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Presentation to Engineering Conference International Integrated Continuous Biomanufacturing Conference Implementing process closure and continuous processing.

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Presentation on theme: "Presentation to Engineering Conference International Integrated Continuous Biomanufacturing Conference Implementing process closure and continuous processing."— Presentation transcript:

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

2 THE BIOPHARMACEUTICAL INDUSTRY IS CHANGING FINALLY! THE SAFEST PROCESS IS CLOSED, WHERE THE ENVIRONMENT IS A PARAMETER WITHOUT CRITICAL ASPECT WE HAVE THE TECHNOLOGY

3 ASME BPE, ISPE, BPOG Collaboration

4 STEP 1: DEFINING CLOSED

5 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)

6 APPLYING CLOSED SYSTEM CONCEPTS: THE INCREDIBLE SHRINKING FUTURE FACILITY

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

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

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

10 Not new concept Courtesy Scott Probst, Bayer, BPOG

11 TELL QA PEOPLE TO CLOSE THEIR EYES AND PLUG THEIR EARS REMINDER: FOR THE REST OF US…

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

13 EUROPE/ USA FDA (approx) GRADEISO CLASSIN OPERATION MAX # PARTICLES 0.5 µ & LARGER / M 3 MAX # OF VIABLE MICROORGANISMS (CFUs) / M 3 A53500<1 N/A B C D"9" (at rest)200 Risk Management

14 Eureka! Bioreactors are closed! DECLASSIFY REMOVE WALL

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

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

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

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

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

20 If Environment = No Critical Aspect Single redundancy likely sufficient

21 If Environment = No Critical Aspect Sterile Filter all Buffers or Use < 24 hours 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 If Environment = No Critical Aspect Regulatory Concern If closed

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

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

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

28 If Environment = No Critical Aspect 9900 m m m 2 buffer hold UC

29 If Environment = No Critical Aspect 4000 m 2 ISO 8, 1000 m2 ISO m 2 ISO 8 How might this look?

30 HOW CAN CONTINUOUS PROCESSING HELP SHRINK THE FACILITY?

31 Batch  Continuous Smaller volumes & areas required

32 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

33 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

34 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 m 2 batch  3000 to 3800 m 2 continuous (  -24 to -40%)

35 Batch  Continuous Assume 24% reduction Assume no change

36 Batch  Continuous Further 1000 m 2 space savings or more achievable

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

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

39


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