biological agents

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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’.

HSE Books

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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)

Thelarge-scalecontaineduseofbiologicalagents Page3of56


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



Smoking,eating,drinking,cosmeticsandmedicines 46Respiratoryprotectiveequipment 46

Appendices1 Classificationofbiologicalagents 482 Generalcharacteristicsandstandardsforthelarge-scaleuseof micro-organisms 493 Engineeringstandardsinbiotechnologyindustries 54

References 55

Further information 56



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.



Amoderncomputercontrolledcontainedfermenter



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.



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.



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.



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.



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.



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;



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.



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



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.



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



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



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



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.



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.



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



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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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.

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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.



139 Itisimportanttoconsiderthepressuresdevelopedinthepipeworkconfigurationofahomogeniserinstallation.Careshouldbetakentoensurethatanyjoints,sealsandcouplingsinhigh-pressurelinesaresuitablefortheirduty.Manyofthecouplingsandsealsnormallyusedinbiotechnologyapplicationsarenotintendedtobeusedatthepressuresdevelopedinpartsofhomogeniserinstallations.



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

Pho

togr

aphe

dat

CA

MR



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.

Pho

togr

aphe

dat

CA

MR



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



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.



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



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.



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.



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



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.



201 TheRPEchosencaneitherbeapoweredrespiratorwhichwillprobablyhaveabelt-mountedassemblyconsistingofabatterypoweredpumpandfilterssupplyingpurifiedairtothefaceviaahose.Alternatively,therespiratorfacepiecemayhaveanindependentpureairsupplyfromacompressedaircylinderorairline.

202 Respiratorsfittedwithparticulatefiltersarenotsuitableforuseinatmospheresdeficientinoxygenorcontaininghazardousconcentrationsofgasesorvapours.Theuseofcanisterrespiratorsisnotrecommendedbecauseoftheconcentrationsandthewidevarietyofgasesandvapourswhichmaybeencounteredinafermentationfacility.

203 Equipmentsuppliedwithcompressedaireitherfromapipedsupplyviaahoseorfromcylindersinthecaseofself-containedbreathingapparatus,willbemoresuitable.Ineithercaseappropriateproceduresmustbeinplacetoensurethatpersonnelarenotexposedtobiologicalhazardsbefore,duringorafteruseoftheequipment.WhereRPEisrequiredunderCOSHH,attentionisdrawntotheneedfortraining,maintenance,testingandrecordkeeping.



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.



Appendix 2 Summary of industry characteristics

Sys

tem

feat

ure

Ant

i-bi

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sB

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yeas

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Bre

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Che

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Cid

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Food

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Was

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syst

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Was

tes-

clos

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Win

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Bui

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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

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nar

eas

No

No

No

No

No

No

No

Ap

pen

dix

2 S

umm

ary

of

ind

ustr

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arac

teri

stic

s



Sys

tem

feat

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Ant

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Win

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Ferm

enta

tio

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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



Sys

tem

feat

ure

Ant

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Bre

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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



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



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



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



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

[email protected]

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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