ISPE DVC/NJ Seminar
Facility of the Future
Bruce Snyder
Director, Process Automation
Integrated Project Services (IPS)
30 September 2015
Automation Considerations for Continuous
Downstream Processing
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Business Drivers for Continuous DSP Processing
Technical Enablers
mAb Process and References
Overall Automation Strategy
Detailed Discussions
Opportunities and Challenges
Business Drivers for Continuous Downstream Processing
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Increased bioreactor titers (2 g/L -> 10 g/L) drives very large tank
sizes to handle batch volumes in DSP
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Continuous DSP will reduce facility footprint and equipment sizes
(~75% reduction)
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Continuous DSP can be accomplished with fewer process steps
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Faster process cycle times reduces WIP inventory and improves
product stability
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Continuous processing is widely used in other industries, but has
been slow to be adopted by biotech
Recent technological innovations bring us
to the cusp of continuous DSP
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Single use
– fully disposable wetted paths eliminate CIP and SIP
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Continuous single use centrifugation
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Continuous multi column chromatography
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Membrane Chromatography
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Single pass tangential flow filtration
mAb Process and References
50L SU BAG
on WEIGH
SCALE
DOWNSTREAM PROCESSING
2000 L SUB
50 L
50 L
CENTRIFUGATION
50 L
DEPTH
FILTRATION
50 L
PRO A
CMCC
ACID/
BASE
VIRAL
INACTIVATION
50 L
MEMBRANE
CHROMATO
GRAPHY
50 L
50 L
CATION
CMCC
SPTFF
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Brower, Mark; Hou, Ying; Pollard, David; Monoclonal Antibody Continuous Processing Enabled by Single Use; Continuous
Processing in Pharmaceutical Processing; Wiley-VCH Verlag GmbH & Co., 2015.
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Godawat et al; Periodic counter-current chromatography – design and operational considerations for integrated and
continuous purification of proteins; Biotechnology Journal 2012.
Overall Automation Strategy
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Synchronization of unit operations, to maintain flow balance between unit
operations
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Each unit operation presents new, unique challenges
– Flexibility in instrument and equipment setup
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Continuous DSP will require a new approach for product release decisions
– Process measurements, alarms and data collection to support real time
product release decisions
– How will boundaries for release decisions be defined?
Synchronization of the DSP Unit Operations
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Disturbance – unwanted increase/decrease in
output flow
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Bag fill weights will fluctuate to isolate other unit ops from the
disturbance.
Accomplished by High Weight Control Loop (setpoint 35 kg) and
Low Weight Control Loop (setpoint 15 kg)
Disruption – a stoppage in output flow of significant
duration
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If a bag becomes filled or empty, flow rates at all unit
operations must be adjusted to balance with the disrupted unit
operation
Detected by High Weight Alarm (45 kg) and Low Weight Alarm
(5 kg)
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Comparable schemes are used for level control in
reflux drums and column bottoms in multi
distillation column, continuous processing
applications
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A modern DCS is required to handle the complex
requirements
This diagram to be replaced
with an accurate picture of
the control scheme, to be
drafted in Autocad
Each Unit Op Presents New, Unique Challenges
Protein A Chromatography
 Periodic Counter Current (PCC) from GE
Healthcare features rapid cycling of small
columns (3 to 9 at a time)
 Significantly higher column loading reduces
media and buffer usage
 ΔUV method compensates for changes in feed
stream composition and media performance
 Sequencing = f(target protein breakthrough)
 Challenges
 UV calibration (for dilute product
concentrations, or high impurity loads)
 Must operate for 60 days without mechanical
failure while maintaining low bioburden
Continuous DSP will require a new approach for product
release decisions
Product release decisions may be periodic (ie daily) instead of gravimetric (ie batch quantity)
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The process cell produces 2 products: medicine and data
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New logic will be required to calculate start and stop times for queries into the continuous
and event historians
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Rhythm wheel technique works as long as operating rates and hold up volumes remain constant
Must compensate for flow rate measurement error, as it is compounded over time
Must compensate for Non-plug flow and mixing in bags
Opportunity to learn from discrete parts manufacturing control systems
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The control system must generate a complete data set, including exception messages, which are
relevant to the quantity of material presented for release
Data must be “time shifted” to compensate for residence times, operating rates, and hold up
volumes
Divide the process stream into 100’s of “containers”, moving through the train on a “conveyour”
Record the entry and exit times of each container at each unit operation
Associate the alarm start and stop times with “last in” and “next out” container
Calculate “conveyor speed” as a function of residence time, hold up volume, and operating rate
Predict the arrival time of each container into the “output basket
Generate the data and alarm messages for each output basket based on the time stamps of every
container in the basket
Continuous DSP will require a new approach for product
release decisions
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Process Analytic Technologies (PAT) will be required to measure all Critical Quality Attributes
in line or at line. You may not achieve real time release without it.
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PAT must be developed in conjunction with (at the same time as) process development and
scale up.
– Chances are regulatory approvals will be unobtainable if we try to “bolt it on” at full scale.
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Develop a rational Process Validation Strategy which carefully considers CPPs and CQAs.
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Multi Variate Data Analysis (MVDA) is a very powerful tool for process scale up and process
control
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Robust process ranging studies at bench scale to develop the target envelope for each unit
operation.
It doesn’t have to be complicated to be powerful
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If a parameter is well controlled, then it doesn’t have to be a Critical Quality Attribute
Example – DNA clearance at polishing step
Virus inactivation via pH treatment. Parameters are composition, contact time, temperature,
mixing, flow rate, and mass balance.
A MVDA model developed during process development can yield a well justified basis for controls
and alarm limits to enable real time release.
In Summary…
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Single Use yields dramatic simplification in instrumentation, valves, and
controls by eliminating CIP and SIP
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However, Continuous Downstream Processing will drive increased automation
complexity
• Synchronization of the unit operations
• New, unique challenges for controls at each unit operation
• Process measurements, exception messages, alarms, and data collection to support
product release
• Process Analytical Technology
•
Continuous DSP will require a new approach for product
release decisions
•
Process Analytic Technologies (PAT) will be required to measure all Critical Quality
Attributes in line or at line. You may not achieve real time release without it.
•
PAT must be developed in conjunction with (at the same time as) process development
and scale up.
•
•
Develop a rational Process Validation Strategy which carefully considers CPPs and CQAs.
•
•
•
If a parameter is well controlled, then it doesn’t have to be a Critical Quality Attribute
Example – DNA clearance at polishing step
Multi Variate Data Analysis (MVDA) is a very powerful tool for process scale up and process control
•
•
Chances are regulatory approvals will be unobtainable if we try to “bolt it on” at full scale.
Robust process ranging studies at bench scale to develop the target envelope for each unit operation.
It doesn’t have to be complicated to be powerful
•
•
Virus inactivation via pH treatment. Parameters are composition, contact time, temperature, mixing, flow rate, and mass
balance.
A MVDA model developed during process development can yield a well justified basis for controls and alarm limits to
enable real time release.