The document summarizes CMC Biologics' implementation of a 2000L single-use bioreactor (SUB) and disposable clarification system into an existing cGMP facility. Key points include integrating the larger 2000L SUB to increase production capacity without affecting existing operations, using a disposable system to reduce validation costs and increase flexibility, and lessons learned around vendor selection, control system design, and installation planning. The project was completed on time and proved the concept of implementing larger-scale disposable technologies within CMC's facility.

1. Implementation of 2000L SUB and
Disposable Clarification System in
Existing cGMP Facility
Dave Wolton
CMC Biologics
2011-10-25

2. Overview
• CMC Biologics
• Why is the 2000L a game changer?
• Integration into Existing Facility
• Defining the Bioreactor Process
• Facility Design Challenges
• Disposable Harvest System
• Lessons Learnt
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3. CMC Biologics
Target
Pre- Commercial
& Lead Tox Phase I Phase II Phase III
tox Production
ID
CMC Biologics
Contract Manufacturer of Biological Therapeutics utilizing
MAMMALIAN & MICROBIAL CELL CULTURE TECHNOLOGIES
• Cell-line Development – CHEF1™ technology
• Upstream/Downstream – process development and manufacture
• Analysis, Characterization, Formulation, Quality and Regulatory

4. Background to why I believe the
2000L is a game changer
• 13 years at contract manufacturer in Slough 2000L
scale
• 6 years producing Enbrel in a 6 x 12,000L plant
• 1 year designing 12 x 1000L SUB plant
• Approximately 1 million Euros spent on basis of design
• Moved to CMC 2 years ago
CONFIDENTIAL 4

5. Blockbuster ‘in market supply’
potential of the 2000L SUB factory
Output from model
= 2 x 12,000L stainless plant
– Plant runs for 300 days per year
– Protein A Cycles per batch approx. 4
– Harvest two reactors every 2 days
– Assumed product campaigns are the norm
– Cell culture only work days
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6. Plants of the future
6 x 12,000L x 2,000LxDisposable
12 12 2,000L Disposable
Lean design
stainless Conventional design
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7. Plants of the future
Reactor hall 15M x 15M
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8. Copenhagen 2000L SUB
Implementation and proof of
concept

9. 2000L SUB
• 2000L capacity retrofitted to a 100L stainless
steel suite
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10. Aim of the project
• Increase US/DS capacity to match launch/commercial
production (MAB): 2000L
• Integrate into existing facility without affecting current
clinical manufacturing
• Minimize limited company recourses
• Project used 1 Engineer and two validation resources
• Meet cGMP requirements – EMEA, FDA
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11. 2000L SUB in 100L SS facility
Microbial CCI
2x 1500L 2x 750L
CCII
100L
CCIII
300L
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12. Stainless Steel
SIP
Automatic valves
CIP
DCS
HPW
70 elastomers
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13. Disposable Bioreactor
• Minimize limited
company recourses SIP
• Low level of
atomization CIP
• Off the shelf
• High flexibility
HPW
• Waste – Supported by DCS
existing infra-structure
at CMC Biologics Waste
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14. Defining the Bioreactor Process
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15. Project Plan
7 months from start to finish
Right. On time.
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16. Vendor:
• Security of supply
• Market leader in number of units sold
• Back up in both USA and Europe
• We already use their single use mixers,
100L, and 500L SUBs
• Willingness to negotiate a bag supply
agreement
• Track record in supplying disposables
• Conventional design
• Compact storage
• Wide choice of control systems
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17. Vendor: EZ controller
• Wheel in wheel out seed reactor concept
• Simple
• Robust
• Large number of units sold
• Fast to set up, train on and validate
• Compact (can be mounted on the SUB)
• Cost effective to have multiple units on
multiple SUB’s
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18. Factory Acceptance Testing
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19. Installation
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20. Installation
Reception as
it was
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21. Installation
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22. Installation
Reception as
it looks now….
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23. Engineering Run - Inoculation
XG2Cb
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24. 2000L SUB data
• The light blue
datapoints
represent the
2000L SUB
• The other data is
from 500L SUB
runs of the same
product
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25. Disposable Harvst System
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26. Integrated 2000L depth filter system
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27. Lessons Learnt
• Decide on controller early – This will impact timelines
and complexity
• Agree who mounts the control system and where it will
be mounted
• Do a cost benefit analysis on the seed strategy
• Take into account fabrication and shipping costs/time
• Be careful in regards vessel orientation and hose
location
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28. Summary
• Slide from Johannes R. Roebers, PhD
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29. Thanks to…
• Andreas Mark Arnung, CMC Biologics
• Christian Skjødt, CMC Biologics
• Esben Eggertsen, CMC Biologics
• Gustavo Mahler, CMC Biologics
• Henrik Knudsen, CMC Biologics
• Jakob Ravnsborg, CMC Biologics
• Johannes R. Roebers PhD, Elan
• Mads Laustsen, CMC Biologics
• Martin Oscar Miret Hattel , CMC Biologics
• Martin Kelly, Thermo Scientific
• Ronni Glenn Refstrup Hansen , CMC Biologics
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30. CONFIDENTIAL 30

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