Unblocking the Bottleneck
A Conversation with Fritjof Linz
With another Upstream–Downstream
Processing Forum successfully concluded,
BioProcess International caught up
with Dr. Fritjof Linz, vice president of
marketing purification technologies at
Sartorius Stedim Biotech, to discuss the
event and discover what trends lie ahead
for the bioprocessing industry.
R
egarding the event, Linz
commented, “The Upstream
and Downstream Processing
Forum already is an
institution in the market and has been
organized by our company for many
years. All event presentations have
been excellent and have provided deep
insights. Our aim is to give experts
from the biopharmaceutical industry
the chance to talk about technologies
and products as well as to provide a
networking environment in which to
talk about the latest industry trends.”
The latter is something that
happened during the forum this year,
wherein attendees examined how
companies could run down-scale
models for both upstream and
downstream operations. “For upstream
applications, our ambr systems are
particularly suitable, and a number of
speakers included references to those
products in their presentations. On the
downstream processing side, a key
focus area is mitigating the risks of
virus contaminations. That work starts
at the beginning of a process with
culture media preparation and use of
specifically designed filters for easy
virus removal.”
Another major trend is continuous
processing (CM) or process
intensification and the need to
generate more economical approaches
to biopharmaceutical manufacturing.
“The primary drivers are higher
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yields,” explains Linz. “But shorter
processing times also reduce costs and
labor.” A large part of that (equally
well presented by many speakers) is
quality by design (QbD). “It’s one of
the topics that regulatory authorities
are focusing on to ensure that
manufacturers gain deep knowledge of
their processes.” Regulators advise
companies to run tests at a small scale
so that when the appropriate data have
been collected, manufacturers know
how to progress that operation to
larger scales. “Again, it’s all about
remaining in control of a process,
maintaining consistent quality, and
ensuring patient safety,” Linz adds.
Industry Demands
“Continuous manufacturing is commonly
used as a term for process
intensification,” notes Linz.
“Depending on the final target volume
of a product, different production
modes will be suitable. What we’re
seeing is a greater diversity of annual
production demands. So you have to
decide on the best manufacturing
method to use. For lower volume
products, batch mode may be more
appropriate. For larger-scale demands,
however, continuous manufacturing
often is better.
“Continuous is a single word but
comprises a number of elements,” says
Linz. “Such factors include improved
quality, better process consistency,
higher and more cost-effective yields,
and downsized facility footprints.
Facility footprint has a significant
impact on overall cost. Traditional
stainless steel set-ups can cost up to
€300 million, whereas a single-use,
small-scale alternative can be
downsized to a range of €50–100
million and offer the same capacity.
For industry, that’s important.
Fritjof Linz
Manufacturers are challenged to make
drug products more cost efficiently
because insurance companies no
longer want to pay high prices for such
products. It’s a key driver,” says Linz.
In such cases, down-scale models
can help manufacturers establish
relevant information about process
economies. But at the end of the day,
the method selected will be determined
by an annual forecast. Regulatory
requirements are another factor to
consider in selecting a production
method. In down-scale models you can
show the performance of a certain
mode of manufacturing. Only the
process development time needed to
collect data will differ between CM
and batch mode.
For large-scale production,
however, chromatography is still a
limiting factor. “If you look at
upstream titer development, then
resin-based chromatography is limited
to a certain size and capacity, says
Linz. “Beyond that, from both a
management and an engineering
perspective, the procedure becomes
hard to handle.”
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“What we can do is think in terms
of our client, which means considering
their application — be it an antibody or
a vaccine. Such products have very
specific but different requirements. We
need to fully understand the process
and product and fit our solutions to
meet those needs. We select out of our
portfolio, those products that match
our clients’ requirements.”
Single-use technologies are an
overarching trend. Manufacturers are
using their plant footprints in different
ways, reducing interbatch turnaround
and preparation times, and making
processes more economical,
particularly during downstream
processing. The use of single-use
continuous technologies, such as kSep
centrifuges, introduces new
opportunities: You can work in closed
systems. Sensitive or potent products,
for example, need a fully enclosed
environment. Of course, eliminating
stainless steel components and the
associated cleaning times will make
any process more efficient.
kSep Systems is a recent acquisition
for Sartorius Stedim Biotech. It
specializes in advanced centrifugation
for the purification of recombinant
proteins, cell therapy products, and
vaccines. The systems “provide a
gentle processing environment for cell
separation,” says Linz. “With
conventional centrifugation at high
cell densities, you often need to
sacrifice both recovery levels and
product quality because of high shear
forces. kSep centrifuges overcome that
issue by recovering product from the
interstitial space between cells before
discharge while reducing host-cell
protein contamination by exposing
cells to lower shear forces.”
“kSep’s centrifuges are an
innovative, single-use cell separation
technology that perfectly complements
our downstream bioprocessing. Our
clients will benefit greatly from the
unique ability to collect, wash, and
concentrate cells quickly while reducing
both the time and cost of high-titer
downstream purification.”
Biotech Trends
As Linz observes, one key trend is
that of analytics. “In the
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biopharmaceutical industry, we’re still
struggling with product quality
indicators that we can’t analyze as well
as we can in the chemistry arena.
With chemistry, I can analyze a
molecule and clearly identify it. That
is not yet the case in biotechnology
with the same accuracy. With this in
mind, using analytical parameters to
steer processes to the right quality
levels is one of the biggest challenges
ahead. The more we think about
continuous manufacturing, the more
we need to be capable of putting
analytics in place — next to or within
the process — to fulfill future needs
of the drug manufacturing industry.”
At the event, it was suggested that
a combined upstream and downstream
proposition is where industry should
be heading. Linz agrees: “We must
always think about upstream and
downstream processes together, not as
separate procedures. They can’t really
be separated from each other or
thought of in isolation.Upstream
processes affect how we design
downstream procedures. Of course,
whatever happens upstream will
influence downstream. They are
clearly interlinked in terms of both
capacity and product quality. With
increased upstream titer volumes,
downstream processing has become
the bottleneck!
“One key parameter is that we
always have to build a certain level of
security into a process. But if I control
upstream processes more accurately,
then I can better optimize
downstream systems to deliver cost
savings. Currently, because of
upstream variations, we use safety
margins of about 30%. With better
control, we can improve on that and
improve the entire. It’s not upstream
versus downstream but rather a
combined and better controlled
production method. That’s something
we’re looking at here at Sartorius.”
Forum Feedback
Linz feels that the forum was well
received, and the feedback was very
positive. “Our 120-plus guests enjoyed
the setting and the fact that the
sessions were technologically driven.
They also enjoyed the networking
opportunities during the breaks and
the opportunity to get a first-hand look
at some of the new Sartorius
equipment. It was a lot of fun, a lot of
work, but the organizing team did an
excellent job. It was a wonderful
opportunity to talk to our valued
clients.”
Delving a little deeper into the
forum content, Linz notes: “We had
speakers from Bayer, for example, who
had established single-use antibody–
drug conjugate processes that could be
performed in a facility that is only
typically used for protein purification.
That is uncommon in the market. In
addition, we had speakers from
Boehringer Ingelheim who discussed
the challenges surrounding in-house
custom manufacturing and whether
those procedures met regulatory
requirements. It transpires that it’s not
always as easy as it looks — and it
doesn’t always work out as planned!”
“We also had a very insightful
speaker from the US Food and Drug
Administration (FDA), who explained
that the agency has a research
department that looks into the
technological challenges affecting the
biopharmaceutical industry as well as
ongoing and upcoming trends. This
means that FDA regulators have a
good understanding when they review
and audit and are prepared and aware
of what’s ahead of them. They must
understand and embrace emerging
technologies to be able to approve
them.”
Looking ahead and commenting on
how Sartorius Stedim Biotech can
progress downstream processing, Linz
says, “If you look at our portfolio and
our focus on process intensification,
we’re doing a lot of work with
membrane-based chromatography. We
believe this technology will provide
shorter turnaround times and faster
set-up times. Also, improving overall
system economy is a key driver — not
just for unit operations but for an
entire manufacturing process. Each
step must be optimized to make
biomanufacturing more time- and
cost-efficient. And, with our current
offerings and products in
development, we’re well positioned to
drive that change.” •
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