Process Design for an All Single-Use Manufacturing Facility: Scaling - - PowerPoint PPT Presentation

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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

One Global Company

3

SITES

Billingham, UK College Station, TX RTP, North Carolina

1,100

EMPLOYEES

World Wide

6

LICENSES

For commercial manufacturing.

20+

YEARS

Of Biologics CDMO experience.

280+

MOLECULES

In process development and/or manufacturing.

With you all along the road To clinical success

Regulatory Approval Launch Phase III Phase I Phase II Preclinical

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

with

55

CHO Programs

Our Cell Culture Experience

65+

Cell Culture Programs, including CHO and Baculovirus

10

Baculovirus Programs

1

Commercially Approved Cell Culture Product Manufactured at FDB

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

Creating biomanufacturing capacity

A global partnership

1000 L project 1000 L project 2000 L project

• Single-use WAVE Bioreactor™ systems
• Xcellerex™ XDR cell culture suite
• ÄKTA™ready and ReadyToProcess™

prepacked columns

2013 2012 2014 2015

Billingham, UK

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

2017

2018

2019

• Xcellerex single-use mixers
• Xcellerex XDR cell culture suite
• ÄKTA™ready purification system
• Xcellerex XDR 2000L

bioreactor added

Research Triangle Park, US Research Triangle Park, US

2000 L project

• Xcellerex XDR 2000L

bioreactor added

Billingham, UK

Ongoing partnership

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

200L SUB 1000L SUB 110L SS

50 100 150 200 250 300 2 4 6 8 10 12 14 16 18 20 VCD (105 cells/mL) Time (days)

110LSS Avg (n=3) 200LSUB Avg (n=3) 1000L SUB Avg (n=2)

Stainless Steel vs. Single Use Bioreactor

200 400 600 800 1000 1200

2 4 6 8 10 12 14 16 18 20 Product (g/L) Time (days)

110LSS Avg (n=3) 200L SUB Avg (n=3) 1000LSUB Avg (n=2)

Product Quality: Glycosylation Patterns

SUB Scale Up by Mass Transfer

• O2 kLa characterization performed

for all SUBs

– 10, 50, 200, 500, 1000 and 2000 L

• kLa models are being developed in

MODDE

• CO2 stripping characterization is on

the horizon

± 20% 0 – 50% Dissolved Oxygen (%) O2 Sparge (sLpm) Culture Duration (14 days)

1000 L CHO Process (~30 E6 cells/mL) To achieve peak kLa = 7 hr-1 100 rpm = 50% sparge 120 rpm = 38% sparge

SUB Scale Up to 1000 L GMP

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

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

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

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

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 Column Sizes Resin Capacities Number of Column Cycles Step Yields Filter/Membrane Areas Buffer and Process Volumes SUM Sizes Raw Material Cost per Gram

Unit Operations by Suite

• Harvest one batch per week
• At steady state, up to nine products in flight

Single-Use Upstream PFD

Single-Use Downstream PFD

Super Pro Model

Protein A Viral Inactivation CEX AEX Nanofiltration TFF Bulk Fill

Chromatography Estimates and SUM Sizing

Protein A CEX Protein Titer Column Size Cycles Process Duration Column Size Cycles Process Duration (g/L) (L) (#) (hr) (L) (#) (hr) Small 2 - 3 10 8 - 12 48 - 62 10 6 - 9 20 - 30 Medium 3 - 5 20 6 - 10 31 - 45 20 4 - 7 14 - 24 Large 5 - 8 32 7 -10 31 - 41 32 5 - 7 17 - 24 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 2 - 3 2500 200 200 1000 1000 1000 Medium 3 - 5 2500 500 500 1000 1000 1000 Large 5 - 8 2500 1000 1000 2500 2500 1000 NOTE: SUM sizes were determined from process volumes, which are not shown.

Raw Materials Cost per Gram

TFF Design

Protein Titer (g/L) DS Conc. 2 3 5 8 (mg/mL) TFF Retentate / Final DS Volume (L) 1 10 236 354 590 944 50 47 71 118 189 100 24 35 59 94 180 20 33 52

• Assumption that DF will occur at 10 – 50 mg/mL retentate concentration
• 50 L and 200 L retentate tanks will be used
• 1000 L SUM used for retentate volume > 200 L

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

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

FUJIFILM Diosynth Biotechnologies

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