Shanghai 2010

“The new era of Downstream Processing:
From a Bottleneck to a Pacemaker”

Platzhalter Bild

BioManufacturing World Oct. 19 2010
Uwe Gottschalk VP Purification Technologies, Sartorius Stedim Biotech

Finally there seems to be a Bottleneck ...

6th Annual Survey of Biopharmaceutical Manufacturing.
Eric S. Langer, BioPlan Associates Inc.

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

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

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

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

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


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 Vision of a Disposable Chromatography Process

Robert van Reis: Future Trends in Bioseparations; Recovery XII, 2006

Process Chromatography: What are the Options?

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.

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

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

Contaminant
precipitation
TFF

and step cost

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

Dilution
Capturing
Dilution

Q Membrane Q Membrane HCP < 1000 ng/mg
HCP BDL 2 g/ml
20 g/ml
Dilution
VF
Mix Mode

VF
Process Scale Precipitation of Precipitation of Process-Derived
Impurities in Mammalian Cell Culture Impurities in Non-Protein A
Broth; J. Glynn et al. In: Gottschalk U Purification Schemes for MAb; J. Wang
(ed) Process-scale Purification of et al. BioPharm Intl. 10/2009, 2-9
Antibodies. Wiley, NY.

Source: 2nd Annual Survey of the Bioprocessing Market
for Single-Use Solutions
Aspen Brook Consulting, 2010

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

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

Protein A costs are not an issue at large scale with full total capacity utilization

6th Annual Survey of Biopharmaceutical Manufacturing.
Eric S. Langer, BioPlan Associates Inc.

Alternatives to Protein A Capture

• 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

addresses:

and step cost

D. Low BioManufacturing Paris 2007

Alternative Protein A Chromatography Formats:
Goal: Intensified Use/Volume Reduction
• 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 Formats:
Goal: Low Cost – Real 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.

Convective Media are Part of the Design Space in Polishing

...

The Renaissance of Protein Purification

Michelangelo de Lodovico Buonarotti

Old Enabling Technology: Boring but Reliable

• Centrifugation

• Extraction

• Precipitation

• Filtration

• Crystallization

• UV-Inactivation

Thank you!

Uwe.Gottschalk@sartorius-
stedim.com

Shanghai 2010

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