0. Integrated Continuous Biomanufacturing Conference
Presentation to Engineering Conference International
Integrated Continuous Biomanufacturing Conference
Implementing process closure and continuous processing into the modern biopharmaceutical facility
Oct 23, Castelldefels, Spain

1. The Biopharmaceutical Industry is Changing
Finally!
The Safest Process is Closed, Where the Environment is a Parameter without Critical Aspect
We have the Technology

2. ASME BPE, ISPE, BPOG Collaboration

3. Step 1: Defining Closed

4. Closed Process Defined
Environment does not represent a Critical Aspect (No Impact)
Product is not exposed to the surrounding environment
Additions and withdrawals performed in closed fashion
Validated to show sufficient layers of protection against risk of contamination from the environment
Risk of contamination is not mitigated by housing operation in bioburden-free or particulate-free environment
Contamination of closed system = breach of integrity
NOTE: Closed  Sterile (although sterile is one form)
ALSO: Closed  Single Use Systems (although one form)

5. APPLYING CLOSED SYSTEM CONCEPTS: The INCREDIBLE SHRINKING Future Facility

6. 1980s Traditional Multiproduct Facility
e.g. 2 products

7. 1980s Traditional Facility
Many silos
Highly classified
(to reduce “risk” of bioburden)
Redundant upstream
2 X 3 production BRX
Redundant centrifuges
Redundant downstream

8. 1980s Traditional Facility
Shared
Shared
Product 1
Product 1
Product 2
Product 2
UPSTREAM CELL (+)
DOWNSTREAM CELL (-)

9. Not new concept
Courtesy Scott Probst , Bayer, BPOG

10. Tell QA people to close their eyes and plug their ears
Reminder:
Tell QA people to close their eyes and plug their ears
For the rest of us…

11. 1980s Traditional Facility
Shared
Multiproduct
Unclassified!
And regulatory agencies know about this “secret”

12. Risk Management EUROPE/ USA FDA (approx) GRADE ISO CLASS IN OPERATION
MAX # PARTICLES µ & LARGER / M3
MAX # OF VIABLE MICROORGANISMS (CFUs) / M3 A 5
3500
<1
N/A 6
35000 7 B
350000 10 C 8
100 D
"9"
(at rest)
200
Likelihood is the same (just a matter of time)
Severity or impact is the same (destroy batch)
Level of contamination is lower i.e. more difficult to detect.

13. Eureka! Bioreactors are closed!
DECLASSIFY
REMOVE WALL

14. Solution for Successful Cell Culture:
Close the Bioreactor NOT cove corners!
AIRLOCKS NOT REQUIRED
Closed Media Containers

15. Sterile filter clarified broth = briefly exposed
0.2µ filter after CENTRIFUGATION to close
Logistical segregation

16. Sterile filter clarified broth = briefly exposed
Declassified; HVAC segregation no longer required
Airlocks no longer required

17. When Environment = No Critical Aspect
Product 1 is closed
Product 2 is closed
Physical segregation not required

18. If Environment = No Critical Aspect
Efficiency in Inoc Prep Likely:
Cadence of 1 BRX every 2 days
Ballroom
Multipurpose Room
Efficiency in Centrifugation Use Likely

19. If Environment = No Critical Aspect
Single redundancy likely sufficient

20. If Environment = No Critical Aspect
Sterile Filter all Buffers or Use < 24 hours
Use Protected Powder Additions and Closed Liquid Additions

21. If Environment = No Critical Aspect
Close Systems
Sanitize skids
Blind runs

22. If Environment = No Critical Aspect
Use Single Use Systems

23. If Environment = No Critical Aspect
Regulatory Concern
If closed

24. With Technology Improvements
If concern overcome
If in line dilution used
If cytocentric isolator used

25. If Environment = No Critical Aspect
Consolidated V+ / V-
Smaller volumes required
Note fewer staff

26. If Environment = No Critical Aspect
If all SS: UC space above

27. If Environment = No Critical Aspect
5400 m m2 buffer hold UC

28. If Environment = No Critical Aspect
500 m2 ISO 8
4000 m2 ISO 8, 1000 m2 ISO 7
How might this look?

29. How can Continuous Processing help shrink the Facility?

30. Smaller volumes & areas required
Batch  Continuous
Smaller volumes & areas required

31. Batch  Continuous Mabs Model: Perfusion versus Batch Cell culture
Continuous Harvest/Clarification (ATF, centrifuge, etc
Continuous Capture (SMCC Protein A)
SMB/SMCC where possible in multi-chrom operation
Nanofiltration
UF/DF & Bulk Fill

32. Batch  Continuous Requirements:
All operations must be closed and synchronized for long term operations
Cell Culture must be “bpsterile”
Clarification cannot contaminate upstream (but…)
Capture must be closed (but…)
Any static hold steps must be “bacteriostatic”
If continuous, UF/DF & Bulk Fill must be bacteriostatic

33. 5000 m2 batch  3000 to 3800 m2 continuous ( -24 to -40%)
Batch  Continuous
Metrics from benchmark projects and models:
Assuming 5:1 lower titer in Perfusion versus Batch
15K batch BRX for 1000 kg protein
1K to 4K perfusion BRX for 1000 kg protein
Harvest batch 20K in 4-6 hours after days
Harvest continuous 24/7 (1-3 BRX volumes/day)
5000 m2 batch  3000 to 3800 m2 continuous ( -24 to -40%)

34. Batch  Continuous
Assume no change
Assume 24% reduction

35. Batch  Continuous
Further 1000 m2 space savings or more achievable

36. Closed + Continuous = Low Cost
Closing #1
Less competitive
Higher cost
Less flexible
Closed &
Continuous
Facility Cost
Project Risk
Lower cost
More competitive
Highly flexible

37. Thank You CRB Contributors: Kim Nelson Mark von Stwolinski
Patrick Sullivan