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Platzhalter Bild
BioManufacturing
World Oct. 19 2010
Uwe
Gottschalk VP Purification Technologies, Sartorius Stedim
Biotech
“The new era of Downstream Processing: From a Bottleneck to a Pacemaker”
6th Annual Survey of Biopharmaceutical Manufacturing. Eric S. Langer, BioPlan
Associates Inc.
Finally
there
seems
to be
a Bottleneck
...
Who
is
facing
Limitations?
“Obviously there is no downstream bottleneck
if you have unlimited cash”– K. John Morrow, Jr., PhD., 2009
Agenda
1.Improving
throughput
–
The
Capacity
Disconnect
1.Improving
throughput
–
The
Capacity
Disconnect
2.Process
Economy –
Cost
of Goods
matter
2.Process
Economy –
Cost
of Goods
matter
5.The Future of DSP –
Revisiting the Past
5.The Future of DSP –
Revisiting the Past
4.Benchmarks of the Future –
No best, just better
4.Benchmarks of the Future –
No best, just better
3.Discovering new Shores -
Fortune favors the Brave
3.Discovering new Shores -
Fortune favors the Brave
Data adapted from: F. Wurm
Production of recombinant Protein Therapeuticsin Cultivated Mammalian Cells. Nature Biotechnology 22, 1-6 (2004)
Improving Titres Improving Titres –– MAbsMAbs (Bulk API)(Bulk API)
Titre ImprovementsImportant cost benefits as titres go beyond 1g/LThese diminish as we go beyond 5g/L
Beyond 5g/LDownstream cost dominatesIn this example the plateau is just under $100/g
Challenge in DSPBioreactors decrease in size?Cope with increased titresNeed to drive out costs Implications for facility design Results from Biopharm Services Generic MAb cost model
Bulk API Direct manufacturing costs
0
100
200
300
400
500
600
700
800
0 2 4 6 8 10 12
Titre (g/L)
CO
G ($
/g)
2000L 5000L
4 Bioreactors
Estimate of CoG based on standard MAb process for bulk drug substance
A universal cost model for single use systems in biomanufacturing. Andrew Sinclair, BioPharm
Services; Berlin Oct. 2007
Hot Topic: High Titer
Processes
1.Improving
throughput
–
The
Capacity
Disconnect
1.Improving
throughput
–
The
Capacity
Disconnect
2.Process
Economy –
Cost
of
Goods
matter
2.Process
Economy –
Cost
of
Goods
matter
Agenda
5.The Future of DSP –
Revisiting the Past
5.The Future of DSP –
Revisiting the Past
4.Benchmarks of the Future –
No best, just better
4.Benchmarks of the Future –
No best, just better
3.Discovering new Shores -
Fortune favors the Brave
3.Discovering new Shores -
Fortune favors the Brave
Technical challenge
Sensitive and technically demanding products require processes with inherent
complexity and expensive infrastructure
Need for robust & scalable processes for the entire DSP
Increasing regulatory scrutiny (Comparability!)
Financial challenge
Processes are fixed-cost driven (Investment vs
Consumables)
Manufacturing costs 15 -
25% of sales price
Costs for DSP up to 75% of manufacturing costs
Cost Balance Benefit for innovative treatments
Biosimilars
Challenges
of a Modern Downstream
Process
MAb
manufacturing: 6 x 2,000L tanks, 2g/L, 90% utilisation; 211 #/a; 527 kg/yr; invest 172 Mio Euro;
142 $/g; Sinclair 2006
Category
Typical
COG breakdown
by
Hot Topic: Use
of Disposables
J. Zhou
BPI Vienna 2008
Agenda
2.Process
Economy –
Cost
of Goods
matter
2.Process
Economy –
Cost
of Goods
matter
5.The Future of DSP –
Revisiting the Past
5.The Future of DSP –
Revisiting the Past
4.Benchmarks of the Future –
No best, just better
4.Benchmarks of the Future –
No best, just better
3.Discovering new Shores -
Fortune favors the Brave
3.Discovering new Shores -
Fortune favors the Brave
1.Improving
throughput
–
The
Capacity
Disconnect
1.Improving
throughput
–
The
Capacity
Disconnect
A Consensus –
Value
Chain in Bioseparation
Increasing biomass and contaminant levels
Protein A pool volumes and step cost
DNA & HCP levels post Capturing
Polishing load volumes and conductivity
Pathogen clearance as a moving target
High Titer
Implications:
Downstream
Processing
1980
“If it ain’t
broke, don’t fix it”– Bert Lance, 1977
Downstream
Processing
2010
“Le mieux
est
l’ennemi
du bien”(better is the enemy of good)
– Voltaire, 1772
“没有最好,只有更好”(No best – only better)
– Chinese Movie Cliche
Agenda
1.Improving
throughput
–
The
Capacity
Disconnect
1.Improving
throughput
–
The
Capacity
Disconnect
2.Process
Economy –
Cost
of Goods
matter
2.Process
Economy –
Cost
of Goods
matter
5.The Future of DSP –
Revisiting the Past
5.The Future of DSP –
Revisiting the Past
4.Benchmarks of the Future –
No best, just better
4.Benchmarks of the Future –
No best, just better
3.Discovering new Shores -
Fortune favors the Brave
3.Discovering new Shores -
Fortune favors the Brave
•
New generation
of lenticular filtration
media
•
No Diatomeaceous
Earth; Synthetic
•
Cell
removal, clarification
& early
on contaminant
removal
Biomass
Removal and Early
Contaminant
Clearance
Increasing biomass and contaminant levels
DNA & HCP levels post Capturing
addresses:
Robert van Reis: Future Trends in Bioseparations; Recovery
XII, 2006
The
Vision of a Disposable
Chromatography
Process
BioPharm
Intl. October
2007
John Curling and Uwe Gottschalk
Process Chromatography: What are the Options?
U. Gottschalk. Bioseparation
in antibody manufacturing: The good, the bad and the ugly.Biotechnol
Prog. 2008 May-Jun;24(3):496-503.
Page 26
Unprocessed Bulk
Viral Filtration
CEX
Chromatography
AEX Chromatography
Mixed Modechromatography
Viral Inactivation
3 columns
Unprocessed Bulk
Viral Filtration
CEX
Chromatography
AEX Membrane chromatography
Mixed Modechromatography
Viral Inactivation
Unprocessed Bulk
Viral Filtration
CEX
Chromatography
HCICChromatography
Viral Inactivation
2 columns +
1 membrane 2 columns
1 column +
1 membrane
Unprocessed Bulk
Viral Filtration
CEX
Chromatography
AEX Membrane Chromatography
Viral Inactivation
Alahari
2009
Medarex: Non-Protein A based Purification Processes: Scheme Evolution
CEX
TFF
Q Membrane2 g/ml
Dilution
HCP < 1000 ng/mg
VF
Mix Mode
Fig 7b. TFF based process
Dilution
HCP < 1000 ng/mg
CEX HCP < 10ng/mg
Contaminant precipitation
Q Membrane20 g/ml
Fig 7a. precipitation based process
VF
HCP BDL
Dilution
CEX
TFF
Q Membrane2 g/ml
Dilution
HCP < 1000 ng/mg
VF
Mix Mode
Fig 7b. TFF based process
Dilution
HCP < 1000 ng/mg
CEX
TFF
Q Membrane2 g/ml
Dilution
HCP < 1000 ng/mg
VF
Mix Mode
Fig 7b. TFF based process
Dilution
HCP < 1000 ng/mg
CEX
TFF
Q Membrane2 g/ml
Dilution
HCP < 1000 ng/mg
VFVF
Mix Mode
Fig 7b. TFF based process
Dilution
HCP < 1000 ng/mg
CEX HCP < 10ng/mg
Contaminant precipitation
Q Membrane20 g/ml
Fig 7a. precipitation based process
VF
HCP BDL
Dilution
CEX HCP < 10ng/mg
Contaminant precipitation
Q Membrane20 g/ml
Fig 7a. precipitation based process
VFVF
HCP BDL
Dilution
Two Birds –
one Stone: Contaminant Precipitation at Pfizer and Medarex
Protein A pool volumes and step cost
DNA & HCP levels post Capturing
addresses:
Precipitation of Process-Derived Impurities in Non-Protein APurification Schemes for MAb; J. Wang et al. BioPharm
Intl. 10/2009, 2-9
Process Scale Precipitation of Impurities in Mammalian Cell Culture Broth; J. Glynn
et al. In: Gottschalk U (ed) Process-scale Purification of Antibodies. Wiley, NY.
Source: 2nd Annual Survey of the Bioprocessing Market for Single-Use SolutionsAspen Brook Consulting, 2010
Chromatography Technologies for DSP
Polishing
(Membranes)
• Highly porous structure
• Pore size: 3 –
5μm
• Convective Flow
• Minimal buffer useCapturing/IP
(Resins)
• Bead size distribution: 15 -160 μm
• Average pore size: 15 -
40 nm
• Diffusion limited flow
• High capacity
Capture Costs: Why bother?
Jim Davis, Lonza
Economics of Monoclonal Antibody Production: The relationship between upstream titer and downstream costs; IBC San Diego March 2008
6th Annual Survey of Biopharmaceutical Manufacturing. Eric S. Langer, BioPlan
Associates Inc.
Protein A costs
are
not
an issue
at large scale
with
full
total capacity
utilization
• Product
precipitation
batch/continuous
• Impurity
precipitation
(followed
by
non-Protein
A process)
• Alternative Capturing
(Protein A Mimetics, Mixed Mode, CEX)
Issues: Selectivity, Scale
up, Reproducibility, Comparability
Alternatives to Protein A Capture
D. Low BioManufacturing
Paris 2007
Protein A pool volumes and step cost
addresses:
• Simulated
Moving
Bed
(SMB) and related:
» Tarpon
(„single
use
flow
path“)
» Novasep
» Chromacon
» Chromatan
» ...______________________________________________________________________
• Expanded
Bed
Chromatography
» DSM/Upfront
(„single
use
flow
path“)
Issues: Complexity, Scale
up, Reproducibility, Comparability
Alternative Protein A Chromatography
Formats:Goal: Intensified
Use/Volume
Reduction
Limitation: Oleosin yields < 1kg/ha
2000: Oleosin
Platform 2005: TMV Nanoparticles
Immunoabsorbent
nanoparticles
based on a tobacco mosaic virus displaying protein AS. Werner et al. PNAS 103, 17678 -
17683
Polyester Granule100-300 nm
Grage, K. and Rehm, B.H.A. (2008) Bioconj. Chemistry, 19(1):254-62.
Polyester Synthase
2010: Bio Polyester Platform
Alternative Protein A Formats:Goal: Low Cost
–
Real Single Use
...
Convective
Media are
Part of the
Design Space
in Polishing
Agenda
1.Improving
throughput
–
The
Capacity
Disconnect
1.Improving
throughput
–
The
Capacity
Disconnect
2.Process
Economy –
Cost
of Goods
matter
2.Process
Economy –
Cost
of Goods
matter
5.The Future of DSP –
Revisiting the Past
5.The Future of DSP –
Revisiting the Past
4.Benchmarks of the Future –
No best, just better
4.Benchmarks of the Future –
No best, just better
3.Discovering new Shores -
Fortune favors the Brave
3.Discovering new Shores -
Fortune favors the Brave
The
Renaissance of Protein Purification
Michelangelo de Lodovico
Buonarotti
•
Centrifugation
•
Extraction
•
Precipitation
•
Filtration
•
Crystallization
•
UV-Inactivation
Old Enabling Technology: Boring but Reliable
Uwe.Gottschalk@sartorius- stedim.com
Thank
you!