Dave WoltonVP manufacturing

Large scale Mammalian plant design from 1980’s to present day

1

Overview

• CMC• Development of Large scale

Mammalian Monoclonal factories • 1985-1990• 1990-1995• 1995-2006• Present day

• Next Generation Factories• Impact of the new design on the rest of

the organisation• CMC prototyping of disposable harvest

systems• Summary

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CMC Biologics – Overview

Contract Manufacturer of Biological Therapeutics

utilizing MAMMALIAN & MICROBIAL CELL CULTURE TECHNOLOGIES

• Cell-line Development – CHEF1™ technology• Upstream/Downstream – process development and manufacture• Analysis, Characterization, Formulation, Quality and Regulatory

Target & Lead ID

Target & Lead ID

Pre-tox

Pre-tox

Tox Tox Phase I

Phase I

Phase II

Phase II

Phase III

Phase III

Commercial

Production

Commercial

Production

CMC Biologics

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Late 80’s

Development of Large scale Mammalian Monoclonal

factories

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Late 80’s

The dawn of automationSimple semi manual fermentorsValidation becoming more involvedContainment being actively pursuedCIP/SIP systems becoming more complicatedAutomation seen as reducing

Headcount, Turn-round timeOperator errors

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Early 90’s

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Early 90’s

Some companies begin to realise complex automation systems have drawbacks.

They see increasing HeadcountComplexity of plantTurn-round timesComplexity of investigations (variables)Facility build costsFacility construction times

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Additive manifold

Air Out

Air to headspace

Air to spargerJacket heat exchanger Sample device

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Early 90’s

Example of early 90’s Bioreactor

Late 90’s to 2006

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Late 90’s to 2006

Some companies start to reduce cost by simplifying.

Stainless steel reactors are simplified by reducing numbers of valves/items.

Disposables reduce the need for CIP/SIP.

InnovationsTubing weldersLynx valvesPod filtersWave reactorsSUM’s

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The fastest CIP?

Reduce the number of inlets that need cleaning.

How to simplify stainless vessels

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How to simplify stainless vessels

Additive manifolds

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How to simplify stainless vessels

Air Out

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How to simplify stainless vessels

Air To Head Space

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How to simplify stainless vessels

Air To Sparger

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How to simplify stainless vessels

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Pre Lynx Modifications

Approximately 70

Post Lynx modifications

Approximately 30

Number of sterile boundary elastomers

Present Day

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Single use bioreactors

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Present day

Elan’s plant design breaks new ground (2008).

Large scale disposables are widely accepted

2000L reactors are launched onto the market (2010)

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Next generation factories

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The Facility – the next generation of plant after élan

2g/l monoclonal antibody- fed batch

10 x 4,000L batches per month

80 cm column, 3 cycles

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= 2 x 12,000L stainless plant

The Facility – The next generation after Élan

Foot print Comparison

Media prep.Buffer prep.

Bioreactors.

Purification

XX

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The Facility – the next generation of plant after élan

How do you make media next to the bioreactor without contaminating the

room with powder?

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Contained media mixing – GEA

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Contained media mixing – Hyclone

Hyclone Powdertainer

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Contained media mixing - Lormac

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Use of Buffer towers in Downstream worked example

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The Facility – the next generation of plant after élan

How do you make and store up to 6,000L of buffer and not use large numbers of

buffer bags?

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AnswerBy positioning 2,000L buffer towers close to the column and

‘topping up’ from 1,000L single use mixers.

Buffer towers - Prototype

Prototype

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Buffer Modeling

Buffer storage in 1000L Buffer hold bags VS

Five 2,000L buffer towers; replaced monthly

Buffer b Adsorption chromatography buffer - Max 4,000L

Buffer a Ultrafiltration Diafiltration buffer – Max 6,000L

Buffer towers - worked example

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The Facility – the next generation of plant after élan

Buffer b

Buffer a

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Waste comparison example

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Impact of the new design on the organisation

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The Facility – the next generation of plant after élan

Cell Culture12 technicians – 9:00 to 5:30 – 7 days a week

Purification24-36 technicians – 24hr – 7 days a week

Buffer - Media0 technicians

HR1 manager – 1 admin.

QCNo change from current factories

Maintenance1 HVAC, 1 Utilities, 2 Equipment/Cal

Plant Automation0IT

3-4, Electronic batch records preferableStoresSame as current factories

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CMC prototyping of disposable harvest systems

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Integrated 500L depth filter system

500L

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Integrated 500L depth filter system

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Integrated 2000L depth filter system

2000L

Integration harvest hollow fibber into concentrated fed batch system

Connections for the harvest hollow fiber

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Summary

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Industry trends and expectations

Reduced production costs

Decreased capital investments

More flexible plants with faster turnaround time

Risk management and mitigation

Increased control over products, processes, timelines

Close cooperation, partnership, strategic alliances

Culture with a continuous improvements mindset

Source: www.contractpharma.com, article October 2010: Biotechnology Trends & Outsourcing, Lou Schmukler and John Korte, Pfizer Global Manufacturing

Reduced facility footprintS

ing

le u

se

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What next at CMC……..

Installation of 2000L disposable Bioreactor/Harvest

capacity in 2011

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