PowerPoint Presentation

Workshop 1

Addressing the Process & Economic Dimensions of ICB

Chairs:Suzanne Farid (University College London)Andrew Sinclair (BioPharm Services)

ECI ICB, Castelldefels, Spain, 20-24 Oct 2013Proposed Workshop FormatPART 1 (45 min)16.05-16.10Intro to workshop and format 16.10-16.20Speaker: Timothy Johnson, Genzyme (Theme 1)16.20-16.30Speaker: Jonathan Coffman, Boehringer Ingelheim (Theme 2)16.30-16.45Audience discussion on theme questionsPART 2 (45 min) 16.45-16.55Speaker: Veena Wariko, Genzyme (Theme 3)16.55-17.05Speaker: Paul Jorjorian, Gallus BioPharmaceuticals (Theme 4)17.05-17.10Speaker: Thomas Daszkowski, Bayer (Theme 4)17.10-17.25Audience discussion on theme questions17.25-17.30Session wrap-upThemesPART 1Theme 1 Labile v. stable products business case for continuous bioprocessing?Timothy Johnson, GenzymeTheme 2 Best timing and scale for implementation of continuous bioprocessing?Jonathan Coffman, Boehringer IngelheimPART 2Theme 3 Cost analysis of continuous bioprocessing over a products lifecycleVeena Wariko, Genzyme Theme 4 Is tomorrows process a hybrid of batch and continuous operations?Paul Jorjorian, Gallus BioPharmaceuticals (CMO perspective)Thomas Daszkowski, Bayer Technology Services (Innovator perspective)

ThemesPART 1Theme 1 Labile v. stable products business case for continuous bioprocessing?Timothy Johnson, GenzymeTheme 2 Best timing and scale for implementation of continuous bioprocessing?Jonathan Coffman, Boehringer IngelheimPART 2Theme 3 Cost analysis of continuous bioprocessing over a products lifecycleVeena Wariko, Genzyme Theme 4 Is tomorrows process a hybrid of batch and continuous operations?Paul Jorjorian, Gallus BioPharmaceuticals (CMO perspective)Thomas Daszkowski, Bayer Technology Services (Innovator perspective)

Workshop 1:Business Case Discussion for Integrated Continuous BiomanufacturingTim Johnson, Ph.D.October 21, 2013 |www.genzyme.comJade (with her mother) Fabry disease USAIntegrated Continuous BioManufacturingUnform.DrugSubstanceCaptureBioreactorMedia

Intermediate PurificationPolishViral Inact.CAPEXOPEXContinuous vs. Fed-Batch

CAPEX/OPEX sensitivity analysesViable cell densityCell-Specific Perfusion RateCAPEX Savings(Fed-Batch mAb Continuous mAb)OPEX Savings(Fed-Batch mAb Continuous mAb)

Red = More SavingsPush tohigh VCD,low CSPRbreak-evenbreak-evenFactors influencing costs for continuous manufacturing

mAb CAPEXmAb OPEXOverall: 54%Overall: 20% % of overall costThemesTheme 1 Labile v. stable products business case for continuous bioprocessing?Timothy Johnson, GenzymeTheme 2 Best timing and scale for implementation of continuous bioprocessing?Jonathan Coffman, Boehringer IngelheimTheme 3 Cost analysis of continuous bioprocessing over a products lifecycleVeena Wariko, Genzyme Theme 4 Is tomorrows process a hybrid of batch and continuous operations?Paul Jorjorian, Gallus BioPharmaceuticals (CMO perspective)Thomas Daszkowski, Bayer Technology Services (Innovator perspective)

Jon CoffmanDiscussion on best timing and scale for continuous bioprocessingWorkshop Biopharma CMB - Standard Presentation 201212Perfusion example: mAb productionGivenTypical fed batch integrated viable cell densities: 150 Mcells/mL dayAverage perfusion cell density: 75Mcells/mLFed Batch duration: 12 daysPerfusion duration: 12 days (minimum cell culture time)Then for the same amount of product produced:The perfusion bioreactor is about 1/6th the size of the fed batch (smaller if culture extended)The downstream size is 1/12 the size of the downstream to support the fed batch, if the material is harvested continuously through the downstream,

Biopharma CMB - Standard Presentation 201213How suitable is continuous processing for Phase I / II clinical manufacturing? Perfusion Bioreactors and downstream have a size advantage over fed batch, but use more media3200L Media for Perfusion at 2 v/v/day800L Media for FB12 day Fed Batch800L133LEffectively Continuous DownstreamDownstreamVolume/area to ScaleCapital cost scales roughly with diameter12 Day PerfusionCan continuous Processing be useful for Phase I/II manufacturing?Capital costs lowerRaw material costs lowerSmall size allows more products in the same suite

But there are significant drawbacks that must be addressedBiopharma CMB - Standard Presentation 201215Can Continuous Processes Decrease Cost of Quality? Jon HancockGood science can make qualityGood technology can make qualityGood development can make qualityQuality can be built into the processPaper does not make qualitySignatures do not make qualityVerification does not make quality

Quality assurance does not make quality, it assures the quality that is already there.Quality must be a partner in process development and technology develoment

Jon HancockGood science can make qualityGood technology can make qualityGood development can make qualityQuality can be built into the processPaper does not make qualitySignatures do not make qualityVerification does not make quality

Quality assurance does not make quality, it assures the quality that is already there.Quality must be a partner in process development and technology develoment

Jon HancockGood science can make qualityGood technology can make qualityGood development can make qualityQuality can be built into the processPaper does not make qualitySignatures do not make qualityVerification does not make quality

Quality assurance does not make quality, it assures the quality that is already there.Quality must be a partner in process development and technology develoment

Jon HancockGood science can make qualityGood technology can make qualityGood development can make qualityQuality can be built into the processPaper does not make qualitySignatures do not make qualityVerification does not make quality

Quality assurance does not make quality, it assures the quality that is already there.Quality must be a partner in process development and technology develoment

Jon HancockGood science can make qualityGood technology can make qualityGood development can make qualityQuality can be built into the processPaper does not make qualitySignatures do not make qualityVerification does not make quality

Quality assurance does not make quality, it assures the quality that is already there.Quality must be a partner in process development and technology develoment

Cost of QC or QA does not scale with size, and does not automatically decrease with continuous processingJon HancockGood science can make qualityGood technology can make qualityGood development can make qualityQuality can be built into the processPaper does not make qualitySignatures do not make qualityVerification does not make quality

Quality assurance does not make quality, it assures the quality that is already there.Quality must be a partner in process development and technology develoment

Jon HancockGood science can make qualityGood technology can make qualityGood development can make qualityQuality can be built into the processPaper does not make qualitySignatures do not make qualityVerification does not make quality

Quality assurance does not make quality, it assures the quality that is already there.Quality must be a partner in process development and technology develoment

Jon HancockGood science can make qualityGood technology can make qualityGood development can make qualityQuality can be built into the processPaper does not make qualitySignatures do not make qualityVerification does not make quality

Quality assurance does not make quality, it assures the quality that is already there.Quality must be a partner in process development and technology develoment

Jon HancockGood science can make qualityGood technology can make qualityGood development can make qualityQuality can be built into the processPaper does not make qualitySignatures do not make qualityVerification does not make quality

Quality assurance does not make quality, it assures the quality that is already there.Quality must be a partner in process development and technology develoment

Jon HancockGood science can make qualityGood technology can make qualityGood development can make qualityQuality can be built into the processPaper does not make qualitySignatures do not make qualityVerification does not make quality

Quality assurance does not make quality, it assures the quality that is already there.Quality must be a partner in process development and technology develoment

How can continuous processing impact development costs?

Biopharma CMB - Standard Presentation 201217Is continuous processing inherently easier to develop? Easier to make a platform?How can continuous processing impact tech transfer costs?Biopharma CMB - Standard Presentation 201218Is continuous processing easier to make a platform? Easier to tech transfer to an existing continuous processing suite?DiscussionVOTE: Do you anticipate using continuous processing in your company in the next 5 years?

Theme 1: Labile v. stable products business case for continuous bioprocessing?What strategies are needed to cope with the extra complexity in perfusion processes?

How can we improve our clone screening methods to ensure long-term production stability?

Are there nuances that could inhibit the use of conti processes for non-mAb stable products?Theme 2: Best timing and scale for implementation of continuous bioprocessing?When is the best time for implementing continuous processing Ph I/II? Ph III? Post approval?

Does continuous processing increase or decrease the cost of QC/QA for a single campaign eg for Ph I/II?

Does continuous processing need to be able to cope with multiple products to be a valid option? ThemesPART 1Theme 1 Labile v. stable products business case for continuous bioprocessing?Timothy Johnson, GenzymeTheme 2 Best timing and scale for implementation of continuous bioprocessing?Jonathan Coffman, Boehringer IngelheimPART 2Theme 3 Cost analysis of continuous bioprocessing over a products lifecycleVeena Wariko, Genzyme Theme 4 Is tomorrows process a hybrid of batch and continuous operations?Paul Jorjorian, Gallus BioPharmaceuticals (CMO perspective)Thomas Daszkowski, Bayer Technology Services (Innovator perspective)

|www.genzyme.com

Erik Familial Hypercholesterolemia USACost analysis and Continuous Bioprocessing over a Products LifecycleVeena Warikoo, PhDGenzyme A Sanofi Comapny#genzymeA SANOFI COMPANY22Process ValidationState of control2011 FDA guidance defines process validation as:The collection and evaluation of data, from the process design stage through commercial productionwhich establishes scientific evidence that a processis capable of consistently delivering quality productScientifically sound design practices (QbD)Robust qualification (MFG reproducible)Process verification (continued over lifetime)Inherent to continuous process - robust control strategies, PAT, steady state product quality, limited scale upLeverage perfusion Brx strategiesFDA encouraging of integrated continuous biomanufacturing approachNeed new approachesViral clearance studies etc.Definition of a lottraceability of raw materialsPer manufacturers requirementsTime basedAmount basedCurrently well defined in perfusion cell culture based processesDefinition of steady stateProduct qualityHow to handle deviationsProcess control criticalEngineering solutions

Regulatory challenges23Ease of scale upReduced cycle timeFlexibility: batch size, multi-productSteady state product qualityQuantify Intangible Benefits24ThemesPART 1Theme 1 Labile v. stable products business case for continuous bioprocessing?Timothy Johnson, GenzymeTheme 2 Best timing and scale for implementation of continuous bioprocessing?Jonathan Coffman, Boehringer IngelheimPART 2Theme 3 Cost analysis of continuous bioprocessing over a products lifecycleVeena Wariko, Genzyme Theme 4 Is tomorrows process a hybrid of batch and continuous operations?Paul Jorjorian, Gallus BioPharmaceuticals (CMO perspective)Thomas Daszkowski, Bayer Technology Services (Innovator perspective)

Implementation of Continuous Processing for Biologics Manufacturing - a CMO Perspective23rd October 2013

Paul Jorjorian M.Eng.Head of Purification Development (STL)Gallus BioPharmaceuticalsquantitative market research results 69% Upstream process development 53% Purification process development 40% Batch-fed process development 40% Perfusion process development 34% Perfusion methods with centrifugation, cell settling devices, alternating tangential flow, internal spin filterMotivations for Engaging CMOs for PD :

27200 survey respondents: 49% use CMOs for PD

Survey groupBig Pharma/Biotech 34%Midsized Pharma/Biotech 37%Emerging Pharma/Small/Virtual Biotech 31%Source: Gallus BioPharmaceuticals sponsored surveywhat are customers looking for?stainless technology the historical default and still perceived as lowest risk (today)disposable technology flexible capacityperfusion technologies alternating tangential flow (ATF), internal spin filter, centrifugation and cell settling devicesflexible stainless steel the benefits of disposable with the comfort of SShybrid technologies used for commercial processesfully continuous still in the early stages of development at large pharma/biotech companies although some small/mid-sized companies are looking to adapt.Assessing choices for best process fit 28perfusion technologiesBioreactor prep outside of the suite for rapid turnaroundDisciplined, tenured manufacturing teamEquipment sterilization via autoclaveSingle use tubing w/ Terumo sterile welders, filters, and elastomers for each equipment buildExceptionally stable, clean environmentDe-risking perfusion processes? (f SS)

No Bioreactor Contaminations Since 2007140+ / 60 day runs & >2100 passages On Schedule: 97% of Run Start on time On Track: >94% Batch Release RateHow reliable is perfusion? Gallus experience:29

500L flexible SS bioreactorhybrid optionsSUB are adaptable to perfusion processesEasily increase process outputMassively reduced capital costsPerfusion + SUT Decouples upstream and downstream Reduced footprint Reduced risk Used for multiple commercial processesHybrid Solution30

ThemesPART 1Theme 1 Labile v. stable products business case for continuous bioprocessing?Timothy Johnson, GenzymeTheme 2 Best timing and scale for implementation of continuous bioprocessing?Jonathan Coffman, Boehringer IngelheimPART 2Theme 3 Cost analysis of continuous bioprocessing over a products lifecycleVeena Wariko, Genzyme Theme 4 Is tomorrows process a hybrid of batch and continuous operations?Paul Jorjorian, Gallus BioPharmaceuticals (CMO perspective)Thomas Daszkowski, Bayer Technology Services (Innovator perspective)

hMoBiDiK

ModularBiologicsDisposableKonti A. Vester, J. Magnus

MoBiDiK: Process DesignPage 33 MoBiDiK Update Oct 2013ChromatographyProt AViral InactivationConcentrationFormulationUF/ DFPolishingCapto adhere/ AEXVirus FiltrationDownstream

ClarificationUpstream

Perfusion

33

MoBiDiK Demonstrator Laboratory SCM MoBiDiK Sep, 2013Page 34

AAUSPDSP

Page 35 BTS 4:3 Template 2010 June 2011

Flows Personnel Material Product WasteLayout 1st floor Production LevelCleanroom classification Black Class E Class D Class CDiscussionVOTE:Will we have the process analytics needed for integrated continuous processes in 5 y?

Theme 3: Cost analysis of continuous bioprocessing over a products lifecycle Will continuous processing lengthen or streamline validation times?

What are the ways to model the cost of intangible benefits such as steady state product quality, flexibility, short cycle times, etc.?

Theme 4: Is tomorrows process a hybrid of batch and continuous operations?In your organization who are the biggest advocates and opponents of implementing continuous processes?

Where do you feel it makes sense to retain batch processing?

What gaps exist to create an integrated whole continuous process?ECI ICB, Castelldefels, Spain, 20-24 Oct 2013