Genetic Engineering & Biotechnology News

AUG 2017

Genetic Engineering & Biotechnology News (GEN) is the world's most widely read biotech publication. It provides the R&D community with critical information on the tools, technologies, and trends that drive the biotech industry.

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Page 22 of 37

Genetic Engineering & Biotechnology News | | AUGUST 2017 | 21 Clapp notes that while current molded single-use benchtop bioreactors replicate the geometry of larger systems, they may not use the same polymer types. "By running reac- tions in different polymers, you're setting yourself up to perform time-consuming cy- totoxicity and leachables [and] extractables studies not once, but twice or more." While the economics of single-use are well established above the bench scale, they are not as straightforward for benchtop bioreac- tors, particularly on the basis of cost of goods. Clapp dismisses these considerations. "We're talking about high-value products destined for manufacturing, not basic R&D. Single- use equipment is already commonplace at production scale. Companies that work with- in that framework from the beginning will find that the benefits far outweigh the costs." Scaling = Controls Finesse, a business unit of Thermo Fisher Scientific, known for its bioreactor sensors and controllers, also makes a full range of bioreactors. These include the SmartRocker rocker-type bioreactors up to 50 L, glass ves- sels ranging from 1 L to 15 L, and a single- use 3-L bioreactor. Single-use sizes of 1 L and 15 L are expected in early 2018. In designing its benchtop glass bioreac- tors, Finesse looked at the competition and concluded that obtaining low shear and high k L a in a small bioreactor required a hybrid between Rushton and marine impellers. According to the company, Finesse bench-scale bioreactors provide full scalabil- ity to any of its competitors' large single-use bioreactors. The company achieved this by duplicating key process actuators that apply to all bioreactors, independent of scale. "If you use the right control strategy, all the actuators (such as pumps, mass flow controllers, etc.) are linearly scalable, and all the sensors are the same technology (electro- chemical or single use), you can, in fact, scale cultures up and down once you've deter- mined the k L a, power number, and other key bioreactor process numbers," says Barbara Paldus, Ph.D., vice president and general manager at Finesse. "Once you define how to scale the key parameters and program them into the controller, it works almost like a mathematical transfer function, from small scale to large scale and back again." Subsequently, Finesse noticed that none of the small-volume single-use bioreactor systems on the market resembled their glass counterparts of similar volume, or the larger single-use systems they scale into. So, once the glass design and scalability models into larger single-use bioreactors were in place, Finesse copied the glass-vessel geom- etry into the single-use vessel design. "They look identical except one is made of plastic, the other from glass or stainless steel," Dr. Paldus explains. "We were then able to use electrochemical sensors through top ports, or single-use sensors from the side, or mix and match them as appropriate. Then we tried to match the headplates of the single-use vessels with the headplate of the glass, so users still had four sensor ports available." Moreover, the single-use sensors are iden- tical at 3-L, 15-L, or 500-L scale, and behave exactly the same whether in a rocker, glass, or plastic. The linearity and scalability of the pumps, mass-flow controllers, and transmit- ters remain the same as well. Any compo- nents that change in physical size are linearly scalable; and all transmitters are identical, so there's no controller-to-controller variability. "Scalability boils down to bioreactor design parameters themselves," Dr. Paldus explains. "And there, we've done computa- tional fluid dynamics to understand the dif- ferences and tolerances, which you can use to create control loop parameter mapping, which allows you to go from 3L in our bio- reactors to full-scale production from any manufacturer. Once you have all that data, and know the control and measurement components are identical, you've reduced the variability in scale up, which is where you find the most problems." Bioprocessing Repligen's benchtop single-use XCell™ ATF 2 cell-retention device is shown here in operation with a small bioreactor. The XCell ATF system uses alternating tangential-flow (ATF) technology for cell retention and process intensification. " The reason you don't see perfusion reactors below 2 L or so in volume is not because people don't want them, but because a scalable robust device hasn't been proven yet." — John Bonham-Carter, Repligen Earlier this year, Sartorius Stedim Biotech (SSB) launched its next-generation Biostat STR®, a fully scalable, single-use bioreactor family based on a conventional stirred-tank design. SSB officials say the new bioreactor range features upgraded hardware and software, as well as a fully integrated, new design of Flexsafe STR® single-use bags. The original Biostat STR was introduced to the market in 2008 and has since served as the single-use production platform at a number of major pharma companies, according to Thorsten Adams, Dr. rer. nat., director of product manage- ment, fermentation technologies, at SSB. "Working closely together with our customers, we have incorporated our combined experience to introduce design optimizations to increase robustness and flexibility," he said. "The operator experience has been enhanced by making bag installations even easier. The new Flexsafe STR bags provide robustness, consis- tent cell growth, and control of raw materials." Dr. Adams explained that the bioreactors seamlessly integrate into the customer infra- structure while simultaneously showing signifi- cantly improved heating and cooling times due to optimized double-wall geometries. The control system integrates into an existing distributed control systems (DCS) infrastructure, he added. The systems are completely scalable and the single-use bioreactors possess the same geom- etries as small-scale process-development systems and stainless-steel bioreactors, continued Dr. Adams. "This means that critical process parameters (CPP) can easily be scaled up," he pointed out. "The need of running optimizations at target production scale is dramatically reduced." n Sartorius Stedim Biotech's 2nd-Generation STR Bioreactors Sartorius Stedim Biotech recently launched the Biostat STR family, a range of next-generation bioreactors. The bioreactors, which feature upgraded hardware and software, work with Flexsafe STR single-use bags to facilitate the scale-up of bioprocesses for biologics and vaccines.

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