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!