1/20/2017 OverviewofAsepticFill/FinishManufacturingBioRealty,Inc.

OverviewofAsepticFill/FinishManufacturing
biorealty.com/blog/overviewofasepticfillfinishmanufacturing/

1/11/2016

Editorialnote:ThisarticlewaswrittenpriortothenewFDAGuidanceforAsepticProcessingbeingpublished.The
secondpartofthisarticletobepublishedinthenearfuturewillreflectthenewGuidancerecommendations.

ArticleOverview
Provideanoverviewofthecriticalmanufacturingprocess,asepticfill/finishproductionofsterileproducts.

Thisarticleisthefirstofatwopartseriestoprovideabroadoverviewoftheasepticfill/finishmanufacturing
process.Thisfirstarticlewilldiscussthebackgroundofasepticproductsandtheoperationalrequirementsofthe
asepticoperation.Thiswillincludethepersonnel,cleanroom,preparations,andthefill/finishprocessequipment
andabriefdiscussionofthesterilelyophilzationrequirements.Thesecondarticlewilldiscusstheglobalregulatory
andcompliancerequirementsandwillincludetheprocessvalidationofanasepticmanufacturingoperation.

Introduction
Asepticfillingofsteriledrugs,alsoknowassterilefilling,stillremainsoneofthemostcriticalprocessesin
biopharmaceuticalmanufacturing.Thisisduetoitshighlytechniquedrivenprocessesandthepotentialsafety
impacttotheenduser,usuallyanalreadycompromisedpatient.Thereareonlyindirectsafeguardsforthesterility
ofthefilleddrugafteritisstopperedandcappedinthecleanroom.

Unliketerminalsterilizedfilleddrugs,thestabilityoftheasepticfilleddrugswillbeaffectedbysteamautoclave,dry
heatovens,EthyleneOxide,andirradiation,eitherCobalt60GammaorEBeam.Thustheneedtoutilizean
asepticprocesstofillcertainbiologicals,pharmaceuticalsandbiotechnologydrugs.

Thehistoryofasepticfill/finishprocessingisrelativelyrecentwiththesterilityrequirementsforinjectablesbeing
establishedinthe1920sandlargescalebiologicalmanufacturingofbloodandplasmaproductsduringWWII.
Plasmaproductsdidhave,andsomeproductsstilluse,apostfillpasteurizationprocessoflowheattreatmentof
60Cfor10hours.Pasteurizationdoesnotprovidesterility,butcanreducethecontaminationoffungi.Anti
fungicidalreagentswerealsoaddedtoparenteraldrugstohelpmitigatethecontaminationthatwasoccurringwith
earlyasepticprocessing.

Theninanefforttohelpimproveconsistencyinasepticprocessing,theParenteralDrugAssociation(PDA)
publisheditsAsepticValidationTechnicalReportin1981[8].ThiswasfollowedbytheFood&DrugAdministration
(FDA)in1987withitsAsepticProcessingGuidelines[1].TheInternationalSocietyofPharmaceuticalEngineering
(ISPE)publisheditsSterileFacilitiesaspartoftheirGuidelinesSeriesin1999[14].Recently,theFDApublishedits
ConceptPaper:AsepticGuidelinesin2003[15].

Asepticfillingisanasepticprocessthatrequirestheclosecoordinationandcomplexinteractionbetween
personnel,sterilizedproduct,thefill/finishequipmentsystem,cleanroomandsupportfacilities,andsterilizedfilling
components.

Thereisalsotheperceptionissueforasepticfill/finish,whichisanotherreasonforthemanysafeguardsthatIwill
discussshortly,sincemicrocontaminationisnotreadilyvisible.Microcontaminationisverysmall,andthesurfaces
thatlookcleanandsterilemayinfactnotbe.Thustheasepticfill/finishprocessesarehighlydependenton
technique,detailedprocedures,equipmentandcontrols.

RegulatoryConsiderations

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Aswithourindustry,therearemanyglobalregulatory
requirementsforaseptic/sterilefill/finish
manufacturing.Althougheachcountryorgeography
hasitsregulatoryguidance,wehavenotyetachieved
fullharmonization.Mostofthesearelistedinthis
articlesappendix,andIwillbeonlybrieflydiscussing
thecurrentFDA1987Guidance.ThisFDAGuidance
providesacoupleofnicedefinitionsforus.

Inasepticprocessing,thedrugproduct,containerand
closurearesubjectedtosterilizationprocesses
separatelyandthenbroughttogetherBecausethereis
nofurtherprocessingtosterilizetheproductafteritis
initsfinalcontaineritiscriticaltothemaintenanceof
productsterilitythatcontainersbefilledandclosedin
anenvironmentofextremelvhighquality

WealsohavewrittenintheCodeofFederal
Regulation(CFR),section21CFR211.113(b)that
states

Appropriatewrittenprocedures,designedtopreventmicrobiologicalcontaminationofdrugproductspurportingto
besterile,shallbeestablishedandfollowed.Suchproceduresshallincludevalidationofanysterilization
processes.

Anothersection,21CFR211.167(a)states

Foreachbatchofdrugproductpurportingtobesterileand/orpyrogenfree,thereshallbeappropriatelaboratory
testingtodetermineconformancetosuchrequirements.Thetestprocedureshallbeinwritingandshallbe
followed.

Currently,theFDAhasbeenexpressinganumberofconcernsaboutasepticmanufacturing,citingalldrugs
recalledduetononsterilityoverthelast10yearswereproducedbyasepticprocessing(Spring2002).Ifyoudrill
downintheserecalls,youwillfindthatthereareafewcompanieswhohavemultiplerecalls,andthattherearea
lotofdocumentationrecalls.Thesearesituationsinwhichthedocumentationorprocedureshadomissionsand
errorsandasaresultarecallwasinitiated.Theconsensuswithinourindustryisthat,infact,wehavebeengetting
muchbetterwithourasepticfillingprocesses

AsepticFill/Finish
Whatcanbeasepticallyfilled?Virtuallyanysolution,powderorsuspensionthatcanbeterminallysterilizedpriorto
theasepticfill/finishprocess.Typicallysteriledrugsareasepticfill/finishinmoldedglassbottles,tubularglassvials,
tubularglasssyringesandinEuropemorethantheUnitedStates,glassampoules.Solutionscanalsobe
subsequentlylyophilizedinasteriledryertofurtherstabilizedrugs.Themoreuniquetheproductorcontainer
system,thegreaterthetechnicaloroperationalchallengesthatmayensue.

Howdowecompletetheasepticfill/finishprocess?Youneedtodecontaminatetheoperationalpersonnel,
terminallysterilizethedrugproduct,fillingcomponents,equipmentchangepartsandsanitizethecleanroomand
inplaceequipment.Thenbringitalltogetherwithgoodasepticpractices,andthesimplifiedprocessmapslooklike
theasepticprocessmap.

Theasepticfill/finishmethodscanvarybetweenanearlyclinicalphasehandfill(clinicalsolutionfillphoto),tosmall
volumesemiautomatedfillingtothefullyautomatedhighvolumeovermultipledayproductionbatches.

CleanroomPersonnel

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Thepersonnelinthecleanroomarelikethedoubleedged
sword,theyareabsolutelynecessarytocompletetheaseptic
fill/finishprocess,butatthesametime,providethegreatest
microbialriskforasterileproduct.Youareconstantly
regeneratingyourself,andintheprocesssheddingahuge
amountofdeadskinandotherparticles.Anaveragepersonis
capableofsheddingtenmillionparticlesperday.Thatis
furthercompoundedbythetypesofclotheswornandwhere
youhaverecentlybeen,suchaswhatmightbeonthebottom
ofyourshoesrightnow.

Thustheamountofinvestmentthatismadetolimitthe
operationalpersonnelrisktothesteriledrug.Personnelare
encapsulatedwithextensivesterilegownsandqualified
gowningprocedures.Thecleanroomshaveextensive
unidirectionalflowaircurrentstoprovideabarrieraswellas
sweepthepotentialcontaminationawayfromtheexposed
drugs.

Automatedfill/finishequipmentisinstalledtoreducethe
amountofpersonnelwhoarepresentinthecleanroomduring
theasepticfill/finishprocessing.Developmentofthecurrent
barrierequipmentdesignsandtherecentdevelopmentofthe
isolatortechnologyhavebeenmadetofurtherisolatethe
exposedsteriledrugfromtheoperationalpersonnel.

Lastly,theimplementationofBestAsepticPracticestoprovide
personnelwithmethods,trainingandqualifiedproceduresto
furtherpreventmicrobialcontaminationofthesteriledrugs.

TheBestAsepticPracticesareasetofbestpracticemethods
forpersonneltogovemthemselvesastheymoveandfunction
inthecleanroomenvironmentwhileexecutingtheirprocesses.
Asepticpracticeswillalsoincorporatethespecific
requirementsforyourasepticfill/finishprocessing.Procedures
areneededforbothgowninganddegowningprocesses,and
statehygiene,training,qualificationandrequalification
requirements.

Sterileoutergarmentsareusuallymadeofsyntheticornaturalmaterials,wornasanoutergarment,whichhave
lowornoparticlesheddingorpenetrationcharacteristics.Mostcompaniesoutsourcetheirsterilegarment
preparationtoacompanywhowillwashandsterilizetheirgarments,usuallysterilizewithGamma.Forlowvolume
sterilegarmentingrequirements,youcanutilizesingleusesterilegarmentpacks.Thesterileoutergarmentsactas
apersonnelfiltertoisolatetheindividualandtheircontaminantsfromthecleanroomenvironmentandthesterile
drugs.

Personnelwhofunctionintheasepticfill/finishasepticprocessingcorewillneedtohavecompletedagowning
qualification,especiallytobepresentinthecleanroomcoreduringasterilefilloperation.Thiswouldincludethe
operationalpersonnel,maintenancemechanics,qualityassuranceandqualitycontrolpersonnel,production
management,engineersandtechnicians.Thequalificationshouldincludetrainingonthebasicsofmicrobiology
andtheBestAsepticPractices.Typically,thisisfollowedbyagowningdemonstration,thenagowningcritiqueof
thepersonintraining.

Finalgowningqualificationshouldbecompletedwithmultiplesterilegowninginthecleanroomwithmicrobial
testinginsidethecleanroom.Irecommendthatthesterilegowningandmicrobialeventsshouldbevideotapedto
providetheoperatorwithadditionalfeedbackandassistwiththeanalysisofthegowningtechniques.Gown

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qualificationbestpracticesrequirethegowningqualificationtopassthreeconsecutivemicrobialtestingand
successfulmediaparticipationpriortobeingdeemedgowningqualified.Anexampleofagowningprocessis
providedinTable2.

Facilities:TheCleanroom
Thecleanroomsarecontrolledareasandinconjunctionwiththesupportingutilitysystemsandfacility
infrastructure,createtheenvironmentalenvelopinwhichtheasepticfill/finishprocessoperates.Aswiththeother
componentsoftheasepticprocessing,thecleanroomsareacomplexcombinationofphysicalroomsandareas,
utilizingHighEfficiencyParticulateAir(HEPA)tocreateunidirectionalairpatterns,maintenanceofpositive
pressurebetweenroomsinconjunctionwithconstantairchanges,andsanitizationprocesses.Allofthisoperates
withconstantenvironmentalmonitoring(EM).

Thecleanroomdesignwilltakeintoconsiderationtheflowofpersonnel,product,equipmentandcomponents.
Effectiveasepticfill/finishfacilitydesignswilltakeintoaccounttheflowofallofthesefromthereceiptofraw
materialsatthewarehousethroughthefacilitytofinalwarehousing.Averysimplifiedillustrationisthecleanroom
cascadedefense.

Verybasictothecleanroomdesignistheclassificationofthecleanroomsrelativetotheoperationthatisoccurring
withinitas,wellasadjacenttoit.Harmonizationoftheregulatoryguidelinesforcleanroomshasnotfullyoccurred
yet,butIbelievewearemakingsomeprogress.Inthecleanroomclassificationtable(Table3)isaverysimplified
comparisonbetweentheEuropeanAnnexlandFDAclassifications.Ihavereferencedthevariouscleanroom
compliancedocumentsinthearticleappendix,andanindepthdiscussionofcleanroomclassificationswasnot
intendedforthisarticle.Youwillneedtoknowwhereyourproductsaregoingtobedistributedtoselecttheproper
guidancetofollow,whichforourindustryandglobalproducts,usuallymeansallofthem.

Beforediscussingthecleanroommaterialsofconstructionor
theHeating,VentilationandAirCondition(HVAC),itiscritical
tofirstunderstandtheflowofpersonnel,sterilizedcomponents
andsterileproductindevelopingthecleanroomdesignand
operation.Theflowrequirementsmayvarywitheachsterile
drugproduced.

Thepersonnelflow,asIdiscussedearlier,isverycriticalto
maintainingthesterileenvironment.Thiswouldincludethe
gowning,degowningandallofthenecessarymovements
throughallofthecleanroomfacilities.Itisidealtoensurethat
thepersonnelflowismovingonewayfromgowningto
operationandthendegowning,cleanestareatowardsthe
dirtiest.

Theonewaymovementwithinthecleanroom,especiallythe
sterilecorefortheasepticfill/finishoperation,iscriticalforall
ofthematerial,productsandcomponents.Youwillwanttoensureyourcleanroomdesignwilleliminatetwoway
transfersfromoccurringconcurrently,wheresterilegoodsarephysicallypassingnonsterilegoodswherethereis
apotentialformicrobialcrosscontamination.

Themovementofmobiletankswithsterilefilterbulkdrugpresentschallengesaswell,astheexteriorsurfaces
cannotbeterminallysterilizedwiththedrugenclosedbeforetheasepticfill/finishoperation.Thebulktankswill
requiresanitizationinairlocksoratothertransfermodules.Thesanitizationprocessesformobiletanksare
challengedbytheamountoffixturesonthetanks,clearanceunderthetank,andthetankwheelassemblies.
Frequentlythemobiletanksaresegregatedfromtheasepticcoreandonlythetransferofthebulktanktubing
connectionnecessaryfortheasepticconnection.

Theequipmentlayoutandflowwillalsoinfluencethecleanroomdesign.Theidealasepticfill/finishsystemisa
fullyautomatedinlineisolatorfill/finishsystem.Themostdifficulttomanageandpresentingthegreatermicrobial
risk,isabatchsterilizationandcompletelymanualfillingprocessthatoccursinabiohazardsafetyhood.
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Theequipmentflowshouldalsoreflectthenecessarysterilizedsetuppartsthatwillbechangedforeachsterile
drugbatch,suchasthefillingneedles,stopperbowlandfeedercomponents.Thesterilizedsetupcomponents
mayrequireaspecializedtechnicianormechanictosupporttheasepticfill/finishoperation.Theeaseinwhichthe
asepticsetupcanbeaccomplishedandmaintainedcandirectlyinfluencethequalityoftheasepticfill/finish
operation.Youshouldeliminateanyoperationsthatrequireasterileoperatortoreachoverthefillline.

Theasepticcoreinwhichthesteriledrugisactuallyexposedtothecleanroomenvironmentisthemostcrucial
areaofacleanroom,andwarrantsthemostdetailedattentiontothedesignofthecleanroom.Thisisthearea
wherethesteriledrugistransferredfromthefillingneedlestothesterilecontainer.Typicallythestopperingor
closingofthecontaineroccursimmediatelyafter,withtheexceptionofwhenthedrugrequiressterilelyophilization.
Therequirementsofthelyophilizationprocessrequirethestopperbeonlypartiallyseatedonthevial.

Forsolutiondrugsafterastopperingprocess,sealingoccursimmediately,usuallywithsomekindofaluminium
seal.Thedesignofthecleanroomorequipmentwouldincludeabarrierbetweenthestopperingandsealing
processestominimizeanypotentialaluminiumcontamination.

AnothervariationforsteriledrugsolutionsistheuseofFormFillSeal(FFS).Thisfullyautomatedprocessforms
aplasticcontainersystem,fillingthesolutionduringtheprocessandimmediatelysealingthecontainers.TheFF
Sprocessminimizestheenvironmentalexposureandprovidesmicrobialcontaminationresultssimilartoan
isolatorprocess.

Forlyophilizeddrugs,thefilledandpartiallystopperedvialswouldbetransferredtoasterilelyophilizer(drier)for
thecompletionofthelyophilizationcycle.Itisnormalforthestopperstobeseatedinthevialsinsidethesterile
drierattheendofthelyophilizationcyclepriortoopeningthedoor.Thestopperedvialsarethenremovedfromthe
steriledrierandimmediatelycapped.Thedelayinsealingthecontainer,immediatelyafterthefillingprocess,
allowsthedrugtobeexposedtotheenvironmentisanadditionalriskthatoccurswithsterilelyophilization.

AnessentialcomponenttothecleanroomistheHeating,VentilationandAirCondition(HVAC)systems.TheHVAC
systemsthatsupportpharmaceuticaloperations,especiallycleanroomsandasepticmanufacturing,arecomplex
andextensive.Theheatingandcoolingfunctionsareneededforoperatorcomfortandenvironmentalcontrol.
Ventilationfunctionprovidesthenecessarycirculationandairturnstomaintainenvironmentalcontrol.TheHVAC
willalsobedesignedandoperatedtomaintaintheasepticcorebytheuseofpositivepressurethatextendsaway
fromthecore.

Aruleofthumbfortemperatureintheheavilygownedasepticcoreismid60F,andtherelativehumidityabove
30%tocontrolstatic,andbelow60%tocontrolrust,organismgrowthandpersonnelfromsweating.

Forcleanrooms,theductsterminateatHighEfficiencyParticulateAir(HEPA)filters.FortheHVACthatsupports
theasepticprocessingoperations,includingthepreparationsarea,therewillbeaseriesofprefilterspriortothe
HEPAfilters.TheHEPAfiltersarerated99.95%effectiveformicrobialretentionandfacilitateunidirectionalairflow.
Previously,itwasthoughtthatalaminarairflowpatterncouldbeeffectivelyachievedwiththeHEPAfilters,butwith
theknowledgegainedbyextensivesmokestudiesofclass100asepticcores,themorerealisticexpectationisa
unidirectionalairflowpattern.

TheHEPAfiltersaretheachillesheelofthecleanroomHVACsystem.Theyrequireextensivecareand
maintenanceandcouldhaveadetrimentaleffectonthequalityofthecleanroomenvironmentifnotwell
maintained.HEPAfiltershavethepotentialtofailwithinthefiltermedium,atthegaskets,sealsandframe.

Otherutilitiesthatareneededtosupporttheasepticfill/finishoperationincludeWaterforInjection(WFI),oilless
compressedair,nitrogengas,sterilesteamandvacuum.Thecompressedairandnitrogengaswillalsohavepoint
ofusesterilefiltersinsidetheasepticcore,andthevacuumsystemshouldhaveonewaycheckvalves.TheWFI
ispredominatelyusedinthepreparationsfortherinsingofvials,stoppersandequipmentchangeparts.Theintent
ofthisarticlewasnottoprovideanoverviewoftheutilitydesignandoperationthatsupportcleanroomoperations.

Materialsofconstructionofacleanroomshouldfacilitatetherequiredoperation,whichincludesextensivecleaning
processesandsupporttherequiredenvironmentcontrol.Thesurfacesshouldbehard,smoothandeasily
cleanable.Thefloors,ceilingandwallsshouldbecontinuous,withflushinstallationsandutilizingweldedjoints

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wherepossible.Thewallfixturesshouldbeflushmountedto
surfacesandthelightingfixturesflushmountedandpreferably
remoteaccess.Surfacesshouldnotbedesignedtoallowthe
buildupofparticulatecontamination.

Mostasepticcleanroomshavetelecommunicationequipment
toallowdiscussionswithouttheneedofpersonnelleavingand
enteringtheoperation.Increasingly,videomonitoringand
recordingcamerasareinstalledintheasepticcore.Thevideo
equipmentallowsafurtherreductionofmonitoringpersonnel
insidethecriticalarea,whereeachadditionalperson
incrementallyincreasestheriskofmicrobialcontamination.

Cleanroommaintenanceandsanitizationrequiresthe
qualificationofthecleaninganddisinfectantsagents.The
qualificationofthesanitizationprocesseswillneedtobedone
inconjunctionwithadocumentedprocessandtrained
personnel.Thisqualificationshouldincludethedevelopmentof
theexpirationdatesfortheformulatedsanitizationsolutions.

Someofthecommondisinfectantsandsterilantsare
phenolics,sterilealcohol,hydrogenperoxide,QuaternaryAmmonium,SodiumHypochlorite,andFormalin.
Phenolicswillworkwithorganicmatter,buthaveissueswithresistantspores.Alcoholswillactquickly,buthave
littleeffectonsporesandareflammable(e.g.70%IsopropylAlcohol,IPA).HydrogenPeroxideisanexcellent
sporicidal,butalsonotcompatiblewithallsurfaceagents(e.g.soap).QuaternaryAmmonium(Quarts)arehighly
stableandnontoxic,butaffectedbywaterquality,soap,andnoteffectivewithspores.Formaliniseffectiveagainst
bacteriaspores,willnotcorrodemetal,butitistoxicwithirritatingfumesandresidualsthatcanbedifficulttoclean.
SodiumHypochloriteisanexcellentsporicidalbutaffectsmetals.

Thecleanroomsanitizationprocessrequiresfullsterilegowningandalloftherequiredaseptictechniquesthat
wouldbeutilizedduringtheasepticfilling.Aswiththeasepticfillingprocess,thecleanroomsanitizationprocess
requiresdocumentation,personneltrainingandqualification.EnvironmentalMonitoring(EM)istheprocessto
ensurethatthecleanroomisundercontrolforpotentialviableandnonviablecontamination.YourEMprocess
shouldhavequalifiedmethodologiestoroutinelycollect,evaluateandinterpretEMdata.Thedeterminationof
samplingpointsandrequiredlimitsshouldbedefinedinyourdocumentation.YourEMprogramshouldidentify
periodsofcriticalactivitywheresterileproductmaybeexposedtoenvironmentalconditions(photoEmclass100
BioSafetyHood).

SterileProductFiltration
Yourdrugwillrequiresterilizationbysomemethodpriortotheasepticfillingprocess.Traditionally,thebulkdrug
sterilizationisaccomplishedbyfiltration,normallyadepthfilter.Youwillneedtobulkdrugamethodforsterilization
andasterilecontainersystemthatiscompatiblewiththedrugandyourasepticfill/finishprocess.Thedrugscan
bepresterilefiltered(e.g..45micron),followedbyaseriesofatleasttwosterilefiltersat.22micron.Thesterile
filtersarebothpreandpostbubbletestedtoensureintegrity.TheSterilebulkisthentransferredtotheasepticfill
andasepticallyconnectedtothefillequipment.Currentlythebestinclassforsterilefiltrationisaclosedsystem
thatextendsfromthenonsterilebulktotheasepticfillingequipment.

FillingComponents

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Allcomponentsandsuppliesthatarerequiredduringtheasepticfill/finishoperationmustbeeithersterilizedor
sanitized.Sterilizationisusuallycompletedwithpassthroughsteamautoclaves,dryheatovenortunneland
sanitizedcleanroomairlocks.

Thefillingcomponentscanalsovaryperthedrugandproductionrequirements.TubularTypeIglassvialsare
predominatelyusedforSmallVolumeParenterals(SVP)andsterilelyophilizationandblownTypeIIglassbottles
forLargeVolumeParenterals(LVP).TubularTypeIglassstockisalsopredominatelyusedforasepticsyringe
production.AnumberofmanufacturersareconsideringCyclicOlefinCopolymer(COC)vialsthatfunctionsimilarto
glassvials.

Thestopperingofthevialprovidesthesterilesealofthedrugfromtheenvironmentandacrimpsealcapensures
thelongtermintegrity.Thestopperalsoprovidesabarriertogasandoxygentothedrugensuringlongterm
stability.Elastomericclosures(stoppers)thatareusedforparenteralsolutionsareformulatedtoensureproduct
stabilityandpatientfunctionality.Twoofthebasicstylesofclosuresaretheplugforsterilesolutionsandtheleg
forsterilelyophilization(clinicalsolutionfillphoto).Someoftheconsiderationsshouldbegiventosize,typeand
numberofneedlepunctures,watervaportransmissionrate,abilitytoretainboundwater,gastransmission,
stopperingequipmentofthefillinglineandpotentialextractables.

ComponentPreparation
Therearemanywaystoasepticallyfill/finishsteriledrugs,whichincludesthetraditionalsolutionfillingofglassvials
andsyringes,sterilepowderfills,sterilelyophilization,andblowfillseal.Forthisarticle,Iwillonlybeaddressing
solutionfillingandsterilelyophilization.Therearemanyconsiderationsintheselectionofyourasepticfilling
equipment.Tonamebutafew:solutionvolume,filltolerance,productionthroughput,drugviscosity,drugfoaming,
gasblanketing,drugtemperature,potentcompounds,drugstabilityandreactivity.

Sterilepreparationofthevialsandbottlesisachievedbyrinsing(washing)toremoveendotoxins.Theglassvials
andbottlesaredepyrogenationusuallywithhotair.Thisisaccomplishedinabatchmodewithanoven,ora
continuousprocesswithatunnelthatconnectsthebottlewashertothefillingstation.

Forsmallpartscleaning,suchasfillingneedles,forcepsandstopperingequipment,aswellasstoppers,youwill
completetheinitialwashing/rinsingtoremoveendotoxinsandlooseparticulate.Thenwrapthepartsfor
subsequentsteamautoclaveprocessingtodestroytheendotoxins.Dependingontheformulation,thestoppers
maybeabletobesterilizedbyirradiation.

Asepticfill/finishprocessescanveryfromaclinicalhandfill,tosemiautomatedmonoblock,toahighspeedfilling
lines.FillingequipmentsystemscanbecharacterizedaseitherOpen,Barrier,IsolatorandRABS.

Fillinglinesarecharacterizedashavingnobarriersorotherphysicalrestrictionsbetweenthesterileoperatorand
thesteriledrugs.AsaresultofEUregulation,openfilllinesarenotcommontocommercialasepticoperation,but
canbefoundinPhaseIandIIclinicalmanufacturingoperations.Thebarrierfillinglineshavetransparentpanels
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thatrestrictsterileoperatoraccesstothesteriledrug.Someofthebarrierpanelsmaybedesignedasdoorstothe
Barrierwithveryspecificoperationalproceduresthatsupportaseptictechniquesforuseduringasepticfill/finish
production.

Thesolutionfillingprocesswillincludethetransportof
sterilizedvialsandbottles,orientationtothefillingstation,a
meansforcheckweighing,stopperingandcrimpingstations.
Forhighspeedlines,therewillalsobeaccumulationtables
andvialload/loadingstations.Thefillingequipmentcan
includethesophisticationofinlinecheckweigher,automated
visionsystems,rejectstations,andSCADAinformation
systemsnetworkedfromeachequipmentsPLC.

Asaruleofthumb,thestopperingandcapping(sealing)
shouldbecompletedassoonaspossible.Thereissome
discussionthatthecrimpingofthecapmaynotrequirethe
samecriticalenvironmentasthesolutionfillingprocessand
crimpingmaybeaparticulategeneratingprocess.Thenorm
forsolutionfillingequipmentistoprovideabarrierbetweenthe
stopperingandcappingprocesses.Isolatorsystemsareacurrentalternativetotheclassicbarrierequipment
installation.Isolatorsutilizeagloveboxtechnologyandtheyaredesignedforminimalhumaninterventionwhich
providesincreasedcontaminationcontrol.Amajorityoftheisolatorsaresanitizedbyvaporizedhydrogenperoxide.
Isolatorsrequiremoreexpensivecapitalinvestment,canbemorecomplextoinstall,qualifyandoperateandmay
havelessflexibilitytochangeoverfillsizesandproducts.Theyhavehistoricallybeendesignedforhighvolume
dedicateddrugproductionandmicrobiologicalqualitylaboratoryoperations.Thereisalsoatrendtoutilize
CampaigningforIsolatorstechnologyinstallations[16].

AnalternativetoisolatortechnologyistheRestrictedAccessBarrierSystem(RABS)atermfirstdescribedby
Upjohn,nowPfizer.RABSissimilartotheisolatortechnologyutilizinggloveportsandothersterileoperator
restrictions.Itisalsosimilartothetraditionalbarrierfilllinewiththeutilizationofaconventionalasepticcore
cleanroom.Thegowningandaseptictechniquesarethesameasabarrierfill/finishoperation.Theadvantagesthat
havebeenreportedarereducedcapitalinvestment,quickervalidationsandoperationalstartup,reductioninlotto
lotturnaroundtime.RABSoperationshavedocumentedcontaminationcontroloveratraditionalbarrierfill/finish
system.

SterileLyophilization
Asterilelyophilizationprocessrequiresallofthebasicsforasepticprocessingofasolutionproduct,butwiththe
additionalprocessingrequirementsandrisksofthesteriledryer(Lyo)equipment.Steriledryersarenowdesigned
toutilizeCleaninPlace(CIP)andSterilizationinPlace(SIP)ofboththecondenserandtheproductchamber.

Thechamberwhichholdsthedrugproductbeingprocessedrequiresaloadingmethodologythatisconsistentwith
aseptictechniques.Forhighproductionandlargesteriledryers,themajorityofnewinstallationsalsoinclude
automatedloadandunloadequipment.Theautomatedload/unloadcapabilityreducestheheadcountinsidethe
asepticcoreandshouldreducetherisktomicrobialcontamination.

Thelyophilizationprocessincludesfillingtheproductsolutionaseptically,withthestopperpartiallyseatedinthe
vial.Thepartiallystopperedvialisthentransportedandloadedintothesteriledryer,thusthesterileproducthasan
extendedexposuretotheenvironment.Thedrugsolutionisthenfrozenbyeitherimmersioninliquidnitrogenprior
toloadingorbythesterileshelf.Thelyophilizationcycleincludestheprimaryandsecondary(terminal)drying.After
thelyophilizationcyclehasbeencompleted,thestoppersareusuallyseatedintothevialbyloweringthedryer
shelves.Asteriledrugproducermayneedtostopperthelyophilizedvialsundervacuumorandinertgas.Thenthe
dryerdoorisopenedandthestopperedvialsaretransportedtoacapping(crimping)process.

Mediafillsforprocessvalidationforasteriledryerisnotafullprocesssimulation.Thelyophilizationprocessis
usuallyconductedundernearvacuum,withaslightamountofpressureprovidedbysterilenitrogenandat35C

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orcolder.Allthreeofthesevariableshaveanegative
effectonmediaandwilldistorttheresults.Thus,most
companieswillmodifythemediafillinthesteriledryer
bynotfreezingtheshelves,notevacuatingthe
chamberandconnectingsterileairtothechamber
inlet.

VisualPackagingInspection
Visualpackaginginspectionofasepticfilleddrugsis
usuallycompleted14daysafterfill.Thisisaperiodof
timethatcouldallowthegrowthofanypotential
contaminatingmicroorganisms.Thecriticalinspection
processisforthepresenceofacloudyorhazy
solutionthatwouldindicateacontaminationpotential.
Themanualversionofthisinspectionoccurswiththe
useofwhiteandblackbackgroundviewingareas.

Manualvisualinspectionrequirestrainedandtested
inspectors,andduetotherepetitionoftheinspection
task,itisreallyonlyabout85%effective.Thusa
numberofcompanieshaveimplementeddouble
inspectionoftheproduct,verytightacceptancecriteriaandautomationoftheprocesswithvisionsystems.

Appendix
1.GuidelineonSterileDrugProductsProducedbyAsepticProcesses,FDA,pub.1987.
2.GuidanceforSubmittingDocumentationforSterilizationProcessValidationinapplicationsforHumanand
VeterinaryDrugProducts,FDA,pub.1993.
3.ISO134081AsepticProcessingofHealthCareProducts.
4.ISO14644CleanroomStandard(replacesMILSTD209E,obsolete2001).
5.Annex1,ManufacturerofSterileMedicinalProducts,PharmaceuticalInspectionConvention,pub.2003.
6.USP<61>MicrobialLimits.
7.USP<1116>Cleanrooms.
8.ValidationofAsepticFillingforSolutionDrugProducts,PDATechnicalMonogram,Number2,pub.1981.
9.ProcessSimulationTestingforAsepticallyFilledProducts,PDATechnicalReportNumber22,pub.1996.
10.PointstoConsiderforAsepticProcessing,PDA,pub.2003.
11.CurrentpracticesintheValidationofAsepticProcessing,PDATechnicalReportNumber36,pub.2002.
12.Design&ValidationofIsolatorSystemsfortheManufacturerandTestingofHealthCareProducts,PDA,
TechnicalReportNumber34,pub.2001.
13.AsepticPharmaceuticalManufacturing,published1987byInterpharmPress.
14.ISPEBaselinePharmaceuticalEngineeringGuide,Volume3,SterileManufacturingFacilities,Jan.1999.
15.FDAConceptPaperonAsepticProcessing:www.fda.gov/cder/dmpq/asepticcp.pdf
16.D.Stockdale,IsolatorCampaigningAnIndustrySurvey&DiscussionofOperationalPractices,
publishedbyISPEPharmaceuticalEngineeringMagazine,2004.

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Table1.DefinitionofTermsforAsepticProcessing
Basictermsdefined

Sterile:absenceoflivingorganisms.
Microbialcontamination:Living(viable)organism.
Bacteria:livingsinglecellw/outorganizednucleus(>0.22micron).
Fungi:yeastsandmold(multicellular).
Molds:reproductionbyspores.
Virus:NucleicAcid(DNAorRNA)enclosedbyacoveringofprotein.Notaliveuntilenterintoacell.
CFU:ColonyFormingUnit(viable).
Particulatecontamination:Nonliving(nonviable).
Pyrogens:substancesthatinducefeverwhenadministeredtoanimalsbyvariousroutes.
Endotoxin:pyrogenicmaterialfromoutermembraneofgramnegativebacteriawhichhasbeenshed
fromviablebacteriacellsorwhencellsdie.
Sterilize(Sterilant):destructionofviableorganisms&spores.
Disinfectants:destructionofviableorganisms.
Sanitize:Thatpartofdecontaminationthatreducesviablemicroorganismstoadefinedacceptancelevel,
normallyachievedbyusingachemicalagentorheat.
Decontaminate:reductionofcontamination,viableandnonviable.
Bioburden:numberofcontaminatingorganismsperunit.
Depyrogenation:eliminationordestructionofpyrogens.

(source:ISPEDefinitionofterms)

Table2.BasicAsepticCleanroomGowning
Preparation:changeintocleanroomdedicatedshoesandnonsterilegarments
Applyheadcover
Handwash&sanitize,1ststerilegloves
Moveintohigherclasscleanroomenvironment
Sterilegowning:startattopandworkdown
Sterilizedhood,bodygarment,andfacemask
Typicallymoveintohighestclasscleanroomenvironmentwithgowningsterileboots
Sterilized/SanitizedGoggles
Finalsterilegloves(doubleglove)andsanitize

Note:GowninginCriticalarea(Class100/GradeA)becomesmorestringentwhenworkingwithexposedsterile
drugs.Operatorsshouldgownwithadditionalsterilesleeves,sterileglovechanges,&sanitizeofgloves.

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Table3.CleanroomcIassificationexamples

FDAcategories EUannex1:4categories(AD)

Class100 GradeA(Critical100)

Class1,000(optional) GradeB(Aseptic100nonunidirectional)

Class10,000 GradeC(Controlledl0,000)

Class100,000 GradeD(l00,000)

DouglasStockdaleisthePresidentofStockdaleAssociates,Inc.,whichprovidesextensiveasepticfill/finishand
sterilepackagingconsultingservicesforthelifesciencesindustry.Hehadtwentyyearsofoperational
experiencewithBaxterHealthcarepriortofoundingStockdaleAssociates.Heisaninternationallyknownexpert
consultant,speakenandwriterabouttheissuesofasepticfill/finishandsterilepackaging.Hiscompany
providesinnovativestrategicandimplementationsolutionsforproductdevelopment,manufacturing,
compliance/auditingandvalidation.HeisamemberofPDA,AAPSIOPP&ISPEandamemberoftheBoardof
DirectorsfortheGreaterLosAngeleschapterofISPE.MrStockdalehasaMBAjromUniversityofLaWarne
andB.S.inEngineeringfromMichiganStateUniversity.

Contactingtheauthor:
DouglasStockdale,President,StockdaleAssociates,Inc.
CorporateOffices:10Reata,RanchoSantaMargarita,CA
92688,Phone:9498889488,Fax:9498881560
douglas@stockdaleinc.comorwwwstockdaleinc.com

ThisarticlewasprintedintheSeptember/October2004issueofAmericanPharmaceuticalReview.Copyrightrests
withthepublisher.FormoreinformationaboutAPRandtoreadsimilararticles,visit
www.americanpharmaceuticalreview.comandsubscribeforfree.

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