Post on 28-Nov-2021
BiosafetyinupstreambioprocessingErikKakes,Sales&Marke;ngdirectorApplikonBiotechnology
AboutErikKakes• StudiedBiochemistry• Ac;veinbioreactordesignsince1988
– Projectmanager– Productdevelopment– Marke;ng&Sales
• Co-ownerofApplikonBiotechnologysince2008
ApplikonBiotechnology• Oneofthelargestprivatelyownedbioreactorcompanies• Startedin1974byJanvanBurg• Keywords:
– Reliable– Newtechnologies– Longtermcustomerrela;on– Microscaletoproduc;onscalesystems– Localexpertsforsales,serviceandsupport– Bioreactorsystemsonly
• DaughtercompaniesinNetherlands,UK,USA,ChinaJanvanBurg
Applikonhistoryinvaccineproduc;on• 1970’s:Bilthovenunits
Dr.vanHemert&Ir.vanWezel
• 1989ApplikonandContactFlowmerger
• 1990’s:ChinaVaccineProjectRIVM,DHV,Applikon
• Last30yearsMul;plelargescalevaccineprojects
Laboratorybioreactors
Produc0onsystems
•
• Applikon Inside! SingleUsesystems
Phase4
Pilotmanufacturing,QC&QA
Clinical&Regulatory
Techtransfer
Pharmacovigilance
LeadDevelopment
Preclinical Phase1 Phase2 Phase3 ProductLicensure
Process&AssayDevelopment,Scale-up
Animalmodels
Discovery
QA/QPoversightincludingCMOs,CROs
CMCProjectmanagement
Facilitydevelopment(Seenextdetailslide)
VaccineDevelopment
CommercialManufacturing,QC&QA
Plantdesign&engineering
Procurement
QualitySystemsdevelopment
FacilityConstruc0on
EquipmentDelivery
Comple0onandcommissioning
Techtransferandvalida0on
Projectmanagement,ProjectQAandcompliancemanagement
FactoryLicencing
Qualifica0on
Recruitment&training
Techtransfer
Phase4Phase3 ProductLicensure
FacilityDevelopment
BiosafetyvsGMP• Biosafety
– Protecttheoperator• GMP
– Protecttheconsumer
Keepthemin Keepthemout
Biosafety• Responsibilityofsupplier&customer• Customer:
– Providesafeenvironmentforpersonnel
– Informsupplierofpoten;alrisks• Supplier:
– Intrinsicsafetyasadesigncriterium– Understandandminimizetheprocessrisks
• Communica;oniskey
Projectcommunica;on:Website• Openinforma;onexchange• 24/7accessible• Up-to-dateinforma;on• Documentedcommunica;on• Documenteddecisions• Everybodyworkswiththesamedocuments
• Nosurprises
Recap: Bioreactor
Hea;ng/coolingmedium:TOJACKET
Hea;ng/coolingmedium:FROMJACKET
GasOut
Sampling
DownStream
=RiskArea
Biosafety:Single-UseorRe-Usable• Single-Use
– Shortlead;me– Lowerini;alinvestment– Moreflexibility– Moremanuallaborsomoreproceduresrequired
• Re-Usable– Longerlead;me– Higherini;alinvestment– Lessflexibility– Moreautoma;on
Biosafety:Single-Usebioreactors– ReportApril2016,DutchCommissionforGene;cModifica;on
• Integritytestofbagnotstandardized• Biggestriskisduringinstalla;onwheremanualmanipula;onisthehighestrisk
• Noreliableintegritytestpossibleaferinstalla;on
• Increasedriskforoperator• Con;nuoustrainingprogramsareneeded
Biosafety:Re-Usablebioreactors• Benefitsofprocessautoma;on
– Lessmanualmanipula;on– Automatedtestprocedures– Automateddocumenta;on– Interlocksforincreasedsafety– Verifiedautomatedtransferbetweenunits– Con;nuousfeedbackloops
Recap: Bioreactor Biosafety
Hea;ng/coolingmedium:TOJACKET
Hea;ng/coolingmedium:FROMJACKET
GasOut
Sampling
DownStream
=RiskArea
No virus to exit
No virus to exit
No virus to exit No virus to exit
No virus to exit uncontrolled
No virus to exit uncontrolled
No virus to exit
No virus to exit
Recap: Bioreactor GMP
Hea;ng/coolingmedium:TOJACKET
Hea;ng/coolingmedium:FROMJACKET
GasOut
Sampling
DownStream
=RiskArea
No contaminant to enter
No contaminant to enter
Well defined materials
Homogeneous mixing
Defined gas supply
No contaminant to enter
No organisms to enter or exit uncontrolled
No organisms to enter or exit uncontrolled
Reproducible & Controlled conditions No organisms to enter or exit uncontrolled No contaminant to enter
Gas Filters
Off-gas Incinerator
• 0.2micrometerporesize• Membranefilter• Integritytestpoints• Testintegritybeforeandaferprocess
Exhaustgasfilter
Exhaustgasincinerator
• Temperaturemeasurement&Control• Time&heatkill,con;nuousmonitoring• 200˚C,Upto200l/min
Agitatorsealing• Magne;ccoupling• Nodirectcontactbetweeninsideand
outsideofreactor• Minimalmaintenance• Upto40Nmtorque• Cellcultureupto3000litervolume• Microbialupto500litervolume
Equipmentriskmanagement• Focusontheinterfaces!!!
– Differentsuppliers• Building,upstreamanddownstreamequipment
– Differentequipment• Liquidflowpath,connec;ontypes,temperatures,flows
– Differentsofwaresolu;ons• Handshakesbetweendevices,communica;onanddataintegra;on,valida;on,unifiedoperatorinterfaces
• Useasmanystandardbuildingblocksaspossible– Provenperformance
Hazopstudy• WhatisHazop?
– Hazardandoperabilitystudy– astructuredandsystema;cexamina;onofacomplexplannedorexis;ngprocessoropera;oninordertoiden;fyandevaluateproblemsthatmayrepresentriskstopersonnelorequipment
Hazopstudyreport
Hazopra;ng
Hazopac;onlist
Resuming• Biosafetyisasharedresponsibility• Advancedautoma;onimprovessafety• Buildintrinsicsafetyintodesign• Hazopanalysisiden;fiesproblemsandsolu;ons• Hazopcanbedoneonoldandnewinstalla;ons
Thankyou!