Next generation MAb facilities
2009 ISPE PNW
Biotech Program
Tuesday, June 9th
Seattle Biomedical Research Institute
307 Westlake, Seattle
Niels Guldager, Senior Consultant, NNE Pharmaplan
ngu@nnepharmaplan.com
Topics
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About NNE Pharmaplan
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Objective – Change we can rely on
About MAbs – Process intensification
Single Use technology for MAb production
Designing the next generation facility (cases)
Life in the next generation facility
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Summary
Objective
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Inspiration: Explore impact of higher yields and new process technology
Share learnings from projects with next generation facility elements
The big picture:
- A new paradigm for MAb bulk production facilities
- Massively changed facility design
- Cost and timelines reduced significantly
Single Use
Higher yields
Next
generation
facility
1890
1900
1910
1920
1930
1940
1950
1960
1970
1980
2006: 11 biopharm patents have expired
2008: Biosimilars regulatory roadmap
1982: Humulin, Lilly. 1st recombinant drug
1955: Polio vaccine, Salk, Sabine
1954: TB Ehrlich, Domagk, Waltsman
1940s: Penicillin in bulk
1928: Penicillin, Alexander Fleming
1921: Insulin, Banting and Best
1895: Aspirin, BAYER
1865: Germ theory of disease, Pasteur
Change you can count on
Pharma big picture time line
Monoclonal
Antibody products
1990
2000
Monoclonal Antibodies
Next generation facilities
2010
2020
2009: High titers trend
2009: Single Use maturing
1973: Recombinant DNA. Boyer and Cohen
1953: DNA structure, Watson and Crick
Disruptive technology
Facility impact
About MAbs
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Complex molecule, large compared to other biopharmaceuticals
Very specific binding ability
Various modes of action
Large dose, large volume required
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Example: Arthritis - autoimmune disorder
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Immune system causes inflammation of joints
Exact cause unknown
Rituximab monoclonal antibody binds to white
blood cells, modulates immune system activity
Dose: 0.5-1.0 gram range
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Process - general
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Expression system: Typically CHO cells
Generate biomass
Generate product
Remove biomass
Weeks
Day
Biological processes
Physical-chemical
Bulk Filtration
Isolate product
Virus
inactivation
Virus
Virus clearance, orthogonal methods filtration
Remove impurities, reduce volume, change buffers
Day
Days
Physical-chemical processes
Bulk formulation
Freezer
Yields
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Powerful controls have been turned up:
• Cell line development
• Media optimization
• Bioreactor design, batch duration
Example: PERCIVIA PERC.6 cell line fed batch yields
From percivia.com
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10-100X rise in titers since mid-90’s
Fed batch:
• Production:
3 g/liter
• Clinical:
7 g/liter
• Development:
8-10 g/liter reported
• Future:
15 g/liter seen as realistic
Yields recently reported, various forecasts
Bioreactor - stainless steel
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Very orderly, everything in place, good controls
Valves, piping and instrumentation to clean, sterilize and move liquids around
Design principles originating from dairy and petrochemical industries
Bioreactor seed train (Novo Nordisk)
Bioreactors – Single Use (SU)
No. I/O's for SS vs. SU bioreactors
160
140
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120
Working volumes 50–2000 liters recently available, works
fine
100
Bag: Multilayer film, product contacting layer typical low
density PE polymer
80
60
Flexible tubing, pushing liquids around,
40
Challenges: Agitation, sensors, heat transfer
20
0
Stainless steel
Autom ated
Sta inless Steel
Low
Automation
Single Use
rocker
Single Use
Bioreactor
140
41
22
21
Num bers of I/O's
Sartorius
Hyclone
ATMI
Xcellerex
Case: SU area and cost impact
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Client: Biotech company, new pilot plant
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What’s in the project?
• Investigate SU impact on cost and area in MAb upstream processes.
• Provide design solutions for process and suite configuration for excisting facility
• Media prep, bioreactors, harvest
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Key learnings – single use impact:
• 15-20% area reduction
• 20-30% cost reduction
• Variable cost improved
% area reduction as function of percentage of process modules being single use. Case 1: Stainless steel with a few media bags.
The 6-pack plant
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Typical fed batch design
6 bioreactors in fed batch mode
1-2 capture/purification lines
Media
6-pack
MAb volume forecasts:
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More products, shared markets
1000 kg/year for a few products
100-200 kg/year for many products
From: Guenter Jagschies,
New drivers in MAb process economics
Seed train
Downstream
Buffers
A new 6-pack!
1000 kg Mab/year
Single Use
Bioreactor volume [liter]
Bioreactors
Yield [g/liter]
Output [Kg MAb/year]
Batch time [weeks]
DSP yield
Production [weeks]
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Yields
Single Use
Process intensification
Volume forecasts
Traditional
20000
6
0,5
1013
2000
6
5
1013
2
75%
45
2
75%
45
A new facility design paradigm
Traditional
Single Use
Single Use
mixing
Media prep
Single Use
bioreactors
Upstream
Single Use
Seed train
Single Use
filtration
Media hold
Harvest
Seed train
Downstream
Membrane
Chrom
Single Use
Hold bags
Buffer prep
In-line
dilution
Buffer farm
Case: Single Use for strategic
flexibility
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Client: Generic pharma company, biopharmaceuticals strategy
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What’s in the project?
• No established process: Open book for SU implementation.
• Future of biosimilars not certain – box in the box design
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Key learnings - facility design
• Single production level design - liquids transported around
• Single-use + inline dilution strategy => load calculations critical
• > 250 kg MAb/year capacity per section
Pre-culture
Media prep
Buffer prep
Late
purification
Buffer prep
Culture
Purification
Process intensification
Percivia XD process 27 g/L
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Cells retained in bioreactor
Fresh media supply
Impurities, waste products removed
From percivia.com
From magellanintruments.com
This part optimized
What’s in store here?
Expanded Bed Affinity chromatography
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EBA (Upfront, Denmark): Straight from bioreactor to column
Skip centrifugation, filtration and packing, increase yield
High density 3.5 g/ml tungsten adsorbent beads
From upfront-dk.com
Case: Boosting facility output
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Client: CMO
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What’s in the project?
• Restructure and expand facility to increase output
• Pit stop project: Minimize impact on production
• 5 months from design to operation
• Area restrictions and flows versus single use
• Single use process as much as possible
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Key learnings – facility design
• SU decouples process from facility giving fast and predictable construction phase
• At the same time making a phase approach practical (rooms switching functions)
• Inline dilution will save the day in transport/ergonomics, eventually
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This may be the MAb facility of the near future: Small, retrofitted and cost effective
Future: A greener facility
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10X is 10X: Environmental impact improved on kg MAb basis
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Process intensification largest factor in improving green footprint
• Water
• Energy
• Consumables
• No. people driving to work
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Single Use direct reductions:
• Water, chemicals
• Energy – approx. 50%
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SU solid waste:
• Landfill leaves little CO2-footprint but is not sustainable
• Incineration provides energy recovery
Energy consumption: Comparison of 1000L scale SU and Stainless
steel process. Rawlings and Pora, Bioprocess International, 2009
Case: SU Automation
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Client: Biopharm company
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What’s in the project?
• Production facility
• Farm of SU bioreactors
• Automation strategy for GMP production
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Key learnings – automation
• The need to define each operation
• How to get same control and documentation as in a traditional facility
• S88 batch programming standard serves remarkably well for orchestrating
people, equipment and materials
Automating Single Use Process Technology
Automation Issues/Challenges:
Recommended Automation Solution:
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Warehousing of SU components
Retrieval and assembly of SU components
for each batch
Verification of assembly before batch start
Equipment now becomes a consumable
Tracking of SU components upon use
(inactivation, incineration)
Process skid normally supplied with low
level of automation (start/stop via
operator panel)
Keep local control as simple as possible
Let MES system handle the complexity
Connect local control system to central
data historian for collection of process
values, events & alarms
MES system:
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Track SU components as raw materials (bar-code scanners)
Weighing/dispensing including filling of bags
Guide operator through execution of all process steps (start/stop)
Prompt for sampling
Generation, review and approval of batch documentation
Workflow & System Support
Workflow
Retrieve
& verify
materials
via bar
codes
Assemble
& verify
equipment
via bar
codes
Acknowledge
completion
Ready for
start
Start
process
(Push
button)
Collect
process
values,
events &
alarms
Generate
batch
doc.
Review &
approve
batch
doc.
Complete
process
System Support
Operator guided via central MES,
which is responsible for complete
batch documentation based on
input from operator, barcode
readers, scales and historian
database
MES
Material supply,
equipment assembly
& weighing/dispensing
controlled by MES
Historian
PLC
Scale
OPC
Server
Collection of
Process values
Event & Alarms
In central Historian
database
Standard
OPC interface
to process
Process Skid with disposable
components, plastic bags, hoses &
filters controlled by local PLC
Description
Operation flow
Information
Operation flow diagram
Summary
Next generation MAb facilities: Coming on-line in 2-5 years
New cell lines and process technologies resulting in:
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1000 kg MAb/year capacity in 1000L scale
Smaller, more flexible, more cost effective facility
Process train entirely single use, entirely closed
Automation as production support
…still some hurdles, trends will combine to realize Pipeless Plants Vision
Wave Biotech 1200/500L prototype and final design
Vijay Singh, GE Healthcare, Wave Biotech:
Pipeless Plants for Biological Manufacturing, 2001
References
[1]
[2]
[3]
[4]
[5]
[6]
Magellan, Percivia, Sartorius, Roche, Xcellerex, Hyclone, Upfront websites
Guenter Jaqschies, New drivers in MAb process economics, 2009
Aeby Thomas, NNE Pharmaplan, Process
Jens Bruun, NNE Pharmaplan, Automation
Vijay Singh, Pipeless Plants for Biological Manufacturing, 2001
Bruce Rawlings, Helene Pora, Environmental impact of single use and reusable
Bioprocess systems, 2009
Thank you for your attention!!
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More info:
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ngu@nnepharmaplan.com