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THE STATE OF THE

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Chapter Eight
The Manufacturing
Perspective
Current Approaches to
Bioprocess Intensification

S. Anne Montgomery, Cheryl Scott, and Maribel Rios

Series
2017
B i o P r o c e s s STATE OF THE INDUSTRY
The Production and
Manufacturing Perspectives
Current Approaches to Bioprocess Intensification
S. Anne Montgomery, Cheryl Scott, and Maribel Rios
D
uring BPIs 15 years, weve
generally held to our original
thematic divisions: production,
processing, and manufacturing
(with the latter covering final filling,
packaging, shipping, and other
elements of drug-product
development). In this issue, however,
we decided to look at what people do
that applies to the entire bioprocess,
thus bridging process stages:
functional responsibilities that increase
in specificity and contribute to greater
analytical scrutiny as more and more
data are collected from development
investigations and from clinical trials.
With recent urgings to begin with the
end in mind and thus conceive of
end-to-end processes from the start,
this organizational pattern shines a
spotlight on interdepartmental
communication and collaboration
both of which are intended to
streamline process development,
reduce development costs, and hasten
time to commercial launch.
In the broader sense of
manufacturing here (covering both
drug-substance and drug-product
activities), we encounter a buzzword
that is relatively new to the industry:
bioprocess intensification. Managers and
researchers aim to design smaller-
footprint/volume processes that yield
the same desired results and
performance as larger, more capital-
intensive processes. Another goal of
process intensification (and
optimization in general) is to reduce
eventual costs to patients and
therefore improve global access to
biopharmaceuticals, recombinant
vaccines, and personalized therapies.
2 BioProcess International
some smaller companies: that they
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Our State-of-the-Industry Survey
Production and manufacturing drew
the third-highest number of responses
in our survey after the process
design and bioexecutive categories. In
the manufacturing portion of the
survey, we asked for responses on
three key topics: QbD incorporation,
adoption and further potential of
single-use technologies, and
projections on the future of
continuous processing.
QbD and Risk-Based Processes:
Figure 1 shows agreement among a
majority of respondents (45%) that the
QbD initiative has changed their
approach to bioprocessing. Another
large portion of responses (31%)
indicate that their companies have
increased employee training in the
statistical expertise needed to conduct
risk assessments at the level needed for
a QbD approach. And nearly as many
(27%) are using proprietary platforms
to streamline characterization.
But around 10% of respondents
say their companies have not been
following QbD to any radical extent
even though they may be
benefiting from process analytical
technologies (PAT) to streamline
their work and optimize
characterization efforts. That falls in
line with what weve learned from
15(6) Chapter 8 of 11 State of the Industry 2017
are working as fast as possible toward
proof-of-concept to gain critical
funding and/or to seek out
development partners to fund further
development. So those companies,
while benefiting from PAT and
myriad other development and
optimization tools, may plan to catch
up with quality requirements as they
progress (whether on their own, in
partnership arrangements, or selling
technology to a developer). This also
is consistent with the way PAT is
being received within other job
functions, as other articles in this
issue show.
Single-Use Technologies (SUTs):
With this set of questions, we were able
to confirm our own conclusions about
the industrys uptake of disposable
materials for production and
manufacturing. The results in Figure 2
confirm four trends that weve been
following:
Disposables have enabled and/or
improved cost-effectiveness in
multiproduct development and
manufacturing.
Single-use components are proving
to be more robust at larger scales than
they were only 1015 years ago.
Implementation challenges
remain (this should not be a surprise,
though, given that no one size fits all
in bioprocess applications).
And there may be better options
for interchangeability currently
through some degree of single-use
standardization. But this tally may be
influenced by the ability of
respondents to rely on a scalable suite
of equipment and components from a
major supplier of single-use
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Figure 1: BPIs state-of-the-industry survey shows solid progress in incorporation of quality by
design (QbD) approaches.
Our products are based on proprietary
platform, characterization is streamlined.
Company supports training in statistical
expertise for risk assessments.
Company has not changed approach to
follow QbD but benefits from PAT tools.
QbD changed department's approach to
product transfer from R&D to production.
0% 10%
Figure 2: Single-use technologies have transformed and continue to transform
bioprocessing and biomanufacturing.
Scalable single-use materials enable my company
to develop continuous production platforms.
We could not progress without single-use offerings.
Disposables have enabled cost-effective
multiproduct development/manufacturing.
We still scale-up to stainless steel for manufacturing.
We have seen significant cost savings with SUTs.
Single-use bags still leak/are undependable
at processing scales.
Implementation challenges remain.
Disposable materials have become more
interchangeable through standardization.
Single use components have become
more robust at larger scales.
0%
Figure 3: Although the jury is still out regarding applicability to all products/processes, most
respondents agree that continuous processing will play an important role in the industrys future.
Continuous processing is showing
great promise in hybrid systems.
Continuous processing will prove
viable only at early production.
We outsource all large-scale manufacturing and
develop processes with tech transfer in mind.
Further advancements are needed in scalability
and automation to achieve continuous processing.
The biggest challenge is the interface
between upstream and downstream processing.
The hype is promising, but fully continuous
bioprocesses will apply to only certain products.
I anticipate that we will see fully continuous
bioproduction and manufacturing in 35 years.
0%
technology rather than on
interchangeability of equipment from
different suppliers.
Facilities and Single-Use
Technologies: Disposables have
radically changed the look and feel of
many bioprocess suites over the past
15 years especially those running
pilot, seed-train, and scale-up
operations. We asked some engineers
what kinds of changes that means to
facility design. Nearly three-quarters
of respondents said that the
ballroom concept is making inroads,
with either modules or closed systems
rather than full rooms delineating
4 BioProcess International
20% 30% 40%
. biosimilars while improving quality.
5% 10% 15% 20% 25% 30% 35%
10% 20% 30% 40% 50%
specific process areas. A similar
number told us that modular facilities
designed for single-use technologies
are bringing plug and play closer to
reality. Half of all respondents said,
however, that the overall size of
biomanufacturing facilities hasnt
really changed. And nearly half
already see continuous processing
beginning to integrate upstream and
downstream processing into a seamless
biomanufacturing line.
One reader warned that strategic
management and coordination are key
to progress, otherwise we will have
errors and chaos. A consultant
15(6) Chapter 8 of 11 State of the Industry 2017
reported that few theoretical
improvements have yet materialized
with his clients. But another
respondent confirmed that SUT has
helped to decrease facility footprints
and increase the presence of modular
systems. Aside from the inherent risks
associated with leachables and
extractables, SUT has decreased the
risk of contamination between
50%
batches. The most significant impact
has been on strategies for storing
media and buffers. Facility designs
need to integrate process and
architecture and are beginning to
do so. Consultant James Blackwell of
the Windshire Group told us that the
next challenges will be driving costs
down and increasing efficiencies for
personalized medicines and
Single-use technologies and
continuous processing are enabling
technologies for each other, says
Morten Munk (global technology
partner at NNE). Increasing
automation and implementation of
robotics will make the facilities operate
24 hours a day, seven days a week,
even they are staffed only eight hours a
day and five days a week. He cautions,
however, that the facility of the future
is not one type of facility, but a hybrid
that takes advantage of all available
and emerging technologies wherever
they make the most sense.
To get into more detail, we
contacted Theodore Cohen (process
engineer II at IPS, a facilities design/
engineering and construction firm).
We talked about the engineering
60% challenges both for developers and
users of disposables. I think some of
the bigger challenges come in process
development, he said, which can
decrease the feasibility of using
disposables. He also pointed to the
difficulty of integrating automation
into unit operations.
Early in BPIs history, an industry-
wide manufacturing capacity crunch
was looming. Single-use technologies
and modular facilities helped to
prevent the worst-case scenario.
Retrofitting and renovating existing
facilities is a current issue, Cohen
said. Many have been around for
over 20 years, and they need to be
brought up to the standards of
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current good manufacturing practice
(CGMP).
We ended with a brief look at
automation. Cohen believes that
compliance with good automated
manufacturing practice (GAMP) rules
is the most important issue that has
arisen for software engineers in the
biopharmaceutical industry as well as
its suppliers and service providers over
the past 15 years. He also pointed to
use of 3D building information
modeling (BIM) during the design
phase of facilities engineering. I have
seen an increase in the desire to use
this across the board.
Continuous Processing: This is a
popular topic of discussion (and
debate) lately in production and
processing/manufacturing. As with
other industry innovations, the initial
push (before reality sets in) often is for
total incorporation. And that reality
resides in two key elements of
practicality: process variability and
process complexity. Researchers and
developers have more choices to make
among sensitive analytical methods
and equipment than were available a
decade or more ago. The data
generated are complex and require
more training for people who need to
interpret them.
Options have emerged for new
categories of products, building on
established technologies. So cell
therapies benefit from adaptation of
traditional bioprocessing methods,
antibodydrug conjugates reach from
across the (traditional, at least) small-
and large-molecule divide . . . and so
on. Vaccine and immunotherapy
manufacturers benefit from shared
technologies with other bioprocesses
and present their own challenges.
Another example of increasing variety
(if not also complexity) is in bioreactor
design, with many options these days
specific to the type of cells that are
growing, the lots sizes required, and
where manufacture will take place.
Figure 3 shows that survey responses
mirror much of what weve heard about
continuous processing at industry events:
that it may apply initially to only a few
types of products and otherwise mainly
at early production scales, that its
biggest challenge lies in the interface
between up- and downstream, and that
6 BioProcess International
Editorial Advisors Speak Up
On the State of the Art: We are seeing
a maturing market where end users
have a better understanding of where it
can make best sense to use specific
biomanufacturing models. We are
seeing all the major players working
with facility of the future projects for
which they are evaluating how can they
design facilities and processes that
enable highest productivity, high
quality, and lowest cost. This is what is
really driving process intensification
with highly productive cell lines, high
capacity purification, enhanced process
control using a lot of real-time PAT, and
multivariate modeling of manufacturing
processes for much deeper process
understanding.
Companies are trying to think through
how they can significantly lower the
cost of biomanufacturing working with
alternative hosts for protein production
and different cell lines, and some are
evaluating whether highly automated
bioprocessing could reduce cost of
goods. Miriam Monge (director of
marketing for integrated solutions at
Sartorius Stedim Biotech)
further advances in scalability and
automation are needed. The cost of its
implementation also will need to
decrease significantly before its
widespread adoption. Although some
people have been promoting the
continuous idea for decades, it has
become newly popular with the advent
of novel technologies. But disposables
and automation themselves are still in
development for specialized applications.
State of the Art in Manufacturing
From our state-of-the-industry
survey and from the other articles
in this special issue certain points
emerge about key issues in
biopharmaceutical production and
manufacturing. By the time drug-
substance production begins, work by
other departments has defined a
process and proof of concept, and
critical parameters and operating
ranges are defined, with a goal of
reducing changes to processes and/or
equipment at later stages. Affecting
how production and manufacturing
are conducted, departments tasked
with process design, logistics, and
business planning have already locked
in parts of the process, having
15(6) Chapter 8 of 11 State of the Industry 2017
addressed modes of operation and
issues related to facilities and site
transfer and how to leverage
existing resources.
Upstream Technologies: The current
course of bioreactor development
continues to optimize operations,
parameters, and process-monitoring
technologies with a strong focus on
development of in-line sensors, which
still face gaps in commercial offerings
and reliability. A number of wave-
motion systems are on the market, and
the entrance of cell-therapy into
commercial viability has influenced
bioreactor design for those special needs
(such as adherent cells, as reported on
elsewhere in this special issue). As
predicted, stainless steel reactors and
large-scale fermentation vessels have
not gone away. And in some cases they
are seeing potentially new demands,
including with cell-retention devices for
perfusion processes and in hybrid
processes with SUTs.
Continuous Culture: Protein-
producing cells still are grown mostly in
batch or fed-batch culture mode. But
over the past five years, perfusion
processing has been a major topic of
exploration. Technologies once used
only for difficult-to-express proteins
and those more likely to break down in
solution now are considered for products
across the biopharmaceutical spectrum.
Perfusion culture allows for high-
density cultures that maximize
productivity in relatively small
bioreactors. It requires continual feeding
and thus uses up large volumes of
culture media/supplements as well as
continuous removal of metabolites and
product, with dilution rates exceeding
the cell growth rate. This requires a
means of retaining cells in a bioreactor
while removing (and replacing) the
supernatant around them. Hollow-fiber
reactors offer one solution, with new
technological advancements addressing
their problems of old.
Culture Media: With an eye toward
increasing manufacturing f lexibility,
productivity (yield), and speed to
clinic, suppliers continue to introduce
new media, shear protectants, and
supplements. With efforts toward
media supplementation these days
enhanced by the use of design of
experiments to screen for optimal
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conditions, companies have many
good choices for finding what will be
the best growth environments for
their cells.
Emphasis on continuous culture
puts the spotlight on expensive feeds
making companies look for more
cost-effective options. That has brought
some full circle: Media can either be
purchased as ready-to-use liquids or as
dry powders to mix on site and/or on
demand. The former is most familiar
to small research laboratories; the latter
long has been the choice of large-scale
bioprocess facilities. But in-line buffer
dilution systems, outsourced buffer
preparation, and precision-formulated
liquid media are bringing many
facilities back to the idea of purchasing
ready-made feeds.
Upstream Expression Systems:
Two decades after some proponents of
transgenic animals predicted the end
of cell-culture expression, few
transgenics companies remain. And in
that time, new cell lines have been
continually introduced. In 2012, the
10th year of BPIs publication, we saw
the launch of the Pfnex expression
technology platform based on the
microorganism, Pseudomonas
fluorescens (currently being used for
biosimilar candidates). Plant-based
expression systems (both cell lines and
whole organisms) are now offering
relatively quick, inexpensive
production of some vaccine products
required in large doses.
Cell-line engineering is beginning
to benefit from advanced, site-specific
gene modification techniques such as
zinc-finger nucleases (ZFNs),
transcription activator-like effector
nucleases (TALENs), and the
CRISPR/Cas9 technology. And
several companies are pushing the
envelope: Ajinomoto Althea has a
proprietary system combining
attributes of mammalian and
microbial systems, especially
recommended for difficult-to-produce
proteins; Boehringer-Ingelheims (BIs)
BioXcellence unit uses a proprietary
vector system with its BI-HEX cell
lines.
In 15 years, weve seen steadily
rising antibody expression titers:
100mg/L, 1 g/L, 5 g/L, 10 g/L. . .
Meanwhile, however, expression levels
8 BioProcess International
Editorial Advisors Speak Up
On Downstream Processing: In Japan,
we started a big national consortium four
years ago on next-generation biological
production technologies (http://cho-mab.
or.jp/english/project). Members include
28 companies, four universities, a national
research institute, and three organizations,
and one of the main topics for this project
is single-use technology. We built a good
manufacturing practice (GMP) facility in
Kobe, where we can test all technologies
developed by the consortium. The project
is sponsored by the Japanese Ministry of
International Trade and Industry (MITI)
and Japans Agency for Medical Research
and Development (AMED). My major
research area is modeling and software of
chromatography processes, which I am
also working on for this project.
Shuichi Yamamoto (Yamaguchi University)
for nonantibody proteins have not
progressed so far. What similarities
can be expected? (That will no doubt
be a major topic explored in BPIs
20th-anniversary issue.)
Downstream processing always has
been and for the most part,
remains a step-by-step batch
operation in biopharmaceutical
manufacturing. But what may have
been seen as wishful thinking 15 years
ago is becoming a reality: continuous
downstream processing. As Margit
Holzer (scientific director at Ulysse
Consult) wrote in our most recent
featured report (1), it generally
requires more process knowledge,
equipment, and technological
advances than do batch processes.
Holzer described continuous
chromatography options from a
number of suppliers. Some qualified
systems already are used for producing
clinical material. She also highlighted
productivity gains and reductions of
processing volume achieved when
companies switched from single- to
multicolumn continuous
chromatography processes.
Not only chromatography processes,
but also separation media have
developed over the past few years,
Holzer pointed out. Major
improvements have increased physical
and chemical stabilities, allowing for
processes to be run at higher flow rates
and with more stringent process
solutions than before. Media with very
15(6) Chapter 8 of 11 State of the Industry 2017
tight particle and pore-size distributions
are becoming state of the art, improving
long-term process performance
(important for continuous processing).
Finally, binding capacities of affinity
(mainly protein A) and ion-exchange
(improved salt tolerance) media have
improved significantly. All these
improvements allow for downsizing of
chromatographic unit operations.
The protein A ligand is the most
widely used material in affinity
chromatography purification for the
capture of antibodies and many
antibody-derived proteins (e.g., Fc
fragments). IgG binds to protein A at
its Fc region in a highly specific and
hydrophobic interaction. Its use
removes more than 98% of impurities
from complex solutions (2). But over
the years, bioprocessors have begun to
lament the drawbacks of protein A. As
BPI editorial advisor Blanca Lain
(director of protein science at
Dragonfly Therapeutics) noted in her
2013 article, this type of affinity
chromatography usually necessitates
the use of harsh conditions such as low
pH for elution. That can be
problematic for some antibodies that
are either unstable or tend to aggregate
at low pH levels. In general, only a
small amount of impurities e.g.,
aggregates, residual host-cell proteins,
DNA, and leached protein A will
remain after this single starting unit of
downstream process operation. They
usually can be removed in either one or
two additional chromatography steps
(2). Expense is another notable
drawback to the use of protein A. Some
researchers have proposed alternatives
for protein A chromatography, but the
adoption of those technologies is not
yet widespread (3).
Of equal importance to
chromatography in downstream
processing are filtration and other
membrane separations. Depth and
sterile filtration are used to reduce or
prevent particles/bioburden in frontal
(dead-end) mode. Membranes used for
concentration and separation of
molecules, media exchange, and
formulation steps typically run in
tangential-flow or crossflow mode (1).
Dead-end filtration is a batch
process, Holzer wrote. With
alternating filter devices run in parallel,
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however, a continuous inlet flow can be
treated and a continuous outlet flow
reached. Such methods are already
established in some manufacturing
facilities for sterile and particle filters for
back-up use in case of system failures.
In recent years, Holzer explains,
many buffer-exchange steps have been
eliminated both through the use of more
refined buffers alongside improvements
in chromatographic media and
membrane adsorbers. Thus, the main
process steps for tangential-flow
filtration (TFF) now include harvesting
and final drug-substance concentration
for drug-product formulation. Viral
filtration can run in either frontal or
tangential mode. All these TFF process
steps typically run in a batch, repeated
batch, or fed-batch mode.
Continuous-countercurrent TFF
processes for concentration and
diafiltration are common in other
industries. Holzer says, Continuous
membrane processes such as single-
pass TFF also have been adapted to
process biopharmaceuticals. The main
drivers here include processing time,
buffer consumption, and cost of
operations. Implementing single-use,
continuous TFF can reduce
unproductive membrane-refresh time,
buffer consumption, and resulting
costs greatly (1).
Finally, she pointed to low-pH viral
inactivation treatment as another
batch process step that could be
redesigned for controlled continuous
operation. Plug-flow reactors with
integrated inline-dilution systems can
adjust inlet and outlet pH and tightly
control solution residence times (1).
Coiled-flow inverters could enable
reactors for continuous processing.
Drug-Product Development
Fill and finish is the final step in
manufacturing and includes some of
the most important details in ensuring
a high-quality product. In the past 15
years, the bioindustry has worked to
ensure contamination control by
revising its methods for vial and
prefilled syringe filling. For example,
end users, suppliers, and industry
groups have worked toward improving
elastomer stoppers and development of
specifications and requirements for
controlling particulate levels (5).
10
Preventing degradation is a critical
part of manufacturing because
proteins are susceptible to physical and
conformational degradation because of
excessive temperatures, mechanical
agitation, high shear forces, and the
characteristics of certain excipients (6).
Suppliers have developed advanced
particulate and aggregation detection
and monitoring systems to ensure
product stability and efficacy over
long-term storage of drug products.
And specialized training on handling
sensitive drug products has shown to
reduce the number of errors that have
compromised drug product integrity.
Filters are vital to the sterility of
aseptic drug-product fill and finish
processes. And their performance must
be confirmed through integrity testing.
In a 2014 article, Magnus Stering
(senior product manager for integrity
testing solutions in filtration technology
at Sartorius Stedim Biotech) introduced
an automated filter-management system
(FMS) for that purpose (7). The
automation is fairly straightforward,
with no need for advanced sensor
technology. Over the past 15 years, he
says, we have seen improved methods
for filter drying. This has made
intermediate storing of filters possible
without risk of residual humidity.
Membrane technology has improved as
well. New highly hydrophilic
polyethersulfone (PES) membranes
allow for in-line steaming without
prewetting, which simplifies both
testing and use. That hydrophilicity is
unaffected by post-test drying, Stering
explains, so it does not affect filter
performance or leachables/extractables.
Preuse, poststerilization integrity
testing (PUPSIT) is a traditionally
manual process. It requires additional
protective filters (APFs) that
themselves need to be tested. Risk
assessment helps determine whether
that should be done before or after a
filtration process. Typically the APFs
are tested after product has been
filtered, says Stering. But a failing
APF can jeopardize sterility.
Automation confirms the integrity of
the process filter as well as all APFs
before testing starts.
We asked about the risks of
transferring filters and housings
between a process line and an
BioProcess International 15(6) Chapter 8 of 11 State of the Industry 2017
integrity-test bench. There is no risk
for breaking sterility accidently,
Stering explained. Dropping the
housing could be a potential damage
risk for the filter, but training should
minimize that. And he said that
having three identical filter housings
for the same application would
minimize the necessity of delaying
production processes.
Balancing Risk and Rewards
Biomanufacturers must determine
whether automation and other new
technologies are right for them.
Process intensification must be
balanced against cost, learning curves,
and risks. But the modern industry
has more options in this area than ever
before. And although some ideas have
gone by the wayside over the years,
suppliers are working hard to make
sure that manufacturing groups have
what they need to succeed.
References
1 Holzer M. Is Continuous Downstream
Processing Becoming a Reality: BioProcess Int.
15(5) 2017: I20I28.
2 Lain B. Protein A. BioProcess Int. 11(8)
2014: 3038.
3 Gagnon P. Emerging Challenges to
Protein A. BioProcess Int. 11(10) 2013: 4452.
4 Gagnon P, Nian R. The Secret Life of
Protein A. BioProcess Int. 13(10) 2015: 3245.
5 Gilmore M. Elastomer Stoppers:
Working Toward Adopting and Industry-Wide
User Requirements Specification for Particulate
Levels. BioProcess Int. 15(1) 2017: 4849.
6 Kovarcik DP. Critical Factors for Fill-
Finish Manufacturing of Biologics. BioProcess
Int. 14(5) 2016: 3641.
7 Stering M. Preuse, Poststerilization
Filter Integrity Testing for Single-Use and
12(9) 2014: 5456. c
Stainless-Steel Installations. BioProcess Int.
S. Anne Montgomery is cofounder and
editor in chief, Cheryl Scott is cofounder
and senior technical editor, and Maribel
Rios is managing editor of BioProcess
International, PO Box 70, Dexter, OR 97431;
amontgomery@bioprocessintl.com.
This is an extended version of the article
published in BPIs June 2017 print issue.
To share this article in a PDF or professionally
printed format, contact Rhonda Brown,
rhondab@fosterprinting.com, 1-866-879-9144
x194.
Passion for Performance

Rentschler A world-class
biopharmaceutical CDMO

Full-service provider from gene to vial and from concept to market

Contract development and manufacturing with quality excellence
Experts in mammalian cell culture
State-of-the art facilities and technologies
Extensive track record with more than 40 years in biopharma

We are a biotechnology pioneer

We are listening to our clients
We find solutions where others dont even look

Rentschler Biotechnologie GmbH

Erwin-Rentschler-Str. 21 88471 Laupheim Germany
info@rentschler.de www.rentschler.de