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Health and Safety Executive
The large-scale contained use of biological agents
This is a free-to-download, web-friendly version of The large-scale contained use of biological agents (First edition, published 1998). This version has been adapted for online use from HSE’s current printed version.
ISBN 978 0 7176 1544 5 Price £8.50
Thispublicationprovidesadviceandinformationongoodpracticeinthelarge-scaleuseofmicro-organisms.Itisintendedtosupplementtheguidancegivenin‘Categorisationofbiologicalagentsaccordingtohazardandcategoriesofcontainment’.
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© Crown copyright 1998
Firstpublished1998
ISBN9780717615445
Allrightsreserved.Nopartofthispublicationmaybereproduced,storedinaretrievalsystem,ortransmittedinanyformorbyanymeans(electronic,mechanical,photocopying,recordingorotherwise)withoutthepriorwrittenpermissionofthecopyrightowner.
Applicationsforreproductionshouldbemadeinwritingto:TheOfficeofPublicSectorInformation,InformationPolicyTeam,Kew,Richmond,SurreyTW94DUore-mail:[email protected]
ThisguidanceisissuedbytheHealthandSafetyExecutive.Followingtheguidanceisnotcompulsoryandyouarefreetotakeotheraction.Butifyoudofollowtheguidanceyouwillnormallybedoingenoughtocomplywiththelaw.Healthandsafetyinspectorsseektosecurecompliancewiththelawandmayrefertothisguidanceasillustratinggoodpractice.
Front cover photograph shows a fermenter operating at Containment Level 3. Source: Centre for Applied Microbiology and Research (CAMR)
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Health and Safety Executive
ContentsPreface 5Introduction 7Healthandsafetylegislation 7Purposeofguidance 8
Management systems 9Healthandsafetymanagement 9Qualitymanagement 10Training 10Safeworkingprocedures 10Permit-to-workprocedures 11Plantandprocessmodificationprocedures 11Emergencyprocedures 12Emergencyplanning 12Spillageprocedure 15
Primary containment - fermentation systems for use with biological agents 16Generallayoutdesignparameters 18Fermentersystemcontainment 18Pipework 18Couplings 19Staticseals 20Valves 22Pressurereliefsystems 23Agitatorseals 24Inletairtreatment 26Exhaustairtreatment 26Fermenteroperatingpressure 30Seedsystemsandinoculation 31Samplingsystems 32Measurementprobes 34Additionsystems 35Downstreamprocessing 36
Secondary containment - process rooms and buildings (contained areas) 38Separationoforganismsfromtheenvironment 38Restrictedaccess 39Biohazardsigns 39Internalroomoperatingpressure 39Ventilationandroomairfiltration 41Entrance,exitandchangingareas 41Fumigation 42Personnelwashingarrangements 43Spillagecontainment 43Materialsusedinbuildingconstruction 44
Personal protection 45Lockers 45Overalls,gownsandhats 45Frequencyofchange 45Personalprotectiveequipment(PPE) 45
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Smoking,eating,drinking,cosmeticsandmedicines 46Respiratoryprotectiveequipment 46
Appendices1 Classificationofbiologicalagents 482 Generalcharacteristicsandstandardsforthelarge-scaleuseof micro-organisms 493 Engineeringstandardsinbiotechnologyindustries 54
References 55
Further information 56
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PrefaceThispublicationisintendedtoprovideadviceandinformationongoodpracticeinthelarge-scaleuseofmicro-organisms.ItisintendedasasupplementtoguidanceontherequirementsoftheControlofSubstancesHazardoustoHealthRegulations1994(COSHH),whichcanbefoundintheAdvisoryCommitteeonDangerousPathogen’spublicationCategorisation of biological agents according to hazard and categories of containment.1
Themainfocusofthispublicationistoprovideadviceonsafestandardsofoperationforthelarge-scaleuseofbiologicalagentsinHazardGroups2,3and4.ItisnotprincipallyaimedatthosewhowishtouseHazardGroup1agents.Bydefinitionthesearestillpotentiallyhazardous,forexampletheymaybeallergenicand/ortoxicandtherefore,whereappropriate,referencewillbemadetosuchuses.Italsodoesnotseektoprovideadviceontheuseoflow-riskorganismswhichfalloutsidethedefinitionofabiologicalagent,althoughforthesakeofcompleteness,referencestosuchagentsaremadeinthetextandappendices.
Becauseofthegreatdiversityoftheindustrieswhichusebiotechnologyandtheiracceptedmodesof‘goodpractice’,apublicationsuchasthiscannotcoverindetailalltheacceptedprocessingstandards.Appropriatestandardsarebeinggatheredtogetherforeachsectorintheformofgoodmanufacturingpractice(GMP)guidelines.*Someofthesewillbequotedbutitmustberememberedthattheyareprimarilyconcernedwiththemaintenanceofproductqualityratherthanhealthandsafety.
Appendix1ofthisguidancesetsoutdefinitionsoftheclassificationofbiologicalagentsintofourhazardgroups.
Appendices2and3areincludedwiththeguidanceforinformationonly.ThetableswereoriginallydevelopedfortheEuropeanCommissionaspartofamajorsurveyofalltheimportantindustrysectorswhichusebiotechnology.2
ManyoftheindustrysectorsdonotuseorganismswhicharebiologicalagentswithinthemeaningoftheCOSHHRegulations.Thepracticesshownforeachsectorwillthereforebeappropriatefortheorganismsusedandwillnotnecessarilyapplytotheuseofbiologicalagents.
Appendix2givesasummaryoftheindustrycharacteristicsonasectorbasisandshowsaconsensusviewonsubjectssuchasbuildingconstruction,fermentationsystems,personnelprotectionandrestrictions.
Appendix3summarisesengineeringstandardsonanindustrysectorbasis.Itcoversvalve,pipeworkandbuildingstandardsandshowsindustrynorms.
*Inthecontextofthisguidance,thetermGMPmeansgoodmanufacturingpractice,notgood
microbiologicalpractice.
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Amoderncomputercontrolledcontainedfermenter
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Introduction1 Modernbiotechnologyasweknowit,likemostothercurrenttechnologies,hasdevelopedduringthenineteenthandtwentiethcenturies.Itisbasedinawiderangeoftraditionalindustries,manyofwhichhaveexistedinoneformoranotherforthousandsofyears.Thesetraditionalprocessesenabledproductsliabletoquickspoilage,whichwereoftenseasonal,tobeconvertedintostableandstorableproductsforuseintheleanermonths.
2 Non-pathogenicmicro-organismsarewidelyusedinanumberofmajorindustrysectors,foods,drinks,wastetreatmentandthelarge-scaleproductionofantibiotics.Theyinvolvemicro-organismswithlonghistoriesofsafeuse.
3 Theuseofmicro-organismswithsomeknowncapacitytocauseillhealth,eitherbyinfection,allergicresponseortoxicity,hasalsodevelopedinrecentyears,forexample:
n theproductionofcitricacidusingAspergillusspecies(forexampleAspergillus niger)whichhaveaknownpotentialtocauseallergicresponseand,morerarely,infection;
n thelarge-scalemanufactureofindustrialenzymesforenzymaticwashing powderswhichcancausesensitisationandallergicresponses.
4 Thefirstsuccessfulvaccines,basedontheuseofpathogenicorganisms,weremademorethan100yearsago.Methodshadtobedevisedforthisworktobecarriedoutsafely.Whatwerefertoascontainmentmethodologyhasdevelopedfromthis.
5 Developmentsinmolecularbiologyhaveledtoanumberofnewtechniques,includinggeneticmodification.Thishasallowedmicro-organismstobetailoredtoperformspecificfunctions,ratherthanrelyingontraditionalmethodsofmutationandstrainselection.
Health and safety legislation
6 EuropeanCouncilDirective90/679/EEC,nowimplementedinSchedule9oftheCOSHHRegulations1994,isconcernedwiththeprotectionofworkersfromrisksrelatedtoexposuretobiologicalagentsatwork.Assuchitencompassesmicro-organismswhicharenaturallyoccurring,orresultfromaconventionalstrainselectionprogrammeoraregeneticallymodified.TheDirectivealsoincludestheuseofrelevantcellculturesandhumanendoparasites.
7 ItshouldbenotedthattheDirectiveandthenationallegislationarisingfromit,donotdifferentiatebetweentraditionalandgeneticallymodifiedorganisms.Bothareconcernedonlywiththeriskstoworkerswhichmightariseduetoinfectionordiseasecausedbyexposuretobiologicalagentsincludingallergenicandtoxiceffects.Allthesefactorsmustbetakenintoaccountwhendesigningsafe,large-scaleplant,buildingsandsystemsofworksuitableforusewithsuchagents.
8 Theuseofanybiologicalagentwhichisalsoageneticallymodifiedorganism,requirescompliancewith:
n COSHH1994;n GeneticallyModifiedOrganisms(GMO)(ContainedUse)Regulations1992;n GeneticallyModifiedOrganisms(GMO)(ContainedUse)(Amendment)
Regulations1996.
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9 ManagementofHealthandSafetyatWorkRegulations1992(MHSW)andotherrelevantlegislationalsoapplytoanyworkwithbiologicalagents.
Purpose of guidance
10 ThisguidanceprovidesanamplificationofPartsIIandIIIinSchedule9ofCOSHHandtheassociatedguidancefromtheAdvisoryCommitteeonDangerousPathogens(ACDP).ItalsodrawsonguidanceproducedontheadviceoftheAdvisoryCommitteeonGeneticModification(ACGM).
11 Itisdividedintofourmainsections:
n managementsystems;n primarycontainment-fermentationsystemsforusewith
biologicalagents;n secondarycontainment-processroomsandbuildings(containedareas);n personalprotection.
12 Forthepurposesofthispublicationthemodelusedwillrelatetothepharmaceuticalandalliedindustries’conceptofsterilefermentationwhichalthoughitemploysmainlylow-riskorganisms,doesusehighercontainmentlevelorganismsinHazardGroups2,3and4foraverysmallproportionofitsproducts.Containmentathigherlevelsisalsousedbytheenzymeindustrywhichlargelyfollowssimilarpractice.
13 Itisemphasisedthatthepharmaceuticalindustryconceptisnottheonlywayofcarryingoutlarge-scalefermentationathighercontainmentlevels.Uptonow,however,noothermajorindustrysectorapplicationshavebeendevelopedanditisthereforenotpossibletogivepragmaticandprovenguidanceusingdifferentconcepts.Thiswillnotnecessarilycontinueinthefutureandtheguidancemayberevisedasnecessarytoincorporatenewtechniquesandnewapplications.
14 TheguidanceisbasedprimarilyonContainmentLevel2,wheretraditionallywordssuchas‘minimise’and‘optional’havebeenused.Becausethisistheareaofgreatestuncertainty,theguidancewillattempttoprovidepracticaladvicebyexpansionoftheconceptsbehindtheuseofthesetermsinthelegislation.Aseachsectionisdiscussed,theadditionalrequirementsforContainmentLevels3and4willbeintroducedasnecessary.
15 WhereapplicationsarebeingdesignedfortheuseofHazardGroup4biologicalagentstherequirementsarespecialised.AlthoughgeneralguidanceparameterscanbeindicatedandattentiondrawntothedifferencesbetweenContainmentLevel3facilitiesandthoseatContainmentLevel4,thisguidancecannotberegardedasofferingexhaustiveinformationonthedesignofaLevel4installation.Theinformationnecessaryforsuchaprojectcanonlybefinalisedafteradetailed,in-depthengineeringstudyandriskassessmentcarriedoutjointlybytheprospectiveuserandtheregulatoryauthorities.
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Management systemsHealth and safety management
16 ThemanagementofhealthandsafetyisageneralrequirementoftheHealthandSafetyatWorketcAct1974(HSWAct)and,morerecently,theManagementofHealthandSafetyatWorkRegulations1992(MHSW).Itisveryimportant,insituationswherematerialsbeinghandledcanpresentahazardtohumanhealthandsafety,thatsoundmanagementsystemsareinforceandthattheyaremonitoredandauditedregularly.
17 Therequirementistoprovideahealthyandsafeplaceofwork,so far as is reasonably practicable.Thisinvolvesusingsystemsofworkwhichresultfromdetailedexaminationofeachtask,identifyingthehazardsandassessingtherisks,inordertodefinesafemethodsandtoensurethathazardsareeliminatedorrisksminimised.
18 Employersmusthaveahealthandsafetypolicy(Section2(3)HSWAct)andwhentheyhavefiveormoreemployeestheymustrecordtheirarrangementsforhealthandsafety(regulation4,MHSW).Theorganisationofhealthandsafetyshouldincludedetailsofthemanagementstructureandindividualresponsibilities,togetherwithemployeeinvolvementandresponsibilities.Itshouldmakeprovisionforeffectivecommunicationanddocumentationofhealthandsafetymattersandshouldensurethatallpersonnelareprovidedwithsuitableinformation,instructionandtraining.
19 Themanagementsystemshouldensurethatthereareadequatemeasurestoassesssafetyperformanceandthatthesystemisregularlyaudited,preferablybypersonsindependentoftheactivityconcerned.
20 Employershaveadutytoconsultemployeesonhealthandsafetymatters.TheSafetyRepresentativesandSafetyCommitteesRegulations1977,asamended,requireemployerstoconsultsafetyrepresentativesappointedbyanytradeunionswhichtheyrecogniseand,ifrequested,setupasafetycommittee.UndertheHealthandSafety(ConsultationwithEmployees)Regulations1996,employersmustconsultanyemployeesnotcoveredbythe1977Regulations.FurtherinformationanddetailsofadditionalguidancecanbefoundinthefreeleafletConsulting employees on health and safety: A guide to the law.3
21 Dependingonthetypeofoperationandthecircumstancesoftheuseofabiologicalagent,itmaybeprudenttosetupabiologicalsafetycommittee.Theprecisewayinwhichsuchacommitteeisintegratedwithothercommitteesshouldbeappropriateandbedeterminedfortheparticularcircumstances.WorkusinggeneticallymodifiedagentsnormallyrequiresoversightbyaGeneticModificationSafetyCommittee(GMSC)inaccordancewithregulation11oftheGMO(ContainedUse)Regulations1992,toadviseonriskassessment.FurtherguidanceontheestablishmentandrunningofaGMSCmaybefoundintheACGMCompendium of guidancewhichisavailablefromtheACGMSecretariat,HealthDirectorate,RoseCourt,2SouthwarkBridge,LondonSE19HS.
22 Wherethedecisionistakentoformacommittee,itshouldbechairedpreferablybysomeonewhoiscompetentintheworkandwhohasaccesstothepersonwithoverallresponsibilityforhealthandsafetywithintheorganisation.Thisaccessshouldbeavailablefortheconsiderationofseriousitemsandforanyneedtoresolveoutstandingissueswherethedecisioncannotbemadeatcommitteelevel.
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23 Itisrecommendedthatthecommitteeshouldconsistofrepresentativesofmanagementwithresponsibilityforsuchwork.Thereshouldalsobeanequalnumberofpersonselectedbytheworkers.Itisalsorecommendedthattheagendaandminutesofthecommitteeshouldbeavailableforallemployeestosee.
Quality management
24 TheBritishStandard5750:1987Part0hasbeensupercededby:
n BSENISO9000-1:1994,whichdealswiththeprincipleobjectivesand characteristicsofaqualitymanagementsystem.4
n BSENISO9004-1:1994goesontoconsiderorganisationalgoals,meetingbothcompanyandcustomerneeds,risks,costsandbenefits,managementresponsibilities,thequalityloopsystem,thestructureanddocumentationofaqualitysystem,provisionsforauditandreview,procurementandproductionprocedures.5
25 Theseaspectsofqualitymanagementshouldformpartoftheprocedureswhichcontroltheindustrialapplicationofbiotechnology.Althoughnotmandatory,itisrecommendedthatwherepossibleconformitywiththesestandardsshouldformpartoftheoverallmanagementsystemobjectivesforprocessesinvolvingbiotechnology.
Training
26 Thereistheneedtoensureaclearunderstanding,byallemployees,ofanyidentifiableriskstotheirhealthandsafetyarisingfromworkandtheactionstobetakenindealingwithsituationsinwhichexposuremayoccur.COSHHrequiresthatallemployeesmustreceivesuitableandsufficientinformation,instructionandtrainingontherisksandprecautionstobetaken.UndertheMHSWRegulations,employeesmustreceivecomprehensiveandrelevantinformationontherisks,theirpreventionandthepreventativemeasuresavailable.Employeesmustalsoreceiveadequatehealthandsafetytrainingatalevelwhichwillensurecompetenceintheirwork.Trainingshouldbegivenbeforetheoperativeisallowedtocommencedutiesinthecontainedarea.Itshouldbedocumentedinthepersonalrecordsoftheindividualandbesignedoffbyboththetrainerandthetrainee.
Safe working procedures
27 Whileahealthandsafetypolicystatementmaydealonlyingeneraltermswithanemployer’sintenttodevelopandmaintainasafeworkingenvironment,itcouldalsomakereferencetomorespecificinformationonsafeday-to-dayworking.Thisshouldbecontainedinlocalcodesofpracticeorsafeworkingprocedures.Employershavearesponsibilitytomakethepolicyandcodesfreelyaccessibletoanyperson(whetherornothisemployee)whocarriesoutworkinrelationtotheemployers’duties,eitherbyputtingthemondisplayorbyindividualissue.Alloperationsshouldbecarriedoutaccordingtoagreedsafeworkingprocedures.Informationandinstructionsrelatingtosafepracticesshouldformpartofsuchprocedures.Thestepstodefiningasafesystemofworkare:
n assesseachtask;n identifythehazardsandassesstherisks;n definesafeworkingmethods;n implementthesystem;n monitorthesystem.
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Permit-to-work procedures
28 Aformalpermit-to-workprocedureisawelltestedandeffectivewayofensuringthatasafesystemofworkisinplacetocarryoutengineeringmaintenanceandothernon-productionactivitiesrelatedtobiologicalprocesses.Thekeyfeaturesofsuchaprocedureareasfollows.
n Awrittenpermit-to-work,signedbyadesignatedresponsibleperson,whohascarriedoutariskassessmentoftheworkareaandtheworkproposed.Thisconstitutesaformalauthorisationfortheengineeringwork,whichitdescribes,tobecarriedout.Theworkshouldbecompletedinthemannerdescribed,usingthesafetyprecautionsdetailed,bytherecipientorbypersonsunderhiscontrol.
n Personsappointedtopositionswhichinvolvetheminpermit-to-worksystemsshouldhaveadequateknowledge,experienceandtrainingbeforetheyaregiventheauthoritytoissueorreceivepermits.
Plant and process modification procedures
29 Whenalarge-scaleplantisdesignedforuseinoperationswhichinvolvebiologicalagents,twosetsofdesignparametersshouldbeobserved:
n thosedemandedbyvariousaspectsofhealthandsafetylegislation,includinganyspecificmeasuresrequiredforthesatisfactorycontainmentoftheorganismbeingused;
n anyspecificmeasuresrequiredaspartofGMPforthatproductandinthatindustry.Thesemeasuresmay,incertainindustries,formpartofthe manufacturinglicence,theoriginaldesignbeingpartofthesubmissionmadetotheregulatoryauthority.
30 Fromtime-to-time,variousplantmodificationsandprocesschangesmaybenecessary.Suchalterationsshouldonlybecarriedoutaftertheriskassessmenthasbeenreviewedandamendedasnecessary.
31 Suchproceduresshouldincludeacompetentandcompletereviewofthetechnicaldesign,whichshouldbethoroughlydocumentedandsubjecttoaformalapprovalprocedurebydesignatedcompetentpersons.Thisappliesequallytobothengineeringmodificationswhichoftenrequiredetaileddrawingsandapprovalofspecificationsandcomponents,andalsotoprocesschangeswhichinvolvealterationofchemicalorbiologicalconstituentsandoperatingconditions.
32 Assessmentofanyperceivedoridentifiablechangeinriskshouldbecarriedoutinthedetailrelativetothedegreeofchangeproposed.Normallythiswouldbeconductedinastep-wisefashionstartingwithapreliminaryhazardandriskassessment.Ifsuchanassessmentshowedthatasignificantincreaseinriskmightforeseeablyoccur,thenmoredetailedassessmentmethodologiesmaybenecessary.Thereisalsoarequirementtoconsultemployeesonanychangethatmaysubstantiallyaffecttheirhealthandsafetyatwork(seeleafletConsulting employees on health and Safety: A guide to the law).3
33 Theassessmentsandsubsequentapprovalsshouldonlybecarriedoutbydesignatedcompetentpersonswhohaveadequatequalificationsandexperienceintherelevanttechnologiesandhavereceivedappropriatetraininginthemethodsofassessmenttobeused.
34 WheresuchchangesaffectthecontainmentofabiologicalagentortheGMPprocedureswhichformpartofalegalpermitorlicence,thentheappropriateregulatoryauthority(whichmaynotnecessarilybetheHSE)mustbenotified.
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Emergency procedures
35 Asetofemergencyproceduresforthesiteandthecontainedareashouldbeavailableinanemergencymanual.Alloperativesmustbetrainedinemergencyresponse.COSHHspecificallyrequires:
n planstodealwithaccidentsinvolvingbiologicalagents;n provisionofwritteninstructionsand,ifappropriate,noticestobedisplayed
attheworkplacecoveringwhattodointhecaseofanaccidentalreleaseofbiologicalagentswhichcouldcauseseverehumandisease(HazardGroup3andabove);
n reportingbytheemployeeofanyaccidentorincidentwhichcausedormighthavecausedarelease;
n actiontobetakenbytheemployerininformingemployeesortheir representativesaboutanysuchincident.
36 Themanualshouldspecifyallthemajoremergencieswhichcanbeforeseenforaparticularsiteandshouldspecifyproceduresforeachofthesesituations.Safemethodsshouldbespecifiedfortheshutdownandevacuationofthecontainedareaandsubsequentre-entryattheendoftheemergency.Anemergencyteamshouldbenominatedandtrainedtotakecommandduringanemergencysituation.
37 Regulation14oftheGMO(ContainedUse)Regulations1992requiresspecificactiontobetakenintheeventofanaccidentinvolvinggeneticallymodifiedmicro-organisms.Itshouldbeunderstoodthat,forthepurposesoftheseregulations,‘accident’hasaspecialmeaning,namelyanyincidentinvolvingasignificantandunintendedreleaseofGMOswhichpresentsanimmediateordelayedhazardtohumanhealthortheenvironment.FurtherinformationcanbefoundinA guide to the Genetically Modified Organisms (Contained Use) Regulations 1992,6asamended1996.
Emergency planning
38 Dependingonthesizeandcomplexityofasiteandthematerialsbeinghandled,itmaybeastatutoryrequirementtohaveanemergencysystemandplaninoperation.InallcasesitisconsideredgoodpracticetohavesuchasystemwhenhandlingHazardGroups2,3and4agents.
39 Inthecaseofanemergencywhichinvolvesthegeneralpopulationorisamajorrisktotheenvironment,itbecomesadutyofthepolicetotakeoverallcontrolfortheincident,andcontrolisvestedwiththeseniorpoliceofficerinchargeoftheemergency.
40 However,itwilltaketimeforthepolicetoarriveandassumecontrol.Duringthatperiodtheemergencysituationmustbeproperlycontrolledbythesitemanagementandemergencyteam.Oncethepolicehavearrivedatamajorincident,theywillstillrequiretechnicalknowledgeandadvicefromthesitepersonnelinordertocarryouttheirresponsibilities.
41 Disasterscenarioswhichrequireemergencyactioncanarisefromanumberofsources.Insettingupanemergencysystemitisnecessarytoplanforallthesetypesofeventuality.Suchhappeningsmightbe:
(a) Plant malfunctions Vesselfailure; Pipeworkfailure-steamorprocess; Buildingfailure;
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Fire-solventorelectrical; Explosion; Toxicvapouremission; Flammablevapoursemission; Gasemission; Leakageofmicro-organisms.
(b) Natural disaster Severeelectricalstorm; Flooding; Earthquake.
(c) Actions of third parties Aircraftcrashonfactory; Railwaycrash; Roadcrash; Arson,sabotage,terrorism; Large-scalefoodpoisoning.
42 Thislistisnotexhaustiveandwillvaryfromsitetosite.Thepotentialriskscenariosmustbeassessedforeachparticularsite.
43 Organisationscannormallycopewithminoremergencysituationswhichmayinvolveonlyoneorasmallnumberofemployeesorasmallsectionofaplant.Specificplanswillbeneededincircumstanceswhichmayaffectthehealthandsafetyofalargenumberofemployeesand/orthegeneralpublic.
44 Theemergencymaycausedamageto:
n companyproperty;n theabilitytocontinue/resumenormaloperations;n propertyoutsidethecompanysite;n thenaturalenvironment.
45 Anemergencyplanshouldincludeanumberofproactivesystems,whicharedesignedtoreducethefrequencyandseverityofanysituation.Suchsystemsshouldinclude:
n adherencetoregulations;n comprehensivecompanyemergencysystem;n anorganisationforhealthandsafety;n regularauditing;n regularchecksthatbothsystemsandequipmentworkwhenrequired.
46 Inadditiontotheproactivemeasures,itisalsoessentialtohaveareactivesystemwhichwillrespondifanemergencydevelops.Theassumptioncannotbemadethatthenormallinemanagementisbestequippedtodealwithanextraordinaryemergencysituation.
47 Thereactivesystemsshouldincludedetailsof:
n whodoeswhat;n namesandtelephonenumbers;n orderofactivities;n individualresponsibilities;n jobtasks.
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Figure 1 Emergencyplan
48 Theemergencysystemhastooperate365daysayear,24hoursadayandshouldbedividedintotwosystems:normalhoursandoutofhours.
49 Areactiveemergencyplandependsonateam,allofwhomhavespecificresponsibilitiesunderemergencyconditions.
50 Awelltriedmethodofstatingtheseresponsibilitiesisbyeachmemberoftheteamhavinganemergencymanual,whichconsistsofseveralsectionslabelled‘YOUASA...’.
51 Thesesectionssummarise,inorder,theindividual’sresponsibilities.Eachsectionrelatestotheactivitiesofasingleteammemberanditisnotover-complicatedorconfusedbyreferencestotheworkofothers.
52 Typical‘YOUASA...’sectionsmayrelateto:
Siteemergencyofficer; Firstaider;Director; Fireteammember;Manager; Personnel;Supervisor; Publicrelations;Operator; Maintenanceteam;Securityguard; Health,safetyandenvironmentalspecialist;Doctor; Safetyrepresentative;Nurse; Rollcallmarshall.
53 These‘YOUASA...’sectionsshouldbebasedontheassumptionthatthewholesitehastoacttogetherandthatindividualsmaynothavetimeortheproperopportunitytothinkforthemselves.Alltheinformation,includingthatoncommunication,phonenumbers,etc,whichisrequiredshouldbeontheir‘YOUASA....’sectionandtheiractionslistedinthelogicaloperationalsequence.Intheeventofanemergencyallemployeesshouldgototheirappointedemergencylocationandcarryouttheinstructionsonthecard.
54 Ingeneralguidanceitisnotpossibletoillustrateeffectivelywhattheactionsshouldbe.Thedetailwilldependoneachsiteanditsrangeofoperations.This
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partoftheguidanceisintendedtoillustratethescopeofanemergencysystemandatypeofsystemandorganisationwhichwillbeeffectiveunderemergencyconditions.
55 Partoftheresponsibilityofthoseconcernedwiththeorganisationandmaintenanceofanemergencysystemistodevelopgoodrelationshipswithexternalindividuals,authoritiesandorganisations.Theseinclude:
Police;Fire;Ambulance;Hospital:
– Accidentandemergencyunit;– Burnsunit;– Eyeunit;– Microbiologist;
Waterauthority;PublicHealthDepartment;HealthandSafetyExecutive;EnvironmentAgency;Railways;Airports;MemberofParliament;Localandnationalmedia.
Spillage procedure
56 Wheretheassessmentshowsittobenecessary,thereshouldbeaproperlydocumentedspillageplanforuseinanemergency.Itshouldshowpreciselywhatstepshavetobetakenandwhoisresponsiblefortheirimplementation.Themethodadoptedmustbevalidatedagainsttheagentsandthemethodsused.
57 Itisrecommendedthatthreelevelsofspillageformthebasisofsuchapolicy:
n lessthan1litre;n onelitreto100litres;n morethan100litres.
58 Allpersonnelmustbetrainedintheactionstotake,aspartoftheimplementationofthespillagepolicy.
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Primary containment - Fermentation systems for use with biological agents59 Althoughthereisgreatvariationinfermenterdesign,basedonvariousconceptsforpoweringgas/liquidmixing,themostfrequentlyusedisthesterilepressurevessel,whichhasbeenafeatureoftheantibioticsindustryforthelast50years.
Figure 2 Diagramoftypicalsterilepressurevesselfermenter
60 Thismodel,initsmanyforms,willbeusedasthebasisfortheguidancewhichfollows.Itshouldberecognisedthatmanyofthedesignfeaturesofthesterilepressurevesselarereadilytransposabletoothertypesoffermenter.
61 Manysubmergedculturefermentationsareaerobic;forexample,theproductionofsomeantibiotics,enzymes,steroids,vitamins,aminoacids,biomassandcellculturesofhigherorganisms.Awiderangeofcontainedfermentationequipmenthasbeendevelopedfortheseprocessesinwhichdifferentmethodsareusedtointroducetheenergyrequiredtoobtaingoodgas/liquidmixinginthefermenter.Thefollowingillustrationsshowtherangeofsuchapplications.
Sterile additions
Antifoam
Inlet air �lter system
Exhaust �lter system
Ba�es
Probes:oxygen pHtemperature
Air sparger
Cooling coils
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Figure 3 Drivebymechanicalagitator
Figure 4 Drivebyliquidpump
Figure 5 Drivebygaspressure
Air Air Air
Top driven Bottom driven Draught tube Self aspirating
Air
AirPump
Pump PumpBubble column with forced circulation Jet loop Plunging jet
Air
AirAir Air
PumpBubble column Pressure cycle Air lift Sieve plate
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General layout design parameters
62 Inplanninganewormodifyinganexistingfermenterinstallation,greatcareshouldbetakentoensurethatthegenerallayoutissuitablefortheoperation.Itisimportantthatthereissufficientspacearoundallvesselsandotherequipmentfornormaloperationsandalsoenoughroomforroutinemaintenancework,forexamplevalvereplacement,motorandgearboxremovalandtheprovisionofthenecessaryheadroomtopermitagitatorshaftwithdrawal.Thespaceshouldalsobeadequatetoensurethatspillagescanbemanagedwithoutendangeringthesafetyoftheoperativescarryingoutemergencywork.
Fermenter system containment
63 Thefermentersystemisregardedastheprimarycontainmentandshouldbesubjectedtovalidatedleaktestprocedureswithallconnectionsincludingtheagitatorsealinplace,andbeforetheintroductionofviableorganisms.Thefrequencyofsuchtestingwillbedeterminedbytheriskassessment.
Pipework
64 Gastestingtechniquesusingheliumorhalogencompoundssuchassulphurhexafluoride,shouldnormallybeusedtotestthatpipeworkdoesnotleak.Alternatively,rateoffallofpressureorrateofriseofpressurefromanevacuatedconditioncanbeusedandischeaper.Thechoiceofoneormoretechniquesandthefrequencywithwhicheachisappliedshouldbebasedontheriskassessmentforthesystem.
65 Itisnecessarytoconsidervariousfactorsindeterminingthemostappropriatechoiceofsystemofpipework,jointingmethods,valvesandgaskets.Thereshouldbetheminimumnumberofjointsofanytypeandthesystemchosenshouldbecapableofwithstandingrepeatedtemperaturecyclingfromambientupto121ºCduringcyclesofproduction,cleaningandsterilisation.
66 Whenexaminingthecostofthesystem,itisnotjusttheinitialcapitaloutlay,butalsorunningandmaintenancecostswhichdeterminethetotalbalanceofchoiceofcomponentsforacontainedsystem.Stainlesssteelscheduledpipeisattractiveonthebasisofinitialpurchasecost,buton-sitefabricationmayincreasethetotalcostsabovethoseofaninstallationcarriedoutintubing.Tubingrequiresasmallerspaceandalsohastheadvantageofimprovedappearance,particularlywhenjointedusinginertgasorbitalweldingtechniques.
67 Above80mm(3inches)diameter,valvessuitableforusewithtubingbecomeincreasinglyexpensiveandabovethisdiameter,itisrecommendedthatpipeisused.Piperatherthantubingshouldbeusedforthefabricationofconnectionsfromvesselsbecauseofitsgreaterstrength.
68 Whereverpossible,stainlesssteelpipeworkshouldbeusedfordrainagesystems.Copperisnotsufficientlyrobustandthejointswilleventuallyleak.Mildsteelpipeworkwillinitiallygiveadequatecontainment,butcorrosioncanleadtoearly,sometimesundiagnosedfailureofthesystem.
69 Whenjointsintubingorpipesarenecessary,weldingisthepreferredoption.X-raytestingallowsexaminationofthemechanicalqualityofaweldbutdoesnotguaranteethatitisleak-tight.Theuseofgastestingisthereforepreferredandshouldbeappliedtoeachjointandthentothesystemasawhole.Weldsshouldalsobesubjectedtoahydrostatictestofone-and-a-halftimesthenormalworking
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pressurefortwohours.Wherepossible,inspectionofweldsshouldtakeplaceduringfabrication,ratherthanafterdeliveryofthecompleteplanttothesiteofthecontainedarea.
Couplings
70 ItisrecommendedthatpipeworkforuseatContainmentLevel3shouldbeofallweldedconstructionunlessanotherformofjointisjustified.ItisstronglyrecommendedthatpipeworkforContainmentLevel4beweldedanditisrecommendedthatallweldsaresubjectedtobothX-rayandgastestingbeforeuse.
71 ForworkatContainmentLevel2,avarietyofclampedandflangedjointsmaybeused.Thereareanumberofdifferingtypesofclampavailable,allofwhichhavetheirownspecificadvantages.Inpracticeitisthecorrectfitting,supportandtestingofgasketswhichisthekeyfactor,ratherthanthetypeofclamporflangesystem.Ineachcase,itisimportantthattheuserisabletoshowthatthecoupling/gasketsystemchosenisperformingtothedesignrequirement.Ofthefollowing,theringjointtypecoupling,theinternationaldairyfederationandthein-linecleaningcouplingarenotrecommendedforuseinbiopharmaceuticalplants.TricloverclamptypejointshavebecomethestandardintheUK.
n The ring joint type (RJT) coupling-consistsofamalepartwhichcarriesanexternalthreadandsealinggroove,aliner,asealandahexagonalnut.Oneproblemwiththistypeoffittingisthatthegapbetweenthemalepartandthelinermakescleaninginplaceandsterilisationdifficult.Theproblemdoesnotariseinthoseindustries,forexampledairyandbrewing,whichfavourthistypeofcouplingbecausepipeworkisnormallydismantledandcleanedmanually.
n The international dairy federation (IDF) coupling-consistsofthesamefourbasiccomponentsastheRJTbuttheendsofthemalepartandthelinerarespeciallyshapedtogiveasmooth,crevice-freejoint.Itmaybeusedwithasupportringfortheseal.Thisisoptionalatthesmallersizes,butshouldbeusedforcouplingsofmorethan60mm(2.5inches)diameteratpressuresgreaterthan10bargauge.Onedisadvantageisthatthesecouplingsareonlyavailableinsizesof25mm(1inch)andabove.
n The in-line cleaning (ILC) coupling-thisissimilartotheIDFcouplingbutthesealhasroundededges.Italsohastheadvantagethatitisavailableinallsizesandcanthereforebeusedthroughoutaninstallation.
72 Theabovecouplingsallrelyonahexagonalnutwhichisscrewedontothematchingthreadonthemalepart,inordertoapplycompressiontotheseal.
n Triclover clamp type joints-analternativemethodistouseaclamptoforcetogethertwoliners,eachofwhichisgroovedtolocateashapedseal.Theseal,whichisusuallyflangedandcontoured,canbemadetogiveacrevice-freejointinthepipework.Suchcouplingscanbedismantledeasily,particularlyiftheclampistightenedbyaquick-releaseclip.Theseclampscannotbeaccidentallyover-tightenedunlesstheyaredesignedtobetightenedusingalockingbolt,inwhichcasetheuseofexcessiveforcecanresultinacutseal.Itisessentialtouseatorquewrenchforsuchapplications.
73 Alternativelyapairofflatflangescanbemadeperfectlygas-tightwhenusedwithasuitableseal,thedimensionsofwhicharearrangedtoproduceacrevice-freejoint.Careshouldbetakentoensurethattheflangefacesaresmoothlymachinedanddonotcontainanyradialscratcheswhichcouldcauseleakagepaths.Itisalsopreferablethattheboltswhichjointheflangesaretightenedwithatorquewrenchtoavoiddistortiontotheflanges.
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74 TheuseofscrewedpipeisnotrecommendedatContainmentLevel2,becauseofdifficultyinsterilisationanddecontamination.TheuseofscrewedpipeisnotacceptableatContainmentLevels3or4.
75 Whatevermethodofcouplingisused,itisessentialthatthepipeworkisadequatelysupportedtopreventdistortionofthecouplingsandgivesgoodpipealignment.Thissupportshouldalsotakeintoaccountthedimensionalchangesintroducedbythermalexpansionduringsterilisationcycles.Failuretomakesuchprovisioncanresultindistortionorcutseals
Static seals
76 Thechoiceofmaterialsforsealsandgasketsdependsonthespecificprocessconditionsandfactorssuchastemperature,exposuretosteam,temperaturecycles,chemicalresistanceandotherfactors.Someofthetypicalmaterialscommonlyusedare:
Generaltemperaturerange(°C)
Polytetrafluoroethylene PTFE –40to150
Ethylenepropylenedienemodified EPDM –50to150
Isobutyleneisoprene IIRButyl –30to130
Butadieneacrylonitrile NBR –40to100
Fluoroelastomer FPM –30to175
Silicone –60to230static(175dynamic)
77 Polytetrafluoroethylene (PTFE) Thisexhibitsaverybroadrangeofchemicalandthermalserviceability.However,theeffectsoftemperature,pressureandabsorptionofchemicalsonPTFEandtheirinteractionsshouldbeconsidered.AmodifiedPTFE,developedforusewhereintermittentsteamsterilisationisused,providesimprovedresistancetocreepandelevatedsteamtemperatures.
78 CaremustbetakenintheapplicationofPTFEasasealingmaterialbecauseitisathermoplasticratherthananelastomer,andassuchdoesnothavetheresilientpropertiesdesirableinastaticseal.Toovercomethis,itisrecommendedthatthePTFEstaticsealbedesignedtoutilisearelativelythinlayerofPTFEastheproductcontactmaterial,andareinforcementorbackingmaterialthathasthedesiredresilientproperties,suchasEPDMorFPM.
79 Oneexampleofthisisthe‘envelope’or‘sandwich’gasket.Inthisdesign,aPTFEouterlayersurroundsaninnercoreofFPMorEPDM.ThePTFEprovidesforproductcompatibilitywhiletheFPMinnercoreprovidesheatresistanceandresilience.
80 Anotherexampleofthisisforadiaphragmsealinadiaphragmvalve.AthinlayerofPTFEisincontactwiththeproductandisbackedbyathickerlayerofFPMorEPDM.Similartotheclampuniongasket,thePTFEprovidesforproductcompatibilitywhiletheFPMinnercoreprovidesheatresistanceandresilience.
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81 ItisimportantinbothcasesthatthePTFEisnotbondedtotheelastomerreinforcementbutshouldbeallowedtofloatfreely.Bondingcancauseadditionalstressandprematurefailure.
82 Ethylene propylene diene modified (EPDM)Thisisacuredorganicperoxidewhichprovidesthemaximumheatstabilityandthebestcompressionsetwhichcanbeachievedusingapolymericgasketmaterial.EPDMdoesnotcontainsulphurwhichcanbepoisonousinsomebiotechnologyprocesses.
83 EPDMhasagoodresistancetosteambutaverypoorresistancetooil-basedsolutions.
84 Isobutylene isoprene (IIR) BUTYLThisisresincuredandprovidesexcellentresistancetowater-basedmedia,salts,diluteacidsandalkalis.Lowestpermeabilityofallelastomers.
85 Butadiene acrylonitrile (NBR)Thisisresistanttoaqueousmedia,paraffinichydrocarbonsandalcohols,suitableforusewithantifoamsbasedonanimalfatsoranywater-basedmediacontaininghydrocarbons.
86 Fluoroelastomer (FPM)Thisisresistanttostrongoxidisingagents,chlorinatedsolvents,ozoneandUVlight.Poorinhotwaterandsteam.
87 SiliconeThisisresistanttowater,ozoneandUVlight.Itdoesnotsupportbacteriallifeandcanbeusedoveragoodtemperaturerange.Poortearstrengthandpoorinhighpressuresteamandoils.
88 Storageconditionsforelastomersarealsoimportanttoensurebestperformanceandneedtotakeintoaccount:
Condition Storagerequirement
Temperature below25ºC
Humidity dryenvironment
Light avoiddirectsunlightorartificallightwithahighvioletcontent
Oxygen/ozone ozoneisaggressivetorubberandagesthematerial
Oil/greases avoidcontactduringstorage
89 Someidentificationtoshowtheageofthematerialbeingusedwillavoidtheuseofageingmaterialsandthesubsequentreductioninperformance.
90 O-ringscanbemadeinvarioussectionsorprofiles.ProfiledO-ringsaregenerallyeasiertofitthanroundrings.Theyarenotnecessarilysatisfactoryatlowpressuresandcaremustbetakenininstallationsofthistypewhendesigningthedimensionsofthesealgroove.Athigherpressures,somedeformationoftheO-ringtakesplaceandagoodsealcanbeobtained.WithshapedO-ringswhichinvolveaflatpartinthecross-section,caremustbetakentoensurethatasmoothface,inlinewiththepipeinnerwall,isobtainedinordertoavoidacrevicewhichmayharbourcontamination.Thereislittleevidencetosuggestthatinastaticseal,twoO-ringsarebetterthanone.Thedisadvantagesarethatthecouplingismoredifficulttoassemble,itisdifficulttodetectfailureofoneofthesealsasthesealscannotbetestedindependentlyandthespacebetweenthemmaygiverise
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tocontamination.TheapplicationofasteamsealbetweentwoO-ringshasbeenusedbutthisshouldgenerallyberegardedasanunnecessarycomplication.
Valves
91 Thediaphragmvalveisgenerallythevalveofchoiceforprocessbiotechnologyapplicationsatallcontainmentlevels,althoughballvalvescanbeusedatContainmentLevels1and2.Thechoiceofsealmaterialisimportantinadiaphragmvalve.EitheraPTFEenvelope,EPDMorEPDMcoatedwithPTFEwillgivegoodresults.
Adiaphragmvalvebody Thebodyofadiaphragmvalvewithsteamconnection
Crosssectionofadiaphragmvalve
92 Ballvalvesarepreferableforuseonsteamsystems.WhereballvalvesarefittedonprocessapplicationsatContainmentLevels1or2,theyarelikelytorequiremoremaintenancethandiaphragmvalves.Onedisadvantageofthediaphragmvalveisthatitisnotalwaysclearwhetherthevalveisopenorclosed,inthecaseofaballvalvethisisobviousfromthepositionofthehandle.
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Figure 6Crosssectionofaballvalve
Cutawayviewofaballvalve
93 Butterflyvalvesmaybeconsideredtobesimilartoballvalvesbuttheirassemblycausesdifficultiesforbiotechnologyapplications.SuchvalvesmaythereforebeusedforapplicationsatContainmentLevels1or2,butaregenerallynotusedatContainmentLevels3or4unlessitcanbedemonstratedthattheyarecontained.
Pressure relief systems
94 Pressurereliefassembliescancausesterilisationproblemswhicharebestovercomebytheuseofaburstingdisc,typicallystainlesssteel,butothermaterialsmaybesuitable.Wherepressurereliefvalvesareused,cleanablevalvesareavailablewhichcanbeopenedandsteamedthrough.Itshouldbenotedthatburstingdiscsmustbechangedfrequentlybecausetheydofatigueandthismaycauseprematurefailure.
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Burstingdisccomponentsforassemblyinafermenter
95 Analternativeapproachistoregulatetheutilitiessothatthemaximumpressureswhichcanbedevelopedarelowerthanthesafeworkingpressureofthevesselsandpipework.ThispracticeshouldbeagreedwithHSEinspectorsandtheinsurancecompanyconcerned,beforeproceedingwiththedesignandinstallation.
Agitator seals
96 Agitatorsmaybeeithertoporbottomdriveormaybedrivenbyexternalnon-contactsourcessuchasmagnetism.Magneticdriveshavetheadvantagethatfermentercontainmentisnotbreachedandmechanicalsealsarethereforenotrequired.Inthecaseofagitatorswhichuseanexternallyprotrudingdrivenshaft,aneffectivesealisrequired.ForContainmentLevel1applications,eitherastuffingboxorasinglefacemechanicalsealwillsuffice.
Figure 7 Stuffingboxwithsteambarrier
Steam outlet Steam inlet
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97 SingleordoublefacemechanicalsealsaresuitableforfermenteragitatorshaftsworkingatContainmentLevel2.Thesewillminimiseleakageandtheescapeoforganisms.AlthoughthelegislationallowstheuseofsinglesealsatContainmentLevel1and2,engineeringconsiderationsconcerningthelifeandeffectivenessofthesealfacemaydeterminethatadoublesealrepresentsamorepracticalsolution.Singleanddoublesealsareavailablewitheitherliquidorgasrubbinglubrication.The‘dry’contactsealfaces,whicharetraditionallyused,utilisecarbon/graphiteagainstaceramiccarbide,typicallysiliconcarbideinEuropeandtungstencarbideintheUS.Thesesealsreallyrequirethepresenceofsomewatervapouriftheyaretofunctioninanoptimummanner.Usuallythisneedismetintheatmosphereinsideafermentervesselbutitbecomesimportantinagitateddownstreamprecessingvesselswhichmaybeblanketedwithdrynitrogenordoublesealswhichuseadrynitrogenbarrier.Undertheseconditionsfastdeteriorationofthesealfacesmayoccur.Specialisedmaterialsarenowavailableforcontactingsealswhichusedrynitrogenservices.
98 Aninnovationintheindustryhasbeenthedevelopmentofdoublenon-contactingsealswithgaslubrication,whichbenefitinhavingnowearoftherubbingfaces.Gasconsumptionlevelsarehigherandthesealsupplierwillgenerallyspecifyaminimumgasbarrierpressuredifferentialabovethevesselpressure.
99 ForContainmentLevels3and4itisessentialtouseadoublefacemechanicalsealwitheithersteamorsterilecondensateunderpressure,fedtotheinterspace.Itisessentialthatthesteamorcondensatepressurebegreaterthanthevesselpressure.Steamorcondensatetemperatureshouldbehighenoughtosterilisetheinterspaceintheseal.Condensateshouldbepipedtokilltanks,orsteamtreatedpriortodischarge.
Figure 8 Crosssectionofamechanicalseal
Cutawayviewofamechanicalseal
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100 Oneoftheproblemsassociatedwiththeuseofsteamindoublemechanicalsealsisthatifthesteampressurefails,thesealsmayleak.
101 CondensatepressureshouldbecontinuouslymonitoredandalarmedforContainmentLevel3and4applications.
102 Sealfacechangesshouldbethesubjectofapreventivemaintenanceprogramme.Asweartakesplaceonthesealfacesofamechanicalseal(aninevitableoccurrencewithgaslubricatedcontactseals)weardebrisisformedandwouldnormallyfallintothevesselbelowtheseal.Sealsarenowavailableinwhicharingispresenttocollectthisdebrisandsopreventcontaminationoftheprocessmaterial.
Mechanicalsealwithdebriswell
Inlet air treatment
103 Mostaerobicfermentationsrequiresterileair.Thisshouldbegeneratedusinganoil-freemeansandbefilteredthrougha0.22µmcartridgefilter.Someusersatlargescaleachievesatisfactoryresultsusingbedspackedwithcottonwoolorglassfibretoachievesterilisationoftheinletairstream.ThisisanacceptabletreatmentforHazardGroup2organismswhereitcanbeshowntobeeffectiveandappropriate.PackedbedsshouldnotbeusedinapplicationsusingorganismsinHazardGroups3or4,whichusesterilisablefilterhousingssimilartothoseusedforexhaustgases,theperformanceofwhichcanbevalidated.
Exhaust air treatment
104 ForHazardGroup2organisms,thelegislativerequirementistominimisethereleaseofviableorganisms.
105 Inpractice,thisisanareaofconsiderablevariationinstandard.Forexample,insomeapplicationscommercialconfidentialityisoftheutmostimportanceandusersprefertopreventthereleaseoforganismseitherbytheuseofa0.22µmfiltersystemorbyincineration.Itshould,however,bestressedthatthisisanoptional,process-baseddecision.Theminimisationrequired,ieacceptablelevelsofrelease,shouldbecalculatedfromtheriskbaseoftheworkbeingundertaken.
106 Userswouldnormallyberecommendedtouseacentrifugalseparatororahighefficiencyparticulateabsorption(HEPA)gradecartridgefilterbutwithoutthe
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needtohaveaparallelinstallationtoensurecompletesterilityattimesoffilterchanging.Whereusersdecidetousecartridgefilters,considerationshouldbegiven,dependingonthefoamingcharacteristicsofthefermentermedium,totheuseofcycloneseparatorsand/orimpingementfiltersasapre-stageinordertopreservetheintegrityofthecartridges.
107 Alternatively,apre-heatingstagemaybeplacedintheexhaustairlinetoensurethatanywatervapourdropletsareevaporated,thusonlypresentingthefilterwiththegaseousphase.Itmayalsobeconsideredgoodpracticetoinstallhydrophobicandhydrophilicfiltersinseriesinordertopresentaneffectivefiltrationsurfaceunderallconditionsoffermenterairdischarge.
Figure 9 AcentrifugalseparatorCondenser/impingementseparatorinfermenterexhaustgasstream.
withtangenitalentryofairThephotogrpahshowstheoutertuberemovedfromtheairlineto
illustratetheimpingementdiscswhicharemountednon-concentric
toimproveseparation.
108 Forsomeworkitissufficienttopassfermenterexhaustgasesthroughacycloneseparator.Thismaybefollowedbyaspraytowerwherethegaseswillbeincontactwithadisinfectanthypochloriteorphenolicspraybeforebeingreleased.Whilethiscan,basedonanadequateriskassessment,beacceptableforalarge-scaleinstallation,smallerscaleusersshouldconsidertheoverallcostofsuchasystemcomparedwiththeuseofcartridgefilterswhichwillprovideatleastthesamereductioninorganisms.Considerationmustbegiventothedisposalofthedisinfectantinaccordancewithappropriatelegislation.
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Figure 10 Constructionofanexhaust Cutawayviewofanairfilterhousing
gasfilterelement
Scanningelectronmicrographsshowingthecrosssectionx2500andthesurfacex500ofexhaustgas
filtermedium
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Figure 11 Typicalarrangementofcyclone,heaterandexhaustfilters
109 AtContainmentLevels3and4,therequirementistotreatexhaustgasessoastopreventescape.PreventionisnormallyachievedbyHEPA-filtrationcartridgesinaparallelinstallationtoensurecompletedownstreamsterilityatalltimes.Thespecificationofthecartridgesmustbesuitabletoprovidecompleteretentionofthesmallestparticleswhichmaybegeneratedinthefermentationprocess.Forthesafetyofengineeringpersonnel,thefiltermustbecapableofbeingsteamsterilisedbeforebeingchanged.Theoperationofthesteamsterilisationprocessshouldbeviaavalidatedtechnique,asshouldthere-installationprocessofanewfilter.AtContainmentLevel4,theuseoftwoHEPAfiltersinseriesineachlegisrequiredtoreducetheriskofabreachofcontainmentduetofilterfailure.Inlet/exhaustfiltertestingisavitalaspectofsafetyassurance.
TwoexhaustfiltersinseriesusingtricloverclampfittingsinaContainmentLevel3installation
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Impingement �lter
Hydrophobic �lter
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110 Anewdevelopmentconsistingofafullydisposablefilterassemblymadefromadvancedpolymersandwhichissteamsterilisableinsituisnowavailable.Thisnotonlyprovidesalowercostinstallationthanatraditionalstainlesssteelhousingbutalsoenablestheplanttobecleanedinplace.
Sterilisableinsitudisposablefilter
Fermenter operating pressure
111 Forreasonsofprocesssterilityitisnormalpracticetooperatefermentersatapressurewhichispositivetotheirimmediatesurroundings.Normallyadifferentialofupto0.5barisacceptedpractice.Thepressuredifferentialshouldbemonitoredandalarmed.
112 Itisimportanttoensurethatemergencyventingarrangementsinstalledtodealwithaccidentalover-pressurisation,aresuitablydesignedtocontainemissionsofviablemicro-organisms.ForapplicationsatContainmentLevel2,provisionsareneededtominimiseorpreventtheescapeofviableorganismsintotheworkplace.InthecasesofapplicationsatContainmentLevels3or4,containmentisofcriticalimportanceandequipmentshouldbedesignedtoresistanyforeseeableover-pressureandmustpreventlossofcontainment.
113 Particularattentionshouldbedirectedtosmallfermenterswhereadditionlinesmaybeofplasticratherthanstainlesssteel.Theselines,whichmaycontainacidoralkaliforpHadjustment,couldconstituteahazardiftheyortheirconnectionsweresubjectedtoapositivepressure.Inthesecasesfermentationshouldbecarriedoutat,orasnearaspossibleto,atmosphericconditions.
114 Similarlyitshouldberememberedthatitcansometimesbedifficulttosecurerubberconnectionsfirmlytosmallglassfermenters.AparticularproblemariseswherethefoamingtendencyofthefermentermediuminuseleadstosmallPTFElinefiltersbecomingwet.Thisincreasestheirresistanceandcancauselinestoblowoff.
115 WhileitmaybenecessarytomaintainfermenterpressureabovetheimmediatesurroundingatmosphereforGMPreasons,itisalsonecessarytoensurethatthepressureofthecontainmentareaanditsimmediatesurroundingatmosphereisnegativetotheexternalatmosphere.
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Seed systems and inoculation
116 Inordertoachieveoptimumbiomasslevels,singleordoubleseedstagesareuniversallyused.Theseseedstagesshouldbemaintainedsterileforprocessreasonsandtransfertothefermentershouldbethroughavalidatedsystemofflexible,pressureratedtubing(forexample,meshencasedsiliconetubing)orsolidsterilisablestainlesssteellines.
117 Theprocessrequirementshouldalsosatisfythehealthandsafetyrequirementtominimise(ContainmentLevel2)orpreventreleaseoforganisms(ContainmentLevels3and4)eitherduringtheseedfermentationortransfertothefermentervessel.
118 Inoculationofseedvesselscantakeplaceusingdirectinjectionwithasterileneedle/septumtechnique,withdirectflamingoftheseptumorusingaclosedsystemwithastainlesssteeltransfervesselwhichisfilledinsideamicrobiologicalsafetycabinet.
Componentpartsofaseptuminoculationsystem
Figure 12 Diagrammaticlayoutoftheinoculationprocedure
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119 Inthiscase,thetransferinoculationcontainerwillbeconnectedtotheseedfermenterbyscrewedorquickreleaseconnections,thetransferpipeworkandvalvessteamsterilisedandthecontentstransferredeitherbygravityorbytheuseofsterileairpressure.Thereisaneedtore-steriliseconnectionlinesbeforeremovalofinoculationcontainer.Sterileneedle/septumtechniquesarenotnormallyusedforapplicationsatContainmentLevels3and4,butundercertainwell-controlledconditions,theycanbeconsideredadequate.
InoculationofafermenterusingtheseptumtechniqueoperatingatContainmentLevel3
Sampling systems
120 ForContainmentLevel2applications,samplingshouldbedesignedtominimisetheunintentionalreleaseoforganismsfromthefermenter.Careshouldbetakenthatthereceivingcontainerisdesignedtocontrolthegenerationofaerosols.
121 TheGMPrequirementforsamplingofafermenteristhatthesamplepointandthetakingofsamples,shallnotintroduceanycontaminatingorganismstothefermenter.Forthisreason,allsamplingtechniquesmustbeaseptic.Thisisusuallyarrangedbysteamingthesamplingconnectionwhennotinuse,eitheronthedownstreamsideofthesamplevalveorintothebodyofthevalveitself.
122 Thefermentercontentsarenormallyunderapositivepressureandcanbeejectedataconsiderablevelocityifalargevalveissuddenlyopened.Thesamplecontainershouldbeofadequatesizeandthevalveshouldbepreferablyofthediaphragmtype,whichcanbeopenedgradually,ratherthanaballvalvewhichwillallowrapidopening.
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Steamsealedsamplingvalve
Figure 13 Valvecombinationforsampling
123 Thechoiceofsamplecontainerdependsonthetypeofsamplebeingobtained.Forexample,asterilesamplerequiresafullysterilisableclosedcontainerwhichcanbeattachedtothesamplepoint,thesampletaken,thenallconnectionsre-steamedafterclosingtheinletvalvetothesamplecontainerandfinallydetachingthesamplecontainerinasterilemanner.Itmaybenecessarytofilterthedisplacedairfromthecontainer,dependingontheriskassessment.
124 SamplesofHazardGroups3and4organisms,regardlessoftheirintendeduse,mustbetakeninsuchawayastopreventreleaseoftheorganisms.Forexample,samplesshouldbetakenusingaclosed,aseptictechniqueandHEPA-filteringthedisplacedairfromsamplecontainers.
125 Theuseoflocalisedcontainmentshouldbeconsideredaspartoftheregimeofsampleremoval.Thecontainmentmeasuresintheareaofthesamplepointmustcorrespondwiththehazardclassificationoftheorganismsinthefermenter.
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Figure 14 Layoutofvalvesandvalvesequencingforcontainedsampling
Measurement probes
126 Probesinsertedintofermentersystemsarenormallyoftwotypes,thosethatarefixed,suchastemperatureorpressuretransducers,orthosewhichareretractable,suchasthoseformeasuringdissolvedoxygenandpH,thedesignofwhichallowstheirreplacementduringafermentation.Whilethislatterpracticehasconsiderablemeritfromtheviewpointofthetechnicalmanagementofthefermenter,itisonlyacceptableinthecaseofapplicationsatContainmentLevels1and2andshouldnottakeplaceinapplicationsathighercontainmentlevels.Normally,syntheticelastomerO-ringssealsareusedintheseapplications.DoubleO-ringsaresometimesconsideredforapplicationsatContainmentLevels3and4,butthegeneralcommentabouttheuseofO-rings,whichismadeinthesectiononcouplings,alsoapplieshere.
Fermenter
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Measurementprobeassemblyonafermenterwall
pHelectrodeforinsertioninfermenterwall
127 Forhigh-riskfermentations,duplicatetransducersrepresentasafeprocedurewhenthereisdoubtaboutthereliabilityoftheprobeunderprocessconditions.
Addition systems
128 Additionsystemsfallintotwocategories:
n thosewhichareusedforpHadjustmentandarenormallyself-sterilising,for examplebytheuseofconcentratedacidsorammonia;
n antifoamandnutrientadditionswhichnormallyrequiresterilisationofthelines andconnectionsandtheadditionmaterials.
129 AlladditionstothefermentermustbesterileforGMPpurposesandtheadditionsystemshouldbedesignedtominimisereleaseatContainmentLevel2andpreventreleaseofanyorganismsfromthefermenteratContainmentLevels3and4.
130 Cartridgefilterinstallationsusedforcriticalapplicationssuchasadditionsystemsorproductsterilisationpresentparticulardifficultieswhenfilterreplacementisrequired.Thisismademoredifficultwhenthedemandsforcleaningandcleaningvalidationaretakenintoaccount.Suchfiltersaretypicallypolymericandareinstalledinastainlesssteelhousingtoenablethemtobesteamsterilisedinsitu.Filtersmustbechangedaftereachbatchisprocessedandthehousingscleaned
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readyforre-use.Filterhousingsdonotreadilylendthemselvestobecleaned‘inplace’becauseoftheirgeometry.Traditionally,housingshavebeenremovedandcleanedseparatelyfromthemainplant.
131 Fullydisposablefiltercapsulesconsistingofafilterpermanentlybondedintoaplasticcasinghavebeenavailableforsometimebut,althoughtheycanbeautoclavedorinsomecasesgamma-sterilised,theycannotbesteamsterilisedinplaceandthereforemustbeinstalledaseptically.Thistypeoffilterremovestheneedforcleaningofthefilterhousingandmakescontainmenteasiertomanagebuttheneedtosteriliseoff-linecreatesotherdifficulties.
132 Noteshouldbetakenofthefullydisposablefilterswhichmaybesteamsterilisedinsitu.Thesearealsoavailableforuseinliquidsterilisationapplications.
Downstream processing
133 IndefiningthecriteriaandrequirementsforContainmentLevels2,3and4,COSHHspecifiesthatbulkculturefluidsshouldnotberemovedfromtheclosedsystemunlesstheviableorganismshavebeeninactivated.
134 Thisrequirementhasbeenthesubjectofconsiderablevariationininterpretation.Someusersconsiderthattheclosedsystemonlyincludesthefermenter.Therearesomeapplicationswheretokilltheorganismswithinthefermenterwoulddamageordestroytheproductortheviableorganismswhichmayconstitutetheproduct.Therequirementcanbebetterunderstoodiftheclosedsystemisextendedtoincludethepreliminarystagesofdownstreamprocessing.Thiscouldinclude,asanexample,centrifugationinasolid-liquidseparator,cellruptureinanhomogeniserandre-centrifugationinasecondsolid-liquidstagecentrifuge.
135 Inthosecaseswhereitisdesirabletoretainviableorganismsoriftheproductitselfistoxic,itisnecessarytomaintaincorrectcontainmentatalltimes.Theimportantfactoristheremovalofthehazardbeforethereislossofcontainment.Themethodofhazardremovaldependsontheproductandwhetherthisiscontainedwithinthecellsorintheliquidcomponentsofthedownstreamprocessingstage.
136 A0.22µmhydrophilicfiltermayberegardedastheouterbarrierofthecontainedsystem.Alternatively,ifacceptablefromtheprocessviewpoint,achemicalorheat-killmethodofinactivationmaybeused.Inthiscase,thematerialsmaybeinactivatedeitherbyreturntothefermentationvesselorbyprocessinginakilltankwhichmustalsoberegardedaswithinthecontainedsystem.Whichevermethodisused,validationofthesystemwillberequired.
137 Iftheyarepartofthecontainmentsystem,desludgingcentrifugesmustbeadaptedtominimisereleaseatContainmentLevel2.AtContainmentLevels3or4theyshouldpreventrelease.Theventsfromsuchmachines,whichshouldbetotallyenclosed,shouldbeexhaustedthroughHEPAfilters.
138 Mostindustrialhomogenisersare,innormaloperation,completelyclosedsystems.Theyoperateathighpressureandshouldafaultdevelop,whichresultsinaleak,theybecomeasourceofaerosols.Undertheseconditions,viableorganismsorproteinfragments,whichalthoughtheymaynotbebiologicallyviablecanbepotentallergens,maybereleasedintotheatmosphere.Homogenisersthereforeneedtobelocatedinaflexiblefilmisolator,safetycabinetorequivalentenclosurewhichisventedthroughaHEPAfilter.
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139 Itisimportanttoconsiderthepressuresdevelopedinthepipeworkconfigurationofahomogeniserinstallation.Careshouldbetakentoensurethatanyjoints,sealsandcouplingsinhigh-pressurelinesaresuitablefortheirduty.Manyofthecouplingsandsealsnormallyusedinbiotechnologyapplicationsarenotintendedtobeusedatthepressuresdevelopedinpartsofhomogeniserinstallations.
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Secondary containment - Process rooms and buildings (contained areas)Separation of organisms from the environment
140 Biotechnologyprocessesmaybedividedintotwoclasses,thosewherethefermentationequipmentisclosedtopreventtheleakageoforganismsortheingressofcontaminationandthosewherethefermentationisopentotheexternalair.Thisguidanceisonlyconcernedwithprocesseswhichuseclosedandcontainedequipment.
141 Allprocessesshouldbecarriedoutinequipmentwhichisdesignedtominimise,inthecaseofContainmentLevel2,orprevent,inthecaseofContainmentLevels3and4,thereleaseoforganisms.Thesystemshouldbesuchthatthefermentationequipmentactsastheprimarycontainmentandthatinadditiontheequipmentishousedinsideaclosedbuilding-acontainedarea,whichmayormaynotbeequippedwithventilationandairfiltration,dependingonthehazardarisingfromtheagentbeingused.
142 Suchabuildingmaybetheonlyoneonasite,oralternativelyitmaybeadesignatedbuildingwithinanexistingsitewhereothercompatibleworkiscarriedout.Acontainedareamayalsobeaseparatepartofanexistingbuilding,withinwhichotherindustrialprocessesarecarriedout.Inthisthirdcaseparticularcareshouldbeexercisedtoensurethatitisnotpossible,intheeventofanaccident,tocontaminateanotherpartofthebuildingwhichisnotequippedtodealwiththeagentbeingused.
143 Ideally,theairinsidetheprocessbuildingswouldbeexpectedtobecompletelyfreefromcontaminationbyanyprocessbiologicalagentasitwouldberetainedbytheprimaryfermentationcontainmentsystem.Caremustbeexercisedinthedesignandpositioningofbothinletandexhaustairstackstoensurethatexhaustaircannotbedrawnintotheventilationinletsofthecontainedareaoranotherinstallation.
FermenterinstalledinacontainedcabinetforworkwithHazardGroup3agents
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AcascadeofcontainmentcabinetsforworkwithHazardGroup4agents
Restricted access
144 ItisimportantthataccesstoworkareasprocessingHazardGroups2,3and4agentsshould,forhealthandsafetyreasons,berestrictedtothoseworkerswhohavespecificworktodointheareaandwhohavereceivedtrainingintheoperation,engineeringandprocedurestoadoptwheninthearea.
145 GMPconsiderationsrequirerestrictedaccesstoallinstallationsinvolvingbiotechnology.Suchaccessshouldbelimitedtothosepersonswhohavealegitimatereasonforbeinginthearea,suchasmanagement,processpersonnel,engineersandapprovedvisitors.
146 Primaryrestrictionbymeansofentrytoaproductionsitethroughthenormalfactoryentranceisnotsufficientbecauseofthepresenceofunauthorisedpeoplewhoarenotawareoftheprecisenatureofthework.Itisrecommendedthatentryisrestrictedtoonlythosepeoplewhohavedirectbusinessbyuseofaswipecard,cardkeyordigitallockentrysystemorequivalentsecurityaccesssystem.Therigourwithwhichaccessisrestrictedwillincreasewithincreasingcontainmentlevel.Whereaccessisrestricted,signsshouldbedisplayedonallentrances.AtContainmentLevels3and4itisoftenappropriatetohaveasigninginandoutsysteminoperation,tologfacilityusage.
Biohazard signs
147 BiohazardsignsmustbedisplayedontheexternalsidesofalldoorwaysofbuildingshandlingHazardGroup3or4agents(optionalforHazardGroup2).TheapproveddesignappearsinSchedule9ofCOSHH.
Internal room operating pressure
148 ForroomshandlingagentsinHazardGroup2,thereisnospecificneedtooperateprocessroomsatnegativepressure.Althoughthereisnorequirement,manyuserschoosetooperatesuchareasatnegativepressure.ItisalsoacceptedthatthedemandsofGMPoftenrequirethatroomsareunderpositivepressuretominimise/eliminatecrosscontamination.
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Figure 15 AirpressurerequirementsforGMPandnon-GMPareas
149 InordertobalanceboththehealthandsafetyandGMPrequirementsofprocessesusingHazardGroup2agents,considerationcanbegiventohavinganegativepressurecascadesystemoftheorderof30Pa,60Paand90Parelativetotheoutsideatmosphere.Theminimumrecommendeddifferentialbetweenroomsis15Pa(1Bar=100000Pa).
150 Itisnecessaryundertheseconditionstohaveabalancedairflowusingdampersandalarmstocounteracttheeffectsofnormaleventssuchasopeningdoors,aswellasabnormaleventssuchasaroomleakorsystemfailure.
151 Alternatively,considerationcanbegiventotheuseofacorridororlobbywithaHEPA-filteredpositiveairflow.Theairpressureinthelobbyshouldbepositivetoboththeplantsidetopreventorminimiseescapeofairborneorganisms,asrequiredbytheContainmentLevelinquestion,andalsototheoutsidetopreventorminimisecontamination.
152 Insuchasystemthecorridorwouldbeatpositivepressuretotheprocessingarea,throughacascade,consistingoffirstthechanginglobby,thenthecontainmentareaandthirdlyanycontainedequipment.Thefermenterwouldbeatpositivepressuretothecontainedarea,butnegativetotheoutsideatmosphere.
Figure 16 Typicalairpressurecascade
Outside
Outside
Corridor
+ve
Changing lobby
-1ve
Contained area
-2ve
Contained equipment
-3ve
-ve
+ve
-ve
Fermenter positive to contained area
Fermenteris negativeto outside
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153 Theplantwouldstillrequiresecondarycontainmentcabinetsforanyaerosolgeneratingactivities.ItisimportanttouseHEPA-filteredairforthisapplicationtopreventcontaminatedairfrombeingdrawnin.
154 Foractivitiesthatarecarriedoutinlaboratorysettings,usersshouldrefertothemoredetailedadviceonContainmentLevel3and4laboratoriesandtheuseofmicrobiologicalsafetycabinetsintheACDPguidance.1
Ventilation and room air filtration
155 TheroomairinanareaoperatingatContainmentLevels2,3and4shouldbefreefromcontaminationbythebiologicalagentswhichwillberetainedwithintheprimarycontainment.InthecaseofoperationsatContainmentLevel2thereisnorequirementformechanicalventilationandthereforeonlyaneedtoventilatewherenecessaryforcomfortofoperatingpersonnel.Tenairchanges/hourisarecommendedcirculationrate,althoughtwentychangesperhourmayberequiredforGMPoperations.ThereisnospecificrequirementtofiltertheexhaustairfromaContainmentLevel2facility.IfHEPAfiltersareinstalledintheoutletorintheinletandoutletforGMPreasonsthenitisrecommendedthattoconservefilterlifeacoarsefiltershouldbeinstalledbeforetheHEPAfilters.Supplyandextractairhandlingunitsshouldbeinterlockedtopreventover-pressurisationandreleaseofpossiblecontaminants.Extractfiltersshouldbeofsafedesigniftheareaisnotfumigableorifroutinefumigationisnotproposed.
156 InthecaseofprocessareasdesignedtooperateatContainmentLevels3and4,ventilationoftheroomspaceshouldbeprovidedatbetween10and25airchanges/hour.
157 Inthesecircumstances,forworkatContainmentLevels3and4,HEPA-filtrationmustbeprovided.ForContainmentLevel3suchfiltrationismandatoryontheextractairstreamandoptionalontheinletair.ForContainmentLevel4work,HEPA-filtrationcanbesinglefortheinletsidebutmustbedoublefortheoutletairstream.Theventilationsystemsshouldbealarmedandindicated.
158 Fixedspeedfanswithaproperlydesignedandreliablefail-safealarmsystem,canbeusedbutconsiderationshouldbegiventotheuseofdynamicallycontrolledvariablespeedfanmotorstocompensateforfilterclogging.Alarmsonmanometersshouldbelinkedtoindicateatthecontrolstation.
159 ForworkatContainmentLevel4,itisrecommendedthattheairexhaustfromthecontainedareashouldbethroughtwinfans,eachdrivenbytwo,variablespeedmotors.Eachfanwouldnormallyrunat50%load,butwiththeoptiontoincreasetheloadto100%intheeventoffailureofonefan.Ifbothfansfail,theinletfanmuststopandanyextractionshouldbeviathesafetycabinetsortheprimarycontainmentunitwhichshouldbesizedtoremovebetween50%and70%oftheairinordertopreventover-pressurisationandlossofcontainment.
Entrance, exit and changing areas
160 Apartfromthecorrectdesignoftheprocessareaandallofitsservicerequirements,itisalsonecessarytoensurethatthecorrectfacilitiesaredesignedfortheentryandexitofpersonnel,materials,samples,equipmentandwaste.Correctlysequencedchangingfacilitiesmustalsobeprovided.NoairlocksarerequiredforContainmentLevel2facilities,unlessthisisforGMPpurposes.ThedesignofachangingareaforContainmentLevel2shouldfollowtheadviceoninternalroomoperatingpressure.
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161 Occasionallyitmaybenecessarytousepersonalprotectiveequipmentsuchaspositivepressureairsuits.Thismethodofworkingcreatesadditionalrequirementswithintheexitsideofthechangingarea.Theairsuitmustbedecontaminatedbeforeitisremoved.Oneofthespecificrequirementsrelatestoairlinecouplings.Itisessentialthatthesecanbecleanedwithoutcontaminationandthereafterprotectedinpreparationforfutureuse.Withasystemsuchasthis,discardedworkclotheswouldberemovedfromtheareaviatheautoclave.
162 BeforecommencinganyworkatContainmentLevels3or4,inwhichfullcontainmentatsourceisnotdesignedintothesystemofwork,theapplicationmustbediscussedthoroughlyandagreedwiththeregulatoryauthority.
Figure 17 AtypicallayoutforsequencingentryandexitofaContainmentLevel4facility
163 Althoughitisnotaregulatoryrequirement,airlocksareoftenfittedinContainmentLevel3installations.ItisalsorecommendedthatinstallationsdesignedtooperateatContainmentLevel4shouldhaveaseparateairlockforgoodsinwardsandoutwards.Thiswouldbefittedatbothendswithgastightdoorstoallowfumigation.Theexitrouteshouldalsocontainadunktank(double-endedtankcontainingdisinfectant,intowhichanitemiscompletelyimmersedpriortoremovalfromtheotherside)whichwouldenabletheoutsideofsamplecontainers,etc,tobedisinfectedbeforeexit.
Fumigation
164 Theneedforfumigationdependsontheparticulartypeoforganismbeingused.Nogeneralrulecanbeestablished.Theneedwillbeassessedonacase-by-casebasis.Asageneralrule,theprovisionoffumigationcapabilityisnotrequiredforContainmentLevel2applications.WithContainmentLevel3applicationsfumigationisoptional,butitisnormalpracticeandwouldbeexpectedunlesstherearegoodreasonsagainst.FumigationisarequirementforapplicationsinvolvingContainmentLevel4.
165 MoredetailedadviceontheapplicationoffumigationtechniquescanbefoundintheACDPpublicationCategorisation of biological agents according to hazard and categories of containment.1
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166 Usersareremindedofthetoxicdangersofusingformaldehydeasafumigant.Roomsfumigatedusingthismaterialshouldbecarefullyexhaustedtotheatmosphereandtestsshouldbecarriedoutbeforere-entrytoensurethatthelevelofformaldehydeisbelowthemaximumexposurelevel(MEL)of2ppm.
167 Followingafumigationoperationconsiderationshouldbegiventotheuseofpermanganatefiltrationoftheexhaustairwhichcanreducetheformaldehydelevelto15ppmbeforeemissiontoatmosphere.Workerscarryingoutthetestsshouldwearappropriateprotectiveclothingandmasks.Ventingoftheroomsmustbecarefullycontrolledtoensurethatpersonswhomaybeneartheinstallationarenotendangered.Ifnecessary,barriersshouldbeerectedinsiteroadwaysneartheplantuntiltheoperationhasbeensuccessfullycompleted.
Personnel washing arrangements
168 FacilitiesshouldbeprovidedforwashinganddecontaminationinallContainmentLevel2,3and4processareas.Theuseoffoot,kneeorelbowoperatedtapsisrecommendedinallsuchinstallations.
169 Emergencyshowersandeyewashstationsshouldalsobeprovidedforuseinanaccidentinvolvingthecontaminationofaworker.Inanemergencysuchasthis,theworkershouldcallforhelpindecontaminationandshouldremoveallaffectedclothingwhileinsidetheworkingarea.Thisshouldthenbebaggedandautoclavedorincinerated.
170 Foroperatorcomfort,showerscanbeprovidedforuseafternormaloperations.TherequirementforshowersaspartofthesafetyandhygieneprogrammeisonlymandatorywhenworkingatContainmentLevel4,thoughoptionalatContainmentLevel3.
171 TheeffluentsfromthesinksandshowersmustbecollectedandinactivatedbeforebeingsenttodraininContainmentLevel4facilities,andpreferableforContainmentLevel3.
Spillage containment
172 WhilethereisnospecificrequirementforaninstallationoperatingwithagentsinHazardGroup2tobedesignedtocontaintheentirecontentsofafermenterintheeventofcatastrophicfailure,itisconsideredgoodpractice.Ifincorporatedintotheinitialbuildingdesign,thisrequirementcanoftenbesatisfiedatlittleornoadditionalcost.
173 Containmentmaybearrangedinseveralways,eitherasabundedareabelowthefermenter,orasenlargeddrainchannelsundertheoperatingfloororbydrainagetoakilltank.
174 Inallcasesitisimportantthatnotonlycanthespilledcontentsbesatisfactorilyinactivatedbychemicalorheattreatment,butthatitisalsonotpossibletomovethespillagefromthecontainmentareawithoutthedeliberateperformanceofanactiondesignedtodoso,forexamplethestartingofapump.Lineswhichdrainfromthebottomofthecontainmentareashouldbeavoidedastheisolationvalvesmaybeinadvertentlyleftopeninwhichcasespillagecouldbedischargedtoaneffluentsystemwithouttreatment.Goodpracticewouldbetoemptythespillagecontainmentareabypumpingfromabove.
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175 Besidesgrossspillage,provisionalsoshouldbemadeforminorspillagesresultingfrom,forexample,thebreakageofglassequipment,anoperatingerrororleakagefromapipeflangeoravalve.
176 Intheeventofaspillageorbreachofcontainment,thenormalarrangementshouldbetoevacuatetheareaandforoperatorsonlytore-enterwhenanyaerosolswhichmayhavebeengenerated,havesettledandtheareahasbeenfumigated.
177 Sealeddrainsshouldbeprovidedforthesubsequentdisposalofdecontaminatedspills.ForinstallationsoperatingatContainmentLevels3and4thisisanecessity.SafeguardsinsuchfacilitiesmustbedesignedtopreventeffluentcontaminatedwithviableorganismsinHazardGroup3or4fromreachinglanddrainsortofoulsewersunderallconditions.
Materials used in building construction
178 Inrecentyears,buildingfinishesinfermentationplantshavebecomemorestandardised,particularlyinsmallplants.InalargeindustrialplantoperatingatContainmentLevel2,concretefloorsandstandardindustrialwallcladdingareacceptable.Floorsareusuallyofconcrete,oftenofaspecialnon-poroustypeandeithersprayedwithanepoxycoatingorcoveredinweldedvinyl.Ineithercasethecoatingshouldberadiuscurvedupthewallsome300mmtogiveacontinuouscornereffect.
179 Wallsandceilingsareeitherepoxyorglassfibre/epoxysprayed,orofweldedvinylorresinbondedfibre.Weldedvinylmaybeusedasawall‘covering’insomeinstallationsbutisnotsuitablefornegativepressureoperationswherethepressuredifferentialmaycausethevinyltoliftfromthesupportsurface.
180 Particularattentionshouldbepaidtosealingplateswherepipesenterandleavetheplant.
181 Thefloor,wallandceilingsurfacesforContainmentLevel3shouldbethesameasforContainmentLevel2,exceptthattheuseofindustrialcladdingisnotacceptablebecauseofthedifficultyofachievingcontainmentwiththismaterial.
182 ItisrecommendedthatforinstallationsoperatingatContainmentLevels3or4,theceilingsshouldconsistoftwolayersarrangedsothatthecentresofthelowersheetsareoverthejointsbetweenthesheetsoftheupperlayer.Thisarrangementwillreducethepossibilityofleakagethroughthejoints.
183 Lightfittingsshouldbesplash-proofandinconformitywithBSEN60529wherepossible.8Considerationshouldbegiventoaccessformaintenancepurposesfromabovethecontainedarea,particularlyinthecaseoffacilitiesforworkatContainmentLevels3and4.
184 Floors,walls,ceilings,doors,windowsandfixturesshouldbeflushfittingtoalloweasycleaning.Noledgesshouldbepermitted.Pipeworkshouldbeenclosedasmuchaspossible.Allcornersandanglesshouldberadiusedforeasycleaning.
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Personal protection185 CorrectpersonalprotectiveclothingandequipmentmustbeprovidedforallpersonnelwhoenteraninstallationdesignedforoperationwithHazardGroups2,3or4agents.
Lockers
186 Alloperativesshouldbeissuedwithapersonallockerinwhichtostorepersonalclothing.ForHazardGroup2,eitheraseparatelockershouldbeprovidedforworkclothingwhichisusedonmorethanoneoccasionoradequateindividualstoragespaceshouldbeprovidedexternaltothecontainedareaforthestorageofworkclothes.
Overalls, gowns and hats
187 Asinglepieceoverallortwo-piecesuitconsistingofjacketandtrousers,andahat,shouldbeprovidedonanindividualissuebasisforeachoperator.Provisionmustbemadeforthesafestorageoftheseclotheseitheradjacenttotheentranceoftheareaorinasecondlockerspeciallyprovidedforthispurpose.ReferenceshouldbemadetotheApprovedCodeofPracticefortheCOSHHRegulations1994,Schedule9,PartI,paragraph9whichgivesspecificinformationaboutrequirementsforstorage,cleaningandsegregationofcleanclothingandequipment.7
Frequency of change
188 Frequencyofchangeofprotectiveclothingvarieswiththenatureoftheworkandtherateatwhichtheclothingbecomessoiledinnormaluse.GMPrequirementswillalsoconsiderablyinfluencethefrequencyofchanges.
189 Changefrequencyshouldbemorethanonce-a-weekandonce-a-dayispreferred.ForworkatContainmentLevel3,soiledclothingshouldbeautoclavedafteruseandpriortowashing.
190 ForworkatContainmentLevel4,allpersonnelshouldremoveallstreetclothingincludingunderclothesandbeprovidedwithallthenecessaryworkclothes.Fortheseoperations,achangeofclothingshouldbeprovidedoneachentryintothearea.
191 Workinvolvingmicro-organismsinHazardGroup4requiresthatafteruse,theclothingisautoclavedbeforeremovalfromthecontainmentareaandthenincinerated.
192 Whereclothingisknowntohavebeencontaminated,specialcaremustbetakentoensurethatitisplacedinasealedcontainerpriortoautoclavingandincineration.
Personal protective equipment (PPE)
193 WhilePPEshouldnotnormallybeusedasanalternativetorenderingaworksysteminherentlysafebyeliminatingthehazard,itmayberequiredtoprotect
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workersfromrisksnotassociatedwithexposuretotheorganism.ConsiderationshouldbegiventothepersonalissueofthefollowingitemsofPPE:
n gloves;n goggles,safetyspectacles,visorsandhelmets;n safetyshoes;n safetyhat.
194 TheneedforspecificitemsofPPEwillvarywiththenatureofthework.ItsselectionshouldformpartoftheriskassessmentunderCOSHH.
Smoking, eating, drinking, cosmetics and medicines
195 Noeating,drinking,smokingorapplicationofcosmeticsshouldbeallowedinanyworkplacewhichprocessesbiologicalagentsorinthedownstreamprocessingplantassociatedwithsuchwork.Restareasshouldbespecificallyprovidedforsuchpurposes.Ifthesiterulespermitsmokingonsiteaspecialseparatedareashouldbeprovidedforsuchpurpose.Medicinesforpersonaluseshouldnotbebroughtintotheworkareas.
Respiratory protective equipment (RPE)
196 AtContainmentLevel2,RPEwillnotnormallybeneededunlessriskassessmentshowsthatitisnecessary.Undertheseconditions,RPEwillneedtobeavailableincaseofabreachofcontainmentcausedbyaleak,spillageorescapeofculture,tohelpindealingwiththeemergencyandsubsequentcleanup.InroutinefermentationoperationstheuseofRPEwillnotnormallyberequiredsinceexposuretobiologicalagentsshouldbeadequatelycontrolledatsourcebytheuseoftotallycontainedplantorlocalexhaustventilationsuchasmicrobiologicalsafetycabinetsorisolators.
197 TherecouldwellbearequirementfortheuseofRPEinroutineactivitiesotherthanfermentation,suchaswhendispensingmaterialsusedinmakingculturemedia,handlingdryactivematerialsderivedfromdownstreamprocessingorinanimalwork.Workingpracticesandmeasureswhichcontrolexposureshouldpreferablybeusedbutmaynotalwaysbereasonablypracticable.
198 IfformaldehydefumigationsareperformedtheremaybeaneedforsuitableRPEtobekeptavailableincaseofemergency,althoughsystemsandprocedureswhicheliminatetheneedtoenterahazardousatmosphereshouldbeused.
199 ForoperationsinvolvingthecleaningupofspillsofculturefluidsatContainmentLevel2orabove,agreaterlevelofprotectionwillberequiredthancanbeofferedbydisposablemasksornegativepressureRPE.Itislikelythatsufficientprotectionwillonlybeprovidedbyapoweredpositivepressurerespiratororindependentairsupplydevice.Theoptionsavailableare:
n hoods;n blouses;n fullfacepiecemasks;n fullsuit.
200 Nominalprotectionfactors(NPFs)intherange500to2000shouldbeaimedat,havingregardtothenatureofthebiologicalagentbeinghandled.
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201 TheRPEchosencaneitherbeapoweredrespiratorwhichwillprobablyhaveabelt-mountedassemblyconsistingofabatterypoweredpumpandfilterssupplyingpurifiedairtothefaceviaahose.Alternatively,therespiratorfacepiecemayhaveanindependentpureairsupplyfromacompressedaircylinderorairline.
202 Respiratorsfittedwithparticulatefiltersarenotsuitableforuseinatmospheresdeficientinoxygenorcontaininghazardousconcentrationsofgasesorvapours.Theuseofcanisterrespiratorsisnotrecommendedbecauseoftheconcentrationsandthewidevarietyofgasesandvapourswhichmaybeencounteredinafermentationfacility.
203 Equipmentsuppliedwithcompressedaireitherfromapipedsupplyviaahoseorfromcylindersinthecaseofself-containedbreathingapparatus,willbemoresuitable.Ineithercaseappropriateproceduresmustbeinplacetoensurethatpersonnelarenotexposedtobiologicalhazardsbefore,duringorafteruseoftheequipment.WhereRPEisrequiredunderCOSHH,attentionisdrawntotheneedfortraining,maintenance,testingandrecordkeeping.
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Appendix 1 Classification of biological agentsInregulation2(1)oftheControlofSubstancesHazardoustoHealthRegulations1994,‘biologicalagent’meansanymicro-organism,cellcultureorhumanendoparasite,includinganywhichhavebeengeneticallymodified,whichmaycauseanyinfection,allergy,toxicityorotherwisecreatearisktohumanhealth.
Schedule9,paragraph3,sub-section4,providesthefollowingcriteriaforhazardclassificationofbiologicalagents:
n HazardGroup1-unlikelytocausehumandisease;n HazardGroup2-cancausehumandiseaseandmaybeahazardto
employees;itisunlikelytospreadtothecommunityandthereisusually effectiveprophylaxisortreatmentavailable;
n HazardGroup3-cancauseseverehumandiseaseandmaybeaserioushazardtoemployees;itmayspreadtothecommunity,butthereisusuallyeffectiveprophylaxisortreatmentavailable;
n HazardGroup4-causesseverehumandiseaseandisaserioushazardtoemployees;itislikelytospreadtothecommunityandthereisusuallynoeffectiveprophylaxisortreatmentavailable.
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Appendix 2 Summary of industry characteristics
Sys
tem
feat
ure
Ant
i-bi
otic
sB
aker
’s
yeas
tB
eer
Bre
ad
Che
ese
Cid
er
Edi
ble
prot
ein
Food
enzy
mes
&
flavo
urin
gs
Food
grad
een
zym
es
Was
tes-
open
syst
em
Was
tes-
clos
edsy
stem
Win
eY
oghu
rt
Bui
ldin
gs
(a)
Via
ble
orga
nism
s
hand
led
insi
de
bu
ildin
gsin
clo
sed
sy
stem
s
Yes
Yes
Par
tlyN
oN
oY
esY
esY
esY
esN
oY
esY
esY
es
(b)
Pla
ntv
entil
ated
Com
fort
on
lyN
oN
oN
oY
esN
oN
oC
omfo
rton
lyC
omfo
rton
lyO
pen
air
Ope
nai
rN
oN
o
(c)
Bui
ldin
gs:
–ne
gativ
e
pres
sure
No
N
oN
oN
oN
oN
oN
oN
oY
es_
_N
oN
o
–po
sitiv
e
pres
sure
No
No
Yea
stN
oro
oms
Yes
No
No
No
No
__
No
No
(d)
Bui
ldin
gfil
trat
ion:
–H
EP
AN
oN
oN
oN
oN
oN
oN
oN
oN
o_
_N
oN
o
–In
let
No
No
No
Yes
Yes
No
No
Yes
No
__
No
No
–O
utle
tN
oN
oN
oN
oN
oN
oN
oY
esN
o_
_N
oN
o
(e)
Con
tain
spi
llage
No
No
No
No
No
No
No
No
Yes
No
No
No
(f)
Sui
tabl
efo
r
fum
igat
ion
No
No
No
No
InN
oce
rtai
nar
eas
No
No
No
No
No
No
No
Ap
pen
dix
2 S
umm
ary
of
ind
ustr
y ch
arac
teri
stic
s
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Sys
tem
feat
ure
Ant
i-bi
otic
sB
aker
’s
yeas
tB
eer
Bre
ad
Che
ese
Cid
er
Edi
ble
prot
ein
Food
enzy
mes
&
flavo
urin
gs
Food
grad
een
zym
es
Was
tes-
open
syst
em
Was
tes-
clos
edsy
stem
Win
eY
oghu
rt
Ferm
enta
tio
n sy
stem
s
(a)
Inoc
ulat
ion:
–S
teril
eYe
sYe
s_
No
No
No
Yes
Yes
Yes
No
No
No
No
–C
lean
__
Yes
Yes
Yes
Yes
No
__
No
No
Yes
Yes
–D
irect
__
Yes
Yes
Yes
Yes
No
No
No
Yes
Yes
Yes
Yes
(b)
See
dst
ages
Two
stag
eTh
ree
stag
eN
oN
oN
oN
o?
Sin
gle
Sin
gle
No
No
No
No
(c)
Agi
tatio
n:
–A
gita
tion
used
Yes
No
No
Yes
Yes/
No
No
Yes
Yes
Yes
No
No
No
Yes
–P
acke
dgl
ands
Yes
__
No
No
_N
oN
oN
o_
__
_
–S
ingl
ese
als
Yes
__
Yes
Yes
_N
oN
oN
o_
__
Yes
–D
oubl
ese
als
Yes
__
No
No
_Ye
sYe
sYe
s_
__
_
–S
team
sea
led
mec
hani
cal
Yes
__
No
No
Yes
No
Yes
__
__
(d)
Air
filtr
atio
n:
–S
teril
eYe
sP
relim
st
ages
Not
us
edN
ot
used
Not
us
edN
ot
used
Yes
Yes
Yes
No
No
Not
us
edYe
s
–C
lean
__
__
__
__
_N
oN
o
Sum
mar
y o
f in
dus
try
char
acte
rist
ics
Thelarge-scalecontaineduseofbiologicalagents Page51of56
Health and Safety Executive
Sys
tem
feat
ure
Ant
i-bi
otic
sB
aker
’s
yeas
tB
eer
Bre
ad
Che
ese
Cid
er
Edi
ble
prot
ein
Food
enzy
mes
&
flavo
urin
gs
Food
grad
een
zym
es
Was
tes-
open
syst
em
Was
tes-
clos
edsy
stem
Win
eY
oghu
rt
(e)
Ferm
ente
r
pres
sure
:–
Neg
ativ
eN
oN
oN
oN
oN
oN
oYe
sN
oN
oN
oN
oN
o
–A
tmos
pher
icN
oN
oYe
sYe
sYe
sN
oN
oN
oYe
sYe
sYe
sN
o
–P
ositi
veYe
sYe
sN
oN
oN
oYe
sN
oYe
sN
oN
oN
oYe
s
–O
pen
No
No
Yes
Yes
No
No
No
No
Yes
No
No
No
–C
lose
dYe
sYe
sN
oN
oN
oYe
sYe
sYe
sN
oN
oN
oYe
s
–C
over
edN
oN
oYe
sYe
sYe
sN
oN
oN
oN
oYe
sYe
sN
o
(f)
Sam
plin
g:–
Ste
rile
Yes
Yes
Yes
No
No
No
Yes
Yes
Yes
No
No
No
No
–C
lean
__
Yes
No
No
Yes
__
_N
oN
oYe
sYe
s
(g)
Exh
aust
/air:
–Fi
ltere
dN
oN
oN
oN
oN
oN
oN
oYe
sN
oN
oN
oN
oN
o
–Tr
eate
dYe
sN
oN
oN
oN
oN
oYe
s_
Yes
No
No
No
No
(h)
Add
ition
sys
tem
s:–
Ste
rile
Yes
No
Not
us
edN
ot
used
Not
us
edN
ot
used
Yes
Yes
Yes
Not
us
edN
ot
used
Not
us
edN
ot
used
–C
lean
No
Yes
__
__
__
__
__
_
(i)
Was
tes:
–S
teril
eO
ptio
nal
No
No
No
No
No
No
No
No
No
No
No
No
–Tr
eate
dO
ptio
nal
No
No
No
No
No
No
No
No
No
No
No
No
Sum
mar
y o
f in
dus
try
char
acte
rist
ics
Thelarge-scalecontaineduseofbiologicalagents Page52of56
Health and Safety Executive
Sys
tem
feat
ure
Ant
i-bi
otic
sB
aker
’s
yeas
tB
eer
Bre
ad
Che
ese
Cid
er
Edi
ble
prot
ein
Food
enzy
mes
&
flavo
urin
gs
Food
grad
een
zym
es
Was
tes-
open
syst
em
Was
tes-
clos
edsy
stem
Win
eY
oghu
rt
Bio
haza
rd s
igns
No
No
No
No
No
No
No
Yes
No
No
No
No
No
Acc
ess:
–S
emi-r
estr
icte
dYe
sYe
sYe
sYe
sYe
sYe
s_
Yes
Yes
Yes
_Ye
sYe
s
–R
estr
icte
d_
_Ye
ast
area
s_
Yes
_Ye
s_
__
Yes
__
Per
sonn
el p
rote
ctio
n &
res
tric
tio
ns
Clo
thin
gpr
ovid
edYe
sYe
sYe
sYe
sYe
sYe
sYe
sYe
sYe
sYe
sYe
sYe
sYe
s
Cha
nges
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Equ
ipm
ent
Yes
Yes
Yes
Yes
Yes
Not
Yes
used
Yes
Yes
Yes
Yes
Not
Yes
used
1Lo
cker
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
_Ye
s_
Yes
Yes
2Lo
cker
sO
ptio
nal
No
No
No
Yes
No
No
No
Yes
_Ye
sN
o_
Sm
okin
gal
low
edN
oN
oN
oN
oN
oN
oN
oN
oN
oN
oN
oN
oN
o
Eat
ing
allo
wed
No
No
No
No
No
No
No
No
No
No
No
No
No
Drin
king
allo
wed
No
No
No
No
No
No
No
No
No
No
No
No
No
Jew
elle
ry&
cos
met
ics
allo
wed
Opt
iona
lYe
sN
oN
oN
oYe
sYe
sYe
sYe
sYe
sYe
sYe
sN
o
Hai
rnet
sN
oYe
sN
oN
oN
oN
oN
oN
oN
oN
oN
oN
oN
o
Was
hha
ndb
asin
sYe
sYe
sYe
sYe
sYe
sYe
sYe
sYe
sYe
sYe
sYe
sYe
sYe
s
Dis
infe
ctan
tso
apN
oN
oYe
sYe
sYe
sN
oN
oN
oN
oN
oN
oN
oN
o
Foot
bat
hsN
oN
oYe
sN
oYe
sN
oN
oN
oN
oN
oN
oN
oN
o
Sum
mar
y o
f in
dus
try
char
acte
rist
ics
Thelarge-scalecontaineduseofbiologicalagents Page53of56
Health and Safety Executive
Sys
tem
feat
ure
Ant
i-bi
otic
sB
aker
’s
yeas
tB
eer
Bre
ad
Che
ese
Cid
er
Edi
ble
prot
ein
Food
enzy
mes
&
flavo
urin
gs
Food
grad
een
zym
es
Was
tes-
open
syst
em
Was
tes-
clos
edsy
stem
Win
eY
oghu
rt
Sho
wer
sop
tiona
lYe
sYe
sYe
sYe
sYe
sN
oYe
sYe
sYe
sN
oYe
sN
oYe
s
Sho
wer
sco
mpu
lsor
yYe
sN
oN
oN
oN
oN
oN
oN
oN
oN
oN
oN
oN
o
Em
erge
ncy
show
erYe
sN
oN
oN
oN
oN
oYe
sN
oYe
sN
oYe
sN
oN
o
Eye
was
hYe
sN
oN
oN
oN
oN
oYe
sN
oN
oN
oN
oN
oYe
s
Med
ical
exa
min
atio
nYe
sYe
sN
oN
oYe
sN
o?
No
No
*
chec
kN
o*
chec
kN
oN
oN
o
Tra
inin
gYe
sYe
sYe
sYe
sYe
sYe
sYe
sYe
sYe
sYe
sYe
sYe
sYe
s
Sta
ndar
d p
roce
dur
esYe
sYe
sYe
sYe
sYe
sYe
sYe
sYe
sYe
sYe
sYe
sYe
sYe
s
Sp
illag
e p
olic
y:Ye
sN
oN
oN
oN
oN
o?
Yes
Yes
No
No
No
No
Con
tain
men
tO
ptio
nal
No
No
No
No
No
No
No
Yes
No
No
No
No
Env
iro
nmen
tal m
oni
tori
ngYe
sN
oN
oYe
sYe
sin
tern
alN
oin
tern
al?
Yes
No
No
No
No
No
Sum
mar
y o
f in
dus
try
char
acte
rist
ics
Thelarge-scalecontaineduseofbiologicalagents Page54of56
Health and Safety Executive
Sys
tem
feat
ure
Ant
i-bi
otic
sB
aker
’s
yeas
tB
eer
Bre
ad
Che
ese
Cid
er
Edi
ble
prot
ein
Food
enzy
mes
&
flavo
urin
gs
Food
grad
een
zym
es
Was
tes-
open
syst
em
Was
tes-
clos
edsy
stem
Win
eY
oghu
rt
Val
ve
stan
dar
ds
Nor
mal
indu
stria
l
Cle
an
Sup
erc
lean
Pip
ewo
rk
stan
dar
ds
Nor
mal
indu
stria
l
Cle
an
Pol
ishe
dsa
nita
ry
Bui
ldin
g
stan
dar
ds
Floo
rsC
oncr
ete
Con
cret
eC
oncr
ete
orti
led
Con
cret
eC
oncr
ete
orti
led
Con
cret
eC
oncr
ete
Con
cret
e
orti
led
Con
cret
eC
oncr
ete
Con
cret
eC
oncr
ete
orti
led
Con
cret
eor
tile
d
Wal
lsN
orm
al
indu
stry
Nor
mal
in
dust
ryM
ostly
tile
dN
orm
al
indu
stry
Was
habl
eN
orm
al
indu
stry
Nor
mal
in
dust
ryW
asha
ble
Nor
mal
in
dust
ryN
orm
al
indu
stry
Nor
mal
in
dust
ryN
orm
al
indu
stry
Nor
mal
in
dust
ry
Cei
lings
Nor
mal
in
dust
ryN
orm
al
indu
stry
Was
habl
epa
inte
dN
orm
al
indu
stry
Was
habl
eN
orm
al
indu
stry
Nor
mal
in
dust
ryW
asha
ble
Nor
mal
in
dust
ryN
orm
al
indu
stry
Nor
mal
in
dust
ryN
orm
al
indu
stry
Nor
mal
in
dust
ry
Spe
cial
are
asTi
led
Tile
dTi
led
Tile
dTi
led
Key
App
lyD
on’t
appl
y
Appendix 3 Engineering standards in biotechnology industries
Thelarge-scalecontaineduseofbiologicalagents Page55of56
Health and Safety Executive
References1 HealthandSafetyCommission’sAdvisoryCommitteeonDangerousPathogensCategorisation of biological agents according to hazard and categories of containment(4thedition)HSEBooks1995ISBN0717610381
2 CommissionoftheEuropeanCommunitiesBRIDGEreport:The development of good industrial large scale practice in biotechnologyJFThorleyforDirectorate-GeneralXII(Science,ResearchandDevelopment)1993,RuedelaLoi200,B-1049,Brussels,Belgium
3 Consulting employees on health and safety: A guide to the lawINDG232HSEBooks1996
4 BritishStandardENISO9000-1:1994ISBN058023438XBritishStandardsInstitution,London
5 BritishStandardENISO9004-1:1994ISBN0580234428BritishStandardsInstitution,London
6 HealthandSafetyExecutiveA guide to the Genetically Modified Organisms (Contained Use) Regulations 1992,asamendedin1996L29HSEBooks1996ISBN0717611868
7 HealthandSafetyCommission Control of Substances Hazardous to Health Regulations 1994, as amended by the Control of Substances Hazardous to Health (Amendment) Regulations 1996. General COSHH ACOP, Carcinogens ACOP and Biological Agents ACOPL5HSEBooks1996ISBN0717613099
8 BritishStandardEN60529:1991Degreesofprotectionprovidedbyenclosure
Note:theAdvisoryCommitteeonDangerousPathogenscanbecontactedviatheSecretariatat
Further informationForinformationabouthealthandsafetyringHSE’sInfolineTel:08453450055Fax:08454089566Textphone:08454089577e-mail:[email protected],CaerphillyBusinessPark,CaerphillyCF833GG.
HSEpricedandfreepublicationscanbeviewedonlineororderedfromwww.hse.gov.ukorcontactHSEBooks,POBox1999,Sudbury,SuffolkCO102WATel:01787881165Fax:01787313995.HSEpricedpublicationsarealsoavailablefrombookshops.
BritishStandardscanbeobtainedinPDForhardcopyformatsfromtheBSIonlineshop:www.bsigroup.com/ShoporbycontactingBSICustomerServicesforhardcopiesonlyTel:02089969001e-mail:[email protected].
PublishedbyHSE07/10 Page56of56
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