RESIDENTIAL COMPOUND’S SECURITY GATE REDESIGN, Shanghai (China), 2010
Shanghai 2010
Transcript of Shanghai 2010
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!