INDUST
OF RY
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AR
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2003 2017
TEEN YE
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THE STATE OF THE
INDUSTRY
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Chapter Eight
The Manufacturing
Perspective
Current Approaches to
Bioprocess Intensification
Series
2017
B i o P r o c e s s STATE OF THE INDUSTRY
D
uring BPIs 15 years, weve some smaller companies: that they
generally held to our original are working as fast as possible toward
thematic divisions: production, proof-of-concept to gain critical
processing, and manufacturing funding and/or to seek out
(with the latter covering final filling, development partners to fund further
packaging, shipping, and other development. So those companies,
elements of drug-product while benefiting from PAT and
development). In this issue, however, myriad other development and
we decided to look at what people do ADOBE STOCK (HTTP://STOCK.ADOBE..COM) optimization tools, may plan to catch
that applies to the entire bioprocess, up with quality requirements as they
thus bridging process stages: Our State-of-the-Industry Survey progress (whether on their own, in
functional responsibilities that increase Production and manufacturing drew partnership arrangements, or selling
in specificity and contribute to greater the third-highest number of responses technology to a developer). This also
analytical scrutiny as more and more in our survey after the process is consistent with the way PAT is
data are collected from development design and bioexecutive categories. In being received within other job
investigations and from clinical trials. the manufacturing portion of the functions, as other articles in this
With recent urgings to begin with the survey, we asked for responses on issue show.
end in mind and thus conceive of three key topics: QbD incorporation, Single-Use Technologies (SUTs):
end-to-end processes from the start, adoption and further potential of With this set of questions, we were able
this organizational pattern shines a single-use technologies, and to confirm our own conclusions about
spotlight on interdepartmental projections on the future of the industrys uptake of disposable
communication and collaboration continuous processing. materials for production and
both of which are intended to QbD and Risk-Based Processes: manufacturing. The results in Figure 2
streamline process development, Figure 1 shows agreement among a confirm four trends that weve been
reduce development costs, and hasten majority of respondents (45%) that the following:
time to commercial launch. QbD initiative has changed their Disposables have enabled and/or
In the broader sense of approach to bioprocessing. Another improved cost-effectiveness in
manufacturing here (covering both large portion of responses (31%) multiproduct development and
drug-substance and drug-product indicate that their companies have manufacturing.
activities), we encounter a buzzword increased employee training in the Single-use components are proving
that is relatively new to the industry: statistical expertise needed to conduct to be more robust at larger scales than
bioprocess intensification. Managers and risk assessments at the level needed for they were only 1015 years ago.
researchers aim to design smaller- a QbD approach. And nearly as many Implementation challenges
footprint/volume processes that yield (27%) are using proprietary platforms remain (this should not be a surprise,
the same desired results and to streamline characterization. though, given that no one size fits all
performance as larger, more capital- But around 10% of respondents in bioprocess applications).
intensive processes. Another goal of say their companies have not been And there may be better options
process intensification (and following QbD to any radical extent for interchangeability currently
optimization in general) is to reduce even though they may be through some degree of single-use
eventual costs to patients and benefiting from process analytical standardization. But this tally may be
therefore improve global access to technologies (PAT) to streamline influenced by the ability of
biopharmaceuticals, recombinant their work and optimize respondents to rely on a scalable suite
vaccines, and personalized therapies. characterization efforts. That falls in of equipment and components from a
line with what weve learned from major supplier of single-use
2 BioProcess International 15(6) Chapter 8 of 11 State of the Industry 2017
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Editorial Advisors Speak Up
current good manufacturing practice addressed modes of operation and
(CGMP). On the State of the Art: We are seeing issues related to facilities and site
We ended with a brief look at a maturing market where end users transfer and how to leverage
automation. Cohen believes that have a better understanding of where it existing resources.
compliance with good automated can make best sense to use specific Upstream Technologies: The current
biomanufacturing models. We are
manufacturing practice (GAMP) rules course of bioreactor development
seeing all the major players working
is the most important issue that has with facility of the future projects for
continues to optimize operations,
arisen for software engineers in the which they are evaluating how can they parameters, and process-monitoring
biopharmaceutical industry as well as design facilities and processes that technologies with a strong focus on
its suppliers and service providers over enable highest productivity, high development of in-line sensors, which
the past 15 years. He also pointed to quality, and lowest cost. This is what is still face gaps in commercial offerings
use of 3D building information really driving process intensification and reliability. A number of wave-
modeling (BIM) during the design with highly productive cell lines, high motion systems are on the market, and
phase of facilities engineering. I have capacity purification, enhanced process the entrance of cell-therapy into
seen an increase in the desire to use control using a lot of real-time PAT, and commercial viability has influenced
this across the board. multivariate modeling of manufacturing bioreactor design for those special needs
processes for much deeper process
Continuous Processing: This is a (such as adherent cells, as reported on
understanding.
popular topic of discussion (and elsewhere in this special issue). As
debate) lately in production and Companies are trying to think through predicted, stainless steel reactors and
how they can significantly lower the
processing/manufacturing. As with large-scale fermentation vessels have
cost of biomanufacturing working with
other industry innovations, the initial alternative hosts for protein production
not gone away. And in some cases they
push (before reality sets in) often is for and different cell lines, and some are are seeing potentially new demands,
total incorporation. And that reality evaluating whether highly automated including with cell-retention devices for
resides in two key elements of bioprocessing could reduce cost of perfusion processes and in hybrid
practicality: process variability and goods. Miriam Monge (director of processes with SUTs.
process complexity. Researchers and marketing for integrated solutions at Continuous Culture: Protein-
developers have more choices to make Sartorius Stedim Biotech) producing cells still are grown mostly in
among sensitive analytical methods batch or fed-batch culture mode. But
and equipment than were available a further advances in scalability and over the past five years, perfusion
decade or more ago. The data automation are needed. The cost of its processing has been a major topic of
generated are complex and require implementation also will need to exploration. Technologies once used
more training for people who need to decrease significantly before its only for difficult-to-express proteins
interpret them. widespread adoption. Although some and those more likely to break down in
Options have emerged for new people have been promoting the solution now are considered for products
categories of products, building on continuous idea for decades, it has across the biopharmaceutical spectrum.
established technologies. So cell become newly popular with the advent Perfusion culture allows for high-
therapies benefit from adaptation of of novel technologies. But disposables density cultures that maximize
traditional bioprocessing methods, and automation themselves are still in productivity in relatively small
antibodydrug conjugates reach from development for specialized applications. bioreactors. It requires continual feeding
across the (traditional, at least) small- and thus uses up large volumes of
and large-molecule divide . . . and so State of the Art in Manufacturing culture media/supplements as well as
on. Vaccine and immunotherapy From our state-of-the-industry continuous removal of metabolites and
manufacturers benefit from shared survey and from the other articles product, with dilution rates exceeding
technologies with other bioprocesses in this special issue certain points the cell growth rate. This requires a
and present their own challenges. emerge about key issues in means of retaining cells in a bioreactor
Another example of increasing variety biopharmaceutical production and while removing (and replacing) the
(if not also complexity) is in bioreactor manufacturing. By the time drug- supernatant around them. Hollow-fiber
design, with many options these days substance production begins, work by reactors offer one solution, with new
specific to the type of cells that are other departments has defined a technological advancements addressing
growing, the lots sizes required, and process and proof of concept, and their problems of old.
where manufacture will take place. critical parameters and operating Culture Media: With an eye toward
Figure 3 shows that survey responses ranges are defined, with a goal of increasing manufacturing f lexibility,
mirror much of what weve heard about reducing changes to processes and/or productivity (yield), and speed to
continuous processing at industry events: equipment at later stages. Affecting clinic, suppliers continue to introduce
that it may apply initially to only a few how production and manufacturing new media, shear protectants, and
types of products and otherwise mainly are conducted, departments tasked supplements. With efforts toward
at early production scales, that its with process design, logistics, and media supplementation these days
biggest challenge lies in the interface business planning have already locked enhanced by the use of design of
between up- and downstream, and that in parts of the process, having experiments to screen for optimal
6 BioProcess International 15(6) Chapter 8 of 11 State of the Industry 2017
Collaboration.
Reliability.
Quality.
angus.com
Editorial Advisors Speak Up
conditions, companies have many tight particle and pore-size distributions
good choices for finding what will be On Downstream Processing: In Japan, are becoming state of the art, improving
the best growth environments for we started a big national consortium four long-term process performance
their cells. years ago on next-generation biological (important for continuous processing).
Emphasis on continuous culture production technologies (http://cho-mab. Finally, binding capacities of affinity
or.jp/english/project). Members include
puts the spotlight on expensive feeds (mainly protein A) and ion-exchange
28 companies, four universities, a national
making companies look for more research institute, and three organizations,
(improved salt tolerance) media have
cost-effective options. That has brought and one of the main topics for this project improved significantly. All these
some full circle: Media can either be is single-use technology. We built a good improvements allow for downsizing of
purchased as ready-to-use liquids or as manufacturing practice (GMP) facility in chromatographic unit operations.
dry powders to mix on site and/or on Kobe, where we can test all technologies The protein A ligand is the most
demand. The former is most familiar developed by the consortium. The project widely used material in affinity
to small research laboratories; the latter is sponsored by the Japanese Ministry of chromatography purification for the
long has been the choice of large-scale International Trade and Industry (MITI) capture of antibodies and many
bioprocess facilities. But in-line buffer and Japans Agency for Medical Research antibody-derived proteins (e.g., Fc
dilution systems, outsourced buffer and Development (AMED). My major fragments). IgG binds to protein A at
research area is modeling and software of
preparation, and precision-formulated its Fc region in a highly specific and
chromatography processes, which I am
liquid media are bringing many also working on for this project.
hydrophobic interaction. Its use
facilities back to the idea of purchasing Shuichi Yamamoto (Yamaguchi University) removes more than 98% of impurities
ready-made feeds. from complex solutions (2). But over
Upstream Expression Systems: the years, bioprocessors have begun to
Two decades after some proponents of for nonantibody proteins have not lament the drawbacks of protein A. As
transgenic animals predicted the end progressed so far. What similarities BPI editorial advisor Blanca Lain
of cell-culture expression, few can be expected? (That will no doubt (director of protein science at
transgenics companies remain. And in be a major topic explored in BPIs Dragonfly Therapeutics) noted in her
that time, new cell lines have been 20th-anniversary issue.) 2013 article, this type of affinity
continually introduced. In 2012, the Downstream processing always has chromatography usually necessitates
10th year of BPIs publication, we saw been and for the most part, the use of harsh conditions such as low
the launch of the Pfnex expression remains a step-by-step batch pH for elution. That can be
technology platform based on the operation in biopharmaceutical problematic for some antibodies that
microorganism, Pseudomonas manufacturing. But what may have are either unstable or tend to aggregate
fluorescens (currently being used for been seen as wishful thinking 15 years at low pH levels. In general, only a
biosimilar candidates). Plant-based ago is becoming a reality: continuous small amount of impurities e.g.,
expression systems (both cell lines and downstream processing. As Margit aggregates, residual host-cell proteins,
whole organisms) are now offering Holzer (scientific director at Ulysse DNA, and leached protein A will
relatively quick, inexpensive Consult) wrote in our most recent remain after this single starting unit of
production of some vaccine products featured report (1), it generally downstream process operation. They
required in large doses. requires more process knowledge, usually can be removed in either one or
Cell-line engineering is beginning equipment, and technological two additional chromatography steps
to benefit from advanced, site-specific advances than do batch processes. (2). Expense is another notable
gene modification techniques such as Holzer described continuous drawback to the use of protein A. Some
zinc-finger nucleases (ZFNs), chromatography options from a researchers have proposed alternatives
transcription activator-like effector number of suppliers. Some qualified for protein A chromatography, but the
nucleases (TALENs), and the systems already are used for producing adoption of those technologies is not
CRISPR/Cas9 technology. And clinical material. She also highlighted yet widespread (3).
several companies are pushing the productivity gains and reductions of Of equal importance to
envelope: Ajinomoto Althea has a processing volume achieved when chromatography in downstream
proprietary system combining companies switched from single- to processing are filtration and other
attributes of mammalian and multicolumn continuous membrane separations. Depth and
microbial systems, especially chromatography processes. sterile filtration are used to reduce or
recommended for difficult-to-produce Not only chromatography processes, prevent particles/bioburden in frontal
proteins; Boehringer-Ingelheims (BIs) but also separation media have (dead-end) mode. Membranes used for
BioXcellence unit uses a proprietary developed over the past few years, concentration and separation of
vector system with its BI-HEX cell Holzer pointed out. Major molecules, media exchange, and
lines. improvements have increased physical formulation steps typically run in
In 15 years, weve seen steadily and chemical stabilities, allowing for tangential-flow or crossflow mode (1).
rising antibody expression titers: processes to be run at higher flow rates Dead-end filtration is a batch
100mg/L, 1 g/L, 5 g/L, 10 g/L. . . and with more stringent process process, Holzer wrote. With
Meanwhile, however, expression levels solutions than before. Media with very alternating filter devices run in parallel,
8 BioProcess International 15(6) Chapter 8 of 11 State of the Industry 2017
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