PDA TR77吹灌封技術用于無菌制劑生產(chǎn)-2017（英文）

TechnicalReportNo.77

TheManufactureofSterilePharmaceutical

ProductsUsingBlow-Fill-SealTechnology

PDATheManufactureofSterilePharmaceuticalProductsUsingBlow-Fill-SealTechnology

TechnicalReportTeam

Authors

MartinHaerer,HolopackVerpackungstechnik,TeamCo-leader(BFSIOA)

KennethMuhvich,Micro-Reliance,LLC,TeamCo-leader(PDA)

PeterAkerman,AstraZeneca

JaimeBlanco,Genentech

NerminCchajic,KemPharm,Inc.

KevinDowney,TevaPharmaceutical

TyDuginske,Baxter

AndrewGoll,WeilerEngineering,Inc

TimKram,RommelagUSA,Inc.

StaceyLargent,Merck

JesperLaursen,MELITEKA/S

MattPayne,RitedoseCorporation

PatrickPoisson,UnitedTherapeutics

ChuckReed,ReedsandRushes,LLC

OttoSchubert,MaropackAG

JerryWebb,NephronPharmaceuticalCorporation

TheManufactureofSterile

PharmaceuticalProductsUsingBlow-Fill-Seal

Technology

TechnicalReportNo.77

ISBN:978-0-939459-94-0

◎2017ParenteralDrugAssociation,Inc.Allrightsreserved.

ThistechnicalreportwasdevelopedandwrittenincooperationwiththeBlow-Fill-SealInternationalOperators

Association(BFSIOA).Thecontentandviewsexpressedinthistechnicalreportaretheresultofaconsensus

achievedbythePDAauthoringtaskforceandarenotnecessarilyviewsoftheorganizationstheyrepresent.

TableofContents

1.0INTRODUCTION

1

1.1Purpose

1

12Scope

1

1.3BFSProcessOutline

1

2.0GLOSSARYOFTERMS

3

2.1Abbreviations

3

3.0BFSEQUIPMENT

3

3.1ShuttleTypeMachines

(0penParisonProcess)

3

3.2RotaryFilingMachines(ClosedPanisonProcess) 4

3.3AdditionalApplications

5

4.0BENEFITS&SPECIALCONSIDERATIONSOFBFS

TECHNOLOGY

6

4.1Benefits

7

4.2SpecialConsiderations

7

5.0DESIGN

8

5.1ProductDesign

8

5.1.1AsepticProcessingversusTerminal

Sterilization

8

5.1.2TerminalSterilization

8

5.1.3Polymer

9

5.1.4ProductApplications

9

5.1.5ContainerDesign

10

5.1.6SecondaryPackaging

10

5.2EquipmentDesign

10

5.2.1General

10

5.2.2ProductPathway

11

5.2.3MoldDesign

11

5.2.4VacuumSystem

11

5.2.5Deflashing

12

5.2.6EquipmentMonitoring

12

5.3FacilityDesign

12

5.3.1AsepticProcessingArea

12

5.3.2PolymerStorageandDistribution

12

5.3.3Utilities

13

6.0OPERATIONALANDQUALIFICATION

CONSIDERATIONS

13

6.1BFSProcessValidationandAdvanced

Technology

13

forQualityandSterility

14

6.2EvaluatingCriticalBFSProcessParameters

6.3QualityAttributeCriticalProcessParameters 15

6.3.1AirFlowRate

15

6.3.2MainMoldVacuumDelayTimer

15

6.3.3BottleBlowingTimer

15

6.3.4SealMoldVacuumDelayTimer

16

6.4SterilityAssurance-relatedCriticalProcess

Parameters

16

6.4.1FillNozzleDownDelayTimer

16

6.4.2BottleBlowingTimer

16

6.4.3BottleVentTimer

16

6.4.4MasterFillTimer

16

6.4.5IndividualFillTimers

16

6.4.6FillNozzleUpDelayTimer

16

6.5Implementation

16

6.6Pre-processPreparationofCriticalAreas 17

6.6.1SanitizationofMachineSurfaces

17

6.6.2CleaningofProductContactSurfaces

17

6.6.3SterilizationofProductPathway

18

6.7ProductValidation

18

6.7.1ContainerClosureIntegrityTesting

18

6.7.2LeakDetection

19

6.7.3CampaignFill/HoldingTime

19

6.7.4In-ProcessSampling

19

6.8EquipmentValidation

19

6.8.1CriticalZoneControl

19

6.8.2AirShowerDesign(OpenParison

Machines)

20

6.8.3BFSMachineRoomEnvironment

20

6.8.4FiltrationConfiguration

20

6.8.5FilterIntegrity

20

6.8.6Air/GasFiltration

20

6.8.7AsepticCompoundingandOtherPre-BFS

ProductSteriizationApproaches

21

6.8.8EnvironmentalMonitoring

21

BFSShuttleMachines

21

BFSRotaryMachines 22

6.8.9ExtrusionConsiderations 22

6.8.10Controls 22

6.8.11DownstreamProcess 22

6.9ProcessSimulation(MediaFill)forAseptic

FillingLines 22

6.9.1Design 22

6.9.2Interventions 23

6.10Gowning 24

6.11FacilityValidation 24

7.0QUALITYRISKASSESSMENT 24

7.1ProductContamination 25

8.0REFERENCES 26

9.0APPENDIXI:EXAMPLEOFAQUALITYRISK

ASSESSMENT 28

10.0APPENDIXII:ENVIRONMENTALPARTICLE

MONITORINGLEVELS 32

FIGURESANDTABLESINDEX

Figure3.1-1

Figure3.2-1

Figure3.2-2

Table5.1.3-1

Table5.1.5-1

Figure6.2-1

Table6.5-1

Table7.2-1

Table7.2-2

DiagrammaticRepresentationofthe

OpenParisonBFSProcess

4

RotaryBFSMachineSchematic

5

BFSProcessDetailforRotary

Machines

6

ParametersforAssessingPolymer

Selection

9

ContainerDesignConsiderations 10

Sterility-relatedProcessParameters

duringBFSOperations

15

MachineParameterTestSheet

Example

17

ExamplesofContamination

RiskTypesRelatedtoOperation 25

Equipment-relatedSourcesof

Contamination 26

Table

Table

Table

Table

Table

Table

Table

Table

9.0-1

9.0-2

9.0-3

9.0-4

9.0-5

9.0-6

9.0-7

10.0-1

SeverityScoringCriteria 28

ProbabilityofOccurrenceScoring

Criteria 28

LikelihoodofDetectionScoring

Criteria 28

RiskDecisionMatrix 28

RiskPriorityMatrix1-Severity×

Occurrence 29

RiskPriorityMatrix2-Severity×

Occurrence×Detection 29

QualityRiskAssessmentReport

Example 30

AirClassificationsandPrescribed

EnvironmentalParticleLevels 32

1.0Introduction

Blow-Fill-Seal(BFS)technologyistheintegrationofplasticblowmoldingandasepticfillingonasingle

machine.Thetechnologyhasbeenusedinmanufacturingliquidpharmaceuticalproductsincethe1960s.

Thefinalcontaineriscreatedwithinthemachinejustpriortoasepticfillingandhermeticallysealedimme-

diatelyafterfillinginonecontinuous,automatedoperation.ItprovidesauniquecombinationofHexibility

inpackagingdesignandenhancedsteriliryassuranceandhasbeenacceptedworldwideforbothasepticand

terminallysterilizedliquidproducts.BFStechnologyiscurrentlyusedinmorethan50countries(1-4).

Considered“advancedasepticprocessing,”BFStechnologyprovidesadvantagesoverconventionalfilling

whendesigningcontrolsfortheprocesses.Theadvancedasepticprocessingdesignationissupportedby

variousexperimentsthatchallengedBFSsystemsthroughcontaminationloadingofboththesurrounding

environmentandplasticcomponents(5).

BFSprocessingoffersanumberofotheradvantagesaswell.Itsupportsasimplifiedsupplychain,whichcan

resultinalevelofqualityandcontrolofprimarypackagingmaterials(i.e.,resinonly)thatisnotpractical

inpre-formed(glass,plastic,etc.)vial/stopperfilling.Andduetotherapidcool-downfollowingcontainer

formation,biologicalandprotein-basedproductscanbesafelyprocessedinBFSmachines.Theequipment

supportssingle-dosecontainerpackagingwithflexibilityforfrequentchangeoverifshortproductionrunsare

desired.BFSprocessingisalsocapableofincorporatingpre-moldedandpre-sterilizedcomponents(inserts)

inthebasiccontainer,suchassiliconestoppersforparenteralapplicationsandinjection-moldedtip/capin-

sertsformetereddropcontrolinmulti-doseeyedropcontainers.

1.1Purpose

TheobjectiveofthistechnicalreportistoproviderecommendationsspecifictotheoperationofBFStechnol-

ogyforthemanufactureofsterilepharmaceuticals(e.g.,ophthalmic,parenteral,andinhalation).Theintent

istoprovidesupplementalinformationtoassisttheuserwithinterpretationofinternationalstandardsand

regulatoryguidancefromtheperspectiveofBFSoperations.ConsiderationisgiventospecificaspectsofBFS

operationsnotcoveredinpublishedinformation.

1.2Scope

ThistechnicalreportaddressesconsiderationsforBFStechnologyrelatedtotheinstallationandoperation

ofthemachineryandevaluationofrelatedmaterialsandfinalproductcontainers.Supportareas,suchas

laboratory,solutioncompounding,gowningairlocks,etc.,arenotconsideredspecifictoBFSandarenotin-

cludedwithinthescopeofthisdocument.Thistechnicalreportisintendedasaguideforthepharmaceutical

industryandisnotmeanttosupplantorduplicateanyexistingregulatoryguidance.Thecontentandviews

expressedinthistechnicalreportaretheresultofaconsensusachievedbythemembersoftheauthorizing

TaskForceandarenotnecessarilytheviewsoftheorganizationstheyrepresent.

1.3BFSProcessOutline

BFStechnologyisapharmaceuticalprimarypackaging-fillingprocessthatcombinesthreeoperations(con-

tainerformation,filling,andclosure)thataretypicallyperformedseparatelyinconventionalfillingoperations.

BFScontainersareformedfromanextrudedthermoplasticparison,filledwithproduct,andthenscaledin

acontinuous,integrated,highlyautomatedoperation.Originallydevelopedforuseinotherindustries,BFS

technologyhasbeenadaptedforuseinthemanufactureofsterilepharmaceutical,medicaldevice,biological,

andveterinaryproducts.ThetwomostcommontypesofBFSmachinesaretheshurtlingmachine(openor

cutparison)andtherotarymachine(closedparison),whicharebothconsideredinthisdocument.Allsteps

oftheBFSprocessareconductedunderhighlyclassifiedconditionspercurrentregulatorystandards(1,2).

InBFSprocesses,athermoplasticpolymerisusedtoformtheprimarycontainer.Granulatedpolymer(plas-

ticpellets)issuppliedbyaclosedpathwayviavacuumtransfer.Thesystemfeedspolymerpelletsintoa

standardplastichotmeltextrusionprocess.Intheextrusionprocess,thepolymerisheatedtotemperatures

inexcessof170°Candsubjcctedtopressuresover20,000kPa(200bar).

Thetemperature,pressure,andencapsulationwithintheplasticintheextruderreducetheprobabilitythatanycontaminants(suchasparticulates,fungalandbacterialendospores,andendotoxins)maycomeincon-tactwiththefinalfilledproduct(6).

Theplasticpolymerisextrudedintooneormorecontinuousplastictubescalledparisons.Sterilefilteredairorothergasesaresuppliedthroughtheextruderheadatsufficientpressuretopreventtheparisonsfromcollapsing.TheBFSprocessusesoneofrwomechanicalmethodstoformthecontainer(s):1)vacuumonthemoldonly;or2)ablowingprocessincombinationwithvacuumonthemold.Vacuumisemployedwithbothmethodstoremoveairaroundthecontainertoaidincontainerformation.Containerslargerthan30mLtypicallyrequiretheadditionofblowingwithsterileairtocompletethecontainerformation.

Duringoperations,theliquidformulationissuppliedtotheBFSsystemthroughaclosed,sterileproductpathway.TheproductpathwayinBFSisaninherentlysafedesign.Itiscompletelyclosedandallproduct-contactsurfaces,includingthetank,hoses,filterhousings,fillsystem,andfilters(ifprovided,basedonprod-uctspecifications)aretypicallycleanedandsterilizedinplacebeforeproductionbegins.

Themostcommondosingmechanismistimepressuredosing(TPD).Otheracceptabledosingsystemsincludepumpsandpositivedisplacementsystems.Uponcompletionofthedosingstep,thetopportionofthemoldeithercloses(shuttlestyle)orrotatesintocompression(rotarystyle)tosealthecontainer(s)andcompletetheBFSprocess.

TherangeofproductsthatcanbefilledusingBFStechnologyincludessolutions,emulsions,suspensions,andlowandhighviscosityproducts,suchasgels,creams,andointments.

Typicalsolutionscanbeprocessedwithintegratedsterilefiltration.Suspensions,emulsions,andhighlyvis-cousproductscanbeprocessedwithrecirculationandwithoutterminalfiltrationwhereabulksterilizationprocessisimplemented.Inaddition,BFScontainerscanbeterminallysterilizedbysteamandothermethodswhenrequired.Certainlargemoleculeproductscannotbesterilefilteredorterminallysterilized,however,thusaseptictransferoftheproducttotheBFSmachineisrequired.

BFSmachineoutput(containersperhour)isdependentuponproductandpolymerphysicalcharacteristics,andcontainerdesign.Thenumberofcontainersproducedpercycleisonlylimitedbythenumberofcontain-ersthatcanbeformedbythemold.Thecycletimeisdependentupontheproductfllingcharacteristics(c.g,viscosity,foaming)andtheresin-dependentformationtimerequiredinmold.

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2.0GlossaryofTerms

AdvancedAsepticProcess

Aprocessinwhichdirectinterventionwithopenproductcontainersorexposedproductcontactsur-facesbyoperatorswearingconventionalcleanroomgarmentsisnotrequiredandneverpermitted(3).

AirShower

AdevicefittedtoaBFSmachinewhichprovides,ataminimum,acontinuousHowofGradeAqualityairsupplyoverthefillingneedlesandthepoint-of-fill.Theairshowerisalsoknownasanozzleshroudinshuttletypemachines.

CriticalProcessingZone

Thelocationwithintheasepticprocessingareainwhichproductandproductcontactsurfacesareex-posedtotheenvironment.TheCriticalProcessingZoneisdependentuponmachinedesignandin-cludes,butisnotnecessarilylimitedto,theparisonextrusionandcuttingarea,moldtransferarea,airshower,andpoint-of-fill.

2.1Abbreviations

BFSBlow-Fill-Seal

CIPClean-in-place

CClContainerclosureintegrity

EtOHEthylAlcohol

HDPEHighdensitypolyethylene

LDPELowdensitypolyethylene

Dynamic(inoperation)

BFSmachinelinefullyoperationalandfilling,withthenumberofallowedoperatingpersonnelpresentasduringnormalrunningconditions.

Mandrel

SpecializedfillingneedlesoncertainBFSmachineswhichalsoacttoformthecontainer.

Parison

The"tube"ofpolymerextrudedbytheBFSmachinefromwhichthecontainersareformed.

Static(atrest)

BFSmachinelinewithconveyorbeltsatrestbutwithairshowerandroomventilationinoperation,extruder(heated,notrunning)andmoldcarriageinstandby.Nooperatingpersonnelpresent(1,2).

ZoneofProtection/MachineShroud

AsystemfittedtoaBFSmachinetodirectaHowofHEPA-filteredairovertheCriticalProcessingZoneofthemachine.

LVP

PP

QbD

SIP

SVP

WFI

Largevolumeparenteral

Polypropylene

QualitybyDesign

Sterilization-in-place

Smallvolumeparenteral

Water-for-Injection

3.0BFSEquipment

ForbothshuttleandrotarytypeBFSmachines,thefillingmandrelsaretypicallycleanedpriortousewitha

clean-in-place(CIP)processfollowedbysterilization-in-place(SIP).Thefillingenvironmentismaintained

underGradeAconditionswithHEPA-orsterile-filteredoverpressureair(2).

3.1ShuttleTypeMachines(OpenParisonProcess)

Inanopenparisonprocess,aparisoniscontinuouslyformedthroughtheplasticextrusionprocess.Adown-

wardflowofsterilefilteredair(parisonsupportair)ispassedthroughtheparisontopreventthemolten

plastictubefromcollapsing.Othergases(e.g.,inertgases)canbesubstitutedfortheprocessairduringthe

BFSprocess.Thetwohalvesofamoldclosearoundtheparisontoformthebodyofthecontainer.Simul-

taneously,thenewlyformedcontainerinthemoldiscutfreefromtheparisonbya“knife.”Vacuumisthen

appliedtothemoldtobegincontainerformationandcontinuesuntilformationiscompleted.Figure3.1-1

illustratesanopenparisonBFSprocess.

Step1Parisonpositioning

Step2FilingmandreVnozleinsertion

andcontainerformation

Step3Containerfillingwithproduct

Step4Sealing

Step5Containerrelease

Figure3.1-1DiagrammaticRepresentationoftheOpenParisonBFSProcess

Onceformed,themoldisrapidlytransferred(shuttled)ashortdistancefrombeneaththeparisonheadintothefillingposition(Figure3.1-1,Step1).Thistransfertypicallytakeslessthanonesecond.Thefill-ingmandrel(fillingnozzle)isloweredintotheplastictube.Atthispoint,sterilefilteredairissuppliedtocompletecontainerformation,ifnecessary(blowingstep;Figure3.1-1,Step2).Subsequently,thecontainerisfilledwithameteredvolumeoftheproduct(Figure3.1-1,Step3).Duringtheliquidfil,headspacegasisdisplacedfromwithinthecontainer,eitherthroughthemandrelordirectlytotheambientatmosphere,dependingoncontainerconfiguration.Thefillingmandrelisthenraisedandtheuppersectionofthemold(head/sealmold)isclosed,hermeticallysealingandautomaticallyformingthestill-hotplasticabovethemainmold(Figure3.1-1,Step4).Theentiremoldassemblythenopens,releasingtheformed,filled,andsealedcontainer(Figure3.1-1,Step5).

Containerscanbedischargedfromthemachineassinglecontainers,"packs"ofseveralcontainers,orstripsofmultiplecontainers,dependingonproductrequirements.Afterdischarge,containersaremechanicallydefashed(i.e.,plasticwasteremoved)andseparared.Deflashingtypicallyoccursdirectlyafterdischargeofthecontainer.Thedefashingunitcanbeplacedinthecleanroom,directlyconnectedtothemold,orplacedoutsidethecleanroominthepackagingarea,justdownstreamoftheBFSfillingprocess,tominimizethepotentialforparticulategenerationinthecleanroom.Thismaydependontheresintypeusedandcontainerdesign.Defashingcanbedoneinthecleanroom,ifdesired,becausethecontainerisalreadyclosed.BFSisacontinuousprocesswithonecompletecycletypicallycompletedwithin10-20seconds,dependingoncontainerdesignandfill-volume.

3.2RotaryFillingMachines(ClosedParisonProcess)

BFStechnologycanalsobeappliedtoanoperationusingarotarysysteminwhichthecontainersareformedusingaclosedparisonprocess.Theforming,filling,andsealingofthecontainersintheclosedparisonprocessisidenticaltotheopenparisonprocess,exceptthatthereisnoparisoncuttingbetweeneachBFScycle.Rath-er,thecontainersemergeinacontinuousribbonandareseparatedafterbeingdischargedfromthemachine.Intheclosedparisonprocess,thepossibilityofenvironmentalcontaminationismarkedlyreduced.Eachmoldsetonthechainclosesontheparison,sealingthepreviouscontainerandforminganewcontainer.

RotaryBFSmachinesusemultiplematchedmoldsetsaffixedtotwochainsthatmoveincontinuousmir-rored,counter-rotatingloops.Withrotarytechnology,thefillingmandrelspassdirectlythroughtheextruderhead,asillustratedinFigure3.2.1.Duringcleaningandsterilization,thefillingmandrelsareretractedbackintotheextruderhead.

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Figure3.2-1RotaryBFSMachineSchematic

Theextruderformsacontinuoussingleovalparisonwhichisfedintotherotatingmoldmechanism.Themolds

andchainmoveatthesamespeedastheextrudedplasticparison.Sterileflteredairorothergasunderpositive

presureispassedintotheparisontopreventitfromcollapsing.Asthemoldsetsrotate,theyclosearoundthe

parisontubetoformnewcontainerbodiesandsealofftheprecedingsetofmoldedcontainers.Thecontainersare

formedwithinthemoldthroughvacuumonly.ThisprocessisillustratedinFigure3.2-2.

Toprotecttheproductfromtheheatpresentintheextruderhead,eachfillingmandrelisenclosedwithin

adouble-walledcoolingjacket.Inproduction,thefillingisperformedimmediatelyafterthecontaineris

formed.Duringliquidfilling,theheadspacegaswithinthecontainerisdisplacedbackintotheenclosed

parisonarea.Thecontainersarethendischargedfromthemachineinacontinuousstriporribbon.Typically,

theribbonofcontainersisthenmechanicallydeflashedandseparatedoutsidethefillingroom,accordingto

sterileprocessingguidance(2).Asinglemoldingandfillingcycle(step)takesapproximatelythreetofour

secondstocomplete.

3.3AdditionalApplications

OpenparisonBFSmachinedesignscanaccommodateinsertionofsecondarycomponents,suchasneedles,

rubberstoppers,andcontrolled-dropinserts,beforethecontainerissealed.Anysuchcomponentsshouldbe

sterilizedusingavalidatedprocesspriortoaseptictransferintotheBFSmachinethroughadecontaminated

isolator.Bagscontainingthesterilesecondarycomponentsneedtobedecontaminatedusingaqualifiedpro-

cessastheyaretransferredintotheisolator.

Avariationoftheshuttletypemachinepartitionsthefillingstepfromthesurroundingenvironment;blow-

ingandfillingactivitiestakeplaceattwoseparatestations.Thismachinevariationhasmultiplemoldsrotat-

ingonahorizontalplane.

SealingFilling

Figure3.2-2BFSProcessDetailforRotaryMachines

SomeBFSmachinesalsohaveco-extrusioncapability,whichenablesproductionofamulti-layercontainertoprovideparticularbarrierpropertiesaccordingtotheapplication(c.g.,tominimizevaporlossorpreventgasingress).

Areciprocatingsingle-moldvariation,basedontheclosedparisonrotarytechnology,alsoexists.Reciprocat-ingBFSmachinesuseasingle,verticallyreciprocating,matchedmoldsettoproduceacontinuousribbonoffinishedproduct.

Additionally,BFSmachinescanbeadaptedtoaccommodateheat-sensitiveproducts(e.g.,proteins,vaccines,biologics,andotherlargemolecules).Processvariablescanbemodifiedtoensurethatthereisnodegradationoftheproduct,suchasmodifyingthechilledwaterloopandcontrollingtheproducttemperature(chilling)priortoandafterfilling.Machineparameterscanalsobeadjusted,includingmodificationoffillsystems,toprovideadditionalcooling.

4.0Benefits&SpecialConsiderationsofBFSTechnology

ProperlydesignedandcontrolledBFStechnologyoperationscanofferadvantagesoverconventionalasepticprocessingandfillingoperations,asoutlinedinScction4.1.However,implementationofBFSoperationsrequiresacomprehensiveassessmentandunderstandingoftheprocesstoensuremanufacturingcompatibilitywithBFStechnology.TheseconsiderationsarepresentedinSection4.2.

TechnicalReportNo.77◎2017ParenteralDrugAssociation,Inc.◎2017ParenteralDrugAssociation,Inc.TechnicalReportNo.77

4.1Benefits

1.Durationofexposedproductandcontainer:IntheBFSprocess,thefinalcontainerisformedimmedi-

atelypriortofilling,filled,andsealedinacontinuousoperation,typicallyexposingtheopencontainer

forarelativelyshortdurationoflessthan10seconds.Theresultingbenefitmaybeariskreductionfor

viablemicrobialandforeignparticlecontaminationofproduct.

2.Containerprocessing:Theriskofforeignparticlegenerationduringproduction,processing,packag-

ing,andstorage/transportofglassvialsandrubberstoppersarereducedduetothedirectnatureofBFS

technologycontainerformationandsealingprocess.Inaddition,sincethefinalcontainerisformedjust

priortofilling,proceduresforlineclearancearesimplified.

3.Levelofautomation:BFSmachinesarehighlyautomated,reducingthenumberofoperationsandper-

sonnelrequired.Thereductionofpersonneandinterventionsreducesthepotentialforhumanerrorand

contaminationrisksresultingfromhumanintervention.

4.Machinerydesign:BFSmachinescanbedesignedwithairmanagementconfgurations(e.g.,critical

fill-zoneareashroudedunderacontinuousfowofpositive-pressure,sterilefilteredair),thusminimizing

theimpactandrisksposedbyhumanintervention.Afteranycriticalintervention,theproductpathway

issteamsterilized-in-placebeforeasepticfillingisresumed.

5.Manufacturingspace:BFSprocessdesignallowsforreducedspacerequirementssincethecriticalfill

zoneresideswithintheBFSmachine.TheBFSprocessdoesnotrequirewashing,depyrogenation,cool-

ing,accumulation,filling,stoppering,orcappingstations.

6.Materialsupplychain:BFSreducesthenumberofsuppliersandlogisticsofmaterialsupply,forprimary

packagingrawmaterials,anditprovidesaddedcontrols.ForBFS,theresinsupplieristheonlyprimary

packagingrawmaterialvendorinthesupplychainforthecontainerformedintheBFSprocess.

4.2SpecialConsiderations

1.Processingtemperature:Containersareformedatelevatedtemperarures.Producttemperaruresensitiv-

ityshouldbeconsideredwhendesigningtheprocess.Processparametersandequipmentmayberequired

tominimizehightemperatureimpacttotheproduct.

2.Containermaterialpermeability:PlasticsusedtoformBFScontainersmaybepermeabletogasor