Workshop 1 Addressing the Process & Economic Dimensions of ICB

1. 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 2013

2. Proposed Workshop Format

3. Themes PART 1 Theme 1 Labile v. stable products – business case for continuous bioprocessing? Timothy Johnson, Genzyme Theme 2 Best timing and scale for implementation of continuous bioprocessing? Jonathan Coffman, BoehringerIngelheim PART 2 Theme 3 Cost analysis of continuous bioprocessing over a product’s lifecycle VeenaWariko, Genzyme Theme 4 Is tomorrow’s process a hybrid of batch and continuous operations? Paul Jorjorian, Gallus BioPharmaceuticals(CMO perspective) Thomas Daszkowski, Bayer Technology Services (Innovator perspective)

4. Themes PART 1 Theme 1 Labile v. stable products – business case for continuous bioprocessing? Timothy Johnson, Genzyme Theme 2 Best timing and scale for implementation of continuous bioprocessing? Jonathan Coffman, BoehringerIngelheim PART 2 Theme 3 Cost analysis of continuous bioprocessing over a product’s lifecycle VeenaWariko, Genzyme Theme 4 Is tomorrow’s process a hybrid of batch and continuous operations? Paul Jorjorian, Gallus BioPharmaceuticals (CMO perspective) Thomas Daszkowski, Bayer Technology Services (Innovator perspective)

5. Workshop 1: Business Case Discussion for Integrated Continuous Biomanufacturing Tim Johnson, Ph.D. October 21, 2013

6. Integrated Continuous BioManufacturing Media Bioreactor Capture Intermediate Purification Unform. Drug Substance Viral Inact. Polish

7. CAPEX • Parameters • Number of unit operations, tank sizes, utilities, etc. • Upstream Example: • Assume a market demand • For a given market demand • Increasing VCD  decreases reactor size  decreases CAPEX • Perfusion can lead to >100 Mcell/ml and substantially reduced bioreactor size

8. OPEXContinuous vs. Fed-Batch • Parameters • Upstream: Media, single use systems, etc. • Downstream: Resins, buffers, etc. • Labor • Upstream Example: • Media usage and cost is an important contributor to OPEX • Facilities with equal production rates  equal number of cells and duration • Simplifies comparison to media consumption rates (or CSPR) • Decreasing CSPR  decreases media usage  decreases OPEX

9. CAPEX/OPEX sensitivity analyses Red = More Savings OPEX Savings (Fed-Batch mAb – Continuous mAb) CAPEX Savings (Fed-Batch mAb – Continuous mAb) break-even Push to high VCD, low CSPR Cell-Specific Perfusion Rate break-even Viable cell density

10. Factors influencing costs for continuous manufacturing mAb CAPEX mAb OPEX % of overall cost Overall: –20% Overall: –54%

11. Themes Theme 1 Labile v. stable products – business case for continuous bioprocessing? Timothy Johnson, Genzyme Theme 2 Best timing and scale for implementation of continuous bioprocessing? Jonathan Coffman, BoehringerIngelheim Theme 3 Cost analysis of continuous bioprocessing over a product’s lifecycle VeenaWariko, Genzyme Theme 4 Is tomorrow’s process a hybrid of batch and continuous operations? Paul Jorjorian, Gallus BioPharmaceuticals (CMO perspective) Thomas Daszkowski, Bayer Technology Services (Innovator perspective)

12. Workshop Discussion on best timing and scale for continuous bioprocessing Jon Coffman Biopharma CMB - Standard Presentation 2012

13. Perfusion example: mAb production Given • Typical fed batch integrated viable cell densities: 150 Mcells/mL day • Average perfusion cell density: 75Mcells/mL • Fed Batch duration: 12 days • Perfusion 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, How suitable is continuous processing for Phase I / II clinical manufacturing? Biopharma CMB - Standard Presentation 2012

14. Perfusion Bioreactors and downstream have a size advantage over fed batch, but use more media 12 day Fed Batch 800L 12 Day Perfusion 133L Downstream Effectively Continuous Downstream 3200L Media for Perfusion at 2 v/v/day 800L Media for FB Volume/area to Scale Capital cost scales roughly with diameter

15. Can continuous Processing be useful for Phase I/II manufacturing? • Capital costs lower • Raw material costs lower • Small size allows more products in the same suite • But there are significant drawbacks that must be addressed Biopharma CMB - Standard Presentation 2012

16. Can Continuous Processes Decrease Cost of Quality? Good science can make quality Good technology can make quality Good development can make quality Quality can be built into the process Paper does not make quality Signatures do not make quality Verification 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 Good science can make quality Good technology can make quality Good development can make quality Quality can be built into the process Paper does not make quality Signatures do not make quality Verification 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 Good science can make quality Good technology can make quality Good development can make quality Quality can be built into the process Paper does not make quality Signatures do not make quality Verification 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 Good science can make quality Good technology can make quality Good development can make quality Quality can be built into the process Paper does not make quality Signatures do not make quality Verification 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 Good science can make quality Good technology can make quality Good development can make quality Quality can be built into the process Paper does not make quality Signatures do not make quality Verification 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 Good science can make quality Good technology can make quality Good development can make quality Quality can be built into the process Paper does not make quality Signatures do not make quality Verification 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 Good science can make quality Good technology can make quality Good development can make quality Quality can be built into the process Paper does not make quality Signatures do not make quality Verification 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 Good science can make quality Good technology can make quality Good development can make quality Quality can be built into the process Paper does not make quality Signatures do not make quality Verification 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 Good science can make quality Good technology can make quality Good development can make quality Quality can be built into the process Paper does not make quality Signatures do not make quality Verification 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 Good science can make quality Good technology can make quality Good development can make quality Quality can be built into the process Paper does not make quality Signatures do not make quality Verification 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 processing Jon Hancock Jon Hancock Jon Hancock Jon Hancock Jon Hancock Jon Hancock Jon Hancock Jon Hancock Jon Hancock Jon Hancock

17. How can continuous processing impact development costs? Is continuous processing inherently easier to develop? Easier to make a platform? Biopharma CMB - Standard Presentation 2012

18. How can continuous processing impact tech transfer costs? Is continuous processing easier to make a platform? Easier to tech transfer to an existing continuous processing suite? Biopharma CMB - Standard Presentation 2012

19. Discussion VOTE: 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 complexityin 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 – PhI/II? PhIII? 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?

20. Themes PART 1 Theme 1 Labile v. stable products – business case for continuous bioprocessing? Timothy Johnson, Genzyme Theme 2 Best timing and scale for implementation of continuous bioprocessing? Jonathan Coffman, BoehringerIngelheim PART 2 Theme 3 Cost analysis of continuous bioprocessing over a product’s lifecycle VeenaWariko, Genzyme Theme 4 Is tomorrow’s process a hybrid of batch and continuous operations? Paul Jorjorian, Gallus BioPharmaceuticals(CMO perspective) Thomas Daszkowski, Bayer Technology Services (Innovator perspective)

21. Cost analysis and Continuous Bioprocessing over a Products Lifecycle Veena Warikoo, PhD Genzyme A Sanofi Comapny Erik Familial Hypercholesterolemia USA | www.genzyme.com

22. Process Validation 2011 FDA guidance defines process validation as: “The collection and evaluation of data, from the process design stage through commercial production which establishes scientific evidence that a process is capable of consistently delivering quality product” Scientifically sound design practices (QbD) Robust qualification (MFG reproducible) Process verification (continued over lifetime) State of control • Inherent to continuous process - robust control strategies, PAT, steady state product quality, limited scale up • Leverage perfusion Brx strategies

23. Regulatory challenges • FDA encouraging of integrated continuous biomanufacturing approach • Need new approaches • Viral clearance studies etc. • Definition of a lot • traceability of raw materials • Per manufacturer’s requirements • Time based • Amount based • Currently well defined in perfusion cell culture based processes • Definition of steady state • Product quality • How to handle deviations • Process control critical • Engineering solutions

24. Quantify Intangible Benefits Ease of scale up Reduced cycle time Flexibility: batch size, multi-product Steady state product quality

25. Themes PART 1 Theme 1 Labile v. stable products – business case for continuous bioprocessing? Timothy Johnson, Genzyme Theme 2 Best timing and scale for implementation of continuous bioprocessing? Jonathan Coffman, BoehringerIngelheim PART 2 Theme 3 Cost analysis of continuous bioprocessing over a product’s lifecycle VeenaWariko, Genzyme Theme 4 Is tomorrow’s process a hybrid of batch and continuous operations? Paul Jorjorian, Gallus BioPharmaceuticals(CMO perspective) Thomas Daszkowski, Bayer Technology Services (Innovator perspective)

26. Implementation of Continuous Processing for Biologics Manufacturing - a CMO Perspective 23rd October 2013 Paul Jorjorian M.Eng. Head of Purification Development (STL) Gallus BioPharmaceuticals

27. quantitative market research results 200 survey respondents: 49% use CMOs for PD • Survey group • Big Pharma/Biotech – 34% • Midsized Pharma/Biotech – 37% • Emerging Pharma/Small/Virtual Biotech – 31% Source: Gallus BioPharmaceuticals’ sponsored survey • 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 filter • Motivations for Engaging CMOs for PD :

28. what are customers looking for? • stainless technology – the historical default and still perceived as lowest risk (today) • disposable technology – flexible capacity • perfusion technologies – alternating tangential flow (ATF), internal spin filter, centrifugation and cell settling devices • flexible stainless steel – the benefits of disposable with the comfort of SS • hybrid technologies – used for commercial processes • fully 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

29. perfusion technologies • Bioreactor prep outside of the suite for rapid turnaround • Disciplined, tenured manufacturing team • Equipment sterilization via autoclave • Single use tubing w/ Terumo sterile welders, filters, and elastomers for each equipment build • Exceptionally stable, clean environment • De-risking perfusion processes? (f SS) • No Bioreactor Contaminations Since 2007 • 140+ / 60 day runs & >2100 passages • On Schedule: 97% of Run Start on time • On Track: >94% Batch Release Rate • How reliable is perfusion? Gallus’ experience: 500L flexible SS bioreactor

30. hybrid options • SUB are adaptable to perfusion processes • Easily increase process output • Massively reduced capital costs • Perfusion + SUT • Decouples upstream and downstream • Reduced footprint • Reduced risk • Used for multiple commercial processes • Hybrid Solution

31. Themes PART 1 Theme 1 Labile v. stable products – business case for continuous bioprocessing? Timothy Johnson, Genzyme Theme 2 Best timing and scale for implementation of continuous bioprocessing? Jonathan Coffman, BoehringerIngelheim PART 2 Theme 3 Cost analysis of continuous bioprocessing over a product’s lifecycle VeenaWariko, Genzyme Theme 4 Is tomorrow’s process a hybrid of batch and continuous operations? Paul Jorjorian, Gallus BioPharmaceuticals (CMO perspective) Thomas Daszkowski, Bayer Technology Services (Innovator perspective)

32. hMoBiDiKModularBiologicsDisposableKonti • A. Vester, J. Magnus

33. MoBiDiK: Process Design Upstream Perfusion Clarification Chromatography Prot A Concentration Downstream Formulation UF/ DF Viral Inactivation Polishing Capto adhere/ AEX Virus Filtration • MoBiDiK – Update • Oct 2013

34. MoBiDiK – Demonstrator Laboratory A A DSP USP • SCM MoBiDiK • Sep, 2013

35. Layout 1st floor – Production Level Cleanroom classification Black Class E Class D Class C Flows Personnel Material Product Waste • BTS 4:3 Template 2010 • June 2011

36. Discussion VOTE: Will we have the process analytics needed for integrated continuous processes in 5 y? Theme 3: Cost analysis of continuous bioprocessing over a product’s 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 tomorrow’s 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?

37. ECI ICB, Castelldefels, Spain, 20-24 Oct 2013