Acs 2010 Handout

“Downstream Processing 2.0:
From a Bottleneck to a Pacemaker”
Platzhalter Bild

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.

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

2.Process Economy – Cost
of Goods matter
of Goods matter

3.Discovering new Shores -
Fortune favors the Brave

4.Benchmarks of the Future
– No best, just better
5.The Future of DSP –
Revisiting the Past
Revisiting the Past
Data adapted from: F. Wurm Production of recombinant Protein Therapeutics
in Cultivated Mammalian Cells. Nature Biotechnology 22, 1-6 (2004)

Hot Topic: High Titer Processes

Improving Titres – MAbs (Bulk API)

Titre Improvements 4 Bioreactors
800
Important cost benefits as
titres go beyond 1g/L 700 Estimate of CoG based on
These diminish as we go 600
standard MAb process for
beyond 5g/L bulk drug substance
500

COG ($/g)
400
Beyond 5g/L 300
Downstream cost dominates
In this example the plateau 200

is just under $100/g 100

0
Challenge in DSP 0 2 4 6 8 10 12

Bioreactors decrease in size? Titre (g/L)

Cope with increased titres
2000L 5000L
Need to drive out costs
Implications for facility
design Results from Biopharm Services Generic MAb cost model
Bulk API Direct manufacturing costs

A universal cost model for single use systems in biomanufacturing.
Andrew Sinclair, BioPharm Services; Berlin Oct. 2007

DSP is Mass not Volume driven

Jim Davis, Lonza Economics of Monoclonal Antibody Production: The relationship between upstream titer and
downstream costs; IBC San Diego March 2008

Agenda


2.Process Economy – Cost of
2.Process Economy – Cost of
Goods matter
Goods matter

4. Benchmarks of the Future
4. Benchmarks of the Future
Revisiting the Past
Revisiting the Past

Challenges of a Modern Downstream Process

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

Bringing Biosimilars to the Market

Biosimilars: Margin Squeeze translate into lower COGS

Typical COG breakdown by

Category

MAb manufacturing: 6 x 2,000L tanks, 2g/L, 90% utilisation; 211 #/a; 527 kg/yr; invest 172 Mio Euro;
142 $/g; Sinclair 2006

Agenda


of Goods matter
of Goods matter



Revisiting the Past
Revisiting the Past

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


Off the Shelf Platform for Rapid Process Train Assembly

Cell Removal/
Cell Removal/ Intermediate
Intermediate Virus
Virus
Fermentation
Fermentation Capturing
Capturing Polishing
Polishing
Clarification
Clarification Purification
Purification Clearance
Clearance

Microorg. CEX HIC Size-Exclusion
Size-Exclusion

BHK X-FLow Mixed-Mode Ceramic HA AEX (B/E)

CHO
CHO Centrifuge
Centrifuge CEX Inactivation

Human Depthfilter
Depthfilter Protein A
Protein A Gelfiltration AEX (FT)

Hybridoma EBA AEX-Membrane
AEX-M Adsorption

CHO Centr./DF New Aprocess CEX
Protein AEX (FT) Orthogonal
New process train
train
New process train ready K. Konstantinov
Bayer Corp, USA

Medarex: Non-Protein A based Purification Processes: Scheme Evolution

2 columns + 1 column +
3 columns 1 membrane 2 columns 1 membrane
Unprocessed Bulk Unprocessed Bulk Unprocessed Bulk Unprocessed Bulk

CEX CEX CEX CEX
Chromatography Chromatography Chromatography Chromatography

Viral Inactivation Viral Inactivation Viral Inactivation Viral Inactivation

AEX AEX Membrane HCIC AEX Membrane
Chromatography chromatography Chromatography Chromatography

Mixed Mode Mixed Mode Viral Filtration Viral Filtration
chromatography chromatography

Viral Filtration Viral Filtration

Page 26
Alahari 2009

A Consensus – Value Chain in Bioseparation
High Titer Implications:

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

Agenda


of Goods matter
of Goods matter


Revisiting the Past
Revisiting the Past

Biomass Removal and Early Contaminant Clearance
addresses:

Increasing biomass and
contaminant levels

Capturing

• New generation of lenticular
filtration media

• No Diatomeaceous Earth;
Synthetic

• Cell removal, clarification &
early on contaminant removal

The Focus on Column Chromatography is increasing


Packed Bed Chromatography: The Good The Bad and The Ugly

John Curling and Uwe Gottschalk

BioPharm Intl. October 2007

U. Gottschalk. Bioseparation in antibody manufacturing:
The good, the bad and the ugly.
Biotechnol Prog. 2008 May-Jun;24(3):496-503.

Chromatography Technologies for DSP

Polishing (Membranes)
• Highly porous structure
• Pore size: 3 – 5μm
• Convective Flow
Capturing/IP (Resins)
• Minimal buffer use
• Bead size distribution: 15 -160 μm
• Average pore size: 15 - 40 nm
• Diffusion limited flow
• High capacity

Hot Topic: Cost of Capturing


addresses:

and step cost

D. Low BioManufacturing Paris 2007

Two Birds –one Stone: Contaminant Precipitation
at Pfizer addresses:

and step cost

Capturing

Three Birds – one Stone: Contaminant Precipitation at Medarex
addresses:
Fig 7a. precipitation based process Fig 7b. TFF based process

Contaminant Protein A pool volumes
TFF
precipitation and step cost

CEX HCP < 10ng/mg Capturing < 1000 ng/mg
CEX HCP

Dilution Polishing load volumes
Dilution
and conductivity
Q Membrane Q Membrane HCP < 1000 ng/mg
HCP BDL 2 g/ml
20 g/ml
Dilution
VF
Mix Mode

Precipitation of Process-Derived Impurities in Non-Protein A VF
Purification Schemes for MAb; J. Wang et al. BioPharm Intl. 10/2009, 2-9

Hot Topic: Polishing load volume/conductivity
addresses:

Polishing load volumes
and conductivity

• Salt Tolerant Interaction
Chromatography (STIC)

• New cellulose-based
membrane structure

• Primary instead of
quartenary amine ligand

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

Will Protein A Capturing ever be Single-Use?

2000: Oleosin Platform 2005: TMV Nanoparticles 2010: Bio Polyester Platform
Polyester
Synthase

Polyester Granule
Immunoabsorbent nanoparticles based on a 100-300 nm
tobacco mosaic virus displaying protein A
Limitation: Oleosin yields < 1kg/ha S. Werner et al. PNAS 103, 17678 - 17683
Grage, K. and Rehm, B.H.A. (2008)
Bioconj. Chemistry, 19(1):254-62.

Orthogonal Contaminant Removal Technologies
Pathogen clearance as a
moving target

UVC Inactivation

Nanofiltration (20nm)

Membrane Chromatography
Depth filtration

15. October 2008 Seite 2

More Mileage out of Virus Filtration

The problem: Virus filters shows low Vmax and Flow Rate for blocking Feed Streams

Vmax 200 – 1000 L/m²
50 -100 L/m2.h.bar
low or moderatly blocking
e.g. MAb

Vmax <100 L/m²
Vmax2
5 - 30 L/m2.h.bar
highly blocking
e.g. IVIG, Enbrel

The Renaissance of Protein Purification

Michelangelo de Lodovico Buonarotti

Old Enabling Technology: Boring but Reliable

• Centrifugation

• Extraction

• Precipitation

• Filtration

• Crystallization

• UV-Inactivation

Downstream Processing 2010+

“The real voyage of discovery consists not
in seeking new landscapes
but in having new eyes.”
Marcel Proust.

Thank you!

Uwe.Gottschalk@sartorius-
stedim.com

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