Inspiring Advances in Bioprocessing. John Bonham-Carter March 14, 2017

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1 Inspiring Advances in Bioprocessing John Bonham-Carter March 14, 2017

2 Bioprocessing Trends Emerging trends, new challenges Integrated continuous processing Upstream continuous processing (perfusion) proven to increase efficiency for 25+ years Integrating downstream continuous processing Shift to disposables Time-savings driven by aggressive time-tomarket goals Cost-savings Quality improvements Regionalization >40 on the market* and >350 in clinical development Eight FDA approvals in 2014, 14 approvals anticipated Robust pipeline to sustain future growth with superior efficacy, new targets, new disease areas Smaller footprint in smaller facilities Rapid growth in Asia Focus on process economics COGS improvements reduce capital expenditures Healthcare pressure costs *Includes fusion proteins such as Enbrel and Eylea that use a mab manufacturing process Repligen Proprietary ǀ March 28, 2017 ǀ 2

3 How Long Can Biologics Avoid Commoditization? Monoclonal antibodies may become commodities Biopharmaceuticals are not unique and cannot escape the effects of the coming competition Penicillin price product cycle will probably not repeat but prices will fall over the next 20+ years Biosimilars, and multiple drugs for the same indication, will impact cost strategies First-in-class biologics are not likely to be subject to these cost pressures But not enough of these in development to support the industry Future plans must include drugs with mid market sales Cost, flexibility and efficiency are the key focus moving forwards New technologies being platformed in several new commercial facilities Existing steel plants are being modified to boost ( intensify ) production Biotech? Biotech? Pharma? Repligen Proprietary ǀ March 28, 2017 ǀ 3

4 Upstream Production Options Concentrated Traditional Perfusion Perfusion culture manufacturing strategies for cell-culture derived biopharmaceuticals offer the potential of greater daily productivities and hence smaller facility footprints than batch and fed-batch culture manufacturing strategies.. Pollack 2013 Biotech and Bioengin 110: Leading cell separation device in perfusion MAb and rprotein production For perfusion, you don t really need exotic upstream equipment beyond robust cellretention devices. K. Konstantinov, Genzyme Corp, BioProcess International, December 2012 Technology BPI Finalist of the Decade 2012 Award-winning filtration device that delivers high cell concentration and process intensification Applications beyond perfusion - process intensification, cell banking, seed train optimization In 8 of the Top 10 Pharma companies In 7 commercial and 50+ Phase 1-3 processes Repligen Proprietary ǀ March 28, 2017 ǀ 4

5 XCell Devices Utilize Alternating Tangential Flow (ATF) Connect the XCell System to a bioreactor. The system includes: A stainless steel housing comprising: single-use hollow fiber filter cartridge single use diaphragm pump OR A ready to connect single use device 0.2µM filter retains cells inside bioreactor while harvest is a clarified stream ready for DSP Alternating Tangential Flow (ATF) is created within the device by the action of a diaphragm moving upward and then downward, powered by air within a pump head. With each short 10 to 15 second cycle, a small back flush occurs at each end of the filter. This back flush prevents filter clogging and allows cell concentrations of over 300 million cells per ml. XCell Perfusion performance with high-density culture of Drosophila S2 cells Repligen Proprietary ǀ March 28, 2017 ǀ 5

6 Think continuous, think small What is it? Why is it important? Needs and Trends A production method used to manufacture and process materials in a consistent, constant, and uninterrupted manner, in contrast to batch processing. Continuous upstream processing (perfusion) has been in use for over 25 years Steady state operation Consistent product quality Reduced equipment size Increased productivity Streamlined process flow Low cycle times Reduced capital cost and time Process intensification Scale-up Number up, not scale up Single-use technologies for multi-product systems Impact on COGs Integrating upstream and downstream Repligen Proprietary ǀ March 28, 2017 ǀ 6

7 Continuous Biopharmaceutical Manufacturing: The Challenge Science & Technology Organization & Leadership Challenges Regulatory & Quality Economic & Infrastructure Repligen Proprietary ǀ March 28, 2017 ǀ 7 7

8 Continuous Biopharmaceutical Manufacturing: The Challenge Regulatory & Quality Sharmista Chatterjee, CMC Lead for Qbd ONDQA / CDER/ FDA IFPAC Annual Meeting Baltimore, January 2012

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10 Nothing New About cgmp Perfusion, Except Expansion Perfusion Expert The system is very convincing it s the Gold Standard for Perfusion Large European Biotech Today, there are many thousands of trained XCell perfusion engineers compared to hundreds a decade ago Fed-batch company converts after first trial The ATF gives us renewed interest in perfusion technology and how we can easily scale up to a commercial processes. The ATF is really enabling us to start imagining next generation processes Large East Coast Biopharma Industry Experiencing Large Expansion ~30% XCell units go to seed train and N-1 perfusion ~30% people are specifying perfusion for clinical manufacture (Bioplan 2014) ~45% starting or expanding Continuous Processing (AspenBrook 2015) Repligen Proprietary ǀ March 28, 2017 ǀ 10

11 Intensification Options Good What if you already have existing plants and little desire to change manufacturing platforms? 2016 Repligen Corporation. All rights reserved. The trademarks mentioned herein are the property of Repligen Corporation and/or its affiliate(s) or their respective owners.

12 Large Volume, High Density, Cell Bag Directly Inoculates N-1 Perfusion Reactor 1 VVD 2 VVD 2.5 VVD Repligen s high density XCell cell banking process was used to create 1L cryo bags A portion of these cells to inoculate a 1.5L wv bioreactor connected to an XCell ATF 2 perfusion system mimicking a 200L (N-1) perfusion bioreactor An initial drop in the cell viability was expected as reported in the literature (Gargi et al. 2012, Wiley) Viability recovered as normal to produce a high viability high density seed culture for the N reactor Repligen Proprietary ǀ March 28, 2017 ǀ 12

13 What Does N-1 Perfusion Achieve For Production Fed Batch? A 1.5L wv reactor was used to mimic a 2000L production reactor From the single N-1 XCell perfusion reactor, at 100E6 cells/ml, the cells were separately inoculated into low seed (0.5E6 cells/ml) and high seed (10E6 cells/ml) fed-batch production cultures The maximum VCD for high seed culture is 25E6 cells/ml and lasted only 7 days, whereas the maximum VCD for low seed culture is only 19E6 cells/ml and lasted 14 days The same protein quantity was produced in the high vs low seed cultures, but in about half the time Repligen Proprietary ǀ March 28, 2017 ǀ 13

14 Shortening Vaccine Production Time with an Intensified Cell Bank Ad35 TB Vaccine Candidate at Crucell (now Janssen Vaccines) Source: 5 th Bioman Pro Belgium 2008, M de Vocht, Crucell Repligen Proprietary ǀ March 28, 2017 ǀ 14

15 Intensified Virus Production (ivip): Post Infection Perfusion No change in VP/IU ratio compared to standard process Approx. 7.5x increase in volumetric productivity Repligen Proprietary ǀ March 28, 2017 ǀ 15

16 Crucell s Supply Problem 180MM doses required Merck Achieved Merck Projected Bioreactor Size 1,000 L 10,000 L Approx. doses per batch Approx. doses per year Traditional Process based on PER.C6 rad 5 for Phase II HIV 0.25 MM 2.5 MM 6 MM 60 MM 3 x 10,000 L reactors required Repligen Proprietary ǀ March 28, 2017 ǀ 16

17 Process Intensification And Perfusion Achieve a Remarkable Solution For Vaccine Manufacturing Traditional Process based on PER.C6 rad 5 for Phase II HIV Intensified Process (and single use equipment) Merck Achieved Merck Projected Crucell Achieved Crucell Projected Bioreactor Size 1,000 L 10,000 L 10 L 1,000 L Approx. doses per batch Approx. doses per year 0.25 MM 2.5 MM 0.08 MM 8 MM 6 MM 60 MM 1.98 MM 198 MM 3 x 10,000 L reactors required 1 x 1,000 L SUB sufficient Repligen Proprietary ǀ March 28, 2017 ǀ 17

18 Intensification Options Better How can you implement intensification and continuous processing to gain performance quickly? 2016 Repligen Corporation. All rights reserved. The trademarks mentioned herein are the property of Repligen Corporation and/or its affiliate(s) or their respective owners.

19 VCD (106 Cells/mL) VCD (106 Cells/mL) Continuous Upstream Is Not Overly Complex Once You Do the Work To Understand % Viability (Dashed Lines) Cumulative IgG (g) Data from Veronique Chotteau KTH Stockholm University Cell Bleed ATF2 Perfusion-Med Density Fed-batch Culture Culture Time (days) Time (days) Culture Time (days) Repligen Proprietary ǀ March 28, 2017 ǀ 19

20 Identical performance, different configurations XCell ATF 6 - Stainless steel vs. Single-use formats Parameters Stainless steel Single-use Typical BR Volume (L) ATF Pump Rate (LPM) Nominal Max Recommended Min 5 5 Recommended Max for Scale up Filter Types and Surface Area (m 2 ) 0.2um PS um PES Pump/Filter Housing Diaphragm Displacement Volume at 12 LPM (L) Permeate Hold Up Volume (L) Retentate Hold-up Volume (L) XCell ATF 6 Stainless Steel XCell ATF 6 Single-use Height (cm) Weight of Dry Assembly (kg) Repligen Proprietary ǀ March 28, 2017 ǀ 20

21 Connect and Culture in as little as 30 minutes Repligen Proprietary ǀ March 28, 2017 ǀ 21

22 Performance Comparison XCell 2, SS vs SU Beta Test Results VCD: E6 Cells/mL BRV: 2.5VVD Flux: 5.7LMH Filter: PES 0.2um Similar growth profiles were observed between XCell ATF 2 SS and ATF 2 SU Repligen Proprietary ǀ March 28, 2017 ǀ 22

23 Performance Comparison XCell 6, SS vs SU Beta Test Results VCD: CSPR: BR w.v: ~ 40e6 cells/ml 0.05nL/Cell/Day 40L (50L SUB) Similar growth profiles were observed between XCell ATF 6 SS and ATF 6 SU Connectivity, wetting and pre-use integrity procedures proven Sterility maintained for 20 days of operation Repligen Proprietary ǀ March 28, 2017 ǀ 23

24 Cell Specific Productivity XCell 2 & 6, SS & SU Beta Test Results Similar cell specific productivity was obtained with XCell ATF 2 SS, ATF 6 SS and ATF 6 SU devices Demonstrates scale-ability of technology performance between ATF 2 and ATF 6 scales Demonstrates performance equivalence between ATF 6 stainless steel pump housings and ATF 6 Single-use devices Demonstrates compatibility of the XCell ATF Single-use device with Single Use Bioreactors Repligen Proprietary ǀ March 28, 2017 ǀ 24

25 Intensification Options Better What if you have existing facilities what advantage is there in adapting to an intensified process strategy? 2016 Repligen Corporation. All rights reserved. The trademarks mentioned herein are the property of Repligen Corporation and/or its affiliate(s) or their respective owners.

26 Perfusion enables more process flexibility Smaller, more flexible, more productive facility helps manage capacity In early clinical phases perfusion allows: Better utilization of reactor time Produce the same amount of product in a shorter time Product produced will have a more consistent quality In later clinical phases and scale-up Scale up in perfusion is lower risk because development scale is commercial scale In Fed-Batch the scale increases to 10-20x, which takes: more time additional steps additional process risk additional capital risk Repligen Proprietary ǀ March 28, 2017 ǀ 26 Fed-Batch 200L Perfusion 200L 5,000L 500L

27 Would You Retrofit Smaller Fed Batch Facilities With Perfusion Capability, Rather Than Expand To Larger Scale? Each batch provides 5g/L Each batch provides 1.5g/L at 1.5vvd Flexibility of manufacture: managing capacity with a 200L reactor In two weeks, FB produces 1kg; In a similar time, CP produces 0.45kg/day = 2.7kg (two 3 day batches plus wasted start-up time) Which is riskier? If 4kg is required: Depends on your Three further FB runs achieve goal on day 60 or buy a 1000L reactor existing knowledge CP can be simply extended with same quality product, target reached day 16 Repligen Proprietary ǀ March 28, 2017 ǀ 27

28 Would You Build A New Large Scale $B Facility? Would you run 75 SUBs in Fed Batch? Or 10x 15kL?.Or maybe just 10 SUBs in Perfusion is preferable? 3-5 years to build? 1-2 years to build? Assume FB Titer at 5g/L 10kL provides 50Kg in one 14 day batch Similar Qp, 2vvd perfusion may be 1.5g/L/day 1kL provides 9Kg per 3 day batch It will take days for perfusion to make the same 50Kg and with the advantages of: 1000L SUB is used instead of 10kL Steel vessels Less time spent between reactor runs, less downtime Companies without the relevant skills Less cleaning and other non-productive efforts need to improve their knowledge to take advantage of these benefits More constant daily operations, fewer variations Production can be more easily, and more quickly, expanded R&D scale is commercial scale, less scale up risk and late stage development time Repligen Proprietary ǀ March 28, 2017 ǀ 28

29 Intensification Options Best? What if you could develop a new bioprocess platform based on state of the art techniques, leading towards real time release? 2016 Repligen Corporation. All rights reserved. The trademarks mentioned herein are the property of Repligen Corporation and/or its affiliate(s) or their respective owners.

30 Where Can Process Intensification Make An Impact? Concentrating a process to produce higher cell densities and higher product yields in shorter time. Concentrated perfusion Concentrated fed batch N-1 or N-2 Reducing the number of upstream steps through increased cell concentration at each step Cell Banking Cultivate large seed stocks and eliminate seed steps X X X X X Repligen Proprietary ǀ March 28, 2017 ǀ 30

31 New, smaller, intensified manufacturing platform Significantly reduced capital required Smaller cleanrooms & facility, fewer reactors and utilities required Fewer operational steps, no open handling If run in continuous mode, automation provides for same every day Less scale up, saving time & cost R&D scale is commercial scale Reduced tech transfer, changes dramatically the manufacturing risk and flexibility: Rapidity to build allows delayed facility build decisions Market uncertainty can be managed with copy/paste factories as needed Allows flexible geographic and CMO options, without risking capacity Production: Fed-Batch or Continuous? 10L-50L 500L-2000L Repligen Proprietary ǀ March 28, 2017 ǀ 31

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33 Integrated Continuous Bioprocessing Is Regularly Achieved At R&D Scale but not yet in cgmp production Small foot print Low residence time from protein expressed to protein in final formulation buffer less degradation possible Low resin usage Just-enough production Low manual attendance need Continuous monitoring of the cultivation performance End-to-end continuous production of complex recombinant proteins Tiainen P., Integrated Continuous Processing, 2013

34 Varied Drivers And Sophisticated Responses Are Driving Manufacturing Change Capital risks Manufacturing and tech transfer risks COGs is perhaps no longer the main driver for change. Each of these must be assessed for importance: Continuous enablers Manufacturing variability Manufacturing CoG (becomes competitive advantage) Negative perceptions changing due to new reliable technology and increased knowledge Intensification drivers Product Pipeline Mix Tech Transfer Risk Manufacturing Network Management Plant Flexibility Tighter Product Quality Existing Facility Utilization Companies are responding to their specific needs with varied intensification solutions, and sometimes this is continuous processing Technology allowing more consistent, tighter, product quality Process understanding Availability of knowledgeable personnel Demand for smaller, more productive facilities Managing the business and pipeline risk is now the key driver, not COGs, in the move to continuous bioprocessing

35 John Bonham-Carter Director, Repligen 2016 Repligen Corporation. All rights reserved. The trademarks mentioned herein are the property of Repligen Corporation and/or its affiliate(s) or their respective owners.