continuous purity™ marc bisschops tarpon biosystems inc. integrated continuous biomanufacturing...
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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
• 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
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
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
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