Continuous Purity™

1. Continuous Purity™ Technological, Regulatory and Validation Considerations for single-use continuous downstream processing Marc Bisschops Tarpon Biosystems Inc. Integrated Continuous Biomanufacturing Castelldefels – Spain October 20 – 24, 2013

2. Continuous Manufacturing Photo: courtesy Martien Tazelaar (taas.it)

3. Continuous Manufacturing Why are transient processes so hard to design and control? • Generalized Mass Balance for a single phase: Dispersion – Convection + Reaction = Accumulation Gradient in Space Time dependent

4. Continuous Manufacturing Why are continuous processes easier to design and control? • Generalized Mass Balance for a single phase: Dispersion – Convection + Reaction = Steady State Gradient in Space

5. Continuous Manufacturing Over the past 40 years, the vast majority of accidents in chemical industries happened during non-routine manufacturing operations (mainly during start-up). W. Bridges and T. Clark (2011) Chemical catastrophe in 2008 after anomalies during a start-up of a chemical facility in West Virginia. This resulted in a runaway chemical reaction, causing a pressure vessel to explode. The accident killed 2 employees of the company and eight people were injured. (US Chemical Safety Board Report 2008-08-I-WV, Jan.2011)

6. ... or Batch Manufacturing Biopharmaceutical industries: • Product quality is directly related to process control (“The Process is the Product”) • Batch processes are – almost by definition – transient processes So, if batch processes are more difficult to control, and if biopharmaceutical product quality is so tightly related to process control... then shouldn’t we at least considerContinuous Biomanufacturing?

7. Regulatory Aspects Batch Definition: • No specific regulations or guidance for in continuous manufacturing (can be based on time or materials supply) • Should be based on assurance of consistent product quality (e.g. equipment cycles or material properties) Nothing in regulations or guidanceprohibiting continuous manufacturing S. Chatterjee, FDA Perspective on Continuous Manufacturing, IFPAC Meeting, Jan 2012

8. Continuous Manufacturing Translating batch to continuous: Challenges of continuous DSP may be less than continuous USP (in terms of product quality control)

9. Simplifying the PFD MAbmanufacturnig platform, presented by Wolfgang Berthold (2008)

10. Simplifying the PFD

11. Capital Utilization Batch Processing Continuous Processing Continuous processing: • Saves time in suite by 50 – 70% • Minimize footprints of some of the large unit operations • All unit operations sized by volume (instead of mass of protein)

12. Continuous AND Disposable ConfigurationFlexibility CompactSystems Single-useTechnologies ContinuousProcessing

13. Technological Solutions Compatibility chart for common DSP Unit Operations in Continuous and Single-Use format               /  

14. Continuous Disposable Chromatography Tarpon Biosystems’ BioSMB® Key features: • Multicolumn chromatography: continuous and countercurrent process • Higher specific productivity • Single use valve cassette

15. BioSMB® Process Development System

16. System Design & Segregation of Fluids Batch Chromatography Skid Continuous Chromatography Skid UV UV UV UV C C C C pH pH pH pH Segregated: one fluid throughout batch Shared: multiple process solutions throughout batch

17. System Design & Segregation of Fluids Segregation of fluids in batch and continuous systems: Continuous systems have an inherentlybetter segregation of process solutions

18. System Design & Sensors Sensors are dedicated to an individual outlet: • More sensors provide more information on the process • Will be operated in a more narrow range and can therefore be selected to meet higher accuracy (e.g. flow path in UV flow cells) • Can be selected to meet the specifics of that particular outlet (e.g. UV wavelengths)

19. FMEA Risk Ranking (General)

20. FMEA Risk Ranking (Abbreviated) • Probability of column failure can be significantly reduced by using smaller diameters, prepacked & pretested columns • Probability of valve failure can be significantly reduced by implementing valve integrity tests before running a batch

21. Experience with BioSMB – Valve Integrity Mean time to failure of disposable valve technology: Note: Main causes of failure for diaphragm valves are related to the diaphragm, particularly in combination with a steam cycle. Disposable components are generally not steamed. M. Bridge on PharmTech.com, June 2011

22. Experience with BioSMB – Consistency • Rapid cycling provides repetitive response of sensors • Deviations can be immediately recognized Four column BioSMB process for capture of Monoclonal Antibodies using Protein A affinity chromatography

23. Experience with BioSMB – Dynamics Start-up and shut-down cycles: • Dedicated methods for accellerated start-up and shut-down cycles can be used • Product concentration may vary, impurity profile remains constant (only effect is dilution) Recovering from process upsets: • Response to step changes is very fast (less than one process cycle)

24. Overall Process Lay-out Integrated continuous biomanufacturing process: • Large intermediate product hold tanks are eliminated • Small surge bags between unit operations may address flow control and cyclic behaviour • Mitigation of potential process hick-up downstream: emergency surge bag

25. Common Reasons for Batch Failure Contamination: • Disposable components • Minimizing residence times • Segregation of fluids Operator Error: • Automation • Training Equipment Failure: • Automation • Testing protocols E. Langer, BioProcess International, September 2008

26. Common Reasons for Batch Failure Over the past five years, average batch failures have been reduced significantly (appr 50% decline). Mean causes: • Improved process design (including QbD) • Improved process monitoring (including PAT) • Operator Training E. Langer, Pharmaceutical Manufacturing, June 2012

27. Conclusions Although more complex, continuous process technologies are likely to comply to cGMP requirements as well as batch alternatives: • Better segregation of process solutions and shorter processing times minimizes risk of contamination • Immediate feed back & rapid staedy state cycling limits consequence of potential process upsets • Continuous processing fits naturally with PAT initiatives • Continuous processing and disposableprocessing are natural partners

28. It requires courage to take hurdles It may well be that the first implementations of continuous processes may not deliver the full promise • Redefine validationstrategies • Redefine quality systems • Beat organizational hurdles • ... That should not keep usfrom pursuing promisingtechnologies J.L Bower and C.M. Christensen, Harvard Business Review, Jan/Feb 1995

29. Acknowledgements • Tom Ransohoff (BPTC) • Lynne Frick (Tarpon Biosystems) • All companies exploring continuous biomanufacturing "People are moving now to continuous manufacturing and really much more high tech modern ways and it doesn't fit the way good manufacturing practice has been thought about over the years," Woodcock said. "We have to forcibly make sure we allow the better to come about." Janet GoodwinHead of FDA Pharmaceutical Division Reuters, October 10, 2013