SUPPLIER SIDE

Simplifying theBioprocessing 4.0 Journey
Artur Arsenio, Michael Koch, Johannes Wagner, and Ganesh Kumar

B

ioprocessing 4.0, thebiopharmaceutical version ofIndustry 4.0, is on course to
become a reality in the next
decade (1). This is because its “cyberphysical systems” that comprise cloudcomputing, connected systems, anddigital process control offer many
benefits. They include better processmonitoring and management of abiologic’s critical quality attributes(CQAs) and the chance to control
intensified processes for faster, lessexpensive production of protein-based
biologics and vaccines. Automation
also can reduce the number of skilled
operators needed while making
manual tasks less error-prone andmore efficient. That frees scientists towork on multiple processes
simultaneously and respond rapidly toprocess issues, even from remotelocations.

Bioprocessing 4.0 Roadblocks
For many biopharmaceuticalcompanies, Bioprocessing 4.0 remainsa bête noire that is insurmountable.
Their perception is that the cost,
resources, and time required to adopt
best practices are just too much tojustify without a guaranteed return on
investment. Some people also believethat the concept of Industry 4.0 isdifficult to adapt to biopharmaceuticalmanufacturing and is better suited toimplementation in other industries.
Such perceptions are due in part to alack of awareness about the benefits
that digital technologies such as
simulation/data connectivity and theuse of digital twins can bring to abiologics manufacturing environment.
Additionally, insufficient connectivity
across bioprocess equipment from70

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19(9)INCREMENTAL APPROACH
TO BIOPROCESS 4.0

different suppliers and gaps intechnology make end-to-end, fullyautonomous bioprocessing seem
frustratingly out of reach.
Initiatives to develop standard datainterfaces — including the recent
BioPhorum plug-and-play principles (2) —are helping to move the goal posts, andimplementing single-use (SU) technology
can support a Bioprocessing 4.0
approach. But implementation is not as
simple as connecting and qualifying
systems in a manufacturing plant.
Bottlenecks can occur if equipment is
not easy to integrate with higher-levelsupervisory control and data acquisition(SCADA) and/or manufacturing execution
systems (MES). Such issues lead many
companies to think of Bioprocessing 4.0
as “nice to have” and something they will
get around to only after they have solved
existing problems within their
manufacturing networks.
However, increasing adoption ofprocess intensification is pressuring
manufacturers to develop a roadmap
for Bioprocess 4.0 that not only
addresses the roadblocks mentioned
above, but also enables real-timemonitoring, prediction, control, andrelease of critical process parameters(CPPs) at the entire process level.

An Incremental Framework
for Integration
Being ready for Bioprocessing 4.0
does not require completion in one
giant leap but, instead, should be a

September 2021

journey of manageable steps. Adopting
available automation and real-timemonitoring systems enabled byprocess analytical technology (PAT)from suppliers with a global network,
deep process knowledge, andunderstanding of pain points canfacilitate the transition toward
Bioprocessing 4.0.
For example, BiosanaPharma, basedin The Netherlands, is implementing thistype of approach to help manufacture
cost-effective biosimilars. The company
is lowering the cost of goods in its
manufacturing process by adopting
end-to-end continuous manufacturingwith its 3C process. The 3C platform(Figure 1) uses SU technology, PAT, andcurrent good manufacturing practice(CGMP)- compliant plug-and-playsystems from just a handful of suppliers
to make the facility ready for
Bioprocessing 4.0 (3). The simple
pathway for implementation includes
process automation designed foroverarching data collection andfeedback control between SCADA andcontrollers associated with SU systems.
In upstream processing, the SU systems
include a high–cell-density seed train
with a 5-L Biostat STR bioreactor andproduction using 50-L dual SU Biostat
STR bioreactors for alternating use,integrated with a tangential/alternating
flow filtration (TFF/ATF) device followedby cell selection and/or harvest withKsep SU centrifugation technology fromSartorius. The downstream processuses a BioSMB PD multicolumn
chromatography (MCC) platform
combined with flow-through polishingand intermediate filtration steps.
Ard Tijsterman, CEO at
BiosanaPharma, explains: “Thechallenge in continuous processing isSponsoredFigure 1: Representative setup of a highly automated process for intensified biomanufacturing (RT = real-time; PAT = process analyticaltechnology)
Umetrics Simca-Online for RT Monitoring and Control

Biostat RM 20 L

Biostat RM 200 L

SCADA/DCS/MES

Biostat STR 500 L

Seed Train

Biostat STR 1,000/2,000 L

Production Bioreactor

Ksep system

BioSMB Process 80/350 L

Clarification and Direct Capture

Plug-and-Play System Platform with Integrated PAT

to be able to adapt the speed of theDSP to the output of the USP. Volume
and product mass must be managed
because all systems run
simultaneously. To become
Bioprocessing 4.0 ready requires a
step-wise approach, which we havebegun by integrating unit operation
communication and control via SCADA
and moving from off-line sampling toat-line and in-line analysis wherepractically possible. Working withfewer suppliers and using
preintegrated systems makes plug andplay easier as does softwarecommunication for flow control anddata acquisition.”
PAT technology is helping operators
implement real-time data gatheringfrom bioreactors on CPPs, includingpH, cell density, and viable cell count(VCC), to control and monitor
BiosanaPharma’s media and feed
strategies with minimal operator
interactions. In the future,
BiosanaPharma hopes to use Ramanspectroscopy for analyte testing andquality by design (QbD). The company
also wants to implement SIMCA MVDA
tools to analyze, link, and contextualize
the vast amounts of process data,
which will help eliminate islands ofinformation and enable operators toreap maximum benefits/efficiency fromthe data.
Commenting on the benefits ofmaking a facility ready for
Bioprocessing 4.0, Tijsterman adds,“Bringing down the cost of goods is avery strong driver for us. By using
continuous processing, we canSponsored

produce at high productivity andreduce our costs by 10-fold comparedto the competition in biosimilar
manufacturing. With a Bioprocessing
4.0 approach and by partnering with
suppliers like Sartorius, who have asimilar vision, we are confident thatpredicting upper and lower ranges of
our CPPs will be possible in scale-up
and commercial manufacturing. Thisapproach will help to maintain CQAs ofour monoclonal antibodies (MAbs) andvalidate our intensified processes,
ensuring cost-effective, consistentproduct quality.”

Collaboration Is Key

Becoming ready for Bioprocessing 4.0
for current and next-generation
intensified manufacturing seems to bea daunting prospect for smaller
biopharmaceutical companies and forcontract development andmanufacturing organizations (CDMOs).
However, as companies such as
BiosanaPharma demonstrate,
readiness is achievable by adopting apractical step-wise approach for which
a logical, workable starting point is useof PAT, plug-and-play/industrystandard interfaces, data analytics, andimproved controls for CPP monitoring
and control. BiosanaPharma’s
experience also shows that even thefirst step is a team sport in which
partnering with experts such as
Sartorius with experience and the rightsuite of products and capabilities canhelp. Tapping into a supplier’s
expertise ensures that companies canaddress Bioprocessing 4.0 challenges

to optimize a process while focusing
on single-unit operations. This
simplifies implementation of nextgeneration manufacturing enabled byprocess intensification for efficient
production of high-quality, affordable
biologics.

References
1 Demesmaeker M, et al.
Bioprocessing 4.0 — Where Are We with
Smart Manufacturing in 2020?
Pharmaceutical Outsourcing (September2020); https://www.pharmoutsourcing.com/
Featured-Articles/568001-Bioprocessing-40-Where-Are-We-with-SmartManufacturing-in-2020/.
2 BioPhorum Plug and Play Workshop(2018). Accessed May 2021; https://www.
biophorum.com/plug-and-play-workshophow-to-make-standardized-interfaceswork-2/.
3 Press release: BiosanaPharma Gets
Approval to Start Phase 1 Clinical Trial for a
Biosimilar Version of Omalizumab, the First
Monoclonal Antibody Produced with a Fully
Continuous Biomanufacturing Process;https://7301a529-be14-475b-8c71b839f438e656.filesusr.com/ugd/3f142e_
adbf792b6efa47ebb1aa1aa85770ca9c.pdf. c

Corresponding author Ganesh Kumar ismarket entry strategy manager forprotein based therapeutics; ganesh.
kumar@sartorius.com. Michael Koch ishead of sales, integrated solutions in
the Asia–Pacific region; Artur Arsenio ishead of product management for PAT,automation, and software; and Johannes
Wagner is manager of systems
engineering for BPS systems. All arewith Sartorius in Germany.

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