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Continuous Processing in Biotech Production: An alternative to a modern single use, batch, facility ?
Thomas Daszkowski, Bayer Technology Services
Continuous Bioprocessing Barcelona Spain
21.10. 2013, Thomas Daszkowski Page 1
21. 10. 2013, Thomas Daszkowski
Agenda Function and Role of Bayer Technology Services
Biopharmaceutical Market (Trends and Drivers)
Current and new Biotech Manufacturing concepts
Continuous Manufacturing
Conclusion
Page 2
Who is Bayer Technology Services (BTS)
Bayer Technology Services initiates, implements and supports technological innovations over the long term. From product and process development through the planning and construction of plants to the automation and optimization of processes.
21. 10. 2013, Thomas Daszkowski Page 3
Trends / Drivers impacting Manufacturing
Trends / Drivers Impact on Manufacturing
Regional Requirements -> local instead of centralized
Personalized Medicine -> reduced output per drug
Rapid Enhancements in -> allow for changes, decouple
- Cell Biology (Titer) and building from equipment
- Technology (Single Use)
More Potent Drugs -> reduced output per drug
More Competition -> cost pressure on production will increase
Need for localized, yet cost competitive production units
21. 10. , 2013, Thomas Daszkowski Page 4
Status Quo: Recent Facility Announcements Bristol-Myers Squibb (Devens, MA), $750MM,
6x 20,000l bioreactors – 2011 timeframe
Pfizer Biotech Campus (Grange Castle, Ireland), €1.8 billion, 6x 12,5000l bioreactors , additional €145M investment announced in Sep 2011.
MedImmune, ( Fredricksburg ), $ 600 Mill., 2011 Facility of the Year Award in the project execution category.
Xcellerex announces sale of FlexFactory®Bio-production line to R‐Pharm for new manufacturing facility in Russia
Page 5
http://www.xcellerex.com/pdf/Xcellerex_rpharm.pdf
2013, Thomas Daszkowski
Newer Facility Concepts GE Healthcare KUBio™ http://www.GE.com
nne pharmaplan (Flexplant) http://www.nnepharmaplan.com
Merck Millipore, DSM http://www.merckmillipore.com
Jacobs, CRB,…..
Page 6 2013, Thomas Daszkowski
Examples of Bayer Activities
Single-Use Systems
Functionally Closed Processing
Ball Room Concept
Continuous Manufacturing
MoBiDiK
Modular, Bio production, Disposable, Konti
http://biopharminternational.findpharma.com/biopharm/Quality/Challenging-the-Cleanroom-Paradigm-for-Biopharmace/ArticleStandard/Article/detail/733336
Newer Facility Concepts: Bayer Activities
2013, Thomas Daszkowski Page 12
MoBiDiK: Project Set-Up
MoBiDiK
• Industry – Academia Consortium (9 partners)
• Partially Public Funded Project through
State of NRW (Germany)
• Project Start: 1st August 2011
• Project Duration: 3 years
Continuous, disposable and modular technologies to develop a functionally closed mAb process of the future
funded by:
2013, Thomas Daszkowski Page 8
MoBiDiK : Fully integrated and single use Continuous Manufacturing
2013, Thomas Daszkowski Page 9
Current Facilities Newer Facilities Concept
MoBiDiK Concept
• Batch • Stainless steel • Rooms C & D class • e.g. 6x 20,000l
bioreactors
• Batch • Single use • Rooms C & D class
• Continuous • Single Use
pH VI & homogenisation
pH adjustment
UFDF (ATF) & Bags ControlControl
ATF cell retention
Fermenter control
Buffer A200 L
Perf.-medium
200 L
Perf.-medium
200 L
Waste200 L
Tarpon ProtABuffer A
200 L
Buffer C
100 L
Buffer D
100 L
Buffer E50 L
Buffer F
100 L
Buffer A200 L
Concentration adjustment
Virus-filtration
Bioburden Reduction
Waste200 L
Waste200 L
Tarpon – Margie
CaptoAdhere & AEX-
MA
CD adjustment
ATF concen-tration
Buffer B200 L
Buffer J100 L
Buffer K100 L
Waste200 L
Product10 L Bag
20L Bayshake
Fermenter control
MoBiDiK : Why Continuous Manufacturing ?
2013, Thomas Daszkowski Page 10
MoBiDiK Concept
• Continuous • Single Use
pH VI & homogenisation
pH adjustment
UFDF (ATF) & Bags ControlControl
ATF cell retention
Fermenter control
Buffer A200 L
Perf.-medium
200 L
Perf.-medium
200 L
Waste200 L
Tarpon ProtABuffer A
200 L
Buffer C
100 L
Buffer D
100 L
Buffer E50 L
Buffer F
100 L
Buffer A200 L
Concentration adjustment
Virus-filtration
Bioburden Reduction
Waste200 L
Waste200 L
Tarpon – Margie
CaptoAdhere & AEX-
MA
CD adjustment
ATF concen-tration
Buffer B200 L
Buffer J100 L
Buffer K100 L
Waste200 L
Product10 L Bag
20L Bayshake
Fermenter control
1. Further reduction in Manufacturing Footprint and Capex
2. Process Robustness (less manual interactions and higher degree of automation)
3. Reduction in Inventory (days at hand)
4. No scale up during drug development required
USP DSP
Demonstrator disposable, modular & continuous
Process
MoBiDiK – Project Structure Conceptual Design • Conceptual Design • Model-based process
development
Downstream Process • Extraction • Chromatography/
Adsorption • Membrane Technology • Protein Crystallization • Protein Precipitation
Upstream Process • SU-Perfusion • SU-Cell retention • Pulsed Diafiltration • RQ-Control
Conceptual Design
2013, Thomas Daszkowski Page 11
MoBiDiK: Process Design
Page 12 • MoBiDiK – Update • Oct 2013
Chromatography Prot A
Viral Inactivation
Concentration
Formulation UF/ DF
Polishing Capto adhere/ AEX
Virus Filtration
Downstream
Clarification
Upstream
Perfusion
MoBiDiK – Demonstrator Laboratory
• SCM MoBiDiK • Sep, 2013 Page 13
A
A
USP DSP
3D Layout 1st Floor – Production Level
• BTS 4:3 Template 2010 • June 2011 Page 14
September 25, 2013, Jørgen Magnus Page 15
Cell culture pilot plant in Wuppertal
Purpose • Produce material for phase 3 clinical trials Design • Stainless steel equipment • Functionally closed processing • Fed-batch fermentation • Operations are separated in different rooms
Comparison to facility with traditional design and similar production capacity
Biofacility of the future
Purpose • Production for market Design • 100 % S.U. process equipment • Closed processing • Continuous processing • Ballroom production
Building Concept • 5 levels • ~ 5000 m2 total area • ~ 1400 m2 cleanroom (class D and C)
Building Concept • 2 levels • ~ 1200 m2 total area • ~ 360 m2 cleanroom (class D and C)
MoBiDiK – Challenges
Competing with an existing well proven technology platform
GMP readiness of equipment
At / Inline analytics
More complex operation , increase in operator skill set
Regulatory buy in
2013, Thomas Daszkowski Page 16
Conclusions
2013, Thomas Daszkowski Page 17
Need for localized, yet cost competitive production units is real New Single Use batch operated Biotech Facilities are a first response (biggest advantage, technology and mindset readiness)
Conti Manufacturing allows in addition • Next step in Footprint and Capex Reduction • One identical platform for Clinical Development and Product Launch • High degree of automation and reduction in manual interaction (biggest challenge; paradigm shift (technology and mindset) in Development and Production)
Acknowledgment: Mobidik Team, BHC GBD, Invite, Bio NRW,.. Thanks for your attention
Page 18 2013, Thomas Daszkowski
The Biopharma Market in numbers
Biopharmaceuticals account for 15.6% of total market in 2011
Global biopharmaceutical market was valued at $138 billion in 2011
Expected to grow to over
$320 billion by 2020
Growth
>10% each year Monoclonal antibody products are the
fastest growing segment 65% of developmental pipeline
Source: Levine, bptc consultant and IMS Health
21. 10. 2013, Thomas Daszkowski Page 19
The Biopharma Market & BRIC countries
21. 10. 2013, Thomas Daszkowski Page 20
Continuous Manufacturing: Data Points
April 2, 2013, Thomas Daszkowski Page 21
Source: EPSRC,Centre of Innovative Manufacturing
ESPRC and Conti Processing
April 2, 2013, Thomas Daszkowski Page 22
ESPRC and Conti Processing cont‘d
April 2, 2013, Thomas Daszkowski Page 23
„Change from batch to continuous processing in pharmaceutical manufacturing will happen soon“ (Pfizer 2003)
(Bio)pharmaceutical Company
Continuous (bio)manufacturing Remark
Pfizer Continuous Processing in Pharmaceutical Manufacturing new manufacturing technology of continuous processing involving chemistry in a pipe and continuous extraction (implemented at Pfitzer, Ireland 2009)
Matthew J. Mollan Jr., Ph.D. and Mayur Lodaya, Ph.D., Pfizer Inc.
Roche/Genentech Continuous wet granulation process using QbD and PAT presented in December 2012 during PDA/EMA conference
Martin Wunderlich
GSK IChemE 2012 Award: fully integrated and closely controlled tablet production process
Cooperation with Siemens, GEA, Sagentia and academia
Novartis/Sandoz 10-year study MIT-Novartis cooperation on small molecule, pilot plant in headquarter started, 5-10 years forecast to convert all Novartis production sites
Bernard Trout
Sanofi/Genzyme Continuous manufacturing will be presented during BPI europe in 2013
K. Konstantinov
Merck Serono Pilot study for conti downstream presented in BPI Europe meeting Feb 2013
Norbert Rasenack, Thomas Linden
Continuous Manufacturing: Data Points cont‘d
April 2, 2013, Thomas Daszkowski Page 24