SUPPLEMENT 40 BioProcess International 11(4)s APRIL 2013

D I S P O S A B L E S REWARDS
Single-Use Technology
and Modular Construction
Enabling Biopharmaceutical Facilities of the Future
Howard L. Levine, Rick Stock, Jan E. Lilja, sa Gaasvik, Hans Hummel,
Thomas C. Ransohoff, and Susan Dana Jones
T
o enable broad, global access to
life-saving biopharmaceutical
products, our industry is facing
significant pressure to reduce the
overall cost of manufacturing and enable
local manufacturing where possible.
Combined with growing markets
outside the United States and Europe
and development of high-titer, high-
yield processes, that pressure has led to a
shift in the industrys approach to
facility design and construction. Todays
biopharmaceutical production facilities
must be flexible, cost effective, and
readily constructed with minimal capital
investment and construction timelines.
As available single-use products for
biopharmaceutical manufacturing have
advanced and modular facility design
and construction have improved, the
industry has developed modular, flexible
biomanufacturing facilities that can be
easily replicated in multiple locations.
We discussed advantages of
combining single-use technologies with
modular construction in the first of
this three-part series (1). Here we
present an economic model for a
typical monoclonal antibody (MAb)
platform production process along with
a detailed comparison of the operating
costs for that process in facilities
designed and built using either
conventional reusable stainless steel
equipment or single-use technologies to
the maximum extent possible. We also
discuss general concepts and design
features for a standard facility designed
to produce commercial MAb quantities
using the platform process.
DESIGN BASIS OVERVIEW
Our conceptual facility design and
economic analysis is based on the
MAb platform process outlined in
Figure 1. We based our cost analysis
on a cost-of-goods (CoG) model
performed using the industry-standard
BioSolve cost-modeling software,
version 4.0, available from Biopharm
Services Ltd. (2).
The upstream portion of this
platform process begins with cell
expansion from a vial of the working
cell bank (WCB), cultured through a
series of T flasks, shaker flasks, and
small-scale bioreactors up to 500 L,
followed by product production and
accumulation in a 2,000-L bioreactor.
The facility design allows for
installation of bioreactors from any
Figure 1: Standard monoclonal antibody platform manufacturing process
N 3
20 L
N 2
100 L
N 1
750 L
Production
2,000 L
WCB
Vial
Flasks
Depth Filtration
Harvest Hold Bag
2,000 L
Protein A
Virus Inactivation
and pH
Adjustment
Cation
Exchange
Anion-Exchange
Membrane
Bufer Exchange
Nanofltration Hold
Concentration
Bulk Fill
Bulk
Formulation
2.00
m
0.65
m
0.20
m
Author Insights Exclusive App-only Content
SUPPLEMENT APRIL 2013 11(4)S BioProcess International
41
manufacturer(s). After cell growth and
protein production in the 2,000-L
bioreactor, its contents are clarified
through a combination of depth
filtration and membrane filtration unit
operations to yield a clarified cell culture
harvest containing crude MAb product.
That product is then purified from
the clarified harvest using a three-
column purification process including
protein A affinity chromatography,
cation-exchange (CEX)
chromatography, and anion-exchange
(AEX) chromatography. A low-pH
virus inactivation step follows the
protein A column. A nanofiltration
step follows chromatography for
additional viral clearance, after which
purified MAb product is concentrated
and formulated by a combination of
ultrafiltration and diafiltration (UF/
DF) to produce the final purified and
formulated bulk product.
That purified, formulated bulk
MAb will be filled into standard
10-mL glass vials in a separate drug-
product manufacturing process.
Assuming a high-expression cell line
producing 5 g MAb per liter of
bioreactor harvest with industry-
standard purification yields (3), this
standard platform process should
produce about 7 kg of purified bulk
MAb product per batch. That will be
filled into about 60,000 vials.
FACILITY DESIGN PARAMETERS
Using the platform process described
above, we modeled two different
facilities for MAb production.
Although we refer to it as the stainless
steel facility, the first consists of a hybrid
design in which all seed and production
bioreactors as well as mixing vessels for
buffer and media preparation are
reusable stainless steel vessels. But
disposable bags (2,000 L) are used for
storage of media, buffers, and product
intermediates. Each disposable plastic
bag used in those applications is held in
a portable, stainless steel system
designed to hold bags of a desired
volume. Systems used for product and
intermediate storage were also
equipped with disposable mixing
systems (where appropriate) to keep the
product well mixed. Single-use mixing
systems typically involve a magnetic or
mechanical external drive with a
disposable impeller inside the bag.
The second facility, referred to as
the single-use facility, is equipped with
disposable seed and production
bioreactors. In addition, all media and
buffers are prepared in single-use bag
systems consisting of powder transfer
bags, disposable bags with a disposable
internal agitators, external mixing
systems, a weighing station, and a
disposable path (pump, tubing, filters,
and so on) for transfer of prepared
media or buffers into another
disposable bag system for storage.
When necessary, buffers would be
prepared in concentrated solutions to
accommodate transport in disposable
bags at a maximum volume of 500 L,
which is a typical volume limitation for
longer-distance transport within a
facility. In-line dilution skids are placed
at point of use for concentrated buffers.
Media in both facilities are made at
the start of each production batch.
Similarly, buffers in each facility are
prepared in advance and stored within
the facility until needed. A new batch
of media or buffer would be prepared
for each production batch. Table 1
details the number and type of vessels
used for cell culture production, media
and buffer preparation, and storage in
each model facility.
We used traditional equipment in
both models for all recovery and
downstream process (DSP) unit
operations. Each chromatography step
included in the purification process uses
63-cm diameter columns packed to
20-cm bed heights, with each column
being used for multiple cycles per batch.
For the protein A affinity column, five
cycles are required per batch. The CEX
column uses three cycles per batch, and
the AEX column uses two. We set the
titer for both production reactors at 5
g/L, with an overall yield of purified
bulk MAb at 70%.
The total time required for the cell
culture portion of this MAb process is
about 32 days from thawing of a
WCB vial to the production cultures
end, with a 15-day residence time in the
production bioreactor (Table 2). In the
stainless steel case, an additional three
to four days are required at the end of
the production process for bioreactor
cleaning and resterilization, making the
production bioreactor a rate-limiting
step for the overall process. Although
the turn-around time for a single-use
bioreactor is not instantaneous, it is
much shorter (typically no more than
one day) because it involves simply
removing a used bioreactor and
replacing it with a new one.
PROCESS ECONOMIC ANALYSIS
Taking into account the bioreactor
process time and that required to clean
and resterilize a stainless steel bioreactor,
total turn-around time for a stainless
steel production bioreactor can be two
weeks or more. So our facility model is
based on the maximum number of
stainless steel bioreactor runs possible in
a year. Assuming an annual two-week
facility shut-down, about 90% use of
production bioreactor capacity, and one
failed batch per year, a facility based on
stainless steel bioreactors could complete
15 batches each year.
To properly compare the cost and
output of our model single-use facility
with those of the stainless steel model,
we fixed the number of batches in the
former at 15 MAb batches per year. In
reality, the shorter turn-around time
for single-use bioreactors could allow
production of about 19 batches per
year, which increases the productivity
of a single-use facility and lowers its
overall operating costs per batch.
Based on the standard platform
process described above with 15
successful product batches each year,
Table 3 compares estimated operating
costs for the two model facilities.
Materials include the cost of cell
culture media, buffer components,
Table 1: Number and size of tanks required
for media and buffer preparation and storage
Stainless
Steel Facility
Single-Use
Facility
Disposable
bioreactors
0 1 20 L
1 100 L
1 500 L
1 2,000 L
Media
preparation
tanks
1 1,500 L
1 500 L
1 50 L
1 1,500 L
1 500 L
1 50 L
Buffer
preparation
tanks
5 500 L
2 200 L
1 50 L
5 500 L
1 200 L
1 50 L
Media hold
vessels (both
facilities)
1 20 L
2 50 L
1 100 L
1 500 L
1 1,500 L
Buffer hold
vessels (both
facilities)
2 25 L
2 200 L
13 500 L
SUPPLEMENT 42 BioProcess International 11(4)s APRIL 2013
process water (PW), and water for
injection (WFI). Prices are based on
catalog prices for standard,
commercially available versions with
anticipated volume discounts.
Consumables in our model
include such items as
filters preparing buffers and cell
culture media as well as filtering
intermediates during production
disposable bags preparing and
storing cell culture media, buffers,
product intermediates, and final product
disposable bioreactors
ultrafiltration membranes used for
UF/DF
chromatography media used in
the two column-chromatography steps
membrane adsorbers used for the
final polishing step in the process.
For those consumables, we used the
average price for each item based on
standard pricing from different
vendors, again allowing for volume
discounts. And we used the amortized
cost of chromatography media, taking
into account the number of cycles for
which each column would be used
before being repacked.
Labor costs are based on average
US labor rates for operators,
supervisors, and quality assurance and
control (QA/QC) staff in the New
England area. Maintenance costs
include stocking spare parts and labor
associated with equipment upkeep as
well as the overall cost of maintaining
a facility in a clean and GMP-ready
condition. Utility costs include
electricity to operate a facility as well
as the cost of natural gas required for
heating and steam generation. All
costs associated with handling and
disposal of contaminated and
uncontaminated aqueous and solid
waste are included under Waste,
along with the cost associated with
disposing of plastic bags and other
single-use components.
With both facilities producing the
same number of batches using the
same production process, each is
capable of making 7 kg MAb per
batch for a total of 105 kg of bulk
MAb per year. The cost advantage of
using disposable bioreactors, however,
is evident in about 22% savings in
total operating cost per batch for a
single-use facility compared with a
stainless steel facility. Comparing
detailed costs for different components
of the overall manufacturing costs for
these two model facilities, those
associated with materials, labor, and
maintenance/utilities/waste for the
single-use facility are lower than those
for the stainless steel facility, but the
consumables cost is higher.
Material cost savings for the single-
use facility are driven primarily by
savings associated with eliminating
bioreactor cleaning and sterilization. A
single-use facility also eliminates PW,
WFI, and chemicals such as
phosphoric acid and sodium hydroxide
for cleaning stainless steel bioreactors,
which generates a significant cost
savings. That comes primarily from the
different size and types of PW and
WFI systems needed for each facility.
In the single-use facility, a relatively
small but rapid water generation source
is required rather than the slower but
much larger system for the stainless
steel facility, and the water system must
produce less water overall. But if the
single-use facility were to run at its
maximum capacity, it would require a
faster water-generation rate than would
the stainless steel facility because of the
shorter duration of each batch. So the
PW and WFI systems in the single-use
facility actually would be more
expensive per liter of water produced.
The consumables cost difference for
these two model facilities is entirely
attributable to the cost of disposable
bags. Single-use systems for media and
buffer preparation and storage in
addition to the disposable bioreactor
bag systems used in cell culture for
each batch of monoclonal antibody
yield about $40,000 higher consumable
costs per batch for the single-use
facility. That includes the cost of bags
used in an assumed one failed batch per
year, then spread out over the 15
successful runs. If the single-use facility
runs at maximum capacity (limited to
one failed batch per year), then the cost
of disposable bag systems per gram of
product produced would be lower.
The lower maintenance/utilities/
waste costs for the single-use facility are
primarily attributable to elimination of
maintenance costs associated with
stainless steel bioreactors. Also, about
20% of the cost savings in this category
come from reduced use of clean steam
and power for cleaning and sterilizing
those bioreactors. Of note is the almost
negligible cost difference for waste
disposal between these two model
facilities. Thats because the cost of
disposing larger amounts of solid waste
associated with a single-use facility is
offset by the disposal cost of the larger
quantities of liquid waste generated by
the stainless steel facility.
Those results are consistent with a
comprehensive study of the
environmental impact of single-use
systems, which showed significant
reductions in energy demand and water
use for media preparation and buffer
preparation as well as cell culture in a
single-use facility compared with a
stainless steel facility (4, 5). Rawlings and
Pora concluded that a single-use facility
is about 50% less energy intensive due to
significantly lower consumption of
energy otherwise required to heat large
volumes of water for cleaning and
sterilizing stainless steel equipment (6).
In their study, the cost of plastic bag
disposal in a single-use facility was
offset by the energy recovery gained
through their incineration.
As noted above, we restricted
productivity of the single-use facility in
our model to the same number of
batches per year as the stainless steel
facility. But in reality, a single-use
facility with the same size bioreactors
as a stainless steel facility can produce a
higher number of batches each year.
Time saved by eliminating bioreactor
cleaning and sterilization along with
shorter turn-around times allows for
completion of 20 batches/year in a
model single-use facility, for a total
production rate of 140 kg MAb /year.
This large number of batches
effectively lowers the operating CoG
for the single-use facility to $170/g
when it operates at full capacity a
much larger cost savings for the use of
disposable bioreactors and other such
systems.
One key potential benefit derived
from implementing single-use
technologies in biomanufacturing
Table 2: Upstream timing for MAb production
Cell Culture Unit Operation Time
Working cell bank (WCB) vial thaw
and initial growth in T flasks
4.5 days
Cell expansion in shake flasks 2.5 days
Cell expansion in small-scale
bioreactors
12.5 days
Production bioreactor 15 days
SUPPLEMENT APRIL 2013 11(4)S BioProcess International
43
operations is a reduction in labor
requirements for supporting ongoing
GMP manufacturing. Such reductions
come primarily from lowered
requirements for equipment cleaning
between production batches and
associated ongoing cleaning validation/
verification. Those reduced cleaning
requirements can not only lower
headcount for direct manufacturing
operations, but they may significantly
reduce staffing requirements for QA/
QC as well. Also, shorter change-over
times and fewer hard-piped utilities and
systems in a facility incorporating single
use technologies will lower maintenance
and metrology costs, reducing staffing
requirements for those areas as well.
Our model shows significant cost
savings in labor required to operate a
single-use facility compared with a
stainless steel facility primarily due to
time saved in each production batch and
the shorter batch turn-around times.
Table 4 lists staffing estimates based on
labor requirements for a fully
operational facility using output from
our process economic model and recent
benchmarking studies performed by
BioProcess Technology Consultants. As
shown, a single-use facility requires
about 15% fewer manufacturing staff for
drug substance manufacturing and
about 12% fewer QA/QC staff,
resulting in about 13% lower total
headcount than a stainless steel facility.
Those staffing reductions are consistent
with other reports of reduced labor
requirements for facilities based on
single-use technologies (79). For
example, in a case study by Foulon et al.,
estimated labor savings for technology
transfer and ongoing production of a
MAb product in a single-use facility was
56% for technology transfer and 17% for
ongoing production compared with
conventional stainless steel facilities (10).
Our modeling results show
additional labor savings in the single-
use facility because it is running at only
75% capacity to match the output of
the stainless steel facility. That lower
capacity use consequently lowers labor
requirements. If the single-use facility
were to run at full capacity, then its
total headcount would be slightly
higher, but so would the total amount
of product made per year.
The primary difference between
the single-use and stainless steel
(hybrid) facilities manifests in the use
of disposable bioreactors rather than
stainless steel. Downstream processes
and equipment are essentially the
same in both facilities. However, as
more single-use technologies are
developed for downstream processing
and such technologies become routine
for good manufacturing practice
(GMP) manufacturing, we expect the
overall cost of manufacturing to
decrease even further. In a recent
presentation, for example, Malcolm
recently showed that about 75 labor
hours/batch could be saved using
disposable prepacked chromatography
columns instead of reusable, self-
packed columns (11). Those prepacked
columns reduced the total cost of each
chromatography step some $20,000.
NEXT-GENERATION MODULAR FACILITIES
Based on the platform process
described herein, we have developed a
standardized facility layout for a
modern MAb production facility that
can be readily adapted to produce other
recombinant protein products and
different MAb processes. The layout
and cost of this standardized facility
design will be detailed in a future
article. The design consists of several
different functional areas
interconnected by a central spine or
corridor to allow for maximum
flexibility and ease of future expansion.
Functional areas incorporated in
the standardized facility include
administration, QC, QA,
manufacturing, and materials
handling and storage (warehouse). An
optional process development
laboratory could also be included.
Space for the administration, QC,
QA, and materials-handling functions
can be built using conventional
construction. The manufacturing area
is modular in construction both for
bulk drug substance and final-dosage
manufacturing, and it can be installed
either in an existing or new building
shell or as a free-standing structure
using modules specifically constructed
for this purpose.
Bulk Drug-Substance
Manufacturing: Our standard
biomanufacturing facility for bulk
MAb production includes appropriate
space for material staging and
dispensing, media and buffer
preparation and storage, and upstream
and downstream processing, along
with sufficient space for all support
functions and appropriate airlocks and
corridors. Although the standard
design is based on a single 2,000-L
disposable production bioreactor, the
layout can be adapted for bioreactors of
different sizes or readily expanded to
include multiple 2,000-L bioreactors.
By maximizing the use of
disposables in upstream processing
and product storage, the overall
footprint of a bulk MAb production
facility is about 1,200 m
2
. The
standardized facility incorporates
modern requirements and approaches
to design and construction, including
modular construction. If
manufacturing is based on reusable
Table 4: Full-time employee (FTE) staffing estimates for a typical MAb facility
Function Single-Use Facility Stainless Steel Facility
Drug substance manufacturing 29 FTEs 34 FTEs
Drug product manufacturing 8 FTEs 8 FTEs
QA/QC 37 FTEs 42 FTEs
Engineering/maintenance 11 FTEs 13 FTEs
Purchasing/administration/other 17 FTEs 20 FTEs
Total Staff 102 FTEs 117 FTEs
Table 3: Operating costs (in US dollars) for stainless steel and single-use facilities
Operating Costs
Stainless Steel Facility Single-Use Facility
Annual Batch Annual Batch
Quantity of product made 105 kg 7 kg 105 kg 7 kg
Materials $607,428 $40,495 $590,334 $39,356
Consumables $3,611,689 $240,779 $4,268,890 $284,593
Labor (direct/indirect) $17,133,065 $1,142,204 $12,011,414 $800,761
Maintenance, utilities, and
waste
$2,268,686 $151,246 $1,454,109 $96,941
Total $23,620,868 $1,574,725 $18,324,748 $1,221,650
Operating costs per gram
of MAb
$225/g $175/g
SUPPLEMENT 44 BioProcess International 11(4)s APRIL 2013
stainless steel equipment instead, then
the size of the facility increases ~50%
to 1,800 m
2
. The smaller footprint of
a single-use facility primarily comes
from the smaller utilities needed to
operate such a plant, which further
helps to reduce overall facility cost.
The facility design for bulk MAb
production includes unidirectional flow
of materials, product, waste, and
personnel throughout the
manufacturing area. In addition,
separate processing areas are provided
for downstream processing operations
before and after virus removal by
nanofiltration. Fully closed and
contained processing is used wherever
possible, generally within a grade D
environmental classification. Open
processing areas as required for
inoculum preparation, final
purification, and bulk filling are
designed to be grade C, with specific
open operations performed in suitable
biosafety cabinets using laminar air
flow. The facility also includes suitable
staging areas for raw materials,
consumables, and equipment as well as
appropriate locker rooms and airlocks
for staff changing and entry/exit from
the facility. To further ensure
segregation within the facility, our
design includes multiple air handlers.
Using modular construction, the overall
facility design can be readily modified
to achieve appropriate segregation
based on an appropriate risk assessment
of products to be made, details of their
manufacturing processes, and risks of
cross-contamination or contamination
from adventitious agents.
The product processing area is
generally U-shaped, with
unidirectional product flow from one
end of the facility to the other. Media
and buffer preparation areas are
located in the center of the facility to
allow for the most possible adjacencies
to processing areas. Wherever
possible, buffers are stored in closed
containers within controlled but
unclassified space to minimize the
environmental burden and lower
overall heating, ventilation, and air-
conditioning (HVAC) requirements
for the facility. The facility also
includes optimized equipment
positioning to minimize tubing and
piping needed for product and
material transfer. A single access point
is provided for all production
personnel, with a surrounding clean
corridor for easy access to all rooms.
Final Drug-Product Manufacturing:
A final-drug product manufacturing
facility would be built using modular
construction, with
a core area for product formulation
and vial filling, stoppering, capping,
and loading onto trays
space for vial and stopper
washing, sterilization, and
depyrogenization
necessary areas for material
dispensing, washing, and sterilization
of parts.
This module is equipped with
appropriate internal air locks and
corridors and independent HVAC
units, all on a single level. Including
space for personnel gowning and
degowning, lockers, and so on as
well as ingress and egress airlocks
the drug product module will have a
total footprint of ~330 m
2
. If
lyophilization is required, it can be in
the same module, adding ~60 m
2
to
the total facility size.
For drug-product manufacturing, a
vial-filling line has the capacity to fill
6,000 10-mL vials/hour (~40,000 vials/
day) for a single shift operation. Our
model MAb process will make
sufficient product to fill ~64,000 vials,
so filling an entire production batch
would require two days of filling
operations. Allowing time for
preparation, inspection, labeling, and
so on, it would take about a week to fill
the total monoclonal antibody output
from a single 2,000-L bioreactor.
ECONOMICS OF MODULAR FACILITY
DESIGN AND CONSTRUCTION
According to Gilroy and Martini,
modular construction of a
pharmaceutical manufacturing facility
refers to construction of all or part of a
new or renovated facility built at a
remote location, transported to the
owners address, and reassembled on
site (12). Modules consist of structural
frames that are fit out with all
mechanical, electrical, and plumbing
architectural elements complete
with all fixed process equipment.
Estimating the cost of design and
construction for such a modern
biopharmaceutical manufacturing plant
is a complex task that requires careful
consideration of all associated time and
risk factors. Differences in time required
for such critical activities as architectural
and engineering design and construction
management or the increased interest
charges on applied capital resulting from
project delays can significantly affect
the overall cost of building a
biomanufacturing facility. A full risk
assessment of timelines and costs
comparing traditional and modular
construction approaches shows that the
risk mitigation and exemplary
performance associated with modular
construction makes that option the more
cost-effective approach (13). As Figure 2
shows, the time savings is on average
over a year. Furthermore, taking into
consideration the net present value
(NPV) of the potential revenues from
products made in a given manufacturing
facility will further reduce overall capital
cost of design and construction. That
increases the value of the modular
approach.
One key advantage to modular
construction for biopharmaceutical
facilities is the off-site construction of
modules. The benefits of such an
approach include enhanced quality
control, reduced waste, reduced impact
on current operations, and simplified
site logistics. Transferring labor hours
away from the construction site also
reduces both risk and overall cost for a
facility construction project. For
example, building multiple modular
elements in parallel with no weather
impacts can reduce the construction
schedule for a facility project by 50%.
And the ability to leverage factory
acceptance testing (FAT) at a module
construction facility will often shorten
the start-up and commissioning of a
new facility.
By designing and building the
process and facility modules needed for
a biopharmaceutical facility, FAT and
prequalification of all process equipment
and utilities can be performed before
shipping the modules. Once those
modules are delivered to the
construction site, they are assembled
into the final facility so that final testing
and qualification can be completed.
Todays modular wall systems evolved
from prefabricated polyvinyl chloride
(PVC) sheathed aluminum-frame wall
and ceiling panels. They offer a high
degree of flexibility, including
SUPPLEMENT APRIL 2013 11(4)S BioProcess International
45
walkable ceilings and prefabricated
return-air walls. Modular wall systems
can incorporate integrated electrical
lighting and receptacles, HVAC
ductwork, high-efficiency particulate air
(HEPA) filters, and controls (12).
In a study on energy costs for both
single-use and stainless steel facilities,
Rawlings and Pora concluded that the
main contribution to the life-cycle cost
of a biomanufacturing facility comes
from total energy costs incurred in
running it (6). For a traditional
biopharmaceutical manufacturing
facility, ~7080% of total energy
consumption comes from numerous
HVAC systems required to maintain a
clean environment in the manufacturing
areas. Using an optimized room layout
and environmental classifications, the
total energy consumption for a modular
facility can be reduced by 15%.
Furthermore, using modern
manufacturing technologies and
prefabricating facility modules off-site in
a controlled environment provides for a
higher-quality facility with tighter seals,
lessening the chance of air leakage and
energy loss. That in turn reduces the
factors on differential pressures and air
changes, leading to further energy
reductions.
Using a system of nonproduction-
hours setback (with the number of air-
changes reduced during nonproduction
hours that involve low particle burdens
while maintaining correct air quality
and pressure cascades among rooms)
also reduces a facilitys overall energy
requirements. As a result, the efficient
design achieved using disposables and
modular construction provides for a
modern biomanufacturing facility that
is consistent with sustainability
programs such as Leadership in Energy
and Environmental Design (LEED),
Energy Star, and Building Research
Environmental Establishment
Assessment Method (BREEAM).
This modern design is also consistent
with ISO 14001, allowing for efficient
environmental management and
control systems.
Manufacturing plants will
increasingly involve modular building
strategies coupled with maximal use of
disposable process equipment and lean
design concepts. These approaches and
technologies will provide significant
cost savings and greatly reduce facility
start-up times. They incorporate
quality-by-design (QbD) concepts into
facility designs, which should further
reduce costs, increase efficiencies, and
ensure regulatory compliance. When
combined with single-use technologies
for biomanufacturing, modular
construction helps reduce facility
operating costs overall. Savings
resulting from the use of disposables
installed in a low-cost modular
building as well as the significantly
reduced construction schedule will
enable rapid construction of energy-
efficient, economical, biomanufacturing
facilities in both established and
emerging markets.
REFERENCES
1 Levine HL, et al. Efficient, Flexible
Facilities for the 21st Century. BioProcess Int.
10(11) 2012: S20S30.
2 Sinclair A, Monge M. Disposables Cost
Contributions: A Sensitivity Analysis. BioPharm
Int. 22(4) 2009: 1418.
3 BioProcess Technology Consultants, Inc.
The Development of Therapeutic Monoclonal
Antibody Products. Levine HL, Jagschies G, Eds.
Elanders Sverige AB: Molnlycke, Sweden
February 2010.
4 Mauter M. Environmental Life-Cycle
Assessment of Disposable Bioreactors. BioProcess
Int. 8(4) 2009: 1828.
5 Pietrzykowski M, et al. An
Environmental Life-Cycle Assessment
Comparing Single-Use and Conventional Process
Technology. BioPharm Int. 24, 2011: S30S38.
6 Rawlings B, Pora H. Environmental
Impact of Single-Use and Reusable Bioprocess
Systems. BioProcess Int. 7(2) 2009: 1826.
7 Hodge G. Disposable Components
Enable a New Approach to Biopharmaceutical
Manufacturing. BioPharm Int. 17(3) 2004: 3849.
8 Hodge G. The Economic and Strategic
Value of Flexible Manufacturing Capacity. ISPE
Strasbourg Conference: Strasbourg, France, 2829
September 2009. International Society of
Pharmaceutical Engineers: Tampa, FL, www.
ispe.org.
9 Fromison J. Disposables in Clinical
Manufacturing. Am. Pharmaceut. Rev. 12(2)
2009: 2027.
10 Foulon A, et al. Using Disposables in an
Antibody Production Process: A Cost-
Effectiveness Study of Technology Transfer
Between Two Sites. BioProcess Int. 6(6) 2008:
1217.
11 Malcolm F. Implementing Disposable
Chromatography-Process and Technology Fit.
Biopharmaceutical Development and Production
Week: Huntington Beach, CA, 25 February1
March 2013. IBC Life Sciences: Westborough,
MA, www.ibclifesciences.com.
12 Gilroy J, Martini G. Modular
Construction Considerations. Pharmaceut. Proc.
27(10) 2012: 2223.
13 Jameson P. Modularization: Is It Right for
You? CII Annual Conference: Orlando, FL, 2
August 2007. Construction Industry Institute:
Austin, TX; www.construction-institute.org.

Corresponding author Howard L. Levine is

founder, president, and principal consultant
of BioProcess Technology Consultants, Inc.
(12 Gill Street, Suite 5450, Woburn, MA 01801-
1728; 1-781-281-2703; hlevine@bptc.com),
and founder and CBO of Biocrescentia LLC
(1-781-281-2703; hlevine@biocrescentia.com.
br). Rick Stock is a consultant for BioProcess
Technology Consultants, Inc. Jan Lilja is
commercial director and sa Gaasvik is
Senior Design Engineer at KeyPlants AB in
Sweden. Hans Hummel is director, business
development at KeyPlants in Switzerland.
Thomas C. Ransohoff and Susan Dana
Jones are vice presidents and senior
consultants with BioProcess Technology
Consultants, Inc.
To order reprints of this article, contact
Claudia Stachowiak of Foster Printing Service,
1-866-879-9144 x121, claudias@fosterprinting.
com. Download a low-resolution PDF online
at www.bioprocessintl.com.
Figure 2: Comparing modular with conventional facility design and construction; the relative time
for each stage of construction is based on a comparison of design and construction schedules for
several biopharmaceutical manufacturing facilities using either conventional or modular
approaches (ADAPTED FROM CONSTRUCTION INSTITUTE INTERNATIONAL, 2012).
Front-End
Engineering Construction Licensure
Front-End
Engineering
Fabrication Licensure
Capital costs
(1222%)
~$5 million
Operations
~$6 million
Revenue (50
350 million)
~$$$$
Best-Case
Conventional
Project
Modular
Project
Design
6 mos.
Design
5 mos.
Year 1
Year 1
Year 2
Year 2
Year 4
Year 3
Year 3