Eng. Life Sci. 2011, 11, No.

4, 443–451 443

Thorsten Peuker1 Technical Report

Alexandra Bogner2

1
Sartorius Stedim Biotech
Equipment design and facility layout
GmbH, Göttingen, for flexible biomanufacturing processes
Germany
2
Sartorius Stedim Systems In process development and manufacturing, the biopharmaceutical industry
GmbH, Melsungen, requires high flexibility in its production facilities. These suites must be capable of
Germany producing clinical material or even drug substances for the market. Several
products are manufactured in parallel or shortly after one another, which is
challenging especially for the equipment. Product titers are increasing due to
improved cell line performances, and personalized medicine will lead to tailor-
made drugs for a smaller group of patients. The resulting reduced upstream
volumes enhance the opportunities for complete single-use manufacturing trains.
These requirements must be considered already during the design phase of the
manufacturing facility. Engineering efforts have to be reduced as much as possible
in order to reduce cost and timelines. Generic platform concepts for the overall
process enable a shorter execution time as well as more efficient qualification
procedures. In this contribution, the focus is on production processes for
monoclonal antibodies (mAb) as a major product class of the biopharma-
ceutical industry. Two case studies introduce process platform concepts inte-
grating single-use equipment for an existing building and for a greenfield
facility.

Keywords: Bioprocesses / Facility design / Monoclonal antibodies / Process platform /

Single-use and hybrid equipment

Received: September 30, 2010; revised: February 2, 2011; accepted: February 24, 2011

DOI: 10.1002/elsc.201000174

1 Introduction emerging markets, and a continuously growing population will

Antibodies are one of the most efficient weapons of the
immune system. With up to 1011 molecule modifications, the
variety in antibody specificity is nearly endless, which is
necessary for the ability to bind millions of various antigens.
The interaction between a monoclonal antibody (mAb) and its
antigen epitope is highly specific, excluding all other epitopes.
This unique characteristic of mAb opened up the door for the
development of new diagnostic methods and therapeutics,
especially for cancer therapy [1, 2]. mAb generated revenues of
approx. $35 billion in 2009, accounting for 28% of the global
biotech market [3]. The market size of mAb will further
expand and replace some of the small molecules in the top-ten
list of bestselling products, as predicted by EvaluatePharma in
its World Preview 2016 report [4]. A full R&D pipeline,
Correspondence: Dr. Thorsten Peuker (thorsten.peuker@sartorius-
stedim.com), Sartorius Stedim Biotech GmbH, August-Spindler-Street
11, 37079 Göttingen, Germany.
Abbreviations: API, active pharmaceutical ingredient; CIP, cleaning in
place; HVAC, heating, ventilating, and air conditioning; SIP, ster-
ilization in place
primarily fuel the global mAb production demand.
Modern biopharmaceutical production has changed in the
last few years, due to the changes in overall process perfor-
mances on the one hand and the availability of new materials
and components on the other hand. There is a trend toward
the replacement of stainless-steel equipment and the usage of
single-use equipment since implementation of the latter is easy
and very often much more cost efficient. Single-use equipment
is already established in several unit operations and will be
accepted in others in the near future [5–7]. In addition, it is
obvious that flexible multiproduct facilities have different
requirements than large-scale manufacturing of bulk drug
substances, which are produced in stationary and hard-piped
stainless-steel equipment. Time-to-market and cost pressure
on the biopharmaceutical industry are the main issues to solve,
in order to be ahead of the growing competition on the
market.
For the development of new drug substances, a strict and
regulated clinical test procedure has to be followed. If a drug
candidate was successful in toxicological studies and the
preclinical and clinical phases I and II, the material for phase
III must already originate from the same equipment that is

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444 T. Peuker and A. Bogner
designated for market supply [8]. Figure 1 shows a typical
timeline of an active pharmaceutical ingredient (API)
development and the corresponding engineering phases
for facility and equipment. Since the engineering, construc-
tion, and qualification phases for customized production
plants sometimes take more than 3 years, these activities
have to start almost at the same time as drug develop-
ment. As a consequence, companies have to decide for
major investments at an early stage (preclinical) where no
guarantee exists that the product will be successful.
Suppliers should support the manufacturing industry by
predefined configurable unit operations or even generic plat-
form processes. This will reduce time and engineering efforts
during design and construction of such development and
manufacturing plants and hence could enable postponement
of the investment decision until a later phase without loss of
time.
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Eng. Life Sci. 2011, 11, No. 4, 443–451
2 Design of generic process platforms
A biopharmaceutical manufacturing concept is more than the
sum of its elements.
The design of the purification process is influenced by the
physicochemical properties of the product and the nature of
the process- and product-related impurities [9]. Despite small
variations in the chemical nature of mAb, many companies
have defined platform purification processes [10–12]. Each
unit operation is made of standardized technological modules
(e.g. sensors, storage bags, mixing devices, filters, transfer sets,
connectors, sampling devices, etc.). Major benefits of process
platforms are savings in time and cost, process optimization,
and security of supply for single-use components [8, 13, 14].
In order to be fast and efficient in the design and execution of
projects, these technological modules should be well defined
and should not have to be changed or even newly developed.
Figure 1. Timelines of drug development and
corresponding engineering phases for facility
and equipment.
Figure 2. Process platforms available for
mAb production in clinical phases and
production.
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Eng. Life Sci. 2011, 11, No. 4, 443–451 Equipment design and facility layout 445

There are different process platforms available for mAb,
matching the varying product amounts in the different clinical
phases (Fig. 2). A generalized mAb platform process is
described in detail (Fig. 3) [10, 11].
2.1 mAb manufacturing process
Currently, the most efficient expression systems are Chinese
hamster ovary (CHO) cells and mouse myeloma cell lines.
Main criteria in the selection of cell lines are the human

Figure 3. (A) Flow diagram for a mid-scale mAb upstream process with corresponding single-use equipment. (B) Flow diagram for a mid-
scale mAb downstream process with corresponding single-use equipment.

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446 T. Peuker and A. Bogner
glycosylation pattern, a stable expression system of the target
protein, and an as high as possible specific production rate
[15]. The mAb titers usually reach 2–3 g/L. Production levels of
5 g/L have already been reported for highly optimized
mammalian cell culture systems, and titers of >10 g/L are
expected within the next decade [16]. This development
predicts lower upstream volumes in the future and benefits the
usage of single-use bioreactors for the production scale,
which is limited to 2000 L. Downstream processes of mAb
production were not able to keep pace with the rapidly
increasing titers in fermentation; thus, the production bottle-
neck has shifted from upstream to downstream. In particular,
the load capacities of chromatographic and membrane mate-
rials need to be improved [17]. The economy of a mAb
product is intrinsically tied to the titer and the overall recovery
rate in the downstream process. Other significant benchmarks
in an mAb production process are protein quality and purity.
The quality of any biopharmaceutical product is defined by the
production process, which is basically determined by the
process equipment, the sequence of unit operations, and the
operation parameters [15].
The first step after cell culture is separation of the cells/
clarification of the harvest broth. Centrifugation is the most
common method for harvesting operations. Depth filters are
an adequate single-use alternative or are used in combination
with a centrifuge. Which approach turns out as the method
of choice depends on the final cell density in the culture
broth, the turbidity, and the cell viability. A subsequent Protein
A chromatography step serves as capturing step and as key
volume reduction step. The high purity that can be achieved
makes the concept of a platform process suitable for mAb.
Following polishing steps have to remove the remaining
amounts of host cell protein contaminants, DNA, leached
Protein A, endotoxins, or other process-related impurities
[11, 18]. The main drawback of this step is the expensive
Protein A chromatography medium at approx. 10 000 US$/L.
A promising alternative for antibody capturing is cation
exchange chromatography [19, 20]. The low pH conditions of
the Protein A pool benefit a subsequent low-pH viral inacti-
vation step [19]. Two additional chromatography steps are
typically employed in an mAb platform process, with the aim
of further purification and polishing. Common chromato-
graphy methods are cation exchange, anion exchange, hydro-
phobic interaction, hydroxyapatite, and size exclusion chro-
matography. Single-use membrane chromatography found its
place particularly in purification processes for the removal of
impurities and contaminants [21]. In order to comply with the
virus reduction corresponding to the FDA Q5A document, the
mAb purification process includes a virus filtration step
[11, 22] (www.fda.gov/downloads/RegulatoryInformation/
Guidances/UCM129101.pdf). Different filtration techniques
are established in the mAb purification process. Microfiltration
membranes are available with pore sizes between 0.01 and
10 mm. They are used between the main unit operations steps
to protect the chromatography resins or membranes or to
minimize bioburden and endotoxin levels during the purifi-
cation process. Ultrafiltration is used to concentrate the
product or for buffer exchange in order to condition the
load for the next column. Diafiltration enhances either
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product purity or yield. In the purification of antibodies, the
molecular weight cut-off used for ultrafiltration/diafiltra-
tion (UF/DF) varies in the range of 30–500 kDa, depending
on whether the antibody shall be retained or not. Finally, a
microfiltration step under stringent conditions ensures
sterility of the final product, as required [15]. Single-use
equipment is available for all filtration steps, except for
ultrafiltration/diafiltration, in large-scale production.
2.2 Single-use equipment and hybrid solutions
So far, most of the necessary unit operations in mid-scale or
large-scale production processes are made of reusable stainless-
steel equipment. This material has major advantages, such as
mechanical robustness and chemical and temperature resis-
tance; however, high capital investments and less flexibility are
its drawbacks. For reusable equipment, well-established design
criteria and experienced engineers are available to build
production facilities almost everywhere around the world. But
due to long lead items and extensive construction and quali-
fication efforts, it takes more than 5 years to bring such a new
facility into operation.
During the last decade, single-use equipment has been
increasingly implemented [23, 24]. This is due to the fact that
new materials are available that are considered as save and
reliable by the US and European Pharmacopeia (ICH Q7A:
Good Manufacturing Practice Guide for Active Pharmaceutical
Ingredients) [25]. In order to make maximum use of the
benefits that disposables can bring to the manufacturing of
biopharmaceuticals, the challenge is to design and implement
application-specific integrated process solutions that, with
respect to process engineering, automation and control, follow
the same principles as conventional process designs. It is
important to accept that disposables have certain limitations,
but that they can be intelligently integrated in new and existing
process designs. How many disposables to use and where to
use them are issues that have to be evaluated from various
aspects and carefully analyzed with respect to application and
customer-specific need. In addition, the possibility of a
combination of reusable and single-use technologies (i.e.
‘‘hybrid technology’’) must be considered. Currently, dispo-
sables are mainly used during scale-up and clinical produc-
tion. In commercial manufacturing, the use of disposables is
still mostly limited to tubings and filter cartridges. However,
with the expansion of disposable technologies into the area
of commercial production, the need of integrated single-use
process designs becomes absolutely obvious. Although in
the past single-use products were recognized as useful
components in the manufacturing of biopharmaceuticals,
nowadays there are more and more processes that are almost
completely designed with single-use equipment. Even in
mid-scale processes (r2000 L upstream volume), several
single-use package units and in-process fluid handling
systems are used, and their usage will certainly increase in
the future. Currently, there are efforts to standardize single-
use process equipment in the same way as stainless-steel
bioprocess equipment: DIN EN (German/European Indus-
try Standard), ASME BPE (American Society for Mechanical
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Eng. Life Sci. 2011, 11, No. 4, 443–451
Engineering BioProcessing Equipment), and ISPE (Inter-
national Society for Pharmaceutical Engineering).
In general, there are a number of issues that have to be
solved before implementing single-use equipment. Process
compatibility, process efficacy, batch volume, filling and
discharge, degree of agitation (power input), operating pres-
sure and temperature, measurement of process values, material
handling/space requirements, and environmental, health, and
safety aspects are of utmost importance [26].
2.3 Advantage of closed disposable systems
Biopharmaceutical production processes require sterile and closed
containments in order to ensure process and user safety. Single-
use equipment can support this by predefined, configurable
disposable solutions. Such single-use systems must fulfill the
needs of the different unit operations. Reducing the complexity of
predefined, configurable systems by maintaining flexibility
through different configurations will be a key success factor
perceived by the end users. Several suppliers already launched
such closed disposable solutions or systems (e.g. Sartorius Stedim
Biotech: FlexAct; Millipore: Mobius; GE: ReadyToProcess). Once
it is implemented in the process cycle, security of supply and fast
in-time delivery are the main constraints of the industry.
2.4 Automation and instrumentation
Traditional facilities with stainless-steel equipment require a
high automation degree. There are only few procedures with
human interaction, e.g. inoculation or sampling. This leads to
high process safety and less losses of batches due to operational
Figure 4. Facility layout for a mid-scale mAb, single-use mAb manufacturing process.
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Equipment design and facility layout 447
errors. Industrial standards are available for the overall auto-
mation system but also for almost every package unit. The
majority of automations tasks for this kind of plant are
required for cleaning in place (CIP) and sterilization in place
(SIP) of the reusable equipment.
Automation solutions, ranking from dedicated local
controllers to high-level system integration using programmable
logic controller/supervisory control and data acquisition (PLC/
SCADA) or distributed control systems (DCS), cannot be fully
applied for single-use parts yet. Common standards need to be
adjusted considering the different natures of both technologies.
By applying more and more single-use products and equipment,
CIP and SIP are no longer an issue. On the other hand, the unit
operation approach discussed earlier will help to combine unit
operations by using platform technology connection methods
and well-established supervisory control and data acquisition
platforms. The digital control unit (DCU)-4 system of Sartorius
Stedim Biotech is one example of applying well-established
automation systems to single-use and hybrid processes. It serves
mixing systems, cell cultivation systems, and filtration systems at
all stages. All these unit operations can now be equipped with
either reusable or single-use components, relying on a well-
established automation platform.
Disposable sensors that are fully integrated into the
respective single-use containment to control important
process parameters for each unit operation (e.g. dissolved
oxygen (DO), pH, conductivity, etc.). However, if users want
to integrate classical sensors, this is also possible by applying
autoclavable connection systems.
Considering that single-use equipment leads to more
interference of the personnel, integration into a plant-wide
manufacturing execution system (MES) is a prerequisite for a
safe and documented production process.
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448 T. Peuker and A. Bogner
2.5 Facility requirements for implementation of
single-use equipment
The facility design must be according to the current Good
Manufacturing Practice (cGMP). However, most importantly,
it should be process oriented and follow well-established
design principles. It has to consider material and personnel
flows and can be of modular design. In order to make the
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Eng. Life Sci. 2011, 11, No. 4, 443–451
Figure 5. (A–C) Layout for large-scale mAb manufacturing
building.
investment economical, reduction of clean room demands is
essential. On the other hand, employing single-use equipment
requires more space for movement and handling. In this
article, we will introduce two typical scenarios as case studies.
In general, closed containments can be assumed as safe.
However, since there are always interactions (e.g. sampling or
final processing), dedicated clean room environments have
to be considered. At least ISO 8 air classification must be
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Eng. Life Sci. 2011, 11, No. 4, 443–451
Figure 6. Flow diagram for a large-scale mAb production process.
provided if open-top mixing is used. If closed-bag systems are
applied for raw material addition and liquid mixing (e.g.
FlexAct BP), the air classification can be reduced to controlled
but nonclassified (CNC) area. Reduced heating, ventilating
and air conditioning (HVAC) demands lead to cost savings for
ongoing operational costs [26].
3 Case studies
3.1 Retrofitting of an existing facility for process
development
If an existing facility should be used for new processes,
retrofitting is required [13]. In this case study, we will focus on
a new mAb process at a scale of 200 L batch volume and 5 g/L
product titer. The process was designed based on the generic
principles that are commonly accepted by the industry [14].
Figure 3(A) and (B) shows the process flow diagram of a
complete single-use manufacturing train in upstream and
downstream as well as the corresponding equipment. The
complete process can be arranged on one floor, with separate
flows for personnel and material (Fig. 4). Buffer and media
preparation will be done in a CNC environment. Intermediate
storage can be realized in a cold room until the material is
required at the point of use. Palletankss will be stored outside
the process rooms in order to reduce clean room space.
Transfer inside the process rooms is done by aseptic transfer
systems, e.g. SART SystemTM (single-use aseptic transfer
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Equipment design and facility layout 449
systems by Sartorius) or RAFT (rapid aseptic fluid transfer).
We have considered class D environments for cell cultivation
(seed culture will be done in class C) and harvesting, and for
previrus downstream steps. Postvirus steps in downstream will
be carried out in a class C clean room (if required, the final
filling can be done under laminar flow in class B).
For the process design, it is important to realize that making
use of standardized solutions in particular for single-use
components (bags, transfer sets, filters, etc.) will become more
important in the future. The main issues to overcome are
security of supply and especially supply chain strategies for
these consumables.
3.2 Greenfield production facility for market supply
Greenfield production facilities have other requirements
than existing facilities. Besides the process equipment, utility
demands, HVAC requirements, and even construction work
have to be considered, which leads to longer project timelines.
In this contribution, we will focus only on the process
equipment for the production of mAb and the architecture of a
new building.
A manufacturing building for larger-scale production
should contain five stories in order to distribute all necessary
infrastructures. Figure 5 shows the layout for a greenfield
facility. On the first two floors (levels 1 and 0), administration
and technical areas are located. The next two floors (levels 2
and 3) are dedicated to process equipment, and the last floor
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450 T. Peuker and A. Bogner
(level 4) is used for HVAC systems. A technical shaft in the
center of the building provides space for piping and distri-
bution systems for utilities, media, and energy. It will also
support all infrastructural needs that should be not placed in a
clean room.
The process equipment follows, as for the mid-scale case,
well-established unit operations [14]. Hybrid solutions are
combinations of single-use and stainless-steel equipment. The
process design was done based on the following assumptions:
A scale-up factor of 1:5 was considered for the bioreactors; in
total, it was planned to execute 21 batches per year with an
overall product yield of 4.4 kg mAb per batch. In an annual
operating time of 330 days, we could realize a minimum cycle
time of 8.2 days, which would result in a maximum of 37
batches per year. The flow diagram for the complete process is
shown in Fig. 6. The buffer and media preparation is located
on the second level in order to make maximum use of gravi-
metric flow. The distribution of buffer and media will be done
in two different ways. Bags will be used as much as possible,
but there is also still a need for hard-piping. Especially, initial
media load for the production bioreactors (media filling via
media filter into bioreactor) can only be realized in a certain
time frame with this approach. The upstream process and the
downstream process are arranged on the first level of the
building. Both streams are separated by the technical shaft.
For feeding purposes in fed-batch processes, Palletankss
with 500-L 3-D bags are considered. Feeding from the media
bag into the bioreactor for fed-batch operation is conveyed
by a peristaltic pump. The required media filter and valve
groups are shared with the bioreactor. In order to clean and
steam the pipework, SIP and CIP/rinse steps are carried out
in between operations. For this kind of hybrid process
design, it is important to allow for enough space for the
movement of Palletankss with 3-D bags (Flexel) and to
consider handling of filled 2-D bags (Flexboys).
4 Concluding remarks
Single-use equipment has changed the process design in
biopharmaceutical production in the last years. The resulting
new demands have to be taken into account during the design
of processes and even whole facilities. Platform processes and
facility layouts should support producers in postponing their
investment decision until their drug candidate has shown first
positive results in clinical trials. The benefit of these platform
processes is to significantly reduce the upfront engineering and
design work.
The developments in single-use technologies will speed up
in the next years. In the future, they will increasingly penetrate
entire biopharmaceutical manufacturing processes. Conse-
quently, security of supply of these product contact assemblies
is one of the major issues. Worldwide supply chain concepts,
with manufacturing sites all over the world, are a prerequisite
to fulfill the highest level of security of supply for single-use
systems and components.
Reducing human interactions is one of the major require-
ments for the next years. By applying more automation, in
future there may be even fully automated unit operations such
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Eng. Life Sci. 2011, 11, No. 4, 443–451
as media or buffer preparation, as it is already reality in the
food industry. This will also lead to lower costs and overall
improved processes.
The authors have declared no conflict of interest.
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