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

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

ASME BPE, ISPE, BPOG Collaboration

Step 1: Defining Closed

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)

APPLYING CLOSED SYSTEM CONCEPTS: The INCREDIBLE SHRINKING Future Facility

1980s Traditional Multiproduct Facility e.g. 2 products

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

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

Not new concept Courtesy Scott Probst , Bayer, BPOG

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…

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

Risk Management EUROPE/ USA FDA (approx) GRADE ISO CLASS IN OPERATION   MAX # PARTICLES 0.5 µ & LARGER / M3 MAX # OF VIABLE MICROORGANISMS (CFUs) / M3 A 5 3500 <1 N/A 6 35000 7 B 350000 10 C 8 3500000 100 D "9" 3500000 (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.

Eureka! Bioreactors are closed! DECLASSIFY REMOVE WALL

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

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

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

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

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

If Environment = No Critical Aspect Single redundancy likely sufficient

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

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

If Environment = No Critical Aspect Use Single Use Systems

If Environment = No Critical Aspect Regulatory Concern If closed

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

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

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

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

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

How can Continuous Processing help shrink the Facility?

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

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

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

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

Batch  Continuous Assume no change Assume 24% reduction

Batch  Continuous Further 1000 m2 space savings or more achievable

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

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