Commercial Biomanufacturingwith Single-Use Technologies
Modular systems allow to establish flexible facilities
even at the 2,000 L bioreactor-scale

Success Story
One of our multinationalcustomers has adopted asingle-use platform concept
for development and GMP
manufacturing across its
global locations

The global biopharmaceutical market continues to grow and has been
dominated by high volume products such as monoclonal antibodies. Within
the next decade, however, biomanufacturers anticipate that their pipelines
will become more diverse. Low volume-, highly potent products will enter themarket and may require novel processes and smaller manufacturing scales.
There has been an industry-wide increase in the adoption of single-use technologies for the commercial production of these biopharmaceuticals needed
in low volumes. One of our multinational customers has adopted a single-use
platform concept that will allow it to use the same process configurations fordevelopment and GMP manufacturing across its global locations.

Transitioning towards Single-Use Technologies
Our customers’ platform concept uses 100 L, 500 L and 2 kL singleuse bioreactors for the production of clinical phases and commercial supplies. It incorporates the latest single-use technologies
available on the market and a new approach for aseptic andclosed processing that minimizes bioburden and improves safety.
Single-use technology is becoming ubiquitous within thebiomanufacturing industry. Companies regard it as complementary
and, in some cases, an alternative to traditional stainless steel
equipment for the commercial manufacturing of smaller volumeproducts. Until recently, facilities for the commercial productionof biologics contained large stainless steel bioreactors, oftenwith working volumes of 15,000 L or greater. They were typicallydesigned to accommodate processes with cell culture titers below
4 g/L. However, the cost of constructing facilities such as thesecan exceed $500 million and take up to five years. A significant
component of the cost and the facility footprint was dedicatedto utilities for the production of WFI, HVAC, clean steam and CIP
solutions.

» H aving a standardized consumabletoolbox is supporting our customer’s
global demand planning activities.

Advances in bioprocess development are leading to higher titersand greater productivity. Titers of CHO-based production systems
have increased in recent years and nowadays average in the range
6-8 g/L. These developments together with an increased diversifi-2

cation of molecule formats produced in cell culture will change
the biomanufacturing landscape. New requirements may be met
with smaller, more flexible bioreactors established in single-use
facilities. In such facilities, different bioreactor sizes can beinterchanged and allow managers to modulate production
capacity to match fluctuations in product demand. In addition
to improved flexibility, single-use facilities are less complex todesign and have lower upfront investment costs. They are fasterto construct, to commission and to launch. The time needed forchange-overs between products is significantly reduced, allowing
more batches to be run each year in multi-product facilities.

Considerations for Commercial Manufacturingwith Single-Use Technology
Our multinational customer completed the installation of its
2,000 L single-use manufacturing facility in Asia in the firsthalf of 2017. Adopting the platform approach is allowing thecompany to seamlessly transfer processes from its other locations
to this facility. The prototyping of upstream and downstream
technology and the design of consumables were completed inearly 2016. Facility Acceptance Testing (FAT) and Site Acceptance
Testing (SAT) were performed during the second half of 2016
allowing the process qualification runs to start in early 2017.
In the first instance a single 2 kL production line has been installed with the option for further expansions.
To facilitate process transfers across the company’s global
manufacturing network, our customer has worked with Sartorius
Stedim Biotech (SSB) to standardize the many consumabledesigns that were previously in use. This allows consumables tobe transferred between facilities or between unit operations as
the need arises. Having a standardized consumable toolbox issupporting our customer’s global demand planning activities.
Furthermore, using these pre-designed solutions improves therobustness and assurance of supply while reducing lead times.

» T his one piece of equipment canperform depth filtration, nano-filtration,
ultrafiltration and solution adjustment
steps within the downstream process.

Innovative Single-Use Solutions
SSB was able to support our customer further by designing innovative solutions to processing challenges. Sartorius configured aFlexAct® system to perform automated harvests of the commercialscale single-use bioreactor. This configuration incorporates new
single-use pressure and flow sensors, a two-stage depth filter
train and a final filter skid comprised of 0.2 and 0.1 micron
membrane filters that can be readily integrity tested.
The FlexAct® system and associated consumables were designedby SSB to fit the customer’s platform. This one piece of equipment can perform depth filtration, nano-filtration, ultrafiltrationand solution adjustment steps within the downstream process.

SSB is also working closely together with this customer todevelop large-scale, single-use sterile filtration solutions. The
technology developed could be gamma-irradiated and integrity
tested before and after use. The system is extremely flexible andallows users to install nine different filter capsules of different
sizes and yet is a single piece of equipment with one inlet andoutlet. SSB supplies the filter manifold with the necessary valvespre-installed and filters for integrity testing pre-attachedMaxiCaps® MR.

» A pplying ‘system marriage’ techniques,

well established in the automotive industry,
will help reduce risks and accelerate
single-use project execution.

New Competencies for Executing
Single-Use Projects
This project and others we have performed have proven thatconventional project management and execution protocols
developed for the construction of stainless steel facilities are notappropriate for single-use engineering projects. These traditional
execution methods do not allow engineers to take full advantageof the flexibility and speed of implementation that single-use
technologies permit.
Project teams in the biomanufacturing industry need to develop
new competencies that allow the bringing together of hardware,
software and wetware simultaneously. This is in contrast to themore traditional, sequential approach that they have used in thepast. Applying ‘system marriage’ techniques, well established in
the automotive industry, will help reduce risks and accelerate
single-use project execution.

Conclusion
In summary, we see that today’s production technologies withhigh volume stainless steel fermenters are complemented andwill co-exist with the use of disposable production platforms forresearch & clinical manufacturing and for commercial manufacturing of high potent and small volume molecules. The use ofmodular systems allows the industry to establish flexible facilities
even at the 2,000 L bioreactor-scale. A robust concept for closed
system processing is necessary for commercial manufacturing
using disposable. Single-use technologies require new competencies from engineering teams for the design and execution ofbioprocess engineering projects. It makes sense to develop suchcompetencies together in a partnership approach between
supplier and customer.

MaxiCaps® MR: an extremely flexible system in a sinlge piece with one inlet
and one outlet.

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Specifications subject to change without notice. Copyright Copyright Sartorius Stedim Biotech GmbH and Fraunhofer IZI. Printed in the EU on paper bleached without chlorine.
Publication No.: S—1016-e180601 · Order No.: 85034-561-40 · Ver. 06 | 2018

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August-Spindler-Strasse 1137079 Goettingen, Germany
Phone +49.551.308.0
www.sartorius-stedim.com