Continuous Purity™

Marc Bisschops Tarpon Biosystems Inc.

Integrated Continuous Biomanufacturing Castelldefels – Spain October 20 – 24, 2013

Technological, Regulatory and Validation Considerations for single-use continuous downstream processing

Continuous Manufacturing

Photo: courtesy Martien Tazelaar (taas.it)

Continuous Manufacturing

• Generalized Mass Balance for a single phase:

Why are transient processes so hard to design and control?

𝐸 𝛻2𝑐 − 𝛻 𝑐 𝑢 + 𝑟 =𝜕 𝑐𝜕 𝑡

Dispersion – Convection + Reaction = Accumulation

Gradient in Space Time dependent

Continuous Manufacturing

• Generalized Mass Balance for a single phase:

Why are continuous processes easier to design and control?

𝐸 𝛻2𝑐 − 𝛻 𝑐 𝑢 + 𝑟 = 0

Dispersion – Convection + Reaction = Steady State

Gradient in Space

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)

... 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 consider Continuous Biomanufacturing?

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 guidance prohibiting continuous manufacturing

S. Chatterjee, FDA Perspective on Continuous Manufacturing, IFPAC Meeting, Jan 2012

Continuous Manufacturing

Translating batch to continuous:

Challenges of continuous DSP may be less than continuous USP (in terms of product quality control)

USP DSP Longer processing times

increases chance of product heterogeneity

Shorter residence times decreases chance of product degredation or contamination

Impacts micro-environment & chemistry of cells

Utilizes the same fundamental chemistry as batch

Simplifying the PFD

MAb manufacturnig platform, presented by Wolfgang Berthold (2008)

Simplifying the PFD

Capital Utilization

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)

Batch Processing Continuous Processing

Continuous AND Disposable

Technological Solutions

Compatibility chart for common DSP Unit Operations in Continuous and Single-Use format

Process Step Continuous Single-Use Clarification: Centrifugation

Clarification: Depth Filtration

Chromatography: Capture

Virus inactivation

Chromatography: Polishing (AEX)

Chromatography: Polishing (CEX)

Ultrafiltration

Virus filtration

/

Continuous Disposable Chromatography

Tarpon Biosystems’ BioSMB® Key features: • Multicolumn chromatography:

continuous and countercurrent process

• Higher specific productivity • Single use valve cassette

Feature Benefit Countercurrent process Improved resin capacity utilization High specific productivity Reduced resin inventory BioSMB Valve Cassette Fully disposable flow path

Configuration flexibility

BioSMB® Process Development System

System Design & Segregation of Fluids

pH

UV

C pH

UV

C

pH

UV

C

pH

UV

C

Batch Chromatography Skid Continuous Chromatography Skid

Segregated: one fluid throughout batch

Shared: multiple process solutions throughout batch

System Design & Segregation of Fluids

Segregation of fluids in batch and continuous systems:

Continuous systems have an inherently better segregation of process solutions

Process Step Batch Continuous Buffer selection valves Shared NA Pump(s) Shared Segregated Sensors (inlet) Shared Segregated Column bypass valves Shared NA Integrated valve system NA Partly shared Sensors (outlet) Shared Segregated Outlet selection valves Shared NA

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)

FMEA Risk Ranking (General)

Continuous versus Batch Severity Impact on CQA is identical due to nature of the process

Consequence may, however, not affect entire batch but only small increment (small repetitive cycles)

Occurrence More complex equipment may lead to (perception of) higher probability of failure

Detection Continuous process will immediately detect deviations whereas batch process may only detect afterwards

Overall ranking Continuous process might rank better than batch process

FMEA Risk Ranking (Abbreviated)

Severity Occurrence Detection

Column Failure Direct impact on CQA

Very low probability (1) Immediate

Pump Failure Potential impact on CQA Low probability Immediate

Valve Failure Potential impact on CQA

Very low probability (2) Immediate

Detector Failure No impact on CQA Low Probability Immediate

(1) Probability of column failure can be significantly reduced by using smaller diameters, prepacked & pretested columns

(2) Probability of valve failure can be significantly reduced by implementing valve integrity tests before running a batch

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.

BioSMB Valve Technology Basis of Design Based on traditional diaphragm

valve technologies 105 – 106

cycles Tested Rapid cycling tests of BioSMB valve

cassette (all valves) 104 cycles

Intended use Intended use of BioSMB cassette corresponds to column life time

102 cycles

M. Bridge on PharmTech.com, June 2011

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

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)

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

Feature Benefit Controlled residence times Product quality control Shorter processing time Product quality control Smaller process equipment Favors disposable bioprocessing

technologies

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

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

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 disposable

processing are natural partners

It requires courage to take hurdles

It may well be that the first implementations of continuous processes may not deliver the full promise • Redefine validation

strategies • Redefine quality systems • Beat organizational

hurdles • ...

That should not keep us from pursuing promising technologies

J.L Bower and C.M. Christensen, Harvard Business Review, Jan/Feb 1995

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 Goodwin Head of FDA Pharmaceutical Division

Reuters, October 10, 2013