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24 | AUGUST 2014 | GENengnews.com | Genetic Engineering & Biotechnology News See Single-Use Bioreactors on page 26 BIOPROCESSING "Improved automation and monitoring, with better noninvasive sensors and quality- by-design approaches, has led from an un- monitored small-scale process to a controlled process," notes Roman Rodriguez, global market development manager for single-use at EMD Millipore. The need for personalized medicines and the emergence of biosimilars promise a great future for SUBs. "The advent of 2,000 L SUBs has created incentives related to process opti- mization and overcoming challenges in mass transfer, heat exchange, sensing technologies, and plastic flm technologies," Rodriguez says. "I anticipate new services in process op- timization, SUB validation, and accessories such as computational studies, media optimi- zation, scalability, and shear stress." Related is the trend toward continuous processing through perfusion bioreactors. Most current processes remain fed-batch, but many manufacturers are examining combi- nations of SUBs with a single-use perfusion culture. This creates a need for more automa- tion and new inline sensing methodologies. The quest for high cell densities in smaller volumes in shorter time periods have made SUBs the technology of choice in many in- stances, but new challenges have emerged. Scalability, operation at high cell density and power input, oxygen transfer effciency, price, supplier dependability, and overall robustness of SUBs are still issues. "There have been recent advances at small scale to address these, and I have no doubt that ven- dors will soon overcome those challenges at all scales," Rodriguez states. Issues of scalability have been as critical for single-use equipment as they were for glass and stainless-steel bioreactors, accord- ing to Ken Clapp, senior product manager at Xcellerex-GE Healthcare Life Sciences. These issues, he avers, are inescapable when small-scale or fractional single-use bioreac- tors are used for quality-by-design studies and process optimization. "The never-ending quest for higher prod- uct titers, greater cell densities (approaching and even exceeding 100 million cells per mil- liliter), and higher throughput will create new demands," asserts Clapp. "Moreover, these de- mands, which will run the gamut from materi- als to supply chain capacity, will bring about a new level of integration within the manufac- turing infrastructure of biologics companies." Bioreactors with suffciently high turn- down ratios should support the elimination of intermediate vessels and help manage consumables costs. Higher densities and increased throughput will likely require im- proved process equipment, such as perfusion devices, during the production phase. "Downstream, as on the production side, there will there be a need for tighter integra- tion," adds Clapp. "Regulatory compliance will require tight coordination of the unit op- erations and the consolidation of process data under existing automation infrastructure." Scaledown and DOE Bioprocess development strategies fre- quently include some form of small-scale modeling, or scale-down modeling, with the aid of design of experiment (DOE). Several products on the market distinguish them- selves through various features. For example, the ambr™ from TAP Bio- systems has working volumes of 10–15 mL and uses 24 or 48 disposable reactor wells. Dasgip's parallel bioreactor products are larger—up to 100 mL—and are controllable through mobile devices. Pall's Micro-24 Mi- croreactor uses much smaller volumes (3–7 mL) in a single-use cassette format. The micro-Matrix microbioreactor from Applikon Biotechnology makes a good case for keeping reactor volumes smaller, not larger. micro-Matrix provides 24 indepen- dent microreactors with working volumes of 2–4 mL, in a microplate footprint. When Applikon designed the micro-Ma- trix, the prime concern was that results faw- lessly scale to the gold-standard 3 L bench- top bioreactor and beyond. "We produce systems as large as several thousand liters," explains Erik Kakes, the company's director Single-Use Bioreactors Dare to Scale > CMC Biologics, Portola Enter Commercial Supply Agreement CMC Biologics and Portola Pharmaceuticals entered into a commercial supply agreement for the develop- ment of andexanet alfa, a Factor Xa inhibitor antidote in Phase III studies. Andexanet alfa is designed to reverse the anticoagulation activity of Factor Xa inhibitor-treat- ed patients who are experiencing a major bleeding epi- sode or who require emergency surgery. > TxCell to Lead Personalized Cellular Immunotherapy Project TxCell, Gene and Cell Therapy Unit (UTCG), and Bio- safe were awarded a grant of €417,000 ($713,366) by the Conseil Régional Provence-Alpes-Côte-D'azur for the launch of a new consortium. The POSITVE project will focus on the development and establishment of a pro- cedure to automate the frst step of manufacturing of Ovasave, TxCell's personalized cellular immunotherapy for severe refractory Crohn's disease patients. TxCell will receive a grant of €250,000 ($427,678) and UTCG will receive €167,000 ($285,689). Both grants will be for the performance of experiments by TxCell and UTCG and the optimization of the resulting new auto- mated and standardized procedure. Biosafe will also uti- lize its Sepax technology to enable the automated and standardized separation of mononuclear white blood cells for the production of cellular immunotherapy. > Recipharm, Pharmanest Ink SHACT Manufacturing Deal Recipharm and Pharmanest formed a collaboration for the commercial manufacturing and supply of SHACT, which is based on a formulation of lidocaine and an ap- plication device developed to simplify topical applica- tion in the cervix and uterus. According to Pharmanest, SHACT has demonstrated Phase II efcacy data as local anesthesia in connection with IUD insertion. > Xellia Acquires Fresenius Kabi's Manufacturing Plant Xellia Pharmaceuticals acquired Fresenius Kabi's lyophi- lized vial manufacturing facility in Raleigh, NC. The manu- facturing site is Xellia's frst facility in the U.S., expanding the company's manufacturing capacity for injectable phar- maceutical products. The deal includes a continuous man- ufacturing and supply agreement with Fresenius Kabi USA. Xellia intends to retain the approximately 80 staf members currently employed at the site and will contin- ue to manufacture certain products for Fresenius Kabi. > Orgenesis, MaSTherCell Team Up to Fight Diabetes Orgenesis SPRL signed an agreement with MaSTher- Cell to scale manufacturing of insulin-producing liver cells. Orgenesis is developing cellular trans-diferenti- ation to transform a type 1 diabetic patient's own liver cells into new insulin-producing cells. MaSTherCell re- ports that it has the experience, system design, and tech- nology to deliver the control properties and conditions needed for the live cell culture and expansion process that is necessary for commercial-scale manufacturing of Orgenesis cellular trans-diferentiation products. n Angelo DePalma, Ph.D. As GEN readers are well aware, single-use bioreactors (SUBs)— already accepted at research scale for screening and optimiza- tion, as well as at pilot scale and seeding—are now ready for GMP-compliant manufacturing. News BIOPROCESSING A technician configures the EMD Millipore Mobius® SensorReady external loop, which is used to control and monitor the company's CellReady bioreactor.