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Bioprocessing Single-Use Systems conference in San Francisco, and Visongain's upcoming "Single Use Bioreactor" conference in London. Compared to early single-use bio- reactors, which were essentially disposable bags mounted on platforms to achieve mixing, the emerging, more complex generation of single-use systems more closely mimic conven- tional stirred-tank glass and stainless steel bio- reactors. They incorporate impellers, sparge lines, and sensors for better control of process parameters and have aspect ratios that mirror those of traditional stirred tank reactors. With the launch of its new ambr 250™ mL automated, scalable, single-use bioreac- tor system in August, TAP Biosystems (www. tapbiosystems.com) aimed to increase the complexity and functionality of single-use bioreactors for use in process development while maintaining their ease of use in terms of set-up, operation, and user interface. Andrew Tait, product development scien- tist at TAP Biosystems, will describe the com- pany's new technology and how it achieves these dual goals in his presentation at the Vi- songain conference. Meeting its initial goal meant providing core stirred tank bioreactor technology for both microbial and mammalian applica- tions, with an impeller and width-to-height ratios of conventional steel bioreactors. The system's single-use bioreactor incorporates gas and liquid supply lines with connectivity to the bioreactor control unit. The system is configurable for automat- ed, independent, parallel control of 12 or 24 bioreactors, each with a maximum working volume of 250 mL. Each bioreactor can be individually controlled for temperature, pH, and dissolved oxygen, has four liquid feed lines, and off-gas analyzers for microbial ap- plications. Up to 24 bioreactors are integrat- ed into a dedicated biosafety cabinet. Facilitating Flexibility The main advantages of single-use sys- tems are flexibility and speed to a functional, multiproduct facility, reduced footprint, elim- ination of clean-in-place, sterilize-in-place protocols, reduced water use, and increased overall throughput and productivity, accord- ing to Joe Makowiecki, senior manager, pu- rification process development at Xcellerex (www.xcellerex.com). The primary limitation at present is scale. "We are at the 2,000 liter single-use bioreac- tor scale already, and then from harvest all the way down to bulk drug substance it is single-use, except for the chromatography resins," he said. Single-use pumps are gradually replac- ing peristaltic pumps, offering low shear and flow rates >150 L/min, with tubing sets avail- able up to 1 inch in diameter. Flow capacity for sensors is lagging a bit behind—ranging from about 20–80 L/min—but is slowly in- creasing. Makowiecki pointed to several key trends driving technology development in single-use bioprocessing, including high-titer expres- sion systems resulting in increasing amounts of biomass for downstream processing, and higher flow rates leading to, for example, 46 | October 1, 2012 | genengnews.com | Genetic Engineering & Biotechnology News Thermo Scientific HyClone Single- Use Bioreactors shown in a process- development lab illustrating their modularity and scale-out potential. Continued from page 1 the development of membranes with higher binding capacity. Emerging on the market are new types of sensors, multicolumn chromatography, and "smart" mixers for automated adjustment of pH and conductivity. "Smart mixers will be ubiquitous in downstream processing," pre- dicted Makowiecki. "Flexibility is one of the hallmarks of sin- gle-use, and that bleeds into economics," said William Whitford, senior manager at Thermo Fisher Scientific (www.thermofisher.com). "Sin- gle-use lends itself to varying production sched- ules," easing not only normal operations, but making it easier and faster to mothball equip- ment or establish surge capacity." Minimizing up-front expenses reduces risk if a product fails, noted Whitford. In a new or expanded facility, single-use systems can reduce initial plumbing needs, the cost of having to validate complex cleaning sys- tems, and the personnel needed to operate and maintain those systems. "As a CMO, we have to be as flexible as possible," to be able to operate a multiprod- uct facility at different scales, said Kai Lipin- ski, Ph.D., head of cell culture and virus pro- duction at Vibalogics (www.vibalogics.com). "We do not want to invest in equipment for one client that we might not use again." There are a "lot of restrictions currently for scalable adherent cell culture for virus and vaccine production," continued Dr. Lipinski. Several commercially important anchorage- dependent cell lines are not adaptable for sus- pension culture, noted Dr. Lipinski, including WI-38, A549, MRC-5, VERO, and CEF cells. Existing planar systems that support adherent cell culture such as roller bottles, T-flasks, and cell factories are labor intensive. Vibalogics has performed studies using VERO and A549 as model cell lines to assess virus production when the cells are grown in the ATMI (www.atmi.com) iCELLis™ semi- single use cGMP nano bioreactor system. In- stead of containing a donut-shaped basket as in ATMI's fully single-use, commercial-scale iCELLis 500, the nano system has a cylindri- cal fixed bed composed of the same polyethyl- ene terephtalate microfibers. Linear scalability between the systems is given as the bed height is the same, explained Dr. Lipinski. Tracking Trends Higher volumetric productivity is contrib- uting to smaller scale manufacturing. In ad- dition, noted Whitford, volume demand is decreasing, with emerging products such as personalized medicines with companion diag- nostics targeted to screened populations, and cancer vaccines generally required in substan- tially smaller amounts. ReadyToProcess™ columns are high-performance bioprocessing columns that come prepacked, prequalified, and presanitized, according to GE Healthcare. The ÄKTA™ ready is a liquid chromatography system that incorporates ready- to-use, disposable flow paths for process scale-up and production for early clinical phases. Another trend described by Whitford is "scaling out" instead of scaling up, also known as distributed manufacturing. Instead of run- ning one 10,000 L batch, a company might opt to run five 2,000 L reactors in parallel. Among values inherent in this flexibility, this minimizes the potential loss if one batch were to become contaminated or unusable for some other reason. Single-use systems also sim- plify geographic distribution of manufacturing capacity. To duplicate a facility in another loca- tion would require only purchase of the same devices and transfer of the process, whether to an adjacent building or another country. Manufacturers of single-use devices are pur- suing R&D; to create new, cleaner materials for single-use products and new ways of produc- ing these materials. For example, Paul Killian, Ph.D., senior scientist at EMD Millipore (www. emdmillipore.com), described research under way on new methods for sterilizing single-use materials that would reduce the amount of leachables created. At present, most single-use systems are gamma-irradiated, a process that generates small oxygenated compounds that contribute to the leachables load. Raising the ceiling for "large-scale" pro- cessing in single-use bioreactors from 1,000 L vessels to the new generation of 2,000 L ves- sels has expanded the utility of single-use sys- tems for commercial-scale batch production. Sartorius Stedim Biotech (www.sartorius-ste dim.com) plans to introduce a 2,000 L scale single-use bioreactor in 2013. Davy De Wilde, director of marketing for fermentation tech- nologies for the company does not anticipate any volume increase beyond that. "Improved cell strains, media, and pro- cess conditions have led over the past years to a significant increase in product yields per volume," he says. "This enables the in- dustry today to reach their required product volumes already at 1,000 L or 2,000 L scale, while previously required bioreactor volumes were up to five times higher." This is helping to drive uptake of single- use systems overall, according to Alison Rees-Manley, fermentation application spe- cialist at Sartorius Stedim Biotech. Other factors contributing to the increase in adoption of single-use bioreactors, in De Wilde's view, are reduced cost of ownership and increased flexibility, thus allowing users to switch more easily between processes and to increase capacity rapidly due to reduced lead times and utility requirements. User needs are a critical driver of tech- nology and product development, and in response Sartorius Stedim Biotech plans to introduce a point-of-use integrity test for single-use bioreactor bags, beginning with a test for its bioreactors up to the 200 L system by the end of 2012 and shortly followed by tests for bags up to 1,000 L. Need for Standardization The issues and uncertainty surrounding extractables and leachables from single-use systems remain an ongoing topic of discus- sion. "The risks change depending on where the material is used," said Dr. Killian. An overall lack of standardization and regulatory guidance continues to present an obstacle to more rapid adoption of single-use technology. "The regulatory agencies still put the onus on drug companies to demonstrate that there is no or low risk to the patients," continued Dr. Killian. With increased use, confidence in the materials is growing among biopharma- ceuticals producers. As the industry has matured, companies have used their experience to modify their approach to performing extractables and leachables studies and evaluating the data. For example, whereas before companies might have carried out leachable studies across all single-use devices—an expensive and chal- lenging task—now they might take an extract- ables-to-leachables approach in which they would perform leachable studies only on devic-