This document outlines 10 hot topics in biomanufacturing: 1) product mix and business models in biopharma, 2) high-titer processes in mammalian cell culture, 3) downstream processing being driven by mass rather than volume, 4) facility fit considerations, 5) cost of goods and price margin pressures, 6) biosimilars and biobetters, 7) offshore manufacturing, 8) technology platforms and implications of high titer, 9) emerging technologies for biomass removal and contaminant clearance, and 10) single-use technologies and integrated processing. The speaker concludes by emphasizing the need for new perspectives and solutions to address challenges in biomanufacturing.

1. “10 Hot Topics in Biomanufacturing”
Vienna, May 20th 2010
Dr. Uwe Gottschalk, VP Purification Technologies,
Sartorius Stedim Biotech

2. Hot Topic 1: Product Mix, Growth Rates in Business Modells in Biopharma

3. Hot Topic 1: Product Mix, Growth Rates in Business Modells in Biopharma

4. Hot Topic 1: Product Mix, Growth Rates in Business Modells in Biopharma

5. Hot Topic 2: High-Titer Processes in Mammalian Cell Culture
Data adapted from: F. Wurm Production of recombinant Protein Therapeutics
in Cultivated Mammalian Cells. Nature Biotechnology 22, 1-6 (2004)

6. Hot Topic 2: High-Titer Processes in Mammalian Cell Culture

7. Hot Topic 3: Downstream Processing is Mass- not Volume Driven
6th Annual Survey of Biopharmaceutical Manufacturing.
Eric S. Langer, BioPlan Associates Inc.

8. Hot Topic 3: Downstream Processing is Mass- not Volume Driven
Jim Davis, Lonza Economics of Monoclonal Antibody Production: The relationship between upstream titer and
downstream costs; IBC San Diego March 2008

9. Hot Topic 4: Facility Fit
Dr. Christian Eckermann, Boehringer Ingelheim 2007

10. Hot Topic 5: COGs and Price – Margin pressure from both sides
Technical challenge
 Sensitive and technically demanding products require processes with inherent
complexity and expensive infrastructure
 Need for robust & scalable processes for the entire DSP
 Increasing regulatory scrutiny (Comparability!)
Financial challenge
 Processes are fixed-cost driven (Investment vs Consumables)
 Manufacturing costs 15 - 25% of sales price
 Costs for DSP up to 75% of manufacturing costs
 Cost Balance Benefit for innovative treatments
 Biosimilars

11. Hot Topic 5: COGs and Price – Margin pressure from both sides
Biomanufacturing is fixed cost driven
Category
MAb manufacturing: 6 x 2,000L tanks, 2g/L, 90% utilisation; 211 #/a; 527 kg/yr; invest 172 Mio Euro;
142 $/g; Sinclair 2006

12. Hot Topic 6: „Biosimilars“ and „Biobetters“

13. Hot Topic 6: „Biosimilars“ and „Biobetters“

14. Hot Topic 7: „Offshore Manufacturing“

15. Hot Topic 8: Technology Platforms
Cell Removal/
Cell Removal/ Intermediate
Intermediate Virus
Virus
Fermentation
Fermentation Capturing
Capturing Polishing
Polishing
Clarification
Clarification Purification
Purification Clearance
Clearance
Microorg. CEX HIC Size-Exclusion
Size-Exclusion
BHK X-FLow Mixed-Mode Ceramic HA AEX (B/E)
CHO
CHO Centrifuge
Centrifuge CEX Inactivation
Human Depthfilter
Depthfilter Protein A
Protein A Gelfiltration AEX (FT)
Hybridoma EBA AEX-Membrane
AEX-M Adsorption
CHO Centr./DF New Aprocess CEX
Protein AEX (FT) Orthogonal
New process train
train
New process train ready K. Konstantinov
Bayer Corp, USA

16. Hot Topic 8: Technology Platforms– High Titer Implications in DSP
Media
Preparation
Increasing biomass and
contaminant levels
Protein A pool volumes Final
and step cost concentration /
buffer exchange
Virus Removal
DNA & HCP levels post
Capturing
Polishing load volumes Fermentation
and conductivity Cell Removal/
Clarification
Concentration
Capturing Polishing

17. Hot Topic 9: Emerging Technologies

18. Hot Topic 9: Emerging Technologies
Biomass Removal and Early Contaminant Clearance
addresses:
Increasing biomass and
contaminant levels
DNA & HCP levels post
Capturing
• New generation of lenticular
filtration media
• No Diatomeaceous Earth;
Synthetic
• Cell removal, clarification &
early on contaminant removal

19. Hot Topic 9: Emerging Technologies
Three Birds – one Stone: Contaminant Precipitation at Medarex addresses:
(now part of BMS) Fig 7a. precipitation based process Fig 7b. TFF based process
Contaminant Protein A pool volumes
TFF
precipitation and step cost
DNA & HCP levels post
CEX HCP < 10ng/mg Capturing < 1000 ng/mg
CEX HCP
Dilution Polishing load volumes
Dilution
and conductivity
Q Membrane Q Membrane HCP < 1000 ng/mg
HCP BDL 2 g/ml
20 g/ml
Dilution
VF
Mix Mode
Precipitation of Process-Derived Impurities in Non-Protein A VF
Purification Schemes for MAb; J. Wang et al. BioPharm Intl. 10/2009, 2-9

20. Hot Topic 10: Single Use Technologies and „Integrated Processing“

21. Hot Topic 10: Single Use Technologies and „Integrated Processing“

22. Hot Topic 10: Single Use Technologies and „Integrated Processing“
J. Zhou BPI Vienna 2008

23. Summary: Biomanufacturing 2010+
“The real voyage of discovery consists not
in seeking new landscapes
but in having new eyes.”
Marcel Proust.

24. Summary: Yes we can!

25. Thank you!
Uwe.Gottschalk@sartorius-
stedim.com