Genetic Engineering & Biotechnology News

SEP15 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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18 | SEPTEMBER 15, 2017 | | Genetic Engineering & Biotechnology News See Cell Culture Optimization on page 20 regulatory requirements have always driven biopharma to greater heights, the complexity of manufacturing biologically produced molecules has made these demands more moun- tainous than ever. "A bioprocess is a puzzle," explained Dr. Hightower, "and this puzzle has thousands and thousands of pieces, and those pieces need to fit together correctly to make the final picture. If you change those pieces, either intention- ally or unintentionally, that could alter the final picture." In late August 2017, leaders in the bioprocessing industry gathered in Boston, MA, at Cambridge HealthTech Insti- tute's Bioprocessing Summit conference to discuss cost-effec- tive strategies to ensure a picture-perfect product every time. Searching for Hidden Elements with Metabolomics At the conference, Dr. Hightower illustrated how biophar- maceutical manufacturers can use a metabolomics approach to gain insight into the "active biology" of a bioprocess that can help minimize process variability. Dr. Hightower's com- pany, Metabolon, has specialized in metabolic profiling since 2000, and both Metabolon's vast chemical reference library and their multiple points of matching strategy for metabolite identification enable highly accurate and comprehensive me- tabolite measurements. Metabolomics expands on traditional methods that use 10 to 20 indicative biochemical molecules, like oxygen, car- bon dioxide, and glucose, to track cell metabolism, growth, and productivity. While these metabolites "happen to be re- ally useful," said Kirk Beebe, Ph.D., senior director at Me- tabolon, "there are hidden elements of active biology where a precision metabolomics approach could add to the lac- tates, ammonias, and amino acid profiling that people cur- rently do." These "hidden elements" can provide valuable knowl- edge about cell health and protein production. For example, glutathione can relay information about oxidative stress lev- els and the redox capacity of the cells—an important metric for recombinant protein production, which relies on redox potential for disulfide bond formation, proper protein fold- ing, and protein secretion. Assessing the activity of a living system using metabo- lomics requires robust, high-throughput analytical systems that can accurately identify metabolites, a comprehensive understanding of biochemical pathways, and expertise in analytics and biochemistry to successfully interpret and ap- ply the results. However, the reduction in cost and time-to- consumer achieved by applying an extensive metabolomics approach to bioprocess development and monitoring makes these challenges worth overcoming. While Metabolon builds understanding around the in- tegral role different pieces play in creating a reliable pro- cess, companies such as Merck, Valitacell, Cell Culture Company (C3), and Roche have focused their efforts on the pieces themselves, with their respective work on me- dia development, cell-line selection, bioreactor design, and continuous process monitoring. Finding the Perfect (Cell Culture Media) Recipe through Systems Biology Wai Lam Ling, Ph.D., Merck's senior principal scientist and group leader of biologics upstream process and media development, provided GEN with an analogy that com- pared motorcycles to small-molecule drugs and jet planes to biologic therapies: like biologics, jet planes are complex to design and manufacture. Thus, to get their products off the ground, biomanufacturers need to select the right compo- nents—starting with cell culture media—to create a robust, reliable process from production cell lines. Manufacturing engineers formerly used complex media from animal-derived products, but the burgeoning, modern- day industry is quickly adopting chemically defined media wherever possible. In contrast to complex media, chemical- ly-defined media consists of individual, known components and is devoid of animal-derived materials and hydrolysates, which removes much of the mystery and variability inherent in complex media. However, with anywhere from 50 to 100 different components to balance, finding the perfect recipe for chemically defined media is still an industry headache. Even well-planned design-of-experiment methodologies for media development can be both time- and resource-con- suming. By using a systems biology approach that leverages the tools used in drug discovery, such as next-generation se- quencing, shotgun proteomics, and metabolite profiling, Dr. Ling and her team can visualize how changing the selection, concentration, and chronology of different components af- fects cell productivity and product quality. Integrating the data with other important product attribute measurements, like glycosylation, allows the team to generate predictive models for media optimization and reduce the time and money spent finding the perfect formulation to complement their bioprocesses. Identifying Clonal Instability Culprits through ChemStress Fingerprinting While tailoring the media to the process can mitigate cellular stress caused by a bioreactor environment, starting out with a robust, stable cell line is essential to a success- ful process. Nutrient starvation, oxidative stress, toxicity, unfriendly pH or osmolarity levels, and other stressors can cause clonal instability, where productive cell lines become unproductive or produce errant proteins that require exten- sive purification. To suss out instability, biopharmaceutical manufactur- Solving the Puzzle of Cell Culture Optimization Bioprocessing Feature Continued from page 1 Valitacell's ChemStress technology can recreate the stressors experienced by cells in a bioreactor that can lead to clonal instability. After a three-day culture on the plate, cell growth and product titer are measured and plotted against the chemical challenge to produce a fingerprint unique to the cell clone and culture media combination. Changes in the fingerprint over time can be used to predict clonal instability.

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