F l e x - F a c i l i t i e s disposables
Efficient, Flexible Facilities
for the 21st Century
by Howard L. Levine, Jan E. Lilja, Rick Stock, Hans Hummel, Susan Dana Jones
A
number of recent
improvements in the
engineering of high-titer
expression vectors, in
biopharmaceutical process
development, and in facility
construction have converged to present
new opportunities for cost-effective,
flexible, biomanufacturing facility
construction. The evolution of
requirements for biopharmaceutical
facilities is driven by globalization of
the biopharmaceutical industry, patent
expirations of several blockbuster
biopharmaceutical products, and the
increasing shift in new product
development away from blockbuster
drugs and toward more personalized,
niche products.
An increase in product approvals
(primarily monoclonal antibodies,
MAbs) and sales growth of 10% per
year for the past five years have
transformed the biopharmaceutical
industry almost exclusively into a
“monoclonal antibody industry.”
MAb-related products now represent
a significant portion of all
biopharmaceuticals approved to date
and are anticipated to continue to
drive future demand for
biopharmaceutical manufacturing
capacity (1–3). Further, as many early
MAb products come off patent, the
competition to develop and market
biosimilar versions of those products is
rapidly increasing (4).
Not only are biosimilar sales
expected to grow in the US and
European markets, but increasing
demand for access to affordable
biologic products in the emerging
markets of Brazil, Russia, India, and
China (BRIC) will also stimulate
Figure 1: Conceptual modular facility design showing module
installation inside an existing building shell (KeyPlants, www.keyplants.com)
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BioProcess International 10(11)s D ecember 2012
further growth in such sales. Coupled
with a desire for local production of
critical medicines, the anticipated
sales growth will lead to increasing
demand for manufacturing facilities
that can be installed and operated
within those countries. So the need is
clear for relatively simple but flexible
biomanufacturing facilities that can be
easily replicated in multiple locations.
Like all other biopharmaceutical
products, MAbs traditionally have
been manufactured in large facilities
with multiple fixed, stainless steel
bioreactors ranging in size from 100 L
to 20,000 L; fixed and inflexible
downstream processing space; and
complex piping for delivery of buffers
and media, product transport, and
cleaning of the large number of fixed
stainless steel tanks and other
equipment. Such facilities were often
Figure 2: Two-story modular facility design showing a lower process
floor and an upper utility floor (KeyPlants, www.keyplants.com)
Supplement
designed to produce a single product
each or for campaigning just a few
products. But a number of trends are
converging to create a demand for
smaller, more flexible, and costeffective manufacturing facility
options. Those trends include
dramatic increases in product titers
and yield, advancements and
availability of single-use technologies,
pressure to reduce health-care costs, a
desire (or in some cases requirement)
for local production, and increasing
focus on personalized medicine for
small niche markets.
Increasing Product Titers: One of
the most significant trends in
biomanufacturing over the past decade
has been a dramatic increase in
volumetric productivity for processes
based on mammalian cell culture,
particularly MAb expression.
Through development of improved,
engineered parental cell lines and
expression vectors, improved media
and feed compositions, and a more
robust ability to measure and control
bioreactor process conditions, several
groups have reported antibody titers of
10 g/L or higher in cell culture
supernatants (5–8). Combined with
improvements in downstream
processing, overall process yields of
1–3 g/L are now common.
Although such product titers and
yields are not yet routine, more and
more companies are achieving those
levels of productivity. So it is
reasonable to expect that most new
MAb manufacturing processes soon
will routinely reach productivities of
>5 g/L. High product titers coupled
with downstream process yields of
≥70% (9) will result in overall process
yields of >3 g/L for many MAb
products in development — and even
for those already on the market after
next generation processes are
implemented.
With those productivities, a
15,000-L bioreactor will produce
75 kg of drug substance per batch, and
a traditional “six-pack” facility
(incorporating six 15,000-L
bioreactors) could produce a metric ton
(1,000 kg) of product in just six weeks.
The largest currently marketed cell
culture–derived products require about
Supplement
one metric ton per year. So this is a
significant advancement over previous
levels of productivity and suggests that
future biomanufacturing facilities will
be built around fewer and smaller
bioreactors (e.g., two or three 2,000-L
to 5,000-L reactors). Although the
bioreactor scale will be reduced, those
facilities will yet require significant
downstream processing operations to
support purification of their bioreactor
output.
Single-Use Technologies
for Biomanufacturing
Over the past decade, single-use
process technologies have been
increasingly incorporated into the
manufacture of biopharmaceutical
products. Applications range from
Lonza’s use of GE Healthcare’s Wave
bioreactors in the inoculum train for
large-scale production bioreactors in
its Portsmouth, NH facility (10) to
Shire’s reliance on single-use
bioreactors and other disposable
technologies in the upstream portion
of its new ATLAS commercial
manufacturing facility (11, 12).
Companies are now considering
facility designs that incorporate
disposables at all stages of
manufacturing (13, 14).
Many forces are driving adoption
of such technologies in
biomanufacturing, particularly for
multiproduct facilities. Disposables
increase flexibility, reduce
requirements for expensive critical
utilities (e.g., water for injection, WFI,
and clean steam), decrease
requirements for equipment cleaning
and cleaning validation, lower capital
investments, and shorten facility
construction times (15, 16).
Although those reasons for
implementing single-use technologies
in biomanufacturing are compelling,
some challenges and concerns related
to their use remain. Disposables do
increase ongoing operating costs
associated with the purchase and
disposal of consumables. Leachable
and extractable substances from their
product-contact surfaces may
contaminate products. Sourcing
limitations are associated with
purchases of single-use equipment, for
which no consistent and uniform
standards yet cover the numerous
connectors required for installation
and use. And there is a current lack of
regulatory experience with many such
technologies.
Nevertheless, biopharmaceutical
manufacturers — ranging from small
start-up companies to large product
sponsors and CMOs — are
increasingly implementing disposables.
Single-use bioreactors are especially
popular in manufacturing
biopharmaceuticals both for clinical
trials and commercial sale.
Single-use bioreactors currently
come in volumes up to 2,000 L and
have been used to produce clinicaltrial material at 20-L to 2,000-L
scales. The earliest such technology
made widely available for use in
bioprocess applications was the Wave
Bioreactor system (now from GE
Healthcare Life Sciences in Uppsala,
Sweden), a self-contained disposable
bag with agitation/mixing provided by
an external platform rocker (17). After
that early attempt at a disposable
bioreactor, several companies
developed alternatives that resemble
the standard, cylindrical, stirred-tank
design that is already prevalent in the
biopharmaceutical industry’s installed
base of stainless steel bioreactors.
Examples include Xcellerex (now part
of GE Healthcare Life Sciences),
Thermo Scientific HyClone, and
Sartorius Stedim Biotech. For their
single-use bioreactors, a fixed support
containing process control software is
installed in a production facility, then
the disposable bioreactor is provided
as a bag that can be inserted into that
support structure (18). Agitation is
generally provided by an installed
impeller that is disposable like the bag
and attaches to a motor in the support
structure. Feeding, pH, and dissolved
oxygen (DO) are controlled through
installed ports and probes.
Several studies show that cell
culture processes and the critical
quality attributes of products made by
such processes are comparable in
single-use and stainless steel
bioreactors of the same size (19–21).
For example, Smelko, et al.
demonstrated that for high-intensity
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Photo 1: STR 1,000-L single-use bioreactor
system from Sartorius Stedim Biotech (www.
sartorius.com)
Chinese hamster ovary (CHO) or NS0
cell culture processes, product from
single-use bioreactors in standard
configuration up to the 1,000-L scale
is comparable by all biochemical
analyses to that from a 1,000-L
stainless steel bioreactor (22). In that
study, the seed train, harvest, and all
downstream processing steps were
performed using identical equipment
and methods, with the type of
bioreactor being the only difference.
Other disposable bioreactor systems
have been developed with new
geometries and mechanisms of cell
agitation, mixing, and control of
nutrients and pH. Marketed
bioreactors with square or rectangular
shapes from companies such as ATMI
Life Sciences have been shown to
support mammalian cell growth with
mixing characteristics and
productivities similar to those of more
conventional cylindrical geometries
(23). PBS Biotech has introduced
another design using an Air-Wheel
mixer driven by sparging gases (24).
An orbital shaker with ≤1,500-L
production volumes was also
introduced recently (25). When the
unit is operated at suitable speeds, its
geometry provides adequate mixing
and aeration without an impeller. Like
the single-use bioreactors of more
traditional design, these alternativegeometry types also consist of a fixed
support shell in which a disposable
bag is fitted for use.
For single-use bioreactors to realize
their full potential in
biomanufacturing, both users and
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BioProcess International 10(11)s D ecember 2012
Photo 2: Single-use bioreactor from PBS
Biotech (www.pbsbiotech.com)
suppliers have identified a number of
areas and opportunities for
improvement. They’ve pointed to the
need for better disposable sensor
elements, particularly those that can
maintain calibration over the extended
run times of today’s high-performance
cell culture processes (26). Other
potential improvements include larger
transfer ports to facilitate harvesting
and large-volume transfers and
improved construction of disposable
bags to reduce leakage failure rates.
That last issue is of great concern
to companies implementing single-use
bioreactors because bag leaks can
result in costly losses during
production runs. To help address this
problem, ATMI recently introduced a
new test system as part of its release
criteria for disposable bags to confirm
their integrity before they are shipped
to customers (27). The test method
involves flooding a fully assembled
single-use bioreactor with helium and
noting any escape of the gas with
specialized sensors mounted on the
exterior of the bag. ATMI claims that
this method can detect holes as small
as 10 µm, making the technique much
more sensitive than other bag leakage
tests.
All those and many other
innovations in development are certain
to continue improving single-use
bioreactors and facilitate their
implementation in the future.
Single-Use Technologies for
Downstream Processing: Development
of single-use downstream processing
products for effective and economical
Photo 3: Disposable Opus column from
Repligen Corporation (www.repligen.com)
operation at clinical or commercialmanufacturing scales has lagged
behind that of disposable bioreactors.
But recent significant efforts on the
part of both established and new
suppliers of bioprocess equipment and
separations products have brought
about a wide range of scalable, singleuse products for downstream
processing.
For clarification, multiple vendors
now offer disposable depth filters at
multiple scales. So biomanufacturers
can choose between multiuse stainless
steel housings for conventional depth
filters or single-use depth filter
cassettes with disposable productcontact surfaces for clarification
operations. Many commonly used
depth-filter media from different
suppliers are now available in both
conventional and single-use formats
(28, 29).
Similarly, the first single-use
cassettes for cross-flow filtration
applications became available in the
past decade and are now widely used
in biomanufacturing. In addition,
“single-pass ultrafiltration” systems are
in development. They allow for
tangential-flow concentration and
diafiltration without recirculating the
retentate solution. The approach could
be converted to a disposable format in
the future.
One of the most challenging unit
operations to convert to single-use
technologies has been
chromatography, which is the heart of
most biopharmaceutical purification
processes. Several suppliers now offer
prepacked chromatography columns in
plastic or low-cost glass housings.
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They are designed to be discarded
after one or more cycles, but because
of the high cost of chromatography
media, some manufacturers choose to
use them for a campaign of several
batches rather than disposing of a
column after one run.
Although that provides a workable
solution up to a certain scale, some
practical limitations may prevent the
use of disposable chromatography
columns at very large scales. To
circumvent those limitations, several
companies are developing continuous
chromatography technologies such as
simulated moving bed (SMB) to
reduce the scale and capital cost of
chromatography columns and systems
needed for downstream processing. At
least one company, Tarpon
Biosystems, is establishing SMB with
a fully disposable flow path (30). As
with other continuous processes, SMB
is inherently more scale-efficient. So
more material can be purified with
such technology using current-scale
disposable chromatography columns
than would be possible using
conventional batch operations.
As an alternative to column
chromatography, membrane adsorbers
are already widely used for flowthrough applications, in which a
product of interest flows through
while impurities remain bound to the
column. A common application is the
use of anion-exchange membrane
adsorbers for clearance of nucleic acids
or host-cell proteins in MAb processes
(31). Unfortunately, current membrane
adsorbers lack the capacity of column
media for chromatography steps in
which the product binds to the
medium (so-called “capture” steps). So
the industry needs new membrane
adsorber technology that provides
robust, scalable, high-capacity
membrane adsorbers before these
devices can be used widely in
commercial-scale biopharmaceutical
“capture” applications.
The use of disposable bioreactors
and downstream processing products
will continue to increase well into the
coming decade, becoming routine for
production of both clinical trial
materials and commercial products. In
a recent analysis of the economic
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Table 1: Estimated facility costs for a 1,000-L bioreactor facility
Construction Time
Total Facility Area
Total Process Area
Class C area
Class D area
CNC area
Piping Length
Total Equipment Cost
Process Equipment Cost
Stainless Steel Facility
16 months
12,153 ft2
6,372 ft2
1,109 ft2
5,231 ft2
0 ft2
2,854 ft2
€17.3 million
€4 million
aspects of single-use systems for
biopharmaceutical and vaccine
manufacturing, one conference
presenter concluded in 2010 that
although they are more economical for
manufacturing at production scales
roughly <8,000 L, above that level
conventional stainless steel systems
become economically more attractive
(32). Given that and the high efficiency
of modern biomanufacturing processes,
future facilities will predominantly
incorporate multiple single-use
bioreactors of 2,000 L or smaller (13).
For those few products that require
larger production volumes, commercial
manufacturing using traditional
stainless steel bioreactors will continue,
especially as a way to use the existing
large installed base of such
manufacturing capacity.
Modular Biopharmaceutical
Manufacturing Facilities
In a recent discussion of nextgeneration manufacturing facilities, an
author argued that biomanufacturing
facilities can be divided into process,
facility, and infrastructure components
(33). Each plays a significant role in
the success of a manufacturing
enterprise. A failure or weakness in
any one will lead to poor product
quality and/or inefficient
manufacturing. Improvements in
manufacturing technologies and
advancements in single use systems
have clearly transformed bioprocesses.
Hand in hand with those process
improvements comes modular
construction, which has been around
for decades. It will become more and
more common because modular
alternatives can have smaller
footprints than traditional facilities
and be built rapidly in locations where
Single-Use Facility
14 months
745 ft2
6,781 ft2
667 ft2
3,315 ft2
2,745 ft2
886 ft2
€15.0 million
€3 million
cleanroom and piping expertise may
not be readily available.
Together, modular technology and
single-use technologies can reduce
investment and operating costs as well
as potential financial risk for new
biopharmaceutical manufacturing
facilities (34). Table 1 describes an
example of the economic benefits that
could come from combining the
previous-generation modular facility
construction combined with
disposables. As we will show in a
future article, the current generation
of modular construction and design
technology (along with further
advances in single-use technologies)
could lower capital and operating costs
even further while enabling
construction of comparable facilities in
under 12 months.
In Table 1’s preliminary study, the
use of disposables reduced labor costs
by about 30%, although raw materials
costs were almost 20% higher for the
single-use facility. The result is a net
savings for each manufacturing
campaign of about 10%. Additional
savings in operating costs are also
achieved through elimination of
column packing and elastomer
change-outs as well as lowered
validation, calibration, and equipment
preparation requirements. Overall
batch processing time is shorter in the
single-use facility, further improving
process economics through an
increased number of batches that
could be produced there.
As the example shows, modular
construction offers advantages such as
improved quality, increased flexibility,
and (perhaps most important) more
cost-effective construction. Modular
construction generally requires a more
modest up-front capital investment
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Photos 4: A modular facility shown during construction (left) and in full operation (right)
(KeyPlants, www.keyplants.com)
Figure 3: Standard monoclonal antibody platform manufacturing process
µM Rating
2 0.65 0.2
N-3
20 L
Protein A
Column
N-2
100 L
N-1
750 L
Depth
Filtration
Harvest Hold
Tank 2,000 L
CIEX Column
Virus
Inactivation,
pH Adjustment
than do traditional facilities. Each
module making up the final facility
can be fabricated at a company that is
highly familiar with the unique
requirements of biopharmaceutical
facility construction. And much of the
fixed equipment can be installed and
tested at that manufacturing site
before the fully assembled modules are
shipped to an intended manufacturing
site. That minimizes technical and
regulatory challenges that come with
using traditional building strategies to
construct an entire facility on site. A
modular facility can be moved easily if
necessary after its initial installation
— or readily expanded as needed.
Looking Back: Modularization is a
type of outsourcing that involves
moving some construction work from
an actual facility location to a different
site, whether domestic or
international. Varying degrees of
modularization always have been
common in biopharmaceutical facility
design. For example, many
biomanufacturing unit operations
involve process skids, on which
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Production
2,000 L
BioProcess International 10(11)s D ecember 2012
AIEX
Membrane
Nanofiltration
equipment is mounted and moved into
and out of a production cleanroom
area. In addition, equipment modules
are used to divide up the work load or
reduce potentially invasive
construction during retrofits. Both
strategies allow complex, processrelated equipment to be constructed in
a controlled environment before being
installed in an actual facility.
In addition, construction and
installation of complete modular
production facilities for pharmaceuticals
and biopharmaceuticals has been widely
accepted. More than 70 such modular
facilities have been built worldwide
since 1986. One pioneer in such
construction was Pharmadule, a
Swedish company that is now out of
business. Many of the assets and key
personnel of that company, however, are
now part of KeyPlants in Stockholm,
Sweden. Other companies that offer
modular facility construction include
Biologics Modular of Brownsburg, IN
(www.biologicsmodular.com) and
G-Con of College Station, TX (www.
gconbio.com).
Some traditional bioprocess
equipment suppliers such as GE
Healthcare Life Sciences, Sartorius
Stedim Biotech (SSB), NNEPharmaplan, and Merck Millipore
have begun to offer fully equipped
modular facilities. Through its
Enterprise Solutions group, GE
provides fully assembled, qualified,
and ready-to-run KUBio module
facilities equipped with GE
equipment. Similarly, SSB offers a
G-Con FlexMoSys modular
cleanroom facility equipped with SSB
single-use systems and standardized
hardware.
They are attractive and appropriate
for simple installations, but such
prepackaged modular facilities have
some limitations. The KUBio system,
for example, comes only in a standalone facility design and uses GE
process equipment exclusively, which
limits flexibility and choice in design
and precludes its installation within an
existing building shell. A FlexMoSys
facility, on the other hand, comes in
both indoor and outdoor versions, so it
can be used either as a stand-alone
facility or installed inside an existing
shell. The G-Con system does not use
SSB equipment exclusively, so users do
have some choice in process equipment.
However, the current FlexMoSys
design does not accommodate
bioreactors >1,000 L. Another
drawback to all prepackaged modular
facilities currently available is that they
are designed for bulk manufacturing
only, without accommodations for fill–
finish operations.
Looking Forward: KeyPlants has
developed an innovative approach to
modular facility design and
construction that is flexible and cost
efficient, and it allows for the use of
process equipment from all suppliers.
Compared with the above options, the
flexibility of this design allows
installation of any size bioreactors
from any vendor and provides greater
flexibility in the layout and design of
both upstream and downstream
process areas. Modules can be
installed and operated within an
existing building or as a separate
modular building as long as suitable
power sources are available.
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Additionally, the KeyPlants design
can incorporate both bulk drug
manufacturing and fill–finish
operations into a single plant design.
Generally, the more efficient
project execution resulting from
modular design and construction can
significantly reduce time to market,
which increases the net present value
(NPV) and return on investment
(RoI) for a new facility. In a future
article, we will compare and contrast
the costs and economic implications of
modular and traditional facility
designs in more detail. Companies
should consider the time and risk
factors involved in facility construction
as well as more obvious factors such as
capital and engineering costs. When
exploring those economics, it is
important to include such variable
costs such as that of architectural,
engineering, and construction
management services; interest rates on
applied capital; and risk of delays in
facility construction. Those variables
are common in traditional
construction but less so in modular
facilities. The latter approach provides
the best capital efficiency by ensuring
that investments are made only in the
minimal-scope options.
The key to modular design is its
integration with the manufacturing
process and division of that process
into key functional modules that can
be replicated throughout a facility,
which allows for standardization.
KeyPlants has prepared such a
standard design for a MAb
manufacturing facility based on a
typical platform process (Figure 3).
The process design is based on a
2,000-L single-use bioreactor, with a
typical inoculum train and
downstream process (35). It further
incorporates disposable prepacked
chromatography columns; single-use
membrane adsorbers; bags for buffers,
media, and product intermediate
storage; and maximum use of
disposable filters and other process
components. To minimize the cost of
the prepacked columns — especially
for the Protein A affinity
chromatography step — column
recycling is incorporated for each
manufacturing batch.
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Photo 5: Process equipment in place in a modular facility (KeyPlants, www.keyplants.com)
Using that standard platform
process as a basis for design,
prefabrication and fabrication of the
individual process modules is
simplified and variability is minimized
in construction time and project
execution. For modular construction
using such a standardized design,
75–80% of the total construction
process takes place at the modular
facility company’s factory, with the
remaining 20–25% of construction
activities being performed at a final
facility site, which greatly reduces site
congestion while increasing safety.
Consequently, the overall modularconstruction approach significantly
mitigates the inherent risk of
construction, installation, and
validation.
One primary difference in today’s
modular facilities compared with
previous approaches is that they
include all necessary functionality and
equipment required for a
biopharmaceutical facility. The
modular facility can be delivered as a
free-standing building (façade and
roofing included) or as indoor
modules for installation into an
existing building or prefabricated
shell. A modular building (whether
indoor or outdoor) comprises
prefabricated structural modules.
Their structural design meets relevant
codes (for the European Union,
United States, and others), including
earthquake requirements if required.
To ensure full compliance with
global regulatory standards and
expectations, the floors of individual
modules are made of reinforced
concrete or metal sheet plates with
PVC or epoxy coatings. Cleanrooms
for product processing activities are
constructed using a panel system, with
integrated walls, ceilings, doors,
windows, and so on. The cleanroom
design includes walkable ceilings with
adequate space for air-handling
equipment, ductwork and piping, and
electrical distribution, as well as
service access and maintenance from
above. The same design is used in
isolated rooms for electrical supply,
plant utilities, and clean utilities. By
locating all support systems (electrical;
piping; heating, ventilation, and air
conditioning, HVAC; and so on) in
easily accessible space above the
cleanrooms, each prefabricated module
will integrate distribution of such
systems, with only one hook-up
required at the facility site. This
ensures a true “plug-and-play” design
and minimal installation work.
Sustainability: One key advantage to
modular buildings is that they typically
include features that qualify them for
LEED (Leadership in Energy and
Environmental Design) certification
(36). Leveraging factory build processes
and more efficient supply lines, a
modular facility can take significantly
fewer resources to construct and deploy
than a site-constructed, purpose-built
facility would.
Incorporating single-use process
technologies into a modular biotech
facility could further add to its
benefits. Rawlings and Pora have
shown that a facility based on singleD ecember 2012
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BioProcess International 7
use technology is about 50% less
energy intensive than one based on
stainless steel systems because the
consumption and heating of large
volumes of water to clean and sterilize
reusable equipment is more energy
demanding than producing and
disposing of plastic bags that can also
be incinerated for energy recovery (37).
Hodge has estimated that
incorporating single-use technologies
in a modern facility can result in an
about 85% reduction in water usage
and waste compared to a traditional
stainless steel facility (38). However,
the savings resulting from this
reduction in water usage and waste is
partially offset by the cost of disposing
the approximately three-fold increase
in solid waste, primarily plastic from
the disposable bags and bioreactors,
generated by the single-use facility.
Studies by Mauter (39) and
Pietrzykowski, et al. (40) have recently
shown that the overall impact of singleuse technologies on waste flow — and
environmental impact — are
minimized over the entire life-cycle of
such technologies. For example,
Pietrzykowski, et al. showed that over
the full life cycle of production, the
cumulative energy demand (CED) and
global warming potential (GWP) for
MAb production in single-use systems
is 34% and 32% of CED and GWP for
a stainless steel facility, respectively (40).
Taking into account all of that and
the markedly increased yields of
modern, high-titer processes, it
becomes evident that a nextgeneration facility incorporating
single-use technologies will have a
significantly smaller carbon footprint
per kilogram of monoclonal antibody
produced than would a traditional
manufacturing facility using stainless
steel systems.
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Supplement
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Corresponding author Howard L. Levine is
founder, president, and principal consultant
of BioProcess Technology Consultants, Inc.,
as well as founder and chief operating
officer of Biocrescentia LLC (12 Gill Street,
Suite 5450, Woburn, MA 01801-1728; 1-781281-2701; [email protected]). Jan Lilja is
commercial director of KeyPlants AB; Rick
Stock is a consultant for BioProcess
Technology Consultants, Inc.; Hans
Hummel is business development director
at KeyPlants AB; and Susan Dana Jones is
vice president and senior consultant of
BioProcess Technology Consultants, Inc.
To order reprints of this article, contact
Claudia Stachowiak of Foster Printing Service,
1-866-879-9133 x121, claudias@fosterprinting.
com. Download a low-resolution PDF online
at www.bioprocessintl.com.
Supplement
D ecember 2012
10(11)s
BioProcess International 9