1、BRITISH STANDARD BS EN 13311-4:2001 Biotechnology Performance criteria for vessels Part 4: Bioreactors The European Standard EN 13311-4:2001 has the status of a British Standard ICS 07.080 NO COPYING WITHOUT BSI PERMISSION EXCEPT AS PERMITTED BY COPYRIGHT LAWBS EN 13311-4:2001 This British Standard,
2、 having been prepared under the direction of the Sector Committee for Materials and Chemicals was published under the authority of the Standards Committee and comes into effect on 15 May 2001 BSI 05-2001 ISBN 0 580 37600 1 National foreword This British Standard is the official English language vers
3、ion of EN 13311-4:2001. The UK participation in its preparation was entrusted to Technical Committee CII/ 58, Biotechnology, which has the responsibility to: A list of organizations represented on this committee can be obtained on request to its secretary. Cross-references The British Standards whic
4、h implement these international or European publications may be found in the BSI Standards Catalogue under the section entitled “International Standards Correspondence Index”, or by using the “Find” facility of the BSI Standards Electronic Catalogue. A British Standard does not purport to include al
5、l the necessary provisions of a contract. Users of British Standards are responsible for their correct application. Compliance with a British Standard does not of itself confer immunity from legal obligations. aid enquirers to understand the text; present to the responsible European committee any en
6、quiries on the interpretation, or proposals for change, and keep the UK interests informed; monitor related international and European developments and promulgate them in the UK. Summary of pages This document comprises a front cover, an inside front cover, the EN title page, pages 2 to 10, an insid
7、e back cover and a back cover. The BSI copyright date displayed in this document indicates when the document was last issued. Amendments issued since publication Amd. No. Date CommentsEUROPEANSTANDARD NORMEEUROPENNE EUROPISCHENORM EN133114 March2001 ICS07.080;07.100.01 Englishversion BiotechnologyPe
8、rformancecriteriaforvesselsPart4: Bioreactors BiotechnologieCritresdeperformancedesrcipients Partie4:Bioracteurs BiotechnikLeistungskriterienfrBehlterTeil4: Bioreaktoren ThisEuropeanStandardwasapprovedbyCENon4February2001. CENmembersareboundtocomplywiththeCEN/CENELECInternalRegulationswhichstipulate
9、theconditionsforgivingthisEurope an Standardthestatusofanationalstandardwithoutanyalteration.Uptodatelistsandbibliographicalreferencesconcernings uchnational standardsmaybeobtainedonapplicationtotheManagementCentreortoanyCENmember. ThisEuropeanStandardexistsinthreeofficialversions(English,French,Ger
10、man).Aversioninanyotherlanguagemadebytra nslation undertheresponsibilityofaCENmemberintoitsownlanguageandnotifiedtotheManagementCentrehasthesamestatusasthe official versions. CENmembersarethenationalstandardsbodiesofAustria,Belgium,CzechRepublic,Denmark,Finland,France,Germany,Greece, Iceland,Ireland
11、,Italy,Luxembourg,Netherlands,Norway,Portugal,Spain,Sweden,SwitzerlandandUnitedKingdom. EUROPEANCOMMITTEEFORSTANDARDIZATION COMITEUROPENDENORMALISATION EUROPISCHESKOMITEEFRNORMUNG ManagementCentre:ruedeStassart,36B1050Brussels 2001CEN Allrightsofexploitationinanyformandbyanymeansreserved worldwidefo
12、rCENnationalMembers. Ref.No.EN133114:2001EPage2 EN133114:2001 Contents Page Foreword 3 Introduction 4 1 Scope 4 2 Normativereferences. 4 3 Termsanddefinitions 4 4 Hazards . 4 5 Performanceclasses . 4 6 Classificationandverificationofperformance 5 7 Markingandpackaging 5 8 Documentation . 5 AnnexA(in
13、formative)Guidanceontestmethodsfordetermining leaktightnessofbioreactors. 6 AnnexB(informative)Typicalhazardsandpreventivemeasures 7 Bibliography. 10Page3 EN133114:2001 Foreword ThisEuropeanStandardhasbeenpreparedbyTechnicalCommitteeCEN/TC233 “Biotechnology“,thesecretariatofwhichisheldbyAFNOR. ThisE
14、uropeanStandardshallbegiventhestatusofanationalstandard,eitherby publicationofanidenticaltextorbyendorsement,atthelatestbySeptember2001,and conflictingnationalstandardsshallbewithdrawnatthelatestbySeptember2001. ThisEuropeanStandardhasbeenpreparedunderamandategiventoCENbythe EuropeanCommissionandthe
15、EuropeanFreeTradeAssociation. ThisstandardisoneofaseriesofEuropeanStandardsconcernedwithperformancecriteria forvessels.Thesestandardsare: EN133111, BiotechnologyPerformancecriteriaforvesselsPart1:Generalperformance criteria. EN133112, BiotechnologyPerformancecriteriaforvesselsPart2:Pressureprotectio
16、n devices. EN133113, BiotechnologyPerformancecriteriaforvesselsPart3:Glasspressure vessels. EN133114, BiotechnologyPerformancecriteriaforvesselsPart4:Bioreactors. EN133115, BiotechnologyPerformancecriteriaforvesselsPart5:Killtanks. EN133116, BiotechnologyPerformancecriteriaforvesselsPart6:Chromatogr
17、aphy columns. AnnexesAandBareinformative. Thisstandardincludesabibliography. AccordingtotheCEN/CENELECInternalRegulations,thenationalstandardsorganizations ofthefollowingcountriesareboundtoimplementthisEuropeanStandard:Austria,Belgium, CzechRepublic,Denmark,Finland,France,Germany,Greece,Iceland,Irel
18、and,Italy, Luxembourg,Netherlands,Norway,Portugal,Spain,Sweden,SwitzerlandandtheUnited Kingdom.Page4 EN133114:2001 Introduction UseofthisEuropeanStandardwillaidtheequipmentmanufacturerintheclassificationof bioreactorswithregardtosafeperformanceinbiotechnologicalprocesses.Theclassification iseasilyun
19、derstandableandreadilyutilizablefortheuserandtheregulatoryauthorities. 1 Scope ThisEuropeanStandardspecifiesperformancecriteriaforbioreactorsusedin biotechnologicalprocesseswithrespecttothepotentialhazardstotheworkerandthe environmentfrommicroorganismsinuse. ThisEuropeanStandardapplieswheretheintend
20、eduseofbioreactorsincludeshazardous orpotentiallyhazardousmicroorganismsusedinbiotechnologicalprocessesorwhere exposureoftheworkerortheenvironmenttosuchmicroorganismsisrestrictedforreasons ofsafety. 2 Normativereferences ThisEuropeanStandardincorporatesbydatedorundatedreference,provisionsfromother p
21、ublications.Thesenormativereferencesarecitedattheappropriateplacesinthetextand thepublicationsarelistedhereafter.Fordatedreferences,subsequentamendmentstoor revisionsofanyofthesepublicationsapplytothisEuropeanStandardonlywhen incorporatedinitbyamendmentorrevision.Forundatedreferencesthelatestedition
22、ofthe publicationreferredtoapplies(includingamendments). EN133111:2001 BiotechnologyPerformancecriteriaforvessels Part1:Generalperformancecriteria 3 Termsanddefinitions Forthepurposesofthisstandard,thetermsanddefinitionsgiveninEN133111:2001apply. 4 Hazards Typicalexamplesforpotentialhazardsofbioreac
23、torsandrecommendationsforproper designandhandlingareincludedinannexB. 5 Performanceclasses Thebioreactorsshallbeclassifiedforleaktightness,cleanabilityandsterilizabilityin accordancewith5.1to5.4ofEN133111:2001. Theselectionoftheappropriateclassforperformanceofabioreactorshallbemadein accordancewith5
24、.5ofEN133111:2001.Page5 EN133114:2001 6 Classificationandverificationofperformance 6.1 General Thebioreactorsshallconformtothegeneralrequirementsgivenin6.1ofEN133111:2001. Ifthecomponentsareclassified,theusingofanindirecttestmethodtotheassembled bioreactorissufficientforclassification. Ifthebioreact
25、orismadebyassemblyofcomponents,itshallbetestedtoverifyitsoverall classification. NOTEEN12460providesguidanceonselectionandinstallationofequipment relevanttobioreactors. 6.2 Leaktightness Thebioreactorshallconformtotherequirementsgivenin6.2ofEN133111:2001. Ifthebioreactorcontainsmicroorganismsforwhic
26、hthereleaseshallbeminimized,risk analysisshallindicatewhethertheoffgashastobetreated.Ifthebioreactorcontains microorganismsforwhichthereleaseshallbeprevented,theoffgasshallbetreated. GuidanceontestmethodsfordeterminingleaktightnessofbioreactorsisgiveninannexA. 6.3 Cleanability Thebioreactor shallcon
27、formtotherequirementsgivenin6.3ofEN133111:2001. 6.4 Sterilizability Thebioreactorshallconformtotherequirementsgivenin6.4ofEN133111:2001. 7 Markingandpackaging Thebioreactorshallconformtotherequirementsgiveninclause7ofEN133111:2001. 8 Documentation Thebioreactorshallconformtotherequirementsgivenincla
28、use8ofEN133111:2001.Page6 EN133114:2001 AnnexA (informative) Guidanceontestmethodsfordeterminingleaktightnessofbioreactors AlistoftestmethodsforleaktightnessisgivenintableA.1ofEN12298(see13).Fromthat listsuitabletestmethodstothetestingofbioreactorsaregivenintableA.1. TableA.1Suitablealternativeleakt
29、ightnesstestmethodsforbioreactors Number Testmethod 1 Pressurelossgas/air 2 Pressurelossliquid 3 Heliumprobe 4S F 6 ,e.g.Freon a probe 5 Thermalconductivity 6 Ultrasonics 8 Tracerliquiddyes 10 Bubbleformation(onlyqualitative) 11 Electronicparticlecounting 12 Traceraerosol(NaCl) 13 Productaerosol(non
30、microbial) 14 Qualitativebioaerosolmonitoring 15 Quantitativebioaerosolmonitoring 16 Surfaceswabbing 17 Surfaceconductivity 18 Visualinspection(onlyqualitative) 19 Bacteriatightness NOTERestrictiveuseofSF 6shouldbeconsideredduetoenvironment protection a Freonisanexampleofasuitableproductavailablecom
31、mercially.This informationisgivenfortheconvenienceoftheuserofthisStandardand doesnotconstituteanendorsementofCENoftheseproducts.Page7 EN133114:2001 AnnexB (informative) Typicalhazardsandpreventivemeasures B.1 General Cleaningaswellassterilizationisfacilitatediftherearenodeadorstagnantareasinall equi
32、pmentincludingpipework,whichpreventsselfdraining.Afterdrainingstagnantareas withadepthofnotmorethan5mmorinpipingdeadlegslessthan2timestheinternalpipe diametersareconsideredasnotpreventingcleaningandsterilization. Anyopeningorcreviceinthesurfaceofthematerialincontactwiththeprocessfluidcan preventclea
33、ningandsterilizationiftheirshapedoesnotallowgoodcleaningagent penetrationandrinsingaswellassteampenetration. Itisgoodpracticetoperformmaintenanceonthebioreactoronlyafterapplicationof appropriatetargetmicroorganismreductionprocedures,thatcanbecleaninginplaceor sterilizationofthewholesystem. B.2 Backf
34、lowoftargetmicroorganisms Backflowoftargetmicroorganismfromthebioreactorintovesselsorcontainersusedfor additionsduringcultivation(forexamplevesselsforadditionoffeed,acid,alkali,antifoamor nutrient)shouldbepreventedforexamplethroughtheuseofnonreturnvalveor overpressure. B.3 Malfunctioningofsteamtraps
35、 Theeffectiveoperationofsteamtrapsduringsterilizationisoneofthecriticalrequirements ofeffectivesterilization.Properdesignforoperationandaccessibilityduringmonitoringare recommended. B.4 Hazardsassociatedwithcouplings,valvesandpipes Improperusageisahazardassociatedwithcouplings.Ifapplicableweldingins
36、teadof couplingscanimprovecleanability,sterilizabilityandleaktightnessandthereforeminimize therisks.PerformanceofcouplingsaredescribedinEN133122(see5). Reinforcedflexibletubes(e.g.metalmantled)canwithstandpressureencounteredduring normalsterilization.Ifapplicablebendingispreferable,automaticweldingi
37、spreferableto improvecleanability.PerformanceoftubesandpipesaredescribedinEN133124(see6). B.5 Leakagethroughvalves Stemsofvalvescanbeespeciallywellsealed,forexamplebyusingbonnetpackingringsor Oringsorbyincorporatingastaticmembranebetweenstemandvalvechamber. PerformanceofvalvesisdescribedinEN133125(s
38、ee7).Page8 EN133114:2001 B.6 Leakagethroughseals Sealsarerequiredforprimarycontainmentwhereshaftspassthroughthewallofthe bioreactor,likestirrershafts,samplingdevices,probefittingsandallotherfittings.Ifsealsor gasketsareclosetotheproductsidepossibilityofcreatingcrevicesisreduced.Orings shouldbeusedas
39、staticsealsbetweennonmovingsurfaces. Appropriatesealsforrotatingstirrershaftarelipsealsormechanicalseals.Theprobability ofleakagecanforexamplebereducedbyusingadoublemechanicalsealwithan overlayingsealingfluidwhichiskeptatahigherpressurethanthemedium.Inspecificcases theneedforsuchsealscanbeovercomeby
40、theuseofmagneticcouplings.However, aspectslikesterilizabilityandcleanabilityshouldbeconsideredwithcare.Anothersolution canbetheuseofforexampleairliftfermenters.Insuchcasesoffgastreatmentshouldbe properlyconsidered. Byadditionofdisinfectantstothesealingfluidormaintenanceofadequatehigh temperaturesmic
41、roorganismspenetratingthesealafterbreakagecanbeinactivated.To controltheintegrityofthesealaleveltransmitterorapressureindicatorandalarmsystem canbeinstalledintothecircuitsystem.PerformanceofsealsisdescribedinEN12490 (see8). B.7 Releaseofmicroorganismsthroughoffgassystems Treatmenttominimizeleakageca
42、nincludetheuseofsuitablecentrifugalseparators(for examplecyclones).Treatmenttopreventleakagecanincludeheattreatmentoftheoffgas stream,orpassagethroughsuitablefilters(forexampledepthfiltersorhydrophobic membranefilters).Considerationcanbegiventotheuseoftwofiltersinseriesincaseof failureoftheprimaryfi
43、lter.PerformanceofoffgassystemsisdescribedinEN13095 (see9). B.8 Releaseofmicroorganismsbyfoaming Excessivefoamingcanbeamajorhazardinbioreactoroperation.Microorganismscanbe releasedbyfoamleavingthebioreactororfoamcanblockexhaustfilters.Blockedexhaust filterscancauseoverpressureinthebioreactor. Wheref
44、oamformationislikely,suitablemeansforcontrollingofthefoamshouldbeputinto place.Suchmeasurescaninclude: theuseofmechanicalfoambreakers; foamprobewithantifoamagentaddition; theuseofcentrifugalseparator,linkedtoafoamprobe; highlevelalarmfoamprobeandshutoffvalveintheexhaustairducttogetherwith reductionofaerationrate; reducedbioreactor
