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Presentation to Engineering Conference International 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, 2013 Castelldefels , Spain. Finally!.

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Presentation to Engineering Conference International Integrated Continuous Biomanufacturing Conference

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  1. Presentation toEngineering Conference International Integrated Continuous Biomanufacturing Conference Implementing process closure and continuous processing into the modern biopharmaceutical facility Oct 23, 2013Castelldefels, Spain

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

  3. ASME BPE, ISPE, BPOG Collaboration

  4. Step 1: Defining Closed

  5. Environment does not represent a Critical Aspect (No Impact) • Product is not exposed to the surrounding environment • Additions and withdrawals performed in closed fashion • Validatedto 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) Closed Process Defined

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

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

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

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

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

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

  12. 1980s Traditional Facility Shared Multiproduct Unclassified! And regulatory agencies know about this “secret”

  13. Risk Management

  14. DECLASSIFY Eureka! Bioreactors are closed! REMOVE WALL

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

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

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

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

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

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

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

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

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

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

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

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

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

  28. If Environment = No Critical Aspect 9900 m2 5400 m2 + 380 m2 buffer hold UC

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

  30. How can Continuous Processing help shrink the Facility?

  31. Batch  Continuous Smaller volumes & areas required

  32. 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 Batch  Continuous

  33. 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 Batch  Continuous

  34. 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 12-14 days • Harvest continuous 24/7 (1-3 BRX volumes/day) Batch  Continuous 5000 m2 batch  3000 to 3800 m2 continuous ( -24 to -40%)

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

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

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

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

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