Guidelinefor

Good Manufacturing Practice

'"

b!: TetraPak

"

b~TetraPak General

EffectiveManufacturingOperation

An effectivemanufacturingoperationis onein which:

a) Themanufacturingprocess,theequipment,andallotheractivities,associatedwiththem,etc.,arefullyspecifiedin advanceandsystemati-callyreviewedin thelightofexperience;

b) Thenecessaryfacilitiesareprovidedincluding

- adequatelyqualifiedpersonnel,

- adequatepremisesandspace,

- suitableequipment,

- specifiedmaterials,

- suitablestorageandtransport;

c) Relevantwrittenproceduresarelayeddown,in instructionalformandin clear,plain,andunderstandablelanguage;

d) Operatorsaretrainedandre-trained,aswell as educated2 tocarryoutprocedurescorrectly;

e) Recordsaremadeeithermanuallyor;wheneverpossible,byusingrecordinginstruments(orboth)duringpreparationandmanufacture,toverifythatthescheduledprocedures(processes)wereactuallyfollowed.

f) Responsibilitiesandrightsareclearlyspecified,assigned,andenforced.

Footnoteno2:Trainingimpliestellingpeoplewhattodoandhowtoperformatask,whileeducationaimsatexplainingwhyanactivityshouldbedonecorrectlyandinacertainway.

GMP Issue9301 1.3

-

GMPA GuidelinefortheFormulationof

Good ManufacturingPractice

Issue 9301

In-flowsterilizedandasepticpackagedpumpablefoodproducts(long-lifeproducts).

-r8.t(~j P~JJ~Tetra Pak Technical Service AS

Introduction 0

General 1

Long-life Food Products 2

The ProductArea 3

Product Processing 4

Aseptic Packaging 5

PackagingMaterialSterilization 6

Productionof Tight Containers 7

InternalTransportandStorage 8

Record Keeping 9

Recall (Emergency) Program 10

b~TetraPak

Introduction

.....................................:::::::::;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:;:::;:;:::;::';:;:;:::;:;

.Purpose

Thisdocumentis intendedasasupportwhenestablishing"GoodManufacturingPractices".It shouldalsohelpseniorandmiddlemanagementin setting-upGMPs.

Producer

Thisdocumentis producedby:

B YonBockelmannTetraPakTechnicalServiceAB22186LUNDSweden

and:

I vonBocke1mannvonBockelmannHygieneAKARPSweden

Orderingdocument

Furthercopiesof thisdocumentcanbeorderedfrom:

TetraLavalMarketingServicesABCentralTechnicalPublicationsRubenRausingsgata22186LUNDSweden

Copyright

Thisdocumentisprotectedin accordancewiththeCopyrightActandmustnotwithouttheconsentofTetraPak TechnicalServiceABbecopied.

GMP Issue9301 0.1

b~TeiraPak

General

. ............................................ .........................................................................................................................................................."""""""""""""""""'"....................................."""""""""""""""""'""""""""""""""""""'""""""""""""""""""'""""""""""""""""""'"

18Con~n~

General. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1.2

Effective Manufacturing Operation. . . . . . . . . . . . . . . . . . . . . . . .. 1.3

Effective QualityControl/QualityAssurance. . . . . . . . . . . . . . .. 1.4

TroubleShooting. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1.6

~

Sterilizing Effect. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1.7

Operational Procedures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1.8

GMP Issue 9301 1.1

General ~!:TetraPak

GeneralIn thefollowingarelistedandbrieflydiscussedsomeof theareasthatshouldbeconsideredwhenestablishingcompany-basedGMP (GoodManufacturingPractice)guidelines.GoodManufacturingPracticeis asetofwrittendirectivesfortheproductionof safeandwholesomefoodproducts.

Thispapermustberegardedasageneralguide,butit neitherconstitutesacomprehensivelistnordoesit aimatsolvingeachparticularproblem.It isuptoeachenterprisetoensurethatitsownsystemis adequateforitsoperation.

GoodManufacturingPracticesmaybeviewedashavingtwocomplementarycomponents1:

. Effectivemanufacturingoperations,

. Effectiveexerciseofqualitycontrolandqualityassurance.

Onthebasisofexistingguidelinesandregulations,eachindividualcompanyshouldtrytodevelopitsownproceduresin theserespects.

It isnottheintentionof theauthorsof thispapertocoverlegislativeaspectsofGoodManufacturingPractices(GMP's).Likewise,generalaspectsrelatingtobuildings,facilitiesetc.ofanentirefactorywill notbediscussedhere.It should,however,bebornein mindthatsuchrequirementsareoftencoveredbylocalregulations(generalforthefoodindustry),andthatlayout,installation,andconstructiondetailswill influencetheoverallqualitylevelof thefinishedproduct:endproductqualitystartswiththebuildings,facilities,installationetc.Whereatallpossibleconsiderationshouldbegiventotheseaspectsattheplanningstage.It iseasier,lessexpensive,andmoreeffectivetobuildtherightplantfromthebeginningthantochangeanexistingone!Wheneverregulationsexistinthisfield,theymustbefol-lowed.

At thepresenttime,rules,guidelinesandregulationscoveringGMPsforlong-lifefoodproductsarebeingformulatedinanincreasingnumberofcountries,eitheronavoluntaryorlegislativebasis.Theindustryconcernedshouldobservethisdevelopmentcloselyand,wheneverpossible,takeactivepartin it.

Footnoteno1:Basedon;FoodandDrinkManufa~ture- GoodManufacturingPractice:A GuidetoitsresponsibleManagement;PublishedbyTheInstituteofFoodScience& Technology,(UK)

1.2 GMP Issue 9301

General b~Teb'aPak

Effective Quality Controll Quality Assurance

Forthepurposeofthispaper,qualitycontrolandqualityassurancearedefinedasfollows:

. Qualitycontrolcoversactivitiestodeterminewhetheraproductor,whereapplicable,aprocessis withinspecificationsornot.

. Thepurposeofqualityassuranceisnotonlytopreventproductoraprocessfromdeviatingfromspecificationsbutalsototightenexistingqualityspecificationswheneverpossible.

Whilequalitycontrolis performedbyalimitednumberofpeoplespecificallytrainedandeducatedforthistask,everyemployeeshouldbepartofandincludedin aqualityassuranceprogramme.Qualitycontrolstaffplayamajorroleintheimplementationofaqualityassuranceprogramme.Theresponsibilityforcarryingoutthequalitycontrolworkcorrectlyrestswiththequalitycontrolmanager.Sincequalityassuranceactivitiesarecross-departmental,theymustbetheresponsibilityof thegeneral(factory)manager.

An effectivequalitycontrol/qualityassurancesystemrequiresthat:

a) Acceptancespecificationsaredrawnup(acceptancequalitylevels,AQL);

b) Adequatefacilitiesandstaffareavailablefor sampling,inspection,andtestingof:

- rawmaterials,

- intermediateproducts,

- finishedproducts.If required,assistancein fault-findingshouldalsobeprovided

c) Establishedproceduresexistthroughwhichrawmaterialsandsemi-fin-ishedproductsareapprovedforuse,rejected,ordesignatedfortreatmenttobringthemwithinspecifications;

d) An establishedprocedureexists,wheneverappropriate,wherebybatchesof finishedproductsaretemporarilyquarantineduntilofficiallyreleasedforreworking,or intonormalstock;

(Cont'doverleaf)

1.4 GMP Issue9301

b~TetraPak General

(EffectiveQualityControlCont'd..)

e) Sufficientsamplesof finishedproductsareretainedforshelf-lifetestsandtopermitfutureexaminationif necessary;

f) Customer/consumercomplaintsamplesareexaminedandloggedthecauseofdefectsinvestigated,andappropriatemeasuresadvisedtopreventrecurrence;

g) A systemis availabletorecallfromthedistributionchainorthepointofsaleanybatchofproducts,if everit shouldprovenecessarytodoso.

h) A systemisestablishedtodealwithtrouble-shootingsituations,withregardtostaff,funds,material,procedures,etc.

GMP Issue9301 1.5

Generalb~TetraPak

Trouble-Shooting

Trouble-shootingactivitiesmustbeinitiatedwheneveraprocessorthequalityofaproduct(rawmaterial,semi-finishedorfinishedproduct)deviatesfromspecifications.Trouble-shootingisteamworkandshouldbedonebyrepresentativesfrom:

. thedepartmentinvolved,i.e.withinthesectorwheretheproblemis,

Thenucleusofatrouble-shootingteamshouldbeappointedonapermanentbasis,withrepresentativesfromqualitycontrol,qualityassurance,production,etc.Thetaskof troubleshootingis toidentifythereason(s)fortheproblemandtotakeactionstorectifythefaults.Qualityassurancethenhastoadjustthequalityassurancesysteminordertoavoidrepetitionof theoccurrance.It is theresponsibilityoftop(factory)managementtoprovidethemeansnecessaryfortrouble-shooting,suchas:

. anactionplanwhichisestablishedandfollowed

. makingsurethatmethodsandproceduresofactionareelaboratedifpossiblein advance

. aproperrecordingsystemisestablished

. ataskforce

. funds.

Theexecutiveresponsibilityfortrouble-shootingshouldbeclearlyassignedtoeitherthequalitycontrol(qualityassurance)ortheproductionmanager.

GMP Issue93011.6

. qualitycontrol,

. qualityassurance,

. if required,outsideexpertise.

b~TeiraPak General

Sterilizing EffectIn mostcasesthedeathrateofmicroorganismsin generalandthekillingofbacterialsporesinparticularfollowsasemi-logarithmicorder.Consequent-ly sterility(zerosurvivors)cannotbereached,itcanonlybeapproached.Sterilizationprocessesthereforebecomeareductionin thenumberofsurvivingmicroorganismsandcanbeexpressedasthenumberofdecimal(logarithmic)reductionsachievedbytheprocess.Thisinturndefinesthesterilizingefficiencyor sterilizingeffectof theprocessinquestion.

A minimumrequirementdiscussedforthesterilizationprocessesoflow-acidfoodproducts(retortand/orUHT treatment)is 12decimalreductionsasdeterminedwithsporesofClostridiumbotulinum,correspond-ingto9-10decimalreductionswithsporesofBacillussubtilisusingapureheattreatment.

Consequentlythemicrobiologicalresultobtainedfromalong-lifeproductproductionlinecanbeexpressedbythefollowingequation:

DefectiveRate =ProcessSurvivors+Reinfection(DefectiveRate>0)

Forall sterilizationprocessesin use,regardlesswhetherusedtosterilizeloworhighacidproducts,scheduledcontrolledoperationalcharacteristicsshouldbecompiledin writingandverified,implemented,andadheredto.Ina"scheduledcontrolledprocess3", theminimumtreatmentparametersareclearlydefinedand,duringoperation,executedandrecorded.

Footnoteno3:A scheduledprocess"meansthethermalprocessaloneorincombinationwithcriticalfactorschosenbytheprocessorforagivenformulation,containertype,andsizeandthermalprocessingsystemtoachieveatleastcommercialsterilityof theproduct".(RecommendedCanadianCodeofPracticeforLow-acidandAcidifiedLow-AcidCannedFoods).Thescheduledprocessbecomescontrolledif allcriticalcontrolpointsarecontrolledandmonitored.

GMP Issue9301 1.7

General b~TetraPak

OperationalProceduresProceduresforequipmentoperationandmaintenance(preventivemainte-nance)shouldbeprovidedinwritingbythemanufacturer(supplier)oftheequipment.It istheresponsibilityof thedepartmentin whichsuchequip-mentis operatedtoensurethatspecifiedproceduresarecloselyfollowed.

In co-operationwiththeequipmentsupplier,scheduled,controlledpro-cessesmustbeestablished.Anydeviationfromtheprescribedvalues,settings,and/orparametersneedstoberecordedin aprocessdeviationrecord.Thesectionoftheproductionaffectedbytheprocessdeviationmustbequarantineduntilfurtherdecisionshavebeenmadebycompetent,assignedstaff.

1.8 GMP Issue 9301

b~TetraPak

Long-IifeFoodProducts

...................................."""""""""""""'" ..."""""""""""""""""'"..........................................................................""""""""""'" """"""".....................................""""""""""""'" ..."""""""""""""""""'"""""""""""""""""" '"""""'".....................................-Contents

General. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2.2

Commissioning 2.3

LinePerformanceTest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3

ElaboratingRules,GuidelinesandProcedures.. . . . . . . . . . . . . . . .. 2.4

TheImplementationsofGMPs 2.6

RawMaterialQuality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2.6

OrganisationalQuestions.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7

GMP Issue9301 2.1

Long-life FoodProducts b~'RItraPak

GeneralTheborderlinebetweenlowandhighacidfoodproductsisusuallydefinedbylocallegislationasapHof4.5or4.6.Long-lifeproductsarefoodproductswhichhavebeensterilizedbymeansof in-flowheattreatment(UHT4-processforlow-acidandapasteurisationprocessforhigh-acid5foodproducts)andwhicharesubsequentlypackagedusingasepticpackag-ingproceduresinordertomaintainthehighlevelofmicrobiologicalquality.Theproductsthusobtainedare"commerciallysterile".A commer-ciallysterileproductmustbe:

. freefromtoxins,

. freefrompathogenic(disease-causing)microorganisms,and

. freefrommicroorganismscapableofmultiplicationundernormalconditionsof storageanddistribution6.

GoodManufacturingPracticeproceduresmustcover:

. rawmaterialsandintermediateproducts,

. production,

. thefinishedproduct.

In implementingGMPs,twoconsecutivestepsmustbetaken:

. formulatingrules,guidelines,andproceduresin writtenform,and

. developingsuitableschemesfortheimplementationof theseprocedures2

Footnoteno4:UHT-treatment(ultra-high-temperature)asusedforlow-acidfoodproductsusuallyreferstoaheattreatmentin therangeof 135- 150C(275- 302F) withaholdingtimeof "afewseconds"followedbyrapidcoolingtoambient.

Footnoteno5:

Mosthigh-acidfoodproductsare"pasteurised"atatemperatureof85 - 95C(185- 203F) withholdingtimesof 15- 30seconds.Thetime/temperaturecombinationnecessaryvariesdependingontheproductanditspH.Someproductsrequirehighertemperatures.

Footnoteno6:USA FDA definition

2.2 GMP Issue9301

b~'noIraPak Long-lifeFoodProducts

CommissioningAfterdeliveryandinstallation,eachitemofequipmentinaproductionline(s)shouldbeshowntoperformaccordingtoagiven(andagreed)specification.It is theresponsibilityof theequipmentsuppliertocompileequipmentspecifications,testmethods,andprocedures,aswellastocarryoutactualcommissioning.Thecommercialprocessorhastoprovidethetimenecessaryforthecarryingoutofthecommissioningprocedure.

Line Performance Test

Priortostart-upof commercialproduction,along-lifeproductproductionlineshouldbetestedforits- oraspecified- performancelevel.

Toachievethis,suitabletestmethodsandproceduresmustbeestablished,preferablyinc(H)perationwiththeequipmentsupplier(s).Theproductionlinecanonlyberegardedasreadyforcommercialproductionif suchatesthasshownthatthelinecanperformin accordancewithspecifiedqualitystandards.

It is theresponsibilityof thecommercialprocessortoorganizeandcarryoutsuchalineperformancetest.All partiesinvolvedin aninstallationshouldactivelyparticipatein theplanningandperformanceof suchatest.

GMP Issue9301 2.3

Long-life FoodProductsb~TeiraPak

Elaborating Rules, Guidelines andProcedures

Thefirststepin establishingrules,guidelines,andproceduresmustbetoclearlydefineacompanyqualitypolicy.Thisincludesconcurrenceonacceptablequalitylevels(AQL).Suchadefinitionshouldcoverallaspectsrelatingtothequalityof thefinishedproduct.Furthermore,productionsafetyaspectsshouldalsobeincludedinsuchascheme.It is importanttounderlinethatsuchcompanyqualitypoliciesshouldbeambitiousbutmustberealistic:qualitylevelswhich,forwhateverthereason,cannotbeachievedhaveademoralizingeffectontheworkingstaff.Finishedproductqualitylevelsshouldbeestablishedfor:

. chemicalcomposition,

. physicalcharactenstics,

. nutritionalvalue,

. organolepticproperties,

. microbiologicalaspects,etc.

Sincetheabovequalitycharacteristicsareamatterof companypolicy,seniormanagementmustbeactivelyinvolvedinestablishingsuchlevels.Oncesuchqualitystandardsareagreed,suitablemethodsandprocedureshavetobedevelopedforthequalitycontroVqualityassurancework.In thisdocument,themainemphasiswill beonthemicrobiologicalqualityaspectsof theoperationandthefinishedproduct.Twostepsneedtobetakeninordertodevelopsuitableprocedures:

. apropositionofmethodsandprocedures,

. acostevaluation.

MethodsandprocedurescanbedefinedanddocumentedbymiddlemanagementwhilsttheevaluationofcostsrequirestheinvolvementofseniormanagementIf costsprovetobeexcessiveit maybenecessarytorevisethemethodsandprocedures.If theserevisionsareimplementedtheconsequencesshouldbeclearlyidentifiedandcommunicatedtoseniormanagement.

(Cont'doverleaf)

2.4 GMP Issue9301

b~TetraPak Long-life Food Products

(ElaboratingRules...Cont'd)

At theendof thisprocess,thefollowingshouldbedefinedandstatedinwriting:

. productqualitylevels(standards,AQL) forrawmaterials,semi-finishedandfinishedproduct(s),

. methodsandprocedures,

. thecostimplications.

As pointedoutabove,themicrobiologicalresultobtainedfromalong-lifeproductproductionlinecanbeexpressedbythefollowingequation:

MicrobiologicalResult(DefectiveRate) =ProcessSurvivors+Reinfection.

It is importanttokeepin mindthattheresultobtainedfromtheaboveequationcannotbezero,it canonlyapproachzero.Thisshouldbetakenintoconsiderationwhensettingupmicrobiologicalqualitystandards(AQLs)forthefinishedproduct.SuchanAQL couldbebasedupona"maximumacceptabledefectiverate"andcanbeexpressedas:

x defectivespery unitsproduced,

wherex is greaterthanzero.

GMP Issue9301 2.5

Long-life Food ProductsbI:~Pak

The Implementationof GMPsOnlyclearlydefinedobjectivescanbeachievedwithanychanceof success!ImplementationofGMPsmusttakeintoconsideration:

Raw Material Quality

Rawmaterialsarealltheingredientsrequiredtomaketheproductaswellasanyothermaterialsneededinthemanufacturingprocess.Suitableandrealisticqualitystandardsandtestingmethodsneedtobedevelopedforallimportantcharacteristics.Rawmaterialqualitycontrolaswellastheircorrecthandlingaretheresponsibilityof thequalitycontroldepartment.

Fromamicrobiologicalpointofview,attentionneedstobepaidtototalandthermoresistantbacterialendosporecounts(Bacillus)(forlow-acidprod-ucts)andtofungi(yeastandmoulds)andtocertaingroupsofbacteria(Lactobacillus,Streptococcus,etc.)(forhigh-acidfoodproducts).Rawmaterialqualitycontrolaswellastheircorrecthandlingaretheresponsibil-ityofthequalitycontroldepartment..

Packagingmaterialsshouldbestoredandhandledinaccordancewiththerecommendationsof thesupplier.Appropriatetestingproceduresshouldbeestablished,formulated,andimplementedforeachnewassignment.

Chemicalsshouldbepurchasedaccordingtoclearqualityspecificationsandhandledandstoredin accordancewiththemanufacturer'srecommendations.

2.6 GMP Issue9301

. rawmaterialquality,

. organIzation,

. productionarea,

. qualitycontrol/qualityassurance,

. thefinishedproduct

b!:TetraPak Long-life Food Products

Organizational Matters

A companymusthaveaclearpersonelstructure.Organizationschemeswilldependuponthesizeandcomplexityof theoperation.In anyevent,areasofresponsibilityandauthoritymustbeclearlydefinedandenforced.

Thisis ataskof topmanagement,whosecommitmentis essentialforsuccess.It shouldbeborneinmindthatthesuccessfulimplementationofGMP'srequirescloseco-operationbetweendepartments.

Theselectionofdepartmentmanagers- againatopmanagementtask-shouldbedonewithtwoaspectsin mind:

. jobqualification,

. abilitytoworktogether.

Co-operationbetweendepartmentscanbedifficultandrequiresnotonlytherightpeoplebutalsoclearlydefinedareasofresponsibilityandthebackingof seniormanagement.

Suitabletrainingandeducationalprogrammesshouldbeplannedandimplementedregularlytoimprovethelevelof knowledgeGobqualification)aswellastheabilitytocooperateonamiddlemanagementlevel.

GMP Issue9301 2.7

b~TetraPak

The Production Area

.................................................................................................................................."""""""""."""""""'""""""""""""""""""'"....................................."""""'". """.""""".'" ..."""""""""""""""""'""""."" "."""'."" ....."'".'.'.'.'.'.'.'...........................................................................""""" ......................'.'.'.'.'.'.'.'.'.'..'.'. '.'...'."'.'.'.'.'.'... .......................'.'.'...''.' '.'.'.'.'.'. '...'.'.'.'.'.'.'.'.... ....................""""" ......................................................' '.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'...................................................................... ................................................."""""""'" ........."""'"...........""" ""'.'"""'" .......... .........."""'" ".".' .........."" . ..........""""" .......... ............. ....................................................,.".'...'.'.'.'.'.'.'. .'.'.'.'.'.'.'.'.'.'.'.'"""""" .............:Ii."i:::i:.:,,':'i":::.:i:::::::i::::i::i:::::..illl::..'.:i::I:I'li:'

Contents

General.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 3.2

Pre-processTreatment.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 3.3Increasein theTotalMicrobialLoad. . . . . . . . . . . . . . . . . . . . . . . . 3.6

IncreaseinBacterialSporeCounts. . . . . . . . . . . . . . . . . . . . . . . . . 3.7

Cleaningof theEquipment.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8

CirculationCleaning. . . . . . . . . . . . . . . . . . . . . . - . . . . . . . . 3.9

CleaningAgents.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.9

WaterQuality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.10

CleaningProgram. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.12

Concentrationofcleaningsolutions.. . . . . . . . . . . . . . . . . . 3.13

Temperature.. . . . . . . . . . . . . . . . . . . . . . . . . . . . - . . . . . . . 3.14

Flow Rate.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.15

CirculationTime. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.15

CleaningUnits. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16

ControlofCleaningProcedures.. . . . . . . . . . . . . . . . . . . . . . . . . . .. 3.18

GMP Issue9301 3.1

The Production Area b.!TetraPak

GeneralIn along-lifeproductproductionplant,theproductionareamay,andoftendoes,coverthefollowingsections:

. internaltransportandstorage(sometimes).

Eachof thesesectionsmaybeheadedbyamanagerorsupervisor,dependingonthesizeof theoperation.

3.2 GMP Issue 9301

. pre-processtreatment,

. productprocessing,

. productpackaging,

b!:TetraPak TheProductionArea

Pre-processTreatment"Pre-processtreatment"coverstherouteof rawmaterials(ingredients)fromthereceiving(reception,storage)areatotheproductsterilizer.Allproceduresmustensurethatproductdamageis minimized.

Operatingschedulesandproceduresmustbesuppliedinwritingbytheequipmentsupplierandit is theresponsibilityof theproductiondepartmenttoensurethattheproceduresgivenareobservedmeticulouslyandthatmaintenanceroutinesarefollowedandcarriedout.

Fromamicrobiologicalpointof view,attentionshouldbepaidto:

. changesinthetotalmicrobialload(totalcount),

. increaseinthebacterialsporecount(low-acidproducts)orincreaseinthecountof yeastandmoulds(high-acidproducts).

Microbiologicalstandardsshouldbedevelopedforthesevariouscounts,andlevelsof acceptance(AQL) shouldbeestablishedandenforced.Thesecountsareinfluencedby:

. theinstallationingeneral,

. theequipmentused,

. anypre-treatmentproceduresapplied,suchastime/temperaturetreatment(s),

. theprevailinghygienicconditions.(Cont'doverleaf)

GMP Issue9301 3.3

The Production Area ~~TetraPak

(Pre-ProcessTreatmentCont'd)

Theinstallationshouldbe:

"Checkpoints7" shouldbeidentified,andspecialattentionneedstobepaidtoensurethatproperfunctionand/oractionsareimplemented.

It istheresponsibilityof theproductiondepartmenttoensurethatadequatecleaningandhousekeepingproceduresaredocumentedandfollowedwiththenecessaryfrequency:floors,walls,andequipmentmustbekeptclean,i.e.freefromrubbishandwastematerialaswellasfromdetectablesoil(deposits).

Connectionsbetweenpiecesof equipmentshouldbepermanent;rubberand/orplastichosesshouldbeavoidedasmuchaspossible.Unnecessarychangesin levelshouldbeavoided.Attentionmustbepaidto"deadends8".Pipingshouldbeasstraight-forwardaspossible.

Themaximumpermissibletimeforthepre-processtreatmentshouldbeestablishedin writingforeachspecificproductinquestionandshouldbe:

. aslongasnecessary,

. butasshortaspossible.

Productspreparedfrompowders,orwithpowderasaningredient,may-andoftendo- requiresomesoakingtimeinordertoachievecompletewettingof thepowderparticles,necessaryforefficientsterilization.Forsuchproducts,minimumtreatmentconditionsmustbeestablished.

(Cont'doverleaf)

Footnoteno7:A "checkpoint"is anoperationatwhichapreventiveand/orcontrolactionistakenbecauseofgoodmanufacturingpractices,regulations,productreputation,corporateorcompanypolicies,oraesthetics

Footnoteno8:Theratiooflength.to.diametershouldnotbemorethan1.5.

3.4 GMP Issue9301

. suitableforitspurpose,

. asuncomplicatedaspossible,

. ofhygienicdesIgn.

j.~'18IraPak The Production Area

(Pre-ProcessTreatmentCont'd)

Toolongtreatmenttimesmayleadtounnecessarymultiplicationofmicroorganisms,resultinginundesirableproductchangesand/orthepossibledevelopmentof thermo-resistantenzymes,whichmaycausesuchdefectsasrancidity,bitterflavour,orgelationof lowacidfoodsduringstorage.Also,dependingontemperatureconditions,thebacterialsporecountmayincreasetoanunacceptablelevelwithunsterilityasaconse-quence.

Minimumand/ormaximumtemperaturesduringthepre-processtreatmentperiodshouldbedocumented.Thesetemperaturesshouldbe:

. adequatefortheintendedpurpose,

. if possiblebelow4 - 5C(39- 47P),

. orabove65C(149P);(forlow-acidfoodproductsonly).

Temperaturesabove65C(149P)will preventmicrobialmultiplicationbutmayhaveotherundesirableeffectsontheproduct,particularlyforhigh-acidfoods.Low temperatures,i.e.below4 - 5C(39- 47P),reducetherateofmicrobialmultiplication.In thelowtemperaturerange,psychrotrophic(psychrophilic)microorganismsmaymultiply.Someofthesemayinlow-acidfoodsformthermo-resistantenzymes,suchaslipasesandproteaseswhichmaylimitorreducetheacceptableshelf-lifeof theproduct(s).Thisis particularlytrueforPseudomonasandespeciallyin milkandmilkproducts.

In thepre-processingarea,hygienicconditionsrelateto:

. hygienicdesignandinstallationofequipment,

. adequatecleaningandsanitizingprocedures,

. suitablehousekeeping,etc.

In agivenplant,changesin theinstallationareusuallydifficult(andexpensive)toaccomplishbutshould,nevertheless,beconsideredandwheneverfeasible,becarriedoutif hygienicimprovementswill result.

Cleaningandsanitizingproceduresaswellashousekeepingactivitiesshouldbedocumented;it isthetaskof theproductiondepartmenttoensurethattheseproceduresarefollowedandproperlycarriedout.

GMP Issue9301 3.5

The Production Area b!:1IriraPak

Increase in the Total Microbial Load

Duringthepre-processtreatment,acertainincreasein totalmicrobialcountis unavoidableeventhoughheattreatment(s)(thermization,pasteurisation)mayresultin atemporarydecrease.Themagnitudeof theincreaseintotalcountwill dependtoacertainextentontheinstallationbutalsoonthetreatment(s)applied.GMPsareaimingtorestrictthisincreaseasmuchaspossible.Multiplicationofmicroroganismsaboveandbeyondthatwhichisunavoidableshouldbeusedasanindicationof apotentialdeficien-cyinthehygienicconditionsand/orhousekeepingprevailinginthisarea.

Standardsshouldbesetonmaximumacceptabletotalcountsasameasureof:

. adequatetime/temperaturetreatment(s),

. correctcleaningandsanitationprocedures,

. acceptablehousekeeping.

If suchstandardsareexceeded,propermeasures("trouble-shooting")shouldbetakentoanalyseandrectifytheproblem.As faraspossible,actionplansshouldbepreparedwellinadvance.

Inordertoavoidsuchdeviations,thestaffshouldbeencouragedto:

. participateinregulartrainingandeducationonsanitation,

. suggestimprovements,etc.

3.6 GMP Issue9301

b~TetraPak The Production Area

Increase in Bacterial Spore Counts

As pointedoutanddiscussedelsewhere,themicrobiologicalresultobtainedfromasterilizationprocessisdetenninedbytwofactors:

. thesterilizingefficiencyof thesterilizationprocess,Le.thetime/temperaturecombination,

. themicrobiologicalloadfedintothesterilizingprocess(bacterialsporesforlow-acidproductsandyeastandmouldsforhigh-acidproducts).

(ProcessSurvivors=ProcessParameters+Load)As aconsequenceof theaboveequation,standardscanandshouldbedevelopedwithregardtothemicrobialloadof theproductsubjectedtoasterilizationprocess.Suchaspecificationwill bedetenninedby:

. thesterilizingefficiencyof thesterilizationprocess,

. themaximumacceptabledefectiverate(AQL).

It is theresponsibilityof theproductiondepartmenttooperatethepre-treat-mentof theproduct(s)(intermediateproduct)in accordancewithspecifiedwrittenprocedures,aswellasensuringthatadequate,accuraterecordsarekeptof:

. batchesof rawmaterial,

. pre-processingtechniquesapplied,

. cleaningandsanitationproceduresused,etc.

Controlfactorsof importancetothequalityof thesemi-finishedproduct(s)shouldbeidentifiedandlisted.Suitableproceduresshouldbe:

torecordandcontrolthosefactors.Thisappliesparticularlytocleaning/san-itationoperations.Thermosensors,timers,pressuregauges,etc.,regulatingcontrolpoints(heating,cooling,cleaning,etc.)areautomaticcontroldevices(seepage4.4)

GMP Issue9301 3.7

. communicated,

. specified,

. implemented

The Production Area bj.TetraPak

Cleaning of the Equipment

A consistantlygoodresultof anoperationcanonlybeexpectedif theequipmentis reasonablyclean.Cleaningproceduresareof importancewithrespectto:

. corrosionof theequipment,

. theresultof equipmentsanitationor sterilizationprocesses,

. generalproduct quality aspects,

. theenvironment.

Manypiecesof equipmentin theprocessingand preprocessingareaareorcanbecleanedby "cleaning-in-place"(CIP)circulationprocedures.Suchcleaningoperationsimply:

. theproperchoice of cleaning agents,

. adequatewater quality,

. a suitablecleaning programme,

. correctconcentrationsof cleaning agents,

. correcttemperaturesin the cleaning cycles,

. sufficientflow ratesof cleaningsolutions,

. adequatecirculationtime(contacttime).

Other partsof the installation and/orequipmentmay, for different reasons,requiremanual cleaning. Though the samefactors apply,attentionhas to bepaid to theHuman Factor (Seepage 4.5)

In manualcleaning,foamingdetergentsshouldbeused.ThepH valueshouldbemoderate(betweenpH 3 andpH 10).A temperaturearound40C(104F)is recommended.Suitablecontainersfor both thecleaningandthesubsequentdisinfection(sanitation)havetobeprovided.The instructionsbytheequipmentmanufacturerandthedetergentsuppliermustbefollowed.Theresultof manualcleaningor disinfectionshouldbecontrolledregularlybyinspection.

(Cont'doverleaf)

3.8 GMP Issue9301

b~'nItraPak The Production Area

(CleaningoftheEquipment,Cont'd)

Circulation Cleaning

In thefollowing,circulationcleaning(CIP)will bediscussedin somedetail.

CleaningAgents

In choosingoptimumcleaningagents,attentionshouldbepaidto:

. qualityof thewateravailable,

. kindofdeposit(soil),i.e.kindofproductand/orprocessapplied,

. corrosion,i.e.kindofmaterials(surfaces)tobecleaned,

. thecostfactor,

. environmentalaspects,etc.

Oftencleaningagentssuchas;

. nitric(HNO3)orphosphoric(H3PO4)acid

. caustic(NaOH)

will beadequate.In somesituations,compositecleaningagentswillgoptimumresults.

(Cont'doverleaf)

GMP Issue9301 3.9

. existingregulations,

. safetyofhandlingandstorage,

. stabilityduringstorage,

The Production Area b~TetraPak

(CleaningoftheEquipmentCont'd)

WaterQuality

In cleaning,thewaterqualitymayinfluencethechoiceofcleaningagentbutmaybeevenmoreimportantforpossiblecorrosionof theequipment.Watertreatmentmaybecomenecessaryincertainsituations.

Thefollowingwaterqualitieshavebeenrecommended:

a) IDF (InternationalDairyFederation):

Hardness

pHChloride

SulphateIron

3 - 4dH>8.3

b1:TetraPak The Production Area

(CleaningoftheEquipment/WaterQualityCont'd)

Bothrecommendationsrefertominimumcorrosion.Thehardnessofwaterisdefined(inUSA) asfollows:

Veryhard

0- 6dH

6-12dH

12-18dH

>18dH

Softwater

Mediumhard

Hardwater

(1dH =10ppmCaO = 17.9ppmCaCO3)

(Cont'doverleaf)

GMP Issue9301 3.11

The Production Area b!:TetraPak

(Cleaningof theEquipmentCont'd)

Cleaning Programme

In choosingacleaningprogramme,considerationshouldbegivento:

. kindofdeposit,

. timerequired,i.e.down-time,

. possibleriskofproductcontamination.

Forplainwhitemilk,thefollowingcleaningsequenceisusuallysufficient:

Specialproducts,poorrawmilkquality,etc.mayrequiremodificationofthecleaningprogrammestatedabove.

(Cont'doverleaf)

3.12 GMP Issue 9301

. waterrinse,

. alkalineclean,

. waterrinse,

. acidclean,

. waterrinse.

b~181mPak The Production Area

(CleaningoftheEquipmentCont'd)

Concentration

Cleaningagentsshouldbeusedatoptimumconcentrations.Factorstobeconsideredare:

Concentrationshouldbeadequatetocleanthesurfaceinquestionbutshouldpreferablynotexceedthelevelnecessary.Dependingonthekindofdeposit("hot"or"cold"surfaces,kindofproduct,cleaningagent,etc.),concentrationsof thecleaningagentnecessarytoobtainthedesiredresultwill vary.ForplainwhitemilkandUHT treatment,thefollowingconcentrationsareusuallysufficient:

caustic(NaOH) 1 - 2%

acid (HNO3,H3PO4) 0.6 - 1.5%

If compositecleaningagentsareused,thesuppliersrecommendationsshouldbeobtainedin writingandmustbefollowedcarefully.

(Cont'doverleaf)

GMP Issue9301 3.13

. corrOSIon,

. effectiveness,

. cost.

The Production Area b~TetraPak

(CleaningoftheEquipmentCont'd)

Temperature

Theoptimumtemperatureforcleaningisdeterminedby:

. thekindofdeposit,

. thecleaningagent,

. thesurfacecharacteristicsof theobjectsbeingcleaned.

Thecleaningefficiencyof thealkalineclean(caustic)isverydependentontemperature.Evenathightemperatures,corrosionproblemsonstainlesssteelareminimal.Consequently,cleaningtemperaturesusedin thealkalinecleanshouldbeashighaspossible,preferablyin therangeof >80C(>176P)toactualprocessingtemperature.If temperaturesin excessof100C(212P)areapplied,theequipmentmanufacturershouldbeconsultedandtheproductsterilizermusthavespecialprotectioncovers,particularlyarrounditsplateheatexchangerstoensurethesafetyof theoperatingstaff.

Ontheotherhand,theeffectivenessoftheacidcleanis muchlesstemperaturedependent.Acidsathightemperaturesreducetheelasticity("pressureset")ofrubber,additionallyathightemperatures,corrosiononstainlesssteelsurfacesmayoccur.Consequently,thetemperatureof theacidcleanshouldbekeptin therangeof50- 80C(defenitelynothigherthan90C)[140- 176P(194P)].

Again,if compositecleaningagentsareused,thesuppliershouldprovideinwritingoptimumtemperaturerecommendationsthatshouldbefollowedmeticulously.

(Cont'doverleaf)

3.14 GMP Issue9301

b~TetraPak The Production Area

(CleaningoftheEquipmentCont'd)

Flow Rate

In ordertomechanicallytransportdispersedparticlesoriginatingfromdepositsorproductresidues,aturbulentflowisneeded.Turbulentflowinpipesis achievedataflowvelocityof:

>1.5rn/sec.

It is importantthatcirculationofcleaningliquidsiscarriedoutatasuffi-cientflowratetoobtainturbulence.In CIP circuits,usuallycentrifugalfeedpumpsareused.Theflowratein suchacircuitisdeterminedby:

. thecapacityof thefeedpump,

. thepressuredropoverthecircuit.

Bothshouldbeconsidered,andtheactualflowratesachievedshouldbemeasuredand/orcalculated.Anychangein thecleaningcircuitrequiresre-checkingoftheflowratesincesuchchangeswill affectthepressuredrop.

Circulation Time

Sufficientcirculation(contact)timemustbeprovidedfor.Thetimenecessaryis determinedby:

. temperatureof thecleaningagent,etc.

(Cont'doverleaf)

GMP Issue9301 3.15

. kind of deposit,

. kind of equipment,

. desIgnofequipment,

. cleaningagentused,

The Production Area b~TetraPak

(Cleaningof theEquipmentCont'd)

Cleaning Unit

TooperateCIP circulationsystems,cleaningunitsareused.Incarryingoutcleaningoperations,theprocessneedstobe:

. adequate,i.e.cleantheobject,

. repeatable,Le.controlled.

A controlledprocessis notnecessarilyadequate!A controlledprocessisrepeatablewhileanadequateprocessdoeswhatit is supposedtodo:acontrolledandadequateprocessachieveswhatit is supposedtoeverytime.Thecontrolof thecleaningoperationis performedbythecleaningunit.Inthisrespect,adistinctioncanbemadebetweenthreedifferenttypes:automatic,semi-automatic,andmanuallyoperated.

(Cont'doverleaf)

3.16 GM P Issue 9301

b~TetraPak The Production Area

(CleaningoftheEquipmentlCleaningUnitCont'd)

Functionscontrolledbythedifferentunits:

Functions,whicharenotregulatedautomatically,havetobecontrolledbythemachineoperator(s)andthusbecomesubjecttotheHumanFactor.

For semi-automaticandmanuallyoperatedcleaningunits,specialattentionshouldbepaidtothe"concentration".In ordertoachieveacontrolledandsufficientcontacttime,aswellastominimizecorrosion,theconcentratedcleaningagentsmustbeaddedtothesystemduringaperiodof timecorrespondingtoonecirculationcycle.Inordertodeterminethistime,the

. volumeof thecleaningcircuit,and

. theflowrateof thecleaningsolutionhavetobeknown.Theconcentratesarethenaddedduringthetimethuscalculated.

Alternatively,it ispossibletopreparethetotalvolumeofcleaningsolutionrequiredtofill thecleaningcircuitatonce.In thiscase

. thevolumeof thecleaningcircuitmustbeknown,

. astoragetankof sufficientvolumemustbeavailable.

Automaticcleaningunitsrequirecertainmaintenanceandpreventivemaintenance.Thisisespeciallytrueforthe(sensitive)detergentconcentratedosingunit.Maintenance(preventivemaintenance)schedulesshouldbedocumented,preferablyinc~perationwiththemanufacturer(supplier),andimplemented.

GMP Issue 9301 3.17

Function

I

Auto. Semi-auto. Manual

Flow + + +

Time I + +

TemperatureI + +

ConcentrationI +

SequenceI +

TheProductionArea b~UltraPak

Control of the Cleaning Procedures. Thepurposeofacleaningoperationis toobtainphysicallycleansurfaces.Thecontrolof theoperationrequirestwosteps:

. controlof thecleaningprocess,i.e.repeatabilityof theoperation,

. checkingof theactualresultobtained.

Thecontrolof thecleaningprocesshasalreadybeendiscussed(seethesectionon:CleaningUnitspage3.18).Inordertodeterminetheresultofa(controlled)cleaningoperation,attentionshouldbepaidto:

. pocketsin thecleaningcircuit,

. cleanliessof thesurfaces,

Pocketsin cleaningcircuitscanbedetectedbymeasuringthepHand/orconductivityin thereturnlineduringthefinalrinse:thepHorconductivityshoulddecreaserapidlyandcontinuously.Peaksduringthisdecreaseindicateoneormorepocketsin thecircuitwhichcantrapacidoralkaline.

Physicalcleanlinessof surfacesshouldbecheckedvisually.However,theHumanFactor(seepage4,5)shouldbeconsidered.Themostdifficultpartstocleaninacleaningcircuit,suchasdeadends,pumps,valves,topoftanks,etc.,shouldbeidentifiedand,if accessible,inspected.

3.18 GMP Issue9301

b~TeiraPak

Product Processing

..........................................................................'.'.'.'.'.'.'.'.'.'.'...'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.................................................................................................................'.'.'.'.'.'.'.'.'.'."'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.''....................................."""""""""""""""""'" """"""""""""""""""""'"......................................'.'.'.'.'.""""""........................................................................................................................... ...............""""""" ............. ............. ............""'" .. ............. .............. ..............."""'" .. ..'... ............... ............... """"""... ............"""""".'.'.'.'."'.'.'.'.'..'.'.'.'. .'.'.'.'.'.'.'.'.'.'.'.'.........................'.'.'...'.'.'.'.'.'.'.'.'.'. .'.'.'.'.'.'.'.'.'.'.'.'.'.'."'.'.'.'.'.'. "'."'.'.'.'.'.'.'.'...'.'.'.'.'.'.'.'.' '.'.'.'."'.'."'.'.'.'.'.'.'.'.'.' '.'.'.'.'.'.'.'.'.'.'.'.'.'...'...' '.'.'.'.'.'.'.'.'.1IIIIIiililliiliiiiijlliilllilllilillil~~i:.::::~:IIIII111111111I111II111I

ContentsGeneral.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 4.2

AutomaticControlDevice.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . 4.4

FunctionsControlledbytheHumanBeing. . . . . . . . . . . . . . . . . . . . . 4.5

CleaningoftheEquipment.. . . .. . . .. . . . .. .. .. . . ... .. . ... .. . . 4.6

EquipmentSterilizationPriortoProduction.. . .. . ... .. . .. ... . . . 4.6

Product sterilization' . .. . . . . .. . . . . . . . . . . . . ... . . .. .. .. .. .. .. .. 4.8SteamQuality.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9

SterilisingTemperature.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9HoldingTime.. . .. . . . . . . . . . . . . . . . . .. . . . . . . ... . . . . . . . . . 4.10

Capacityof theProductSteriliser 4.11

VolumeoftheHoldingCell. . . .. . . .. .. . . ... . .. ... . .. 4.12

TheAsepticFunctionoftheEquipment... .. .. .. . . ... .. . .. .. .. 4.13SteamBarriers.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.14

GMP Issue9301 4.1

Product Processingb~TetraPak

GeneralProductprocessingcoverstheareafromtheproductinletbalancetankoftheproductsterilizertotheproductvalveof theasepticpackagingequipment,includingtheaseptictransfer.It is theresponsibilityoftheproductiondepartmenttoguarantee

. thattheprocessesappliedarein accordancewiththeprocessesintendedtobeapplied,

. thatproper,accurate,andadequaterecordsarekept.

Fivesubjectsof interestneedtobeconsideredin thisrespect:

. cleaningoftheequipment,

. equipmentsterilizationpriortoproduction.

. productsterilization,

. asepticfunctionof theequipment,

. maintenanceandpreventivemaintenanceoftheequipment.

Generalcontrolpointsaswellascriticalcontrolpoints9 mustbeidentified.Forheatsterilizationprocessesingeneral,thecriticalcontrolpointsare:

. timeofexposure,

. temperature.

(Cont'doverleaf)

Footnoteno9:A criticalcontrolpointis anoperation(practice,procedure,process,location,or parameter)whereapreventiveorcontrolmeasurecanbetakentoeliminate,preventorminimisehazards. .

4.2 GMP Issue9301

b~1etraPak Product Processing

(GeneralCant'd)

Thesecriticalcontrolpointsneedtobecontrolledduringtheexecutionofaheatsterilizationprocess.Suchcontrolcanbedoneeitherby:

. automaticcontroldevices,or

. manuallybytheequipmentoperator.

Boththesemeansofcontrolrequiredifferentproceduresand/ormethodstoensureadequatefunctionandtominimizethehazardandrisk10involved.

Footnoteno10:A hazardis anintrinsiccharacteristicof anoperationwhich,undercertaincircumstances,mayleadtoharmorproductspoilage,whiletherisk is anexpressionof theprobabilityof ahazardbecomingareality.

GMP Issue9301 4.3

Product Processingb!:TetraPak

AutomaticControl DeviceAutomaticcontroldevicesareoftenusedtocontrolcriticaltemperatures,pressures,times,etc.Frequentlytheyhaveadoublefunction:

. regulatingaprocess,

. guardingagainstprocessdeviations.

Theregulatingfunctionshouldbecalibrated,whilechallengingbecomesnecessarytoassureproperoperationof theguardingaction.Calibrationandchallengingneedtobedoneasoftenasnecessarybutshouldbeexecutedatleastonceayear.

Calibrationandchallengingrecordsshouldbekeptandsignedbythepersondoingtheworkandcountersignedbyanauthorizedperson.It istheresponsibilityof theproductiondepartmentthatpropercalibrationandchallengingproceduresareexecutedwiththenecessaryfrequencyandinaprofessionalway.

Automaticregulating,guarding,andcontrollingprocedureslendthemselvestomonitoring,i.e.printorelectronic(disc)recording.Wheneverpossible,suchmonitoringdevicesshouldbeusedincombinationwithmachineoperatorrecordkeeping.

4.4 GM P Issue 9301

b~TetraPak ProductProcessing

FunctionsunderHumanControlSomecontrolpoints/criticalcontrolpointsofalong-lifeproductproductionlinecannotbeorarenotbeingcontrolledbyautomaticdevices.Thecontrolof thesebecomesthetaskof themachineoperatorandthussubjecttotheHumanFactor.

Verycloseattentionshouldbepaidtosuch(critical)controlpointsandmeasuresshouldbetakentominimisetheriskinvolved.By

theriskcreatedbythehumanfactorcanbereducedbutnoteliminated.

It is of greatimportancethatmachineoperatorrecordsarekeptinaproperway,especiallyif controland/orcriticalcontrolpointsarerecordedmanuallyonly.Obviously,theprimarytaskofamachineoperatoris toattendtotheequipment.

Disturbancesin theprocess(equipmentfailures)mustberectifiedasquicklyaspossible.Recordkeepingbecomesamatterof secondaryinterest.As aconsequencetimestatementsarenotalwayscorrect:therecordis filledin, if atall,aftertheevent.

Operativefaults,i.e.mistakesmadebythemachineoperator,areoftennotrecordedatalloradifferentreasonis givenfortheincident.

It is theresponsibilityof theproductiondepartmenttoensurecorrectrecordkeeping.Suitablerecordsheetsneedtobedeveloped,preferablyinco-oper-ationwiththeequipmentmanufacturerandthequalitycontroldepartment.Suchoperatorrecordsshouldconcentrateonpointsof importance.Anydeviationfromthescheduledprocessshouldberecordedonaspecialprocessdeviationrecordsheet(seealsoundersection:MachineOperatorRecords,page9.5).

GMP Issue9301 4.5

. trainingandre-training,

. educationprogrammes,

. motivation,

. supervIsIon,

. supplyofproperequipment,

ProductProcessing b~TeiraPak

Cleaning of the EquipmentRefertothesectiononcleaningunderPre-Processing(seepage3.9).

Equipment Sterilization Prior toProduction

Dependingupontheinstallationinquestion,theproductsupplysidemayeitherhaveoneortwo(orevenmore)sterilizationcyclesin oneandthesameproductionline:

. sterilizersoperatingdirectlywiththeasepticpackagingequipment:onesterilisationcycle,

. sterilizersoperatingviaasteriletank:twoormoresterilizationcycles.

Theproductsterilizerwithconnectedpipe-linescanbesterilizedeitherby

. steam,or

. hotwaterforhigh-acidandsuperheatedwaterforlow-acidproducts.

Thesteriletankcircuitwithconnectedpipe-linesis alwayssterilizedbysteam.Regardlesswhethersteam,hotwater,orsuperheatedwater,is usedassterilizationmedium,theactualequipmentsterilizationprocessis alwaysatime/temperaturetreatmentwhichusuallyis (andshouldbe)controlledby

. atimer,and

. athermosensor.

(Cont'doverleaf)

4.6 GMP Issue9301

b~TetraPak Product Processing

(EquipmentSterilizationPrior toProductionCont'd)

TheseinstrumentsareAutomaticControlDevices,andthecontrolfunctionismeasureddirectly.

Attentionshouldbepaidtotheinstallationin general.If steamisusedassterilizationmedium,condensatepocketsmayleadtoaninsufficienttimettemperaturetreatment.Air pocketsmayinterferewithequipmentsteriliza-tionif hotorsuperheatedwateris used.Thisisespeciallyso,if thecapacityof theproductsterilizeris suchthatturbulentflow(>1.5m/sec)isnotcreatedand/orif longperiodsof timeelapsebetweencleaningandsteriliza-tion.

Thelocationof thethermosensorcontrollingtheplantsterilizationcycleisalsoof importance:thisthermosensormustbeplacedinthereturnline,i.e.afterthelastpieceofequipmentin theproductlinewhichneedstobesterilized.

In installationswithtwo(ormore)cleaningandsterilizationcircuits,oneareaof concernisthepointwheretwosuchcircuitsmeet.Thelocationoftheseshouldbeidentified.Theseinterfacescanbeverysmallsuchasaseatofavalvebutcanalsobeextensivelengthofpipeworkwithsteambarriers,etc.Difficultiesin theseareasarisingduringplantsterilizationmaybeaggravatedbytheirexclusionfromcleaningcircuitsaswell:cleaningandplantsterilizationproceduresareusuallyperformedin thesamecircuit.

Specialattentionshouldbegiventoequipmentsterilizationprocedureswheresteamis admittedfromtwosides(somesteriletanks,etc.):in suchacase,airmaynotbepurgedfromthesystemeffectivelyenoughand,asaconsequence,thenecessarytemperaturesmightnotbereachedatallormightnotbemaintainedfortheintendedand/orrequiredperiodoftime.

Steamcanbeusedtosterilizefoodcontactsurfaceseitherdirectlyorbybeinginjectedintowaterin ordertoobtainhotorsuperheatedwater.In bothcasessteamqualitybecomesanimportantfactor(steamquality:seeProductSterilization,SteamQualitypage4.9).

GMP Issue9301 4.7

Product Processingb~1eIraPak

ProductSterilizationIn theproductionof long-lifeproducts,theprocessofproductsterilizationisatime/temperaturetreatment.By heatingaproducttoapredeterminedtemperatureandholdingit atthattemperatureforaspecifiedtime(holdingtime),acertainkillingeffect11is achieved.

Forhigh-acidproducts12,killingofthemostimportantspoilageorganisms(yeastandmoulds)startsatatemperaturearound75- 80C(167to176F),whilelow-acidproducts13requirehighertemperatures;themostresistantspoilageorganismsarebacterialsporesthekillingofwhichstartsattemperaturesslightlyabove100C(212F).

Forbothtypesofproduct,killingefficiencyincreasesrapidlywithincreas-ingtemperature.Whileonlyindirectheating14is usedforprocessinghigh-acidproducts,low-acidfoodsmaybesterilizedbymeansof indirectaswellasbydirect15heating.

For directsystemsthetotalkilling effectis determinedby theholdingtimeatsterilizationtemperaturewhereastheheatingandcoolingcontributesignificantlyin indirectsystems.

FromaGMP pointofview,theproductsterilisationprocessrequirescontrolof:

. steamquality,

. sterilisationtemperature,

. productholdingtimeatsterilizationtemperature.

Footnoteno11:Thekillingeffectis measuredandexpressedasthenumberofdecimalreductionsof themicrobialcount(lowacid:sporecount)achievedbytheprocess.

Footnoteno12:pH4.5(4.6)orlower.

Footnoteno13:pHabove4.5(4.6).

Footnoteno14:Plateortubularheatexchangers.

Footnoteno15:Injectionandinfusionsystems.

4.8 GMP Issue 9301

b~TelraPak ProductProcessing

SteamQuality

In directheatingsystems,steamcomesintodirectcontactwiththefoodproduct.Equipmentsterilizationproceduresleadtoanindirectcontactwiththefoodtobeprocessed(seeabove),if residuesfromthesteamremainonthefoodcontactsurfaces.In bothcases,steamqualitybecomesafactorinfluencingfinishedproductquality.In addition,equipmentcorrosionmaybecausedbyinferiorqualitysteam.

Waterusedforsteamproductionshouldbeofpotablequality.Inordertoproduceculinarysteam,acycloneandanactivecarbontllterorequivalentshouldbeincorporatedin thesteamsupplyline(closetoitsfinalusagepoint)in ordertoremoveparticles,andcondensateaswellasotherimpuri-ties.Suchfiltersystemsneedtobeoperatedandmaintainedproperly.It istheresponsibilityof theproductiondepartmenttoensuretheproperfunctioningof thesteamsupply,notonlywithregardtoquantitybutalsotoquality.Pipeworkdownstreamoftheactivecarbonfilter(orequivalent)mustbeof stainlesssteel.

As faraswateradditivesandboilercleaningagentsareconcerned,legisla-tiverequirementsmustbemet.All theabove-mentionedparametersaresubjecttotheHumanFactor.

SterilizingTemperature

Theproductsterilizationtemperatureis controlledbyathermo-sensor.Thesame,oroftenaseparate,sensorperformsamonitoringfunction:atacertain,pre-settemperatureanalarmis activatedand/orthesterilizerisshutdown,putinto"flowdiversion16",etc.SuchsensorsareAutomat-ic ControlDevices,andthesterilizationtemperatureis controlleddirectly.

A continuoussterilisationtemperatureprint-outshouldbeobtainedfromathermo-sensorplacedattheoutletoftheproductholdingcell(monitoringtheprocess).It istheresponsibilityoftheproductiondepartmenttoensurethatproperrecordingis carriedoutin accordancewithlaiddownproce-dures.

Footnoteno16:The"flowdiversion"functionis executedbyavalve("flowdiversionvalve")whichiseitherplacedattheendof theholdingcellorattheoutletof theproductsterilizer,divertingtheproductflowbacktotheproductinletbalancetankof thesterilizer,thuspreventinginsufficientlyprocessedproductfrombeingpackaged.

GMP Issue9301 4.9

Product Processing b~1etraPak

Holding Time

In aproductsterilizer,theaverageholdingtimeisdetenninedby:

. thecapacity(throughput)of thesterilizer,

. thevolumeof theholdingcell,

. theviscosityof theproduct.

Theholdingcellis usuallyapipeandtherateofflowthroughapipeis notthesamefortheentireliquid.Someparticleswill movefasterthanotherswhichmeansthattheirholdingtimewill beshorterthantherestoftheliquid.Toensurethatall theproductreceivesatleasttherequiredholdingtime,considerationmustbegiventothefastestparticles.Theflowprofileof theproductthroughaholdingcellis influencedbysuchfactorsas

. viscosityof theproduct,

. flowrateof theproductintheholdingcell,

. characteristicsof theproductcontactsurface,

. geometryof theholdingcell,etc.

It mightbeadvisableto adjustproductsterilizationtemperaturebecauseofdifferencesin flow profilecharacteristicsof variousproducts.

(Cont'doverleaf)

4.10 GMP Issue9301

~~TetraPak Product Processing

(HoldingTimeCont'd)

Capacityof theProductSterilizer

Thecapacity(throughput)ofaproductsterilizerisconstantif apositivefeedpump(homogenizer)is incorporatedin thesystem(providedthepumpis maintainedproperly).

In systemswith,forexample,centrifugalfeedpumps,thethroughputisdeterminedbythecapacityofthepumpandthepressuredropoverthesystem.Asdepositsbuildup,thepressuredropincreasesand,consequently,thethrough-putdecreases,increasingtheaverageholdingtime.As longastheflowprofileremainsunaffected,thekillingefficiencywill ratherincreasethandecrease.If, however,thisreductioninthroughputleadstoachangeinflowcharacteristics- fromturbulenttolaminar- problemsmayresult.Tobeonthesafeside,it maybeassumedthatthefastest-movingparticlehasaholdingtimefor:

. turbulentflowofabout3/4of theaverageholdingtime,

. laminarflowofabout2/3of theaverageholdingtime.(Cont'doverleaf)

GMP Issue9301 4.11

ProductProcessing b~TetraPak

(HoldingTimeCont'd)

VolumeoftheHoldingCell

Duringtheoperationofproductsterilizers,depositsmay/willbuilduponheatexchangesurfacesandintheproductholdingcell.If theholdingcellisapipe,itsvolumeisdeterminedby:

. thelengthof thepipe,

. theinsidediameterof thepipe.

Duringproduction,thelengthof theholdingcelldoesnotchangebuttheinsidediametermight.Asdepositsbuildup,theinsidediameterbecomessmaller.Consequently,thevolumedecreasesresultinginareductionoftheaverageholdingtime.Thesameappliestothefinalheaterandthefirstcoolingsection(indirectheatingsystems).In bothcases,thekillingefficiencyoftheprocessconcerneddecreases.

Inproductsterilizers,twovaluescanbeusedasindirectindicationsof theamountofdepositformed:

. thepressuredropoverthesterilizer,

. thetemperaturedifferentialbetweenheatingmediumandproduct.

DevicesformeasuringsuchvaluesareAutomatedControlDevicesbutareoftendependentontheHumanFactor.

Foratleastone,butpreferablyboth,of theaboveparameters,maximumacceptablevaluesshouldbeclearlystatedinwriting,andusednotonlyasasignaltocleantheequipmentbutalsowithrespecttothemicrobiologicalsafetyof theoperation.Appropriaterecordsshouldbekept.

4.12 GMP Issue9301

b~TeiraPak ProductProcessing

The Aseptic Function of the EquipmentOnceaproducthasbeenproperlysterilized,i.e.thescheduledprocesshasbeenexecuted,reinfectionof thecommerciallysterileproductmustbeavoided.Theequipment(fromtheproductholdingcelldownstream)mustfunctionaseptically,i.e.preventtheentryofmicroorganisms.Leakagesinsuchsystemscanoccurin:

. gaskets,

. valvemembranes,

. pinholes,cracks,

. airfiltersystems(steriletank),etc.

Theriskof reinfectioncannotbetotallyeliminatedbutshouldbemini-mized.Thiscanbeachievedby:

. inspection,

. maintenanceandpreventivemaintenance,etc.

Inspectionandmaintenanceshouldbecarriedoutbytheoperating,qualitycontroland/ormaintenancestaffandthusbecomesubjecttotheHumanFactor.Inspectionschedulesshouldbecompiledandimplementedbytheabovefunctions.Toachieveconsistentquality,preventivemaintenanceisessential!It is theresponsibilityof theproductiondepartmenttoensurethatsuchactivitiesareproperlyperformed.

GMP Issue 9301 4.13

Product Processingb~TetraPak

SteamBarriers

Thefunctionof steambarriersistosealthesterileproductagainstanunsterileenvironment.Theyusuallyconsistofanumberofvalveswithaspacebetweenthemthroughwhichsteamisflushed.Theproperfunctionofsuchbarriersis acriticalcontrolpoint.Meansof controlare

. athennosensor,and/or

. inspection.

If placedcorrectly,thermosensorscontrolthebarrierfunctiondirectlyandareAutomaticControlDevices,whileinspectionhastobemadebytheoperatingand/orqualitycontrolstaffandbecomessubjecttotheHumanFactor.

Theinstallationof steambarriersshouldbedonein suchawaythatthesteamorcondensatedischargefromthesteamtrap(s)canbecheckedeasilybytheoperator.

4.14 GMP Issue 9301

~~TetraPak

AsepticPackaging

,...,'.,.,..", ,....".",."., """"""""","'..,""""""""""""""'""""""""""""""""""'""""""""'.,"""""""'"","""""""""" .'"..'. ',.", "..".., ", ,"...,'"""""""""., .'..'.., ...,...,."""""""',"""'..""""""."...', , ,"""..""""",..." ,.......""'.."', ,., ,...",""",. .,. , , , ,..., ,.,..,...""".",' , ,.,....."""""""""

1"""""""""""""""""""..."""""" .........."""""" ....................".'.. ..,.,.. .,.'.'.',',',"','.'.'.'.' '.'."'.""'.'.','.'.','.'.'.'.'.'.'.'.'.' '.'."'.'..,'.'."'."""'..'" ,.........

1:1Contents

General. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 5.2

CreationofaSterileSurroundingWhileForming,FillingandSealingtheContainers.. . . . . . . . . . . . . . . . . . . . . . . . . .. 5.3

PackagingMachineSterilization. 5.3

Cleaning. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3

SterilizationPrior toStart-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 5.4

HeatSterilization.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4

ChemicalSterilization.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5

Kind of ChemicalUse. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5

ConcentrationoftheHydrogenPeroxide.. . . . . . . . . . . . . . 5.6

Timeof Exposure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6

TemperatureDuringExposure. . . . . . . . . . . . . . . . . . . . . . . . 5.6

ContactwiththeObject.. . . . . . . . . . . . . . . . . . . . . . . . . . .. 5.7

MaintainingSterilityDuringProduction. . . . . . . . . . . . . . . . . . . . . .. 5.9

OverPressurewithSterileAir. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.9

TightnessoftheSystem.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.11

GMP Issue9301 5.1

Aseptic Packaging b~TetraPak

GeneralAsepticpackagingcoversthesectionfromtheproductfillingvalve(connectiontotheproductsupplyline)tothefinalclosureof thecontainers.It is theresponsibilityof theproductiondepartmenttoguaranteethattheprocessesappliedareasintended,i.e.thatthescheduledprocessesarereallycarriedout.

Theobjectivegoalofasepticpackagingproceduresis tomaintainthehighmicrobiologicalqualityof thecommerciallysterileproductfedintothepackagingsystemthroughouttheintendedshelf-lifeof theproduct.

In anasepticpackagingsystem,thefollowingfunctionsmustbefulfilled:

. Creationofasterilesurroundingwhileforming,fillingandsealingthecontainers;

. Sterilizationof thefoodcontactsurfacesof thepackagingmaterial

. Productionof packages/containerswhicharetightenoughtopreventreinfection.

Thoughtheseprincipalfunctionsarethesamefor all asepticfillingoperations,thewayin whichtheyareperfonnedvaries.

Foreachtypeof asepticfillingequipment,controlpointsaswellascriticalcontrolpointsmustbeidentifiedandsuitablecontrolprocedureshavetobeestablished.

5.2 GMP Issue 9301

b~TetraPak AsepticPackaging

Creationof a Sterile EnvironmentwhileForming, Filling, and Sealing theContainers

In anasepticpackagingoperation,containersarefonned,filledandsealed.In thisareasterilitymustbe:

. achieved

. maintainedthroughouttheproductionrun.

PackagingMachineSterilization.

In ordertoregularlyachieveequipmentsterility,twofunctionsneedtobeconsidered:

. cleaningof thefoodcontactandassociatedareas,

. thesterilizationpriortostart-upof thepackagingoperation.

Cleaning

In asepticfillingsystems,partorallof thefillingequipmentis usuallycleanedusingelP circulationcleaning,seethesectionon"Cleaningof theEquipment".

Often,however,somepartsoftheasepticfillingequipmenthavetobedismantledandcleanedlsanitzedmanually.TheHumanFactorneedstobeconsidered( seepage4.5).

Thoughcleansurfacesareapre-conditionforeffectiveandsuccessfulequipmentsterilizationingeneral,thisis particularlytrueif chemicalsterilizationproceduresareapplied.Heathasabetterpenetrationpowerthroughresidualsoilthanchemicalsdo.

GMP Issue9301 5.3

AsepticPackaging ~!:TetraPak

SterilizationPrior to Start-upBeforeproductionisstarted,thepackagingequipmentneedstobesterilized.Propercleaning/sanitationis apre-conditionforeffectivesterilizationoftheequipment.A numberofproceduresexistdependinguponthekindofasepticfillerused.In thisconnection,twoprincipleswill bediscussed:

. heatsterilization,

. chemicalsterilization

bothofwhicharewidelyused.

HeatSterilization

Heatsterilizationcaneitherbeachievedbyapplyingsaturatedsteamordryheat.In eithercase,heatsterilizationis a:

. time,

. temperaturetreatmentandboththeseparametersarecriticalcontrolpointsintheprocessandthusneedpropercontrol.

Thetimeisusuallydirectlycontrolledbyatimer,anAutomaticControlDevice,thecorrectsettingofwhichmay,however,besubjecttotheHumanFactor.

Thoughinprinciplethesame,thetemperatureappliedin sterilizationdependsonwhethersteamordryairis used;onlythetemperaturesettingsaredifferent.Thetemperatureappliedis usuallydirectlycontrolledandmonitoredbyathermo-sensor,anAutomaticControlDevice.

5.4 GMP Issue 9301

b~~ra Pak Aseptic Packaging

Chernical Sterilization

Someasepticpackagingsystems,orpartsthereof,cannotbesterilizedbymeansof atime/temperaturetreatmentalone;someof thecomponentscannotbeexposedtothetemperaturenecessaryand/ortheprocessofheatingandcoolingwouldbetootime-consuming.Suchequipmentorcomponentsareusuallysubjectedtoachemicalsterilizationprocess.Criticalcontrolpointsin chemicalsterilizationorsanitationprocessesingeneralarethe:

In applyingchemicalsterilization,thesecriticalcontrolpointsneedtobecontrolled.

Kind of Chemical Used

Severalkindsofchemicalcanbeconsideredassuitablesterilants.Afrequentlyusedsterilizingagentforasepticpackagingequipmentishydrogenperoxide.Thehydrogenperoxideappliedshouldbeof "foodgrade"qualitysincefoodcontactsurfacesaresubjectedtothesesterilizationprocedures.A "foodgrade"hydrogenperoxidequalityimpliescertainrequirementsonpurity,particularlydegreeofcontaminationbyheavymetals,andplacescertainrestrictionsonadditives(stabiliser,wettingagents,etc.)used.

A sufficientcontrolof thesuitability(kindandconcentration)canbeobtainedbycertification,particularlyif awell-knownsupplierischosen.

(Cont'doverleaf)

GMP Issue93015.5

. kindof chemicalused,

. concentrationofchemical,

. timeofexposure,

. temperatureduringexposure,

. contactwith theobject.

AsepticPackaging b!:1etraPak

(ChemicalSterilizationCont'd)

Concentrationof the Hydrogen Peroxide

The hydrogenperoxide concentrationusedfor machinesterilization is oftenin therange of 30 - 35%, asrecommendedby thesupplierof theequipment.Hydrogen peroxide is unstableand may decomposeinto water andoxygen.No reasonable,automaticdevice is available todayto continuously monitor

thehydrogenperoxide concentration.Consequently,this has to be checkedby the machine operatoror quality control staff and,althoughdirectmeasuringproceduresareemployed,becomessubjectto theHumanFactor.

Timeof Exposure

The time of exposureof the surfacesto be sterilizedto hydrogenperoxideisusually directly controlled by a timer, anAutomatic Control Device, thesettingof which is, however, subjectto theHuman Factor and suitablemeasuresshould be takento check thatthe settingsarecorrect.

This timer is activatedeither at thetime thechemical is appliedor when thesystemhasreachedapredeterminedminimum temperature.

TemperatureDuringExposure

At roomtemperature,evenataconcentrationof30- 35%,hydrogenperoxidehasaveryslowbiocidal(sporicidal17)effect,i.e.longexposuretimesarerequiredtoachievethenecessarykillingefficiency.Therefore,it isusuallyheatedbyhot,sterile,dryairsimultaneouslydryingthesurfaces.

Thecriticalcontrolpointof thisoperationisthetemperatureof thehydro-genperoxideratherthanthetemperatureoftheairusedfordrying.

Thisprocessis usuallyindirectlycontrolledbytheairtemperature,whichinturnis controlledandmonitoredbyathermo-sensor,anAutomaticControlDevice.Inthisrespect,adistinctionshouldbemadebetweencriticalcontrolpointswhicharecontrolleddirectlyandthoseusingindirectcontrolprocedures.Wheneverpossible,directcontroldevicesshouldbeused.

(Cont'doverleaf)

Footnoteno17:"Biocidal"mtianskillingof organisms,in thisconn(;Ctionmicroorganisms.Sporicidalreferstothekillingofbacterialspores.

5.6 GMP Issue9301

b1:TetraPak AsepticPackaging

(ChemicalSterilizationCont'd)

ContactwiththeObject

In ordertoachievecontactwith(coverageof)allsurfacestobesterilized,twofactorsneedtobeconsidered:

. theamountofhydrogenperoxideused,

. thedistributionofthehydrogenperoxideoverthesurfacetobesterilized.

Boththeseparametersneedtobecontrolledin ordertoensurepropercontactbetweenthechemical(hydrogenperoxide)andthesurfacetobesterilized.

The Amountof HydrogenPeroxideUsed

Theamountofhydrogenperoxideusedis oftencontrolledbydischargingapresetvolumeintotheequipment.

Thisvolumeisusuallymeasuredbymeansof levelsensingelectrodes,adirectandAutomaticControlDevice,towhichamonitoringfunctionmaybeconnected,orbymeansof anoverflowcontainer,alsoadirectcontroldevicewhich,however,hastobecheckedbytheoperatingstaff:theHumanFactorhastobeconsidered.

A sufficientamountof thesterilizingagent(hydrogenperoxide)hastobedischargedintotheequipment.

Distributionof the HydrogenPeroxide

Surfacesterilizationbymeansof achemicalrequirescontactwiththeentiresurfaceinquestion.Toachievethis,hydrogenperoxidecanbeappliedby

. fogging,or

. asvapour.

(Cont'doverleaf)

GMP Issue9301 5.7

Aseptic Packagingb~TetraPak

(ChemicalSterilization/ContactwiththeobjectCont'd)

Foggingmeansapplicationofarelativelycold,usuallyroomtemperature,solutionofhydrogenperoxidebymeansofnozzles.In suchasystem,attentionshouldbepaidto:

. clogging,

. spraydirectionsincebothwill affectthedistributionof thesterilantoverthesurfaces.

Cloggingof thespraynozzlescanbeindirectlycontrolledbyatimer,anAutomaticControlDevice,measuringthetimeneededtoemptyadefinedvolumeunderspecifiedconditions(forexampleconstantover-pressureinthespraycontainer).If cloggingoccurs,thesprayingtimewill beprolonged.

Thespraydirection,i.e.orientationof thenozzles,cannotbecontrolledautomatically;ithastobecheckedbytheoperatingstaffand,thoughdirectlycontrolled,becomessubjecttotheHumanFactor.

Whenusinghydrogenperoxidevapour,thechemicalneedstobeheatedsufficientlytovaporize.Thisis oftenachievedbyinjectingliquidhydrogenperoxideintoaflowofhot,sterileair.Ofcriticalimportancehereisthe

. hydrogenperoxideconcentration,

. volumeof hydrogenperoxideused,

. air temperature,

. airflow.

Theconcentrationandvolumeofhydrogenperoxideusedhavebeendiscussedabove.

Theairtemperatureis usuallycontrolledbyathermosensor,whiletheairflowis determinedbyapresetover-pressurein theairsupplysystem,whichiscontrolledandmonitoredbyapressureguard.ThesearebothindirectbutAutomaticControlDevices.

5.8 GMP Issue 9301

b~TetraPak AsepticPackaging

MaintainingSterility DuringProductionOncetheareain whichcontainersareformed,filled,andsealedis sterilized,sterilitymustbemaintainedthroughouttheentireproductionrun.Varioussolutionsexistin differentasepticpackagingsystems.Twocriticalcontrolpointsareusuallyinvolved:

. over-pressurewithsterileair,

. tightnessof thesystem.

Over-PressurewithSterileAir

In ordertocreateanover-pressureof sterileair,theairneedstobesteril-ized.Therearepredominantlytwoproceduresusedfor this:

. sterilefiltrationand/or

. sterilizatipnbyheat.

Differentmethodsarerequiredtocontrolthese.

Air Filtration

In ordertoobtainsterileairthroughfiltration,HEPA 18filtersystemsareoftenused.A combinedcontrolandmonitorfunctionin suchfiltrationsystemsrequiresdeterminationof thepressuredropacrossthefilter,whichcanbeachievedbyusingpressuregauges,indirectbutAutomaticControlDevices.HEPA filtersneedtobeoperatedcontinuouslyin ordertomaintainsterilityof thefilteritself.

Alternativefiltersystemsareavailablewhichcanbesterilizedpriortouse.Thissterilizationoperationis eithercarriedoutbymeansofheat(steam)orchemicals(hydrogenperoxide)incombinationwithheat.

Controlandmonitorproceduresforthesesystemsareidenticalwiththosediscussedpreviously.

(Cont'doverleaf)

Footnoteno18:

HEPA standsfor:HighEfficiencyParticleAir.

GMP Issue9301 5.9

Aseptic Packagingb!:TeiraPak

(OverPressurebySterileAir Cont'd)

SterilizationbyHeat(incineration)

Sterilizationofairbymeansof incinerationis aprocesswithtwocriticalcontrolpoints:timeandtemperature,bothofwhichneedtobecontrolled.

Thetimeofexposureis determinedbythevolumeof thesystemandtheflowratein it.Thevolumehastoberegardedasconstantwhiletheairflowrateiscontrolledbythecapacityoftheairsupplysystem(fanorcompres-sor)andbythepressuredropoverthesystem.

Changesinpressuredroparenotexpectedsincedepositformationisnegligible.Thus,over-pressureis createdin thesystem,whichcanbeusedasanindirectmeasureof theairflowrate.

A pressure-measuringdeviceis introducedintothesystem,theminimumsettingofwhichis usedassafe-guardandthusprovidesanAutomaticControlDevice.Thetemperatureis controlledbyathermosensorwhichalsofunctionsasaguard.Thisthermosensoris adirectandanAutomaticControlDevice.

5.10 GMP Issue9301

b~1IIIraPak Aseptic Packagi ng

Tightness of the System

Dependingonthemechanicalfunctionsof theasepticfonn/filVsealequipment,theareainwhichthesefunctionsareexecutedvariesconsider-ably.Foreachtypeofpackagingmachinethisareashouldbeidentifiedandexaminedfor(critical)controlpoints.Whereapplicable,considerationshouldbegivento:

. gaskets,

. valvemembranes,

. mechanicaltightnessof structures,etc.

Toensureproperfunction(tightness)of thegasketsandmembranes,maintenance,andpreventivemaintenanceaswellasinspectionarenecessary,allofwhicharesubjecttotheHumanFactor.

Suitableschedulesformaintenanceandinspectionshouldbedevelopedandimplemented;botharetheresponsibilityof theproductiondepartment.

Failureof themechanicaltightnessof thesystemmaybecausedby:

. operatingfaults,and/or

. structuraldefects.

(Cont'doverleaf)

GMP Issue9301 5.11

Aseptic Packagingb~TetraPak

(Tightnessof theSystemCont'd)

OperatingFaults

Operatingfaults,suchasopeningofservicedoorsduringproduction,etc.maybeavoidedif guardingdevicesareused;thesearedirectandAutomat-ic ControlDevices,whileothersaresubjecttotheHumanFactor.

Operatingschedulesprovidedbytheequipmentsuppliermustbefollowedstrictly;anydeviationfromestablishedproceduresshouldresultinaninterruptionorashut-downof thepackagingoperation.A processdeviationrecordshouldbekept,andthepartof theproduction,affectedbythedeviationmustbequarantinedandretaineduntilafinaldecisionhasbeenmadebycompetentstaffassignedtothistask.

Proceduresappliedanddecisionsmadeshouldbelistedin theprocessdeviationrecord(seepage9.12).

StructuralDefects.

Structuraldefects,suchascracks,pinholes,etc.,areoftendifficulttodetectandrequireregularinspection,afunctionwhichis direct,butsubjecttotheHumanFactor.

5.12 GMP Issue 9301

b~TetraPak

PackagingMaterial Steri Iization

...................................

:rfjfjfjj)?)j:j)?jfj:::f:jf'j'??::.....................................:.:.'.:.'.:.:.'.:....:.:.:.:.:.: :.:.:.:.:-:.:.:-:.:.:.:.:.,...............' '...' ' ." "'...'................::::j:m:m:j':':?::::::}:: :=mrrjmr:;::::':::':::':::::::::':.:.;.:.:::::,::"",:::::,:,,::,::::,...................................::::):{:::: ':::::::': .::,,)::::((......................................................N '.'... '" '.'...' ' '.. .""..""".'.'".""'.' ' ' " '............ .............................................................................

.~lil!j!.ijiilil:i.lill:.liii..i:I:::I:~::::'i':ii!'i:l,i'il!i!iii.'!lli'

ContentsGeneral. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 6.2

Applicationof HydrogenPeroxidebySpraying. . . . . . . . . . . . . . . .. 6.4

Application of Hydrogen Peroxide by Vaporising ... . .. .. . .. . .. .. 6.6

ApplicationofHydrogenPeroxidebyRollerSystem.. . . . . . . . . . .. 6.9

SterilizationbyPassageThroughanImmersionBath. . . . . . . . . . . 6.10

GMP Issue9301 6~1

Packaging MaterialSterilization b~TeiraPak

General

In asepticpackagingprocedures,withfewexceptions,sterilizationof thepackagingmaterial(foodcontactsurface)isachievedchemically.Onlychemicalsterilizationprocedureswill beconsidered.By farthemostcommonchemicalusedforthispurposeis hydrogenperoxide.

Sincethepackagingmaterialfoodcontactsurfacemustbesterilized,directcontactbetweenthechemical(hydrogenperoxide)andthefoodcontactsurfaceisunavoidable;consequentlythechemicalmustbeof foodgrade(checkwithlocallegislation).

Criticalcontrolpointsin chemicalsterilizationingeneral(seeabove)are:

. kindof chemicalused,

. concentrationof chemical,

. timeof exposure,

. temperatureduringexposure,

. contactwith(coverageof)surface(object).

Dependingon themakeof theasepticpackagingequipment,differentmeansof applyingthesterilantareused:

Dependingonthesystemof application,different(critical)controlpointsneedtobeobserved.Commontothesystemsis theuseofhydrogenperoxide,thekillingefficiencyof whichdependsupontheabove-mentionedcriticalcontrolpoints.

(Cont'doverleaf)

6.2 GMP Issue 9301

. spray,

. vapour,

. rollersystems,

. immersionbath,etc.

b~TetraPak Packaging Material Sterilization

(GeneralCont'd)

Today,thehydrogenperoxideconcentrationcannotbemeasuredandmonitoredautomatically.Consequently,theconcentrationof thehydrogenperoxidesolutionusedhastobecheckedbythemachineoperatororthequalitycontrolstaffand,thoughindirectlycontrolled,becomessubjecttotheHumanFactor.

Thetimeofexposureis usuallycontrolledbythecapacity(speed)of thefillingsystemandbythesizeof packageproduced,bothareconstantandthusareAutomaticControlDevices.

Majormechanicalchangesarerequiredtoalterthecapacityof thepackag-ingequipment.

GMP Issue9301 6.3

PackagingM~terialSterilization b~TetraPak

Application of HydrogenPeroxide bySpraying

Spraying("fogging")ofhydrogenperoxideis usedin someasepticpackag-ingsystemswhichoperateintermittentlyanduseblanks,i.e.acertainamountofhydrogenperoxideis sprayedintoeachpre-erectedcontainerthroughaspraynozzle.Criticalcontrolpointsof thisoperationare:

. volumesprayedperpackage,

. coverageof surfacetobesterilized,

. temperatureofexposure,

. timeofexposure,

. hydrogenperoxideconc.entration.

Theamount(volume)ofhydrogenperoxideusedforeachpackageisusuallydirectlycontrolledbyapositivedosingpump,anAutomaticControlDevice.Suchpumpsdeliveraccuratelyandrepeatedlytherequiredvolume,providedthatthehydrogenperoxidesolutionis notfoamingandthatnoairis enteringthesystem.

In ordertominimizetherisksinvolved,provisionshouldbemadetodeterminetheactualamountofhydrogenperoxideusedatregular,pre-settimeintervals,afunctionwhichhastobeperformedbythemachineoperator,anindirectcontrolprocedurewhichis subjecttotheHumanFactor.

Anydeviationfromthesetconsumptionvalueshouldberecordedin aprocessdeviationrecord.

Forproperfunction(sterilization),thefoodcontactsurfaceofthecontainerneedstobecompletelycoveredwiththesprayedsolution.Thedesignandmechanicalconstructionof thespraynozzle(s)andthewaytheyarefittedwill determinetheresult.

It is essentialthatthecorrectarrangementof thespraynozzlesischeckedregularly.Thishastobedonebytheworkingstaff(machineoperatorsorfitters);theHumanFactorcommandsacontrolpoint.

(Cont'doverleaf)

6.4 GMP Issue9301

b~TetraPak Packaging Material Sterilization

(ApplicationofHydrogenPeroxidebySprayingCont'd)

Thesterilizationtemperatureis achievedbyblowinghot,sterileairintothepackagessimultaneouslyheatinganddryingoffthehydrogenperoxidesolution.In thisoperation,thefollowingcontrolpointshavetobeobserved:

In sterilizationbymeansofheat,thetemperatureusedforairsterilizationisdirectlyregulated,controlledandmonitoredbyathermo-sensor,anAutomaticControlDevice.

If theairis sterilizedbymeansoffiltration(seeabove),thecorrectairtemperaturefordryingoff thehydrogenperoxideisachievedbyanelectricalheatingelementwhichisdirectlycontrolledbyathermo-sensor,anAutomaticControlDevice.

Thetimeofexposureisregulatedbythecapacity(speed)of thepackagingmachinewhichis constantandthusbecomesanAutomaticControlDevice.

Theconcentrationofhydrogenperoxidecannotbecontrolledautomatically.Measuringhastobedonebeforestartofproductionand(atleast)attheterminationofproduction,eitherbythemachineoperatororqualitycontrolstaff.Thoughindirectlymeasured,theHumanFactorhastobeconsidered.

Anydeviationfromthehydrogenperoxideconcentrationrange,asspecifiedbythesupplierof thesystem,mustberecordedin aprocessdeviationrecordanddealtwithaccordingly.

GMP Issue 9301 6.5

. sterilityofdryingair,

. hydrogenperoxidetemperature,

. exposuretime,

. airflow.

PackagingMaterialSterilization b~TetraPak

Application of HydrogenPeroxide byVaporization

In systemsapplyinghydrogenperoxidebyvaporization,liquidhydrogenperoxideis injectedintoastteamofhot,sterileair,vaporizedandsubse-quentlycondensedonthesurfacestobesterilized.In suchsystems,controlpointsare:

. airtemperature,

. amountofair,i.e.hydrogenperoxideconcentrationingas/airmixture,

. amountofhydrogenperoxideused,

. concentrationofliquidhydrogenperoxideapplied.

As discussedabove,theairtemperatureis directlyconttolledbyathermo-sensor,anAutomaticControlDevice.Theamountof airintowhichthehydrogenperoxideisinjected,isdetenninedbyanover-pressuresystemwhichcanbeindirectlycontrolledandmonitoredviaapressuregauge,anAutomaticControlDevice.

Theamountof hydrogenperoxideinjectedintothehot,sterileairisoftendirectlycontrolledbyapositivedosingpump(seeabove),orthroughacontinuoussystemusingpressure,whichcanbeindirectlycontrolledandmonitoredviaapressuregauge,anAutomaticControlDevice.

Again,thehydrogenperoxideconcentrationcannotbecontrolledautomati-callybuthastobedeterminedbythemachineoperatororbyqualitycontrolstaff,bothofwhomrelyontheHumanFactor.

(Cont'doverleaf)

6.6 GMP Issue 9301

b~tetraPak Packaging Material Sterilization

(ApplicationofHydrogenPeroxidebyVaporisingCont'd)

Sterilizationof thefoodcontactsurfacemayeitherbeachievedby:

. hydrogenperoxideinthegaseousphase,or

. condensationofhydrogenperoxide.

If gasis used,pre-heatingof thefoodcontactsurfacebecomesacontrolpoint.In ordertoavoidcondensation,pre-heatingisoftencarriedoutbyflushingthecontainer(foodcontactsurface)withhot,sterileair,whichrequirescontrolof:

thecontrolrequirementsofwhichhavebeendiscussedabove.Possibleresiduesof thesterilantareremovedfromthefoodcontactsurfacebyafinalflushofhot,sterileair.In thisoperation,thesamecontrolpointsapplyasdescribedabove.

If condensationis intended,hothydrogenperoxidevapourisflushedoncoldsurfaces,thehydrogenperoxidecondensingonthecoolersurfaces.Insuchsystems,controlpointsare:

. hydrogenperoxideconcentration,

. timeof exposure,

. temperatureduringexposure,

. surfacecoverage.

HydrogenperoxideconcentrationcannotbemeasuredandcontrolledautomaticallyandbecomesthussubjecttotheHumanFactor.

(Cont'doverleaf)

GMP Issue9301 6.7

. airtemperature,

. timeofexposure,

. airflow,

Packaging Material Sterilizationb~TetraPak

(Applicationof HydrogenPeroxideby Vaporisingcont'd)

Thetimeofexposureisdeterminedbythecapacity(speed)ofthepackagingmachineand,sincethisisconstant,becomesanAutomaticControlDe-vice.

Thenecessarytemperatureduringexposureis achievedbyblowinghot,sterileairintothepackages,resultingin arapidincreaseinthesterilizingefficiencyandevaporationof thehydrogenperoxideapplied.

Thetemperatureof theairisachievedbyaheatingelement,whichinturniscontrolledandmonitoredbyathermo-sensor,anindirectcontrolprocedure,butanAutomaticControlDevice.

Coverageof the(contact)surface(s)requirestheapplicationofacertainamountofhydrogenperoxide,thecontrolofwhichhasbeendiscussedabove.

6.8 GMP Issue9301

~~'nttraPak PackagingMaterialSterilization

ApplicationofHydrogenPeroxidebyRollerSystem

"" If rollersystemsareusedfortheapplicationofhydrogenperoxidetosterilizefoodcontactsurfaces,thefollowingcriticalcontrolpointsneedtobeconsidered:

. surfacecoverage(contact),

. amountofhydrogenperoxideapplied,

. timeof exposure,

. temperatureduringexposure,

. hydrogenperoxideconcentration.

Thetimeofexposureaswellasthehydrogenperoxideconcentrationhavebeendiscussedabove.

Sincechemicalsterilizationrequirescontactwiththesterilant,coverageofthefoodcontactsurfacebecomesacriticalcontrolpoint.Packagingmaterialfoodcontactsurfacesareoftenplasticmaterials(polyethylene).A wettingagentisneededtoachieveevenspreadingof thehydrogenperoxidesolutionoverthehydrophobicsurface.

Surfacecoveragecanbeguardedbyawettingmonitor,adirectandAutomaticControlDevice,and/orbythemachineoperator,alsoadirectcontrolprocedurebutattentionhastobepaidtotheHumanFactor.

Theamountofhydrogenperoxideappliedtothefoodcontactsurfaceisusuallymeasuredasthevolumeconsumedwithinacertainperiodof time,anindirectproceduretocontrolacriticalcontrolpoint.Suchmeasuringisusuallydonebythemachineoperator.Consequently,considerationhastobegiventotheHumanFactor.

Thetemperatureof thefilmofhydrogenperoxideonthefoodcontactsurfaceis eithercontrolledandguardedbysterilehotair(seeabove)orbyradiationheating.Suchheatingis achievedbyanelectricalheatingelementwhichcanbecontrolledandmonitoredbyathermo-sensor,anindirectcontrolprocedure,butanAutomaticControlDevice.

GMP Issue9301 6.9

PackagingMaterialSterilization b~TeiraPak

Sterilizationby Passage Through anImmersionBath

If sterilizationof thepackagingmaterialfoodcontactsurfaceis achievedbypassagethroughanimmersionbathcontainingthesterilant(hydrogenperoxide),thefollowingcriticalcontrolpointsneedtobeobserved:

. concentrationofthehydrogenperoxide,

. timeofexposure,

. temperatureduringexposure,

. surfacecoverage(contact).

Thetimeofexposureis controlledandmonitoredbythecapacityof thepackagingmachine,achangeofwhichwouldrequireamajormechanicaloperation,andthelevelinthebath.

Thislevelcanberegulatedbyanoverflowdeviceand/orbylevelsensors,bothofwhicharedirectandAutomaticControlDevices.

Thetemperatureof thehydrogenperoxidesolutionisdirectlycontrolledandmonitoredbyathermo-sensor,anAutomaticControlDevice.

Coverageof (contactwith)thesurfacetobesterilizedisachievedbythepackagingmaterialpassingthroughtheliquidsterilantsolution.A controland/ormonitoringdeviceis notnecessaryaboveandbeyondthosementionedunder"timeofexposure".

6.10 GM P Issue 9301

b~TeiraPak

ProductionofTight Containers

.........................................................................................................................................................................................".." ""...' ' ".'.' '...........................................,., ,.,.,., "."",......................................... ,.,.,., ,.,...,.,.'.., ',., ".'...'.""'.." "' '.....;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;........j'I:'.:.:.II".:::::::::::::::::::/:;;..;(:::::.::111:".11':':...' '.. ...' "...' '.......;.;.;.;.;.;.;.;.;.;.;.;.;.;.:.:..:.:.:.:.:.:.:.;.:.;.;.;.;.:.;I:::::::::::::;:.:;!:::::::?;::::::::.:.:::;:::::,:::::::.:::::................... ..................;.;.;.;.;.;.;.;.:.;.;.;.; .;.;.;.;.;.;.:.;.:.;.;.;.;.;.;.;.;.;..................I::!:I::::::.:I'..;'I:.:::::::::.:::::I'I...::':::II'I::.!::::!':I:::I.:

Contents

General. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 7.2

GMPIssue 9301 7.1

Production of Tight Containers b!:TetraPak

General

Usingflexiblepackagingmaterial,thetightnessof thecontainerscannottodaybecheckedbyautomaticin-lineprocedures.Dependingonthetypeofpackagingmaterialused,differentmethodsandprocedurescanbeappliedtocheckthetightnessofthepackages.Suchmethodsare:

Suitablecheckingmethodsshouldberecommendedbythesupplierof thepackagingsystemand/orpackagingmaterial.

All theseprocedureshaveto becarriedoutby themachineoperatorand/orqualitycontrolstaffand,thoughdirectmethodsof checking,aresubjecttotheHuman factor.

7.2 GMP Issue9301

. tear-downchecks,

. conductivitymeasurements,

. dyetesting.

b~TetraPak

InternalTransportand Storage

, ,., ,........,...,....................................., ," ,.,...,.....'.'.'.'.','.'.'.'.'.'.'.'.'.'.','.'.'.'.'.'.'.','.'.'.','.'.'.'.'.'.'.'.'.',',','.','.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.','.'.'.'.'.'.'.'.'."'"""""""""""""""",:.:.,,:.:.:.:.;.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.,.:.:.:.;.:.:-:.,,:.:.:.:.:;:::;;::::::::::.'::::::::.:,' :.:,;:::::::::::::::::::::'::.'.','.'.'.'.'.','.'.'.' '.'.'.'.'.'.','.'.'.'.'.'............'.'.'.'.'.'.'.'.','.' '.',','.'.'.'.'.'.','.'.'.'.'.'.'.'.'.'.'" ... .'.',','.'.','.','.'... ,., .... ..,.................. ,...,...............'.'.'.'.'.'.'.'.'.' '.'.'.','.'.'. .'.'.'.'.'.'.','.'.. ..., ' """'".."'" ........... , ... ,........................................................................................................................................................"""'" ............................"""'" ................................................................;.;.:.;.:,:.:.:.: '.:.:.:.:.' ..:.:.:.,,:.:.:.:.::.;.;.:.:.:.:.:.:., ,.. .:.:.:.:.;.,.:.:.:.:.';';"';':':':':':':'. ..:.:.:.:.:.,.:.;.;.:.;"""""" """""":::i:i:I':'::i:i::I'.::I":.':::,i:;::::~".::i:..il.1111:11":1::1:::'1':

Contents

General. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2

Distribution Equipment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 8.2

Storageof theFinished Product. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 8.3

GMP Issue9301 8.1

InternalTransportandStorage b~TetraPak

GeneralInternaltransportandstoragecoversallactivitiesfromtheasepticpackag-ingequipmenttothereleaseof theproducttothedistributionchain.Considerationshouldbegivento:

. distributionequipment,

. storageof thefini