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Developments in facility design
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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
2
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
41
What next at CMC……..
Installation of 2000L disposable Bioreactor/Harvest
capacity in 2011
42