multicolumn chromatography: a step towards continuous ... · •fully continuous biologics...

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

Topics

Background

MultiColumn Chromatography (The Concept)

Manufacturing Scale Business Case

Continuous Processing-

a Promising Paradigm Shift

4

• 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

6

Today

Tomorrow

Future

Illustration modified

from: K.B.

Konstantinov and C.

Cooney: White paper

Continuous

Bioprocessing (2014)

Topics

Background

MultiColumn Chromatography (The Concept)


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

9

Binding Capacity: 35 𝑔 𝑝𝑟𝑜𝑑𝑢𝑐𝑡

𝐿 𝑟𝑒𝑠𝑖𝑛

10% Breakthrough

Multicolumn Chromatography TheoryImproved Capacity Utilization

10

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

11

• Outer circle: Inlets

• Inner circle: OutletsC1 C2 C3 C4

Topics

Background



Batch MCC MCC

Column Size60 cm diameter x

20 cm height

(4x) 30 cm diameter x

10 cm height


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)

13

Feed Wash Elution

Time Resin

Batch MCC MCC


20 cm height


10 cm height


10 cm height




Buffer (L) 6100 4000 4000


Resin Cost ($16k/L) $912k $448k $144k


14

Feed Wash Elution

Time Resin

Batch MCC MCC


20 cm height


10 cm height


10 cm height




Buffer (L) 6100 4000 4000


Resin Cost ($16k/L) $912k $448k $144k


15

Feed Wash Elution

Time Resin

“Utilized” Binding Capacity

16

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

17

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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