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26 | SEPTEMBER 1, 2016 | GENengnews.com | Genetic Engineering & Biotechnology News same—to get the most out of bioprocesses." Measuring intermediate metabolites or sub- strates on which cells grow are gaining impor- tance as well, since controlling these param- eters lead to higher quality and greater yields. Many sensing technologies have emerged but are of little use without demonstrable robust- ness at production scale. In that regard steril- ization remains a barrier for in-process sensors, and noninvasive sensors are highly desirable. Sensing and monitoring will gain even more prominence as continuous bioprocess- ing becomes more commonplace. "With per- fusion cell culture lasting weeks, even months, as many as one to one-and-a-half bioreactor volumes are run through the bioreactor ev- ery day," Clapp observes. "You get a lot of protein, but productivity must be measured against media costs. If sensors could show the way to reducing media consumption, biopro- cessors will save money and obtain more and higher-quality protein." Plastic/Steel Integration Interoperability between disposable sen- sors and fixed-tank bioreactors is still lim- ited, even though it would offer several ad- vantages. Besides lowering overall costs and enhancing flexibility in operations, such in- teroperability could facilitate the cross-plat- form transfer of PAT-related practices. An advocate of such interoperability is Surendra Balekai, senior global product man- ager, Thermo Fisher Scientific. He has argued in favor of standardizing single-use sensors and developing the means to apply them to stainless-steel bioreactors and fermenters. In the August 2016 issue of GEN, in an article entitled "Plastic or Steel, Bioreactors Aim to Put Quality First," Balekai pointed out that single-use probes could, in principal, be used in fixed-tank systems. In most cases, however, they lack the appropriate physical dimensions. Making them fit would require reworking the bioreactors' steam-in-place (SIP)-tolerant plastic ports, and demonstrat- ing equivalence for the sensors themselves. Nonetheless, as Balekai notes here, in- teroperability remains an attractive prospect: "Manufacturers with large fixed-tank instal- lations would readily use the same analytics in steel as in plastic, which would enable easier method transfer in production, as well as for ancillary operations like mixing." This kind of plastic/steel integration will likely remain out of reach until standardiza- tion efforts mature. Analyte sensors (that is, sensors for media components such as glu- cose and lactate) and sensors for osmolarity are generally unavailable for stainless-steel bioreactors. In any case, such sensors are of the offline type and hence unsuitable for PAT. "Some companies claim to have them, but we've seen reliability issues," comments Bale- kai. "They are not in single-use format." Trickle-Down Analytics Underdeveloped standards, limited in- teroperability, and questionable reliability— these adverse factors tend to dampen enthusi- asm for PAT and QbD. Nonetheless, PAT and QbD are often featured in conference pro- grams and trade publications. For example, Chantal Cazeault, the executive director of product quality at Amgen, has spoken on the need for PAT in continuous processing (itself a worthy topic), noting the lack of "guidance specific to continuous bioprocessing." Many similar presentations have been delivered by experts affiliated with best-in-class companies. One wonders, however, about the true depth of interest among rank-and-file compa- nies, whether innovation has actually trickled down to them from leading companies. In theory, these initiatives improve process un- derstanding. In practice, their investigation and deployment may impose resource costs that are unlikely to be recouped. Although some savings may be realized, they may not even matter due to "perfection pricing" for biopharmaceuticals. Bioprocess understanding would at least be more approachable if sensors were more reliable and their readings more reproducible across scales. "Scalability and consistency at dif- ferent scales remain issues," Balekai observes. Single-use technologies are already enjoying significant adoption in downstream processes. Presumably, these technologies are helping to satisfy production demands, which include re- liability and the implementation of PAT. Still, agreeable single-use trends could be reinforced with the development and implementation of better sensors. Ideally, manufacturers would strengthen their regulatory status by clarifying production hurdles and identifying process ef- ficiency and quality gaps. "But you still have to work at it," Balekai insists. What's Next? In bioprocess sensing, two of the more crit- ical parameters are pH and oxygen. "Online measurements of these two parameters allow control of culture conditions, and provide an excellent overview of culture status and per- formance," says Gernot John, Ph.D., director of marketing and innovation, PreSens. Online bioprocess sensing, however, does not stop here. Determinations of parameters such as carbon dioxide are highly desirable. "In cell culture, carbon dioxide is so impor- tant that it could even surpass pH as an in- dicative parameter," notes Dr. John. "This has been discussed for a while and can be verified in real processes only after reliable sensors become be available." Optical sensors are gaining greater signifi- cance in bioprocess monitoring. For example, in the monitoring of oxygen levels, bioproces- sors are replacing Clark-type electrodes with optical sensors. Optical sensors are also being used more frequently in the monitoring of pH, if only in selected applications. "Optical pH measurement," observes Dr. John, is "pri- marily utilized in single-use systems where it offers contactless pH monitoring." In general, however, optical sensors are unlikely to over- take classic pH electrodes, which provide a much broader measurement range. Optical sensors are also becoming more attractive through systems integration efforts. For example, it has recently become feasible to connect optical sensors to standard con- trollers through conversion devices such as the Optrode Dual from PreSens. Expanding the pH measurement range is a current development goal. "PAT encourages the application of more online sensing tech- nologies, but it also stipulates the measure- ment of chemical parameters," Dr. John notes. "The online determination of product titer is what users dream about—so there is plenty of room for further research and development." PAT and QbD have provided great impe- tus for bioprocess sensor development. In- dustry's commitment to PAT, in particular, is stronger than ever. Although PAT has taken more than a decade to reach its current state, there's no doubt that manufacturers under- stand the relationship between sensors, PAT, and quality, asserts Ken Clapp: "The pros- pects for greater competitiveness and lower costs are huge drivers." Sensor Awareness Continued from page 24 BIOPROCESSING This image shows the installation of probes and tubing on the Xcellerex bioreactor, a single- use stirred-tank platform manufactured by GE Healthcare Life Sciences. The company notes that sensing technologies should demonstrate robustness at production scale to ensure they contribute to higher quality and greater yields. > Amyris to Help Biogen Develop Alternatives to Mammalian Cell Lines Amyris entered into a partnership with Biogen to explore the use of Amy- ris's microbe engineering technology to evaluate and develop multiple host microorganisms as alternatives to mam- malian cell lines for the production of therapeutic recombinant proteins. For many recombinant protein thera- peutics, mammalian cell lines are engi- neered to produce the needed protein using a fermentation process. While tre- mendous progress has been made in in- creasing productivity, limitations remain. > Astellas Transfers Manufacturing Subsidiary to Avara Astellas Pharma transferred its whol- ly-owned manufacturing subsidiary, Astellas Pharma Technologies, to Avara Norman Pharmaceutical Services. "We have confidence that Avara is the right company to oversee the con- tinuing supply of the Astellas products that are made at the facility, as well as the fulfillment of capacity use at and ca- pabilities of the facility. Under the terms of the transaction, APT employees will remain employed at the site, and the plant will continue to manufacture certain Astellas products on a contract basis. > Telesta Cutting Jobs, Selling Manufacturing Sites as MCNA Hopes Fade Telesta Therapeutics is continuing to cut its remaining workforce and will sell off its manufacturing sites, terminate its European rights agreement with Ipsen for the bladder cancer treatment MCNA, as well as continue to assess strategic options and cut costs. The company disclosed plans to shrink its workforce to 15 full-time em- ployees—down from 32 as of June 30, and 50 as of March 31. Another four em- ployees will be maintained at Telesta's two manufacturing facilities "during the time required to monetize these facili- ties," the company said in a statement. Telesta is seeking to sell the Belleville Ontario-based Vaccine Manufacturing Cen- tre (VMC) and the Montreal MCNA manu- facturing site. The company said it has seen renewed interest from potential buyers in the Belleville facility and will continue working with its broker, Pharmabiosource, to complete a sale of the VMC, where Teles- ta recently renewed a lease with an undis- closed tenant for an unspecified portion of the space through April 2018. n News Bioprocessing