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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


Revisiting the Past

4.Benchmarks of the Future –

No best, just better



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


Revisiting the Past


Revisiting the Past









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


Revisiting the Past


Revisiting the Past









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


Revisiting the Past


Revisiting the Past









•

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


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.

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

http://www.medarex.com/

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


Dilution

HCP < 1000 ng/mg

CEX

TFF

Q Membrane2 g/ml

Dilution

HCP < 1000 ng/mg

VF

Mix Mode


Dilution

HCP < 1000 ng/mg

CEX

TFF

Q Membrane2 g/ml

Dilution

HCP < 1000 ng/mg

VFVF

Mix Mode


Dilution

HCP < 1000 ng/mg

CEX HCP < 10ng/mg


Q Membrane20 g/ml


VF

HCP BDL

Dilution

CEX HCP < 10ng/mg


Q Membrane20 g/ml


VFVF

HCP BDL

Dilution

Two Birds –

one Stone: Contaminant Precipitation at Pfizer and Medarex



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


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


Revisiting the Past


Revisiting the Past









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!