Continuous Bioprocessing Barcelona Spain

Continuous Processing in Biotech Production: An alternative to a modern single use, batch, facility ?

Thomas Daszkowski, Bayer Technology Services

Continuous BioprocessingBarcelona Spain

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21.10. 2013, Thomas Daszkowski

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

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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

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

2013, Thomas Daszkowski

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

http://www.xcellerex.com/pdf/Xcellerex_rpharm.pdf


Newer Facility Concepts GE Healthcare KUBio™http://www.GE.com

nne pharmaplan (Flexplant)http://www.nnepharmaplan.com

Merck Millipore, DSMhttp://www.merckmillipore.com

Jacobs, CRB,…..

http://www.nnepharmaplan.com/

http://www.nnepharmaplan.com/

http://www.merckmillipore.com/

http://www.merckmillipore.com/

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 DaszkowskiPage 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:



MoBiDiK : Fully integrated and single use Continuous Manufacturing

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 ?

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

Demonstratordisposable, modular & continuous

Process

MoBiDiK – Project StructureConceptual 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


MoBiDiK: Process Design

• MoBiDiK – Update • Oct 2013

ChromatographyProt A

Viral Inactivation

Concentration

FormulationUF/ DF

PolishingCapto adhere/ AEX

Virus Filtration

Downstream

Clarification

Upstream

Perfusion

MoBiDiK – Demonstrator Laboratory

• SCM MoBiDiK • Sep, 2013

A

A

USP DSP

3D Layout 1st Floor – Production Level

• BTS 4:3 Template 2010 • June 2011

September 25, 2013, Jørgen Magnus

Cell culture pilot plant in Wuppertal

Purpose• Produce material for phase 3 clinical trialsDesign• 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 marketDesign• 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



Conclusions

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



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

The Biopharma Market & BRIC countries


April 2, 2013, Thomas Daszkowski

Continuous Manufacturing: Data Points

Source: EPSRC,Centre of Innovative Manufacturing


ESPRC and Conti Processing


ESPRC and Conti Processing cont‘d


„Change from batch to continuous processing in pharmaceutical manufacturing will happen soon“ (Pfizer 2003)

(Bio)pharmaceuticalCompany

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

Continuous Bioprocessing Barcelona Spain

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