Kelly Thom Associate Principal Scientist Fujifilm Diosynth Biotechnologies. Your Biologics and Vaccines CDMO Partner of Choice.

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1 Process Design for an All Single-Use Manufacturing Facility: Scaling Low to High Titer Processes to Fit Standard mab Equipment BioProcess International West March 2, 2017 Kelly Thom Associate Principal Scientist Fujifilm Diosynth Biotechnologies Your Biologics and Vaccines CDMO Partner of Choice.

2 One Global Company 3 SITES Billingham, UK College Station, TX RTP, North Carolina 6 LICENSES For commercial manufacturing. 1,100 EMPLOYEES World Wide 20+ YEARS Of Biologics CDMO experience MOLECULES In process development and/or manufacturing.

3 With you all along the road To clinical success Preclinical Phase I Phase II Phase III Regulatory Approval Launch Gene Expression & Strain / Cell Line Development Process Invention Pre-clinical Manufacture Process Development & Optimization Analytical & Stability cgmp Manufacture Fill/Finish Process Characterization Process Validation cgmp Manufacture Stability Commercial Production Post-approval Activities

4 with Our Cell Culture Experience 55 CHO Programs 65+ Cell Culture Programs, including CHO and Baculovirus 10 Baculovirus Programs 1 Commercially Approved Cell Culture Product Manufactured at FDB

5 FDB Single-Use Bioprocessing Journey Learning from Early Adoption of Single-Use Technologies Process Design Goals for New Facility Facility Layout, Room Classifications, and Closure Strategy Upstream and Downstream Single-Use Processes and Equipment Modeling to Design Small (2 g/l), Medium (5 g/l), and Large (8 g/l) Downstream Process

6 Creating biomanufacturing capacity A global partnership Driven by the industry need for cgmp mammalian cell culture biomanufacturing capacity Four successful capacity expansion projects on two continents Creating the UK s first fully single-use biomanufacturing facility 1000 L project Single-use WAVE Bioreactor systems Xcellerex XDR cell culture suite ÄKTA ready and ReadyToProcess prepacked columns Billingham, UK L project Xcellerex XDR 2000L bioreactor added Research Triangle Park, US 1000 L project 2012 Xcellerex single-use mixers Xcellerex XDR cell culture suite ÄKTA ready purification system Research Triangle Park, US L project Xcellerex XDR 2000L bioreactor added Billingham, UK Ongoing partnership

7 Development of FDB Single Use Bioreactor Platform Why Single Use? Capacity can be increased quickly Capital investment and payback time are less Footprints are reduced Less utilities are required (CIP/SIP) No cleaning verification/validation Less cost for room classifications, EM monitoring, personnel gowning/flow Multi-product manufacture ( ballroom ) suites Multiple products in multiple suites (reduced changeover times) Production Bioreactor Selection Process performance (mixing, mass transfer, sparger flexibility) Engineering design (hardware and bag design) Control system capability and automation tie-in Equipment cost and product support Speed and ease of implementation and qualification Track record

8 Product (g/l) VCD (10 5 cells/ml) Stainless Steel vs. Single Use Bioreactor 110L SS Product Quality: Glycosylation Patterns LSS Avg (n=3) 200LSUB Avg (n=3) 1000L SUB Avg (n=2) 200L SUB Time (days) 1000L SUB LSS Avg (n=3) 200L SUB Avg (n=3) 1000LSUB Avg (n=2) Time (days)

9 Dissolved Oxygen (%) SUB Scale Up by Mass Transfer To achieve peak kla = 7 hr rpm = 50% sparge 120 rpm = 38% sparge O 2 kla characterization performed for all SUBs 10, 50, 200, 500, 1000 and 2000 L kla models are being developed in MODDE CO 2 stripping characterization is on the horizon 1000 L CHO Process (~30 E6 cells/ml) ± 20% 0 50% O2 Sparge (slpm) Culture Duration (14 days)

10 SUB Scale Up to 1000 L GMP

11 Upstream Learning from Early Adoption Hardware Design MFC sizing Automated exhaust filter strategy SUB Bag Design Enough addition lines with correct diameters Tubing is long enough for all connections Multiple exhaust filters Evaluate the bag film Connectivity Minimize the number of sterile connections Welding vs. sterile connectors Solution bags with on-board filters and tubing to match the SUB Raw Materials Liquid media Pre-made solutions (nutrient feeds if stability allows, glucose, glutamine, antifoam) Have capability to formulate if needed

12 Development of FDB Single Use Downstream Platform Manufacturing experience with multiple single-use vendors and equipment Chrom Skids Pre-packed Columns Single Use TFF Skids Single Use Mixers GE AKTAReady GE ReadytoProcess Pall SU TFF GE XDM / XDUO Repligen Opus Sartorius FlexAct Sartorius Palletank Millipore Mobius

13 Downstream Learning from Early Adoption Design Limitations Skids: flow rates, mixing, temperature control, hydroxide exposure, flow kit max usage time (limited tubing lifetime in peristaltic pump) mab throughputs: low chrom skid flow rates, low TFF membrane throughput Instrumentation Limitations Sensor (P, T, UV, flow, conductivity) issues Use of traditional ph probe instead of inline ph probe Installation Limitations Operators must standardize sensors as part of self check Manifold installation is cumbersome Lack of manifold labeling can result in cross connectivity issues Standard manifold tubing sizes may require different connectors (connecting 1 to ½ tubing) Tubing management and consumable design were key early learnings Need to manage customization against cost

14 Process Design Goals for HT, mab Facility Standardized offering All single-use equipment Medium/high density fed batch CHO (10 40 E6 cells/ml) Downstream to process a wide range of upstream titers Small (2 g/l), Medium (5 g/l) and Large (8 g/l) Downstream Scenarios One set of standard equipment with scaling flexibility Define closed processing needs and connectivity strategy Placement of unit operations for optimal suite scheduling and process flow Allowable process duration for each unit operation Off-the-shelf products wherever possible BOMs for small, medium, and large downstream Raw material and consumable costs for a batch

15 Design Approaches GE Flex Factory equipment and automation (USP, partial DSP) Super Pro Modeling: Created a simulation to scale the FDB platform process over a range of 2 8 g/l Model Inputs Model Outputs 2000 L Harvest Titer Unit Op and Total Batch Duration Filter Fluxes Resin Capacities Step Yields Column Sizes Number of Column Cycles Filter/Membrane Areas Buffer and Process Volumes SUM Sizes Raw Material Cost per Gram

16 Unit Operations by Suite Harvest one batch per week At steady state, up to nine products in flight

17 Single-Use Upstream PFD

18 Single-Use Downstream PFD

19 Super Pro Model Protein A Viral Inactivation CEX AEX Nanofiltration TFF Bulk Fill

20 Chromatography Estimates and SUM Sizing Protein A CEX Protein Titer Column Size Cycles Process Process Column Size Cycles Duration Duration (g/l) (L) (#) (hr) (L) (#) (hr) Small Medium Large Clarified Harvest VI SUM 1 VI SUM 2 CEX Eluate AEX Eluate Nanofiltrate Protein Titer SUM A SUM B SUM C SUM D SUM E SUM F (g/l) (L) (L) (L) (L) (L) (L) Small Medium Large NOTE: SUM sizes were determined from process volumes, which are not shown.

21 Raw Materials Cost per Gram

22 TFF Design Protein Titer (g/l) DS Conc (mg/ml) 1 TFF Retentate / Final DS Volume (L) Assumption that DF will occur at mg/ml retentate concentration 50 L and 200 L retentate tanks will be used 1000 L SUM used for retentate volume > 200 L

23 Summary FDB leveraged learnings from early adoption of single-use technologies to guide process/facility design The new facility utilizes the multi-product ballroom approach Harvest of one batch per week Up to nine products in flight at steady state Super Pro modeling was used to define small, medium and large downstream processes Equipment Processes Durations Cost

24 Acknowledgements Upstream Development Sharyn Farnsworth Simon Uphill Downstream Development Patrick Daley Mark Chavez Jonathan Haigh Michael Murray Phil Ropp Kevin Short Matt Teten Process/Facility Design Mike Jones Peter Large Stewart McNaull Thomas Page Mary Vo-Harris GE Flex Factory Design Team

25 FUJIFILM Diosynth Biotechnologies Advancing Tomorrow s Medicines TO LEARN MORE VISIT US AT BOOTH 908