multicolumn chromatography: a step towards continuous ... · •fully continuous biologics...
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MultiColumn Chromatography: A Step Towards Continuous Purification
Presented by Rick Lu, Director, Manufacturing Technology and Innovation
Global Technical Operations - Supply Biologics, AstraZenecaCASSS July Meeting: Next Generation Biotechnology Manufacturing 16July2018
Continuous Processing-
a Promising Paradigm Shift
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• Faster processing enabling
greater yields for labile proteins
• Improved productivity/ process
intensification (grams of
protein/ unit time/ unit cost)
• Decreased equipment size and
facility footprint (COGM)
• Facilitates adoption of single
use technologies and prepack
columns
Batc
h
Fully
Continuous
Change is Challenging
5
Category Resistance Opportunity
Capital Installed infrastructure would be
abandoned. Retrofit is not viable due
to depreciation from existing assets.
New products/ product types
requiring a dedicated facility/
network expansion where no
installed capital exists.
Regulatory Questions raised from new
technology adds risk to successful
product launch.
Consortium approach with
collaboration with regulatory
agencies to technology
development.
Technical Technical challenges within and
between unit operations are too
many to tackle.
Stepwise implementation of “ready
now” technologies.
Resistance Comes from a Variety of Factors
Step-Wise Transformation to Continuous Downstream
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Today
Tomorrow
Future
Illustration modified
from: K.B.
Konstantinov and C.
Cooney: White paper
Continuous
Bioprocessing (2014)
Multi-Column Chromatography
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o Multiple, smaller columns• Smaller diameter
• Shorter bed height
• 2-5 columns
o Simultaneous processing
allows for same
processing time with less
resin
o Same process steps as
batch
o > 50% reduction in resin
Multicolumn Chromatography TheoryImproved Capacity Utilization
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Binding Capacity: 35 𝑔 𝑝𝑟𝑜𝑑𝑢𝑐𝑡
𝐿 𝑟𝑒𝑠𝑖𝑛
10% Breakthrough
Multicolumn Chromatography TheoryImproved Capacity Utilization
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Binding Capacity: 50𝑔 𝑝𝑟𝑜𝑑𝑢𝑐𝑡
𝐿 𝑟𝑒𝑠𝑖𝑛
Supporting Design• Reduced bed heights
• Retained residence time due to
in-series loading
Benefits• 40% higher resin capacity attained
• No product lost to breakthrough
• Reduction in buffer requirement
Multicolumn Chromatography TheoryContinuous Cyclical Design
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• Outer circle: Inlets
• Inner circle: OutletsC1 C2 C3 C4
Batch MCC MCC
Column Size60 cm diameter x
20 cm height
(4x) 30 cm diameter x
10 cm height
(3x) 20 cm diameter x
10 cm height
Resin Requirement 57 L 28 L 9 L
Cycles (Seen by column) 6 8 25
Wet Time (hr) 8 6 20
Buffer (L) 6100 4000 4000
Productivity 20 g/Lresin hr 60 g/Lresin hr 55 g/Lresin hr
Resin Cost ($16k/L) $912k $448k $144k
Multicolumn Chromatography 2000L Scale (5 g/L)
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Feed Wash Elution
Time Resin
Batch MCC MCC
Column Size60 cm diameter x
20 cm height
(4x) 30 cm diameter x
10 cm height
(3x) 20 cm diameter x
10 cm height
Resin Requirement 57 L 28 L 9 L
Cycles (Seen by column) 6 8 25
Wet Time (hr) 8 6 20
Buffer (L) 6100 4000 4000
Productivity 20 g/Lresin hr 60 g/Lresin hr 55 g/Lresin hr
Resin Cost ($16k/L) $912k $448k $144k
Multicolumn Chromatography 2000L Scale (5 g/L)
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Feed Wash Elution
Time Resin
Batch MCC MCC
Column Size60 cm diameter x
20 cm height
(4x) 30 cm diameter x
10 cm height
(3x) 20 cm diameter x
10 cm height
Resin Requirement 57 L 28 L 9 L
Cycles (Seen by column) 6 8 25
Wet Time (hr) 8 6 20
Buffer (L) 6100 4000 4000
Productivity 20 g/Lresin hr 60 g/Lresin hr 55 g/Lresin hr
Resin Cost ($16k/L) $912k $448k $144k
Multicolumn Chromatography 2000L Scale (5 g/L)
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Feed Wash Elution
Time Resin
“Utilized” Binding Capacity
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Cycle
3C
ycle
2C
ycle
1 Pro
tein
Load
Under utilization
Single Column System
Column
4
Column
3
Column
2
Column
1
Column
4
Column
3
Column
2
Column
1
Column
4
Column
3
Column
2
Column
1
Pro
tein
Load
Under utilization
Multi-Column System
MCC allows for “right
sizing” the column to
address feed
variability.
Up to ~25%
improvement in resin
utilization.
Column
capacity
per cycle
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Size Matters
Pictured: Lindsay Arnold Ph.D. Lead MedImmune development scientist for Multicolumn Chromatography and Continuous Purification. Pall Corporation
chromatography columns (not necessarily associated with values shown).
:.
Size (bed diameter) : 180 cm
Height: ~ 300 cm
Weight: > 12,000 kg
Size (bed diameter) : 80 cm
Height: ~ 200 cm
Weight: ~ 1,200 kg
Operator Safety
Floor Loading
Floor Finish
Air Drops
Special Case Benefits
Reduces risk of contamination over successive batches and campaigns
(Resin lifetime consumed within campaign)
OPEX savings for clinical programs that do not move forward
Resin inventory reduction (balance sheet improvement, improved cash flow)
Cost savings in resin storage
Buffer reduction can improve facility fit and increase facility throughput
Enables single use chromatography skids and prepack columns for high
titer processes
Summary
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• Fully continuous biologics manufacturing is not likely to happen overnight.
• The promise of continuous purification may be realized in a step-wise fashion
with multicolumn chromatography as a first step.
• Significant benefits across the spectrum can be achieved with multicolumn
chromatography.
• Business cases will vary based on the particular set of drivers important to
different companies and will vary between clinical vs. commercial settings:
– Safety
– Cash Flow
– Capital Reduction
– Space Constraints
– Capacity Improvement
Acknowledgements
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Thanks to CASSS for the invitation to present.
Special thanks to Lindsay Arnold Ph. D. for her collaboration with the
presentation materials and her work with the bench scale and production scale
multicolumn chromatography systems at MedImmune/ AstraZeneca.
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