoringinBFSmachinesareintroduced
below.

Figure3Bottlepacksampling(locatedatExcelvision)usingthePVDFhose,whichis
connecteddirectlytothefillingarea.(Clicktoenlarge)
Concept1:measurementwiththehosebetweensamplingpointandfilterholder.
ThisconceptdescribestheexampleofExcelvision,apharmaceuticalmanufacturer
basedinAnnonay(France).Atthecompany'splant,BFSmachines(Bottlepack3012
Rommelag,Switzerland)weremonitored.Themachineisusedtofillplasticvialsof
capacitiesrangingfrom0.35mLwitheyedrops.Samplingwasperformedusinga
polyvinylidenefluoride(PVDF)hoseofsufficientlength(Figure3)thatwas
connecteddirectlytothefillingarea(classifiedasgradeA).Thehosewasrouted
approximately2mtotheoutside,whereitwasattachedtoametalfilterholder
specificallydesignedforusewithdisposablegelatinfilters(Figure3inset).Thehose
wasattachedtothedisposablegelatinfilter(1752880ACD)byabayonetcatch.To
preventsecondarycontamination,thefilterswerechangedinsideaCaptair
Flowcap700Scleanbench,theinteriorofwhichwasalsoclassifiedasgradeA.
Throughafurtherconnectedhose,theairdrawnfromthecleanbenchwaspumped
throughtheairsamplerintothegradeCcleanroomenvironment,wheretheair
samplerwaslocated.
TomonitorthefillingareaoftheBFSmachines,oneairsamplepermachineper
weekwastakenatanairflowrateof6m3 /hfor10min.Thiscorrespondedtoatotal
sampledairvolumeof1m3 in10min,whichmeetstherequirementsofEUGMP
regulations.Theculturemedia(trypticsoyaagar[TSA])wereincubatedfor35days
at32.52.5C.Theresultsshowedthatthevalueswerelessthanthelimitsof<1
cfu/m3 requiredforgradeAcleanrooms.Forexample,nomicrobes(0cfu/m3 ofair)

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weredetectedfrom29June2000to13February2001for31batches.Thestandard
operatingprocedure(SOP)forairmonitoringhasbeeninplaceatExcelvisionfor3
yearsandnocontaminationhaseverbeendetected.
Concept2:measurementusinga
metalfilterholdercontaininga
gelatinfilterandconnecteddirectly
atthefillingzone.Another
possibilityforairsamplinginBFS
machinesisusingtheMD8airscan
withaspeciallymanufactured,
reusablemetalfilterholder(Figure
4)inwhichadisposablegelatinfilter
(1752880ACD)isinserted.For
sampling,thegelatinfilter
disposableinthefilterholderis
locatedinthedirectvicinityofthe
fillingzone.Thisconceptisbasedon
theexampleatHolopack,which
Figure4Thespecialmetalfilterholder
usesaBottelpack3012Mtofill
(locatedatHolopack).(Clicktoenlarge)
sterileproducts(smallvolume
parenterals,waterforinjectionandisotonicphysiologicalsaline)inplasticvialswith
capacitiesrangingfrom1040mL.Inthismeasurementsetup,thefilterholderwith
thedisposablegelatinfilterislocatednearthefillingzone(gradeA),inwhichthe
fillingneedleislocated(Figure2).Thespeciallyfabricatedmetalfilterholder,which
hastobesterilizedbeforeeachsamplingprocedure,isconnectedtotheBFS
machinebyaspecialsanitaryfitting.Inthisexample,airsamplingwasperformed
onceperlot(afterfilling)atanairflowrateof6m3 /hfor10minpersample.Thus,1
m3 ofairwassampledin10minperlot.Theculturemedium(CASO)wasincubated
at3035Cfor5days.Theresultsshowedthatduring2003,fromweek3toweek25,
nocontaminationwasfoundforatotalof90lots(thatis,0cfu/m3 air).Hence,the
fillingzonesoftheBFSmachinescompliedwithEUGMPrequirements(1cfu/m3
roomairingradeAenvironments).
ValidationAspartofvalidatingthetwomethods,itmustbeensuredthat1m3 ofair
perproceduremustbesampledtherefore,itisnecessarytocalibratetheair
sampler.Additionally,itmustbeensuredthattheriskofsecondarycontaminationis
eliminatedduringsamplingtopreventfalsepositiveresults.Asshownhere,thiscan
bedonebyusingacleanroomgradeAcleanbenchwhenchangingthedisposable
gelatinfilter,amongothermeasures.Further,anymicrobespresentinthefillingzone
mustnotbeallowedtoescapedetectionthroughimpactionwithinthehose,which
couldleadtofalsenegativeresults.Thismeansthatforsamplingaccordingto
concept1,thelength,innerdiameterandtheroughnessofthehosemustbe
optimizedandvalidated.Ifconcept2isapplied,validationofthehoseisnot
necessaryasthefilterholderwiththegelatinfilterisconnecteddirectlytothefilling
zone.
SummaryToday,thegelatinmembranefiltermethodisarecognizedprocedurefor
airsamplingincriticalcleanroomenvironmentsandisolators.Asdescribedinthis
article,itisalsoidealformonitoringairinthecriticalfillingzoneofBFSmachines
becauseitcanbeusedduringproductionwithoutentailinganyadditionalriskof
contaminationanditcomplieswiththerelevantguidelines.Inthefuture,itis
expectedthatBFStechnologywillcontinuetogainsignificancesimilartoisolator
technology.Withitsadvantages,thegelatinmembranefiltermethodwillbe
increasinglyusedfortestingBFSsystems,asisalreadythecaseforisolators.
AcknowledgementsIwouldliketothankBenoitCarles,microbiologycontrolheadat
Excelvision,andWalterMatheis,QCmanageratHolopackVerpackungstechnik
GmbHforprovidingimagesanddata.
References1.EUGuideforGMP.RevisionofAnnex1,ManufactureofSterile
MedicinalProducts(1997)NewRevisionSeptember2003.
2.RommelagProductInformation,"TheBottlepackAsepticSysteminthe
PharmaceuticalIndustry,"currentEnglishissue.
3.S.R.Parksetal.,"AnAssessmentoftheSartoriusMD8MicrobiologicalAir
Sampler,"J.Appl.Bacteriol.80(5),529534(1996).
4.H.Jaschhof,"SammlungvonVirusaerosolenmitdemGelatineMembranfilter,"
BioTecMikrobiologie4,2226(1992).
TheoriginalGermanlanguageversionofthisarticlewasfirstpublishedinthejournal
Steriltechnik,3rdissue,no.2,Sept.2003(3.Jahrgang,Nr.2).
2016AdvanstarCommunications,Inc.Allrightsreserved.Reproductioninwholeorinpartisprohibited.Pleasesendanytechnicalcommentsorquestionstoourwebmasters.

SourceURL:http://www.pharmtech.com/monitoringairbornemicroorganismsblowfillsealtechnology
Links:
[1]http://www.pharmtech.com/elmarherbig

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