acs 2010 handout
DESCRIPTION
"Downstream Processing 2.0: From a Bottleneck to a Pacemaker" Keynote at ACS 2010, San FranciscoTRANSCRIPT
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Platzhalter Bild
“Downstream Processing 2.0:
From a Bottleneck to a Pacemaker”
ACS Biot
2010
Dr. Uwe Gottschalk, VP Purification Technologies, Sartorius Stedim
Biotech
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What
are
the
hot Topics?
6th Annual Survey of Biopharmaceutical Manufacturing. Eric S. Langer, BioPlan
Associates Inc.
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6th Annual Survey of Biopharmaceutical Manufacturing. Eric S. Langer, BioPlan
Associates Inc.
Finally
there
seems
to be
a Bottleneck
...
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... depending
on who
you
ask
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Who
is
facing
Limitations?
“Obviously there is no downstream bottleneck
if you have unlimited cash”– K. John Morrow, Jr., PhD., 2009
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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)
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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
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Jim Davis, Lonza
Economics of Monoclonal Antibody Production: The relationship between upstream titer and downstream costs; IBC San Diego March 2008
DSP is
Mass
not
Volume
driven
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Platzhalter Bild
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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
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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
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Bringing
Biosimilars
to the
Market
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Biosimilars: Margin
Squeeze
translate
into
lower
COGS
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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
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Hot Topic: Use
of Disposables
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J. Zhou
BPI Vienna 2008
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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
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Downstream
Processing
1980
“If it ain’t
broke, don’t fix it”– Bert Lance, 1977
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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
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Companies
are
questioning
current
Standards
6th Annual Survey of Biopharmaceutical Manufacturing. Eric S. Langer, BioPlan
Associates Inc.
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Gelfiltration
CHO
Human
Hybridoma
BHK
Cell Removal/Clarification
Cell Removal/Clarification CapturingCapturing Intermediate
Purification
IntermediatePurification PolishingPolishing Virus
Clearance
Virus ClearanceFermentationFermentation
Microorg.
New process trainNew process train
X-FLow
Depthfilter
Centrifuge
CEX
Mixed-Mode
Protein A
HIC
Ceramic HA
CEX
AEX (B/E)
AEX (FT)
AEX-M
Size-Exclusion
Adsorption
Inactivation
EBA
K. KonstantinovBayer Corp, USA
CHO
Protein A
CEX
AEX-Membrane
New process train ready
CHO OrthogonalCentr./DF Protein A CEX AEX (FT)
Depthfilter
Centrifuge Inactivation
Adsorption
Size-Exclusion
Off the
Shelf
Platform
for
Rapid Process
Train
Assembly
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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
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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:
![Page 26: Acs 2010 Handout](https://reader034.vdocuments.net/reader034/viewer/2022052506/556dc950d8b42a78768b47ca/html5/thumbnails/26.jpg)
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
![Page 27: Acs 2010 Handout](https://reader034.vdocuments.net/reader034/viewer/2022052506/556dc950d8b42a78768b47ca/html5/thumbnails/27.jpg)
•
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:
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The
Focus on Column
Chromatography
is
increasing
6th Annual Survey of Biopharmaceutical Manufacturing. Eric S. Langer, BioPlan
Associates Inc.
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BioPharm
Intl. October
2007
John Curling and Uwe Gottschalk
Packed Bed Chromatography: The Good The Bad and The Ugly
U. Gottschalk. Bioseparation
in antibody manufacturing: The good, the bad and the ugly.Biotechnol
Prog. 2008 May-Jun;24(3):496-503.
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Pete Gagnon
2007
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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
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Hot Topic: Cost
of Capturing
6th Annual Survey of Biopharmaceutical Manufacturing. Eric S. Langer, BioPlan
Associates Inc.
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D. Low BioManufacturing
Paris 2007
Protein A pool volumes and step cost
addresses:
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Two Birds –one Stone: Contaminant Precipitation at Pfizer
Protein A pool volumes and step cost
DNA & HCP levels post Capturing
addresses:
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Three Birds –
one Stone: Contaminant Precipitation at Medarex
Precipitation of Process-Derived Impurities in Non-Protein APurification Schemes for MAb; J. Wang et al. BioPharm
Intl. 10/2009, 2-9
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
Protein A pool volumes and step cost
DNA & HCP levels post Capturing
Polishing load volumes and conductivity
addresses:
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Hot Topic: Polishing load volume/conductivity
•
Salt Tolerant Interaction Chromatography
(STIC)
•
New cellulose-based membrane
structure
•
Primary
instead
of quartenary
amine
ligand
Polishing load volumes and conductivity
addresses:
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Results
so far achieved:
No CHOP-breakthrough
at 10 kg MAb/ L of membrane
> 4.96 LRV for
MMV at 150m mM
NaCl.
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Downstream Costs: Why bother?
Jim Davis, Lonza
Economics of Monoclonal Antibody Production: The relationship between upstream titer and downstream costs; IBC San Diego March 2008
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Limitation: Oleosin yields < 1kg/ha
2000: Oleosin
Platform
Will Protein A Capturing ever be Single-Use?
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
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Hot Topic: Pathogen Safety
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15. October 2008 Seite 2
UVC Inactivation
Nanofiltration (20nm)
Membrane Chromatography
Orthogonal Contaminant Removal Technologies
Depth filtration
Pathogen clearance as a moving target
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More
Mileage
out of Virus Filtration
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The problem: Virus filters shows low Vmax
and Flow Rate for blocking Feed Streams
Vmax2
Vmax
200 –
1000 L/m²50 -100 L/m2.h.bar
low or moderatly
blockinge.g. MAb
Vmax
<100 L/m²
5 -
30 L/m2.h.barhighly blockinge.g. IVIG, Enbrel
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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
![Page 45: Acs 2010 Handout](https://reader034.vdocuments.net/reader034/viewer/2022052506/556dc950d8b42a78768b47ca/html5/thumbnails/45.jpg)
The
Renaissance of Protein Purification
Michelangelo de Lodovico
Buonarotti
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•
Centrifugation
•
Extraction
•
Precipitation
•
Filtration
•
Crystallization
•
UV-Inactivation
Old Enabling Technology: Boring but Reliable
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“The
real voyage
of discovery
consists
notin seeking
new
landscapes
but
in having
new
eyes.”
Marcel Proust.
Downstream
Processing
2010+
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Yes
we
can!
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Uwe.Gottschalk@sartorius- stedim.com
Thank
you!