Genetic Engineering & Biotechnology News

AUG 2016

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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24 | AUGUST 2016 | GENengnews.com | Genetic Engineering & Biotechnology News See Bioreactors on page 26 term—stand regarding the relative merits of stainless steel and plastic. The arguments and rivalries faded long ago. "There are compelling business reasons for either one," notes Brady Cole, vice president, commercial operations, ABEC. "We take the same custom approach to single-use manufacturing equipment as we have for stainless for over 40 years." Bioprocessors must still perform due diligence when speci- fying new bioreactor capacity. Production scale and econom- ics remain pertinent issues. Yet if anything, adoption of single- use equipment has had a positive effect on how the industry views stainless-steel equipment. Paraphrasing Mark Twain, Cole notes that "reports of the death of stainless-steel equip- ment have been greatly exaggerated." Companies are still us- ing large stainless-steel bioreactor tanks in new facilities, and despite rises in titers for many products, tank sizes have re- mained in the 10 kL to 20 kL working volume range. Larger volumes plus higher titers have generated bottle- necks here and there for downstream operations, but these problems are solvable through appropriate engineering ap- proaches. At the same time, a renewed focus on product quality has provided parallel quality incentives for manu- facturers of stainless-steel equipment. "We need to align our products with customers' quality systems," Cole adds. To that end, he sees a rededication to lifecycle documenta- tion, and "a lot more" qualification at the bioreactor produc- tion facility rather than at user sites. "That makes a huge impact on quality as well as a scheduling advantage," Cole insists. "If you go through installation and operation quali- fication (IQ/OQ) at ABEC, you will decrease your schedule risk and increase your chance of achieving high levels of quality during operation." Realizing Quality Sensors and probes are relatively straightforward modi- fications that make bioreactors more suitable for process analytic technology (PAT) and quality by design (QbD). Ac- cording to Surendra Balekai, senior global product manager at Thermo Fisher Scientific, the lack of standardization in single-use sensors has hampered PAT and QbD efforts in the world of stainless-steel bioreactors and fermenters. Companies adopt single-use sensors for the usual benefits, which overall translate to lower costs. Sensors for stainless- steel bioreactors are multi-use, so their deployment involves steam sterilization and cleaning that disposable probes can- not tolerate. This, says Balekai, is what makes reusable sen- sors so expensive. Theoretically, single-use probes could be used in fixed- tank systems, but their individualized, unique dimensions prevent this for lack of suitable connectivity. "There's a need for our industry to consider connectivity standards to reduce development costs," Balekai says. Such standards would open up fixed-tank processing to the diversity and ease of use of sensors developed for single-use bioreactors, which in turn will improve PAT-ability. Harmonizing connectivity between plastic and steel will require development of two components. The first is an SIP (steam in place)-tolerant plastic port on the bioreactor, either built-in or aseptically retrofitted. This part must be construct- ed of sterilization-friendly material such as polyethersulfone. If this idea is to become attractive for fixed-tank systems, the second connection, on the sensor, must be available in a ready-to-use sterile format. "Unfortunately, not much work has taken place to imple- ment this idea," Balekai tells GEN. Such hybrid structures have lagged stainless- and plastic-only connectivity in terms of actualization. "Yet large-scale manufacturers who have already invested in fixed-tank equipment are eager to use the same analytics in steel and plastic, which would make production methods more easily transferable. This would open up a new world of sensing for stainless steel, while lowering costs." Standardization would also provide new options for other unit operations requiring sensors or controls (opera- tions such as mixing, virus inactivation, and final formula- tion, which have unique sensing requirements), and improve the ability to integrate these process steps, both within the realm of stainless steel and for hybrid systems. Since installed stainless-steel infrastructure will stay for at least another 10+ years, there is a need to harmonize analytical capabilities be- tween stainless-steel and single-use technology for easy tech- nology transfer in hybrid infrastructure. Importance of Hybrid Systems Hybrid systems raise questions of economics that super- sede the usual arguments for single-use systems. Connectors deployed during a process must be sterile, and such a process usually requires that critical components be assembled in highly classified space with the usual issues of cost, time, and inconvenience. Several experts interviewed for this article cit- ed the benefits of Steam-Thru ® Connectors from CPC, which was happy to provide additional information. The Steam-Thru Connector is not new, but its relevance has grown with the idea of marrying stainless-steel and plas- tic components. The device's three-port design allows sterile connectivity in low-classification space, thus relieving bio- processors of having to weld or perform other ad hoc opera- tions in a laminar flow hood prior to assembly. Simply perform an SIP cycle through the connector's lower two ports, then move the connector's valve to create a sterile flow path between the bioreactor and single-use system. This increases process flexibility while maintaining sterility for feed, harvest, or seed train transfer applications. For operations where sterile disconnect is also desired, the Steam-Thru II Connector would allow a second SIP cycle to perform a kill cycle prior to disconnecting the plastic system from the bioreactor. "Customers use these as replacements for stainless-steel valves," says John Boehm, the bioprocessing business unit manager at CPC. Previously, the preferred way to connect systems in sterile fashion was the "block and bleed" method consisting of isolation valves coming off the side of the vessel. This type of connector technology can enable the retrofit BIOPROCESSING As single-use bioreactors become more prevalent, biomanufacturers show more interest in replacement and integration strategies, which rely on single- use/stainless-steel equivalency, an instance of which is illustrated by the Xcellerex XDR bioreactor. The bioreactor, from GE Healthcare Life Sciences, has a probe belt that is equivalent between single-use and stainless-steel bioreactors. It provides an access point for conventional as well as advanced sensors. Continued from page 1 Plastic or Steel, Bioreactors Aim to Put Quality First

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