Continuous Purity™

Marc BisschopsTarpon Biosystems Inc.

Integrated Continuous BiomanufacturingCastelldefels – SpainOctober 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−𝛻𝑐𝑢+𝑟=𝜕𝑐𝜕𝑡

Dispersion – Convection + Reaction = Accumulation

Gradient in Space Time dependen

t

Continuous Manufacturing

• Generalized Mass Balance for a single phase:

Why are continuous processes easier to design and control?

𝐸𝛻2𝑐−𝛻𝑐𝑢+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 considerContinuous 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 guidanceprohibiting 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 ChromatographyTarpon 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 pathConfiguration flexibility

BioSMB® Process Development System

System Design & Segregation of Fluids

pH

UV

CpH

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 FluidsSegregation of fluids in batch and continuous systems:

Continuous systems have an inherentlybetter 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 processConsequence 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 FailureDirect impact

on CQAVery low

probability (1) Immediate

Pump FailurePotential

impact on CQA Low probability Immediate

Valve FailurePotential

impact on CQAVery 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 IntegrityMean 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 bagFeature 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 disposableprocessing 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 usfrom pursuing promisingtechnologies

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 GoodwinHead of FDA Pharmaceutical Division

Reuters, October 10, 2013