‘Using disposable single-use systems
for high volume manufacturing’
Gerald Kierans
Director, Technical Services - Pfizer Global Supply
May 22th, 2014
Disposable Single Use Technologies
Overview

Established as part of bio-manufacturing tool-kit

Promises high productivity, multi-product production in clean,
contained systems

Demands of high volume cGMP manufacturing require further
industrialisation of the available technologies.
1
Content

Pfizer Global Supply, Grange Castle – Background

The Evolution of Disposable Technology for Biotech

The Challenges – ‘the Opportunities’

Understand your Supply Chain

What could the Future look like ?
2
High Volume Biopharmaceutical Manufacturing
Pfizer Global Supply
Grange Castle Site, Dublin
Over 900 FTEs
‘3 Factories in 1’ :
Mammalian Cell Culture
Conjugation/Pegylation
Parenterals Filling
3
The Commercial Products We Supply
Commercial cGMP Context
Large, existing highly automated stainless steel plant
Typically using disposable single use systems to
debottleneck facility, rather than as the fundamental
design principle.
Disposable single use technology are a very significant
cost => implications for fully disposable strategy?
Our context
High Volume Manufacture
=
Zero Tolerance for Defects
5
Content

Pfizer Global Supply, Grange Castle – Background

The Evolution of Disposable Technology for Biotech

The Challenges – ‘the Opportunities’

Understand your Supply Chain

What could the Future look like ?
6
Single Use Technology Evolution
Traditional plasma
fractionation &
vaccine manufacturing
Recombinant
human insulin
Recombinant
DNA technology
SINGLE-USE
DISPOSABLE TECH
EVOLUTION
1970s
Approval of
leading biotech
products
Commercial
biotech start-ups
1980s
Cell culture
capacity
crunch
1990s
CMOs adopt
disposables
Pandemic
virus response
drives rapid
capacity solutions
2000s
Tube welding
Early adopters of
hospital bag
technology
for solution storage
Cell culture
titre
increases
Proliferation
of major new
biotech facilities
around globe
2010s
Aseptic connectors
Initial ‘Plastic
Factory’ concepts
γ - capsule
filters
Vendors produce
‘standard’ disposable
System designs
Single-use
sensor technology
77
Single Use Technology Benefits
Contained,
Dedicated
Fluid Paths
Lower
Capex
Single Use
Technologies Proposed Benefits
Increased Plant
Production
Time
Pre-Sterilised
Components
Reduced
Engineering
Complexity
Near
‘Off-the-Shelf’
designs
8
Disposables - Success & Future Potential
Plastic Plants have moved from Paper to Reality
Semi-auto system
designs
Enabling ‘disruptive’
facility designs
9
Content

Pfizer Global Supply, Grange Castle – Background

The Evolution of Disposable Technology for Biotech

The Challenges – ‘the Opportunities’

Understand your Supply Chain

What could the Future look like ?
10
Issues to be addressed …..
Polymer assemblies
can be fragile
and potentially
leak / break
Leak from aseptic
sampler
Tie-wrap connection between different tubing types
- leak only evident under back-pressure
11
Issues to be addressed …..
Many engineering
Polymers are weakened
by Gamma-irradiation
eg. PTFE
Ideally looking for
Cheap
Accurate
Clean
Robust
Gamma Irradiatable
Instrumentation at
multiple scales
Limited
availability of robust,
gamma-irradiatable
sensor technology
Some components
coming from Medical
Device technology
Generally do a lot of
testing off-line –
more intervention
Limited scalability
of current
instrumentation
Difficult to design
standardised SU systems
if key components do
not exist yet.
One strategy – do as much
as possible off-line or tube-weld
on what you want
(Not an optimal strategy for high
volume manufacturing)
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Issues to be addressed …..
What is an acceptable
level of particles ?
Swab of internal particles
from disposable components
Polycarbonate alien
particle found in a product
sample bag
cGMP requirement for
zero contaminants
Various different particles identified –
some are constituent materials of the assembly
Sometimes they are not !
Regular disconnect between
vendor particle specification
and GMP quality requirement.
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Issues to be addressed …..
Highly complex assemblies
Outsourced aseptic
and material
control
Typically custom designed
Manually assembled
Infrequent, low volume batch runs
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Issues to be addressed …..
Polymer assemblies
can be fragile
and potentially
leak / break
Limited
availability of robust,
gamma-irradiatable
sensor technology
What is the acceptable
level of particles ?
Low volume, manual
production runs
Outsourced aseptic
and material
control
‘What about L&E ?’
…and cost !
15
Content

Pfizer Global Supply, Grange Castle – Background

The Evolution of Disposable Technology for Biotech

The Challenges – ‘the Opportunities’

Understand your Supply Chain

What could the Future look like ?
16
Impact of Material Variability –
A Cautionary Tale ...
Cell culture performance issues for a number of years impacting
certain cell lines at a number of companies using a specific type
of disposable bioreactor.
‘What about L&E ?’
Industry initiative through BPOG to address issue.
A leachate has been identified which is breakdown product
of a common polymer antioxidant.
Additional cell culture issues have been observed using other
single use materials; however the mechanism is not necessarily
understood.
Bis(2,4-di-tert-butylphenyl) phosphate
(CAS 21150-89-0)
bDtBPP – ‘the Two-Arm Bandit’
Identification of a Leachable Compound Detrimental to Cell Growth in
Single-Use Bioprocess Containers - PDA Journal of Pharmaceutical Science
and Technology March/April 2013 vol. 67 no. 2 123-134
Matthew Hammond, Heather Nunn, Gary Rogers, Hans Lee,
Anatolia-Liliana Marghitoiu, Lourdes Perez, Yasser Nashed-Samuel,
Carl Anderson, Michael Vandiver and Sally Kline
Strategy for Selecting Disposable Bags for Cell Culture Media
Applications Based on a Root-Cause Investigation
Joseph Wood, Ekta Mahajan, Masaru Shiratori
`Biotechnology Progress DOI 10.1002/btpr.1802
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Know Your Supply Chain
Antioxidants
Slip Agents
Lubricants
Thermal &
Mechanical
Stress
Thermal &
Mechanical
Stress
Polymer Resin
Compounding
Film
Extrusion
Potential
Mechanical
Stress thru
Handling
Bag
Manufacture
Components
Connectology
Tubing
Capsule Filters
Aseptic Connectors
Sensors
Sub-assemblies
Tube Weld
Tie-Wrap
Mouldings
Hose-barbs
Assembly
Irradiation
Stress
Gamma
Irradiation
Potential
Mechanical
Stress thru
Handling
Delivery &
Storage
Potential to
impact Quality at
multiple nodes
across a long
supply chain
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Content

Pfizer Global Supply, Grange Castle – Background

The Evolution of Disposable Technology for Biotech

The Challenges – ‘the Opportunities’

Understand your Supply Chain

What could the Future look like ?
19
Disposable System Engineering


Huge investment by Vendors and Pharma Engineering functions
How reliable and proven are these solutions for high volume
manufacturing? Requires upfront investment off the ‘critical path’
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Plastic Mab Factory of the Future
Monoclonals continue to be the largest pipeline of prospective biological drug candidates for the future.
Generally standardised production concepts – similar unit operations across industry
‘Higher cell culture titres enabling 100kgs production per year in 100Ls bioreactors’
Disposable
rocking or STR
reactors
Harvest by
Depth Filter
Virus Removal
Filtration by
Capsules
Capture by
Chromatography
Formulation by
UFDF
Polishing by
Flow-thru
Membrane
Absorber
Sterile Capsule
Filtration
& Biobag Storage
‘Continuous production paradigms may enable a further step change in COGs’
Goal :
New capital
plants could
avoid
SIP/CIP/scale
complexity
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The Takeaway

Single use disposable technology promises additional
potential to shape the future of bio-manufacturing.

We all need to step up in terms of our application knowledge.
 Vendors
 End-Users

We need to share our challenges and probably the solutions.
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Discussion