Continuous Purity™

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
Continuous Manufacturing
Photo: courtesy Martien Tazelaar (taas.it)
Continuous Manufacturing
Why are transient processes so hard to design and control?
• Generalized Mass Balance for a single phase:
𝐸
𝛻2𝑐
𝜕𝑐
−𝛻𝑐𝑢+𝑟 =
𝜕𝑡
Dispersion – Convection + Reaction = Accumulation
Gradient in Space
Time
dependent
Continuous Manufacturing
Why are continuous processes easier to design and control?
• Generalized Mass Balance for a single phase:
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:
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
Challenges of continuous DSP may be less than
continuous USP (in terms of product quality control)
Simplifying the PFD
MAb manufacturnig platform, presented by Wolfgang Berthold (2008)
Simplifying the PFD
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)
Continuous AND Disposable
Technological Solutions
Compatibility chart for common DSP Unit Operations in
Continuous and Single-Use format
Process Step
Clarification: Centrifugation
Clarification: Depth Filtration
Chromatography: Capture
Virus inactivation
Chromatography: Polishing (AEX)
Chromatography: Polishing (CEX)
Ultrafiltration
Virus filtration
Continuous
Single-Use
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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
Batch Chromatography Skid
Continuous Chromatography Skid
UV
UV
UV
UV
C
C
C
pH
pH
pH
C
pH
Segregated: one fluid throughout batch
Shared: multiple process solutions throughout batch
System Design & Segregation of Fluids
Segregation of fluids in batch and continuous systems:
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
Continuous systems have an inherently
better segregation of process solutions
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
No impact on
CQA
Low Probability
Immediate
Detector Failure
(1)
(2)
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
Experience with BioSMB – Valve Integrity
Mean time to failure of disposable valve technology:
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
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
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