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"Downstream Processing 2.0: From a Bottleneck to a Pacemaker" Keynote at ACS 2010, San Francisco
Citation preview
Platzhalter Bild
“Downstream Processing 2.0:
From a Bottleneck to a Pacemaker”
ACS Biot
2010
Dr. Uwe Gottschalk, VP Purification Technologies, Sartorius Stedim
Biotech
What
are
the
hot Topics?
6th Annual Survey of Biopharmaceutical Manufacturing. Eric S. Langer, BioPlan
Associates Inc.
6th Annual Survey of Biopharmaceutical Manufacturing. Eric S. Langer, BioPlan
Associates Inc.
Finally
there
seems
to be
a Bottleneck
...
... depending
on who
you
ask
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
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
Platzhalter Bild
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
Bringing
Biosimilars
to the
Market
Biosimilars: Margin
Squeeze
translate
into
lower
COGS
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
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
Companies
are
questioning
current
Standards
6th Annual Survey of Biopharmaceutical Manufacturing. Eric S. Langer, BioPlan
Associates Inc.
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
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
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:
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:
The
Focus on Column
Chromatography
is
increasing
6th Annual Survey of Biopharmaceutical Manufacturing. Eric S. Langer, BioPlan
Associates Inc.
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.
Pete Gagnon
2007
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
Hot Topic: Cost
of Capturing
6th Annual Survey of Biopharmaceutical Manufacturing. Eric S. Langer, BioPlan
Associates Inc.
D. Low BioManufacturing
Paris 2007
Protein A pool volumes and step cost
addresses:
Two Birds –one Stone: Contaminant Precipitation at Pfizer
Protein A pool volumes and step cost
DNA & HCP levels post Capturing
addresses:
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:
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:
Results
so far achieved:
No CHOP-breakthrough
at 10 kg MAb/ L of membrane
> 4.96 LRV for
MMV at 150m mM
NaCl.
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
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
Hot Topic: Pathogen Safety
15. October 2008 Seite 2
UVC Inactivation
Nanofiltration (20nm)
Membrane Chromatography
Orthogonal Contaminant Removal Technologies
Depth filtration
Pathogen clearance as a moving target
More
Mileage
out of Virus Filtration
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
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
“The
real voyage
of discovery
consists
notin seeking
new
landscapes
but
in having
new
eyes.”
Marcel Proust.
Downstream
Processing
2010+
Yes
we
can!
Uwe.Gottschalk@sartorius- stedim.com
Thank
you!