Genetic Engineering & Biotechnology News

DEC 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 | DECEMBER 2017 | | Genetic Engineering & Biotechnology News See Viral Safety on page 20 chemical entities or biotechnological/biological drug sub- stances, there is an inherent limitation in the ability to detect low levels of bacterial or viral contamination." 1 Viral safety is not a discrete test at the end of drug manu- facture or even at any point upstream during production. Viral safety is more of a process, one that is intertwined with the drug manufacturing bioprocess itself, and one that de- mands a control strategy. Such a strategy may incorporate upstream assessments of critical quality attributes or in-pro- cess controls. Control strategies and related topics were discussed at the 2017 BioProcess International conference that was held re- cently in Boston. At this event, speakers addressed diverse virus filtration issues—upstream filtration, filtration of non- protein products, and filtration in continuous processing—as well as more general viral safety issues. Viral Safety and Process Bottlenecks The difficulty of maintaining viral safety while expe- diting process development was addressed at the meeting by Min Zhu, Ph.D., director of protein science, Boehringer- Ingelheim. To design and demonstrate viral clearance takes considerable resources, said Dr. Zhu. No fewer than three of the six major downstream unit operations are devoted exclu- sively or primarily to remove viruses. These are low pH vi- rus inactivation, anion-exchange chromatography, and virus filtration. Measurable clearance also occurs through Protein A capture, cation exchange, and ultrafiltration/diafiltration. Viral clearance imposes bottlenecks throughout down- stream purification, thus slowing down overall process speed. At the same time, virus filtration is considered one of the most expensive downstream steps. It represents a signifi- cant portion of the cost of goods (COG). To overcome process bottlenecks and contain filter costs, Boehringer-Ingelheim is assembling a knowledge database consisting of data from the literature, cross-industrial col- laboration, vendors, and in-house research. The database will be utilized to support development of process design, risk assessment for process characterization studies, and control strategy. "This is an ongoing project relying on open-source in- formation," Dr. Zhu declared. At this stage, the project is proceeding without any formal collaborations with vendors. Given the cost and time required to exploit virus filtra- tion and other clearance strategies for COG improvement, bioprocessing engineers often face the tradeoffs between throughput, flux, log removal, and cost. Navigating these variables becomes trickier for continuous processes. "Viral inactivation and filtration are required for any manufacturing process from mammalian cell culture, as two independent, orthogonal viral clearance steps," Dr Zhu tells GEN. "The challenge is how to incorporate them into con- tinuous processing." Viral inactivation is typically performed at batch mode. To incorporate it into continuous liquid flow, Boehringer- Ingelheim has designed an incubation chamber to allow continuous flow and maintain minimal product contact time and target pH. "The challenge of incorporating viral filtration into con- tinuous processing is demonstrating robust viral removal when the product concentration in feed is variable," Dr. Zhu stated. "A small-scale viral clearance validation strategy needs to be developed further." Harsh Conditions Brian Buesing, senior research associate at Asahi Kasei Bioprocess America, discussed work on his company's Pla- nova TM BioEX virus filter, which contains a bundle of straw- shaped hollow fibers and relies on a filtration mechanism that is based on size exclusion. The membrane structure of Planova allows proteins to easily pass through the hollow fiber walls while viruses are efficiently captured in the mem- brane pores. An advantage of the Planova platform is parvovirus clearance with or without buffer flush under a wide range of modest to harsh pH levels, salt concentrations, pressures, and protein concentrations. "We recently collaborated with Janssen Pharmaceuticals to better define the design space of operating conditions that would work for three of their antibody products," Buesing tells GEN. Results from that collaboration appeared June 2017, in Biotechnology Progress. 2 "We found that both fil- ters under all combinations of operating conditions were ca- pable of achieving a virus removal factor of at least 4 log." Additionally, hollow-fiber Planova filters achieve high flows and mass throughput even in the presence of 500 mM salt, and are compatible with a variety of buffers, according to Buesing. He added that the hollow-fiber membrane ma- Viral Safety Copes with Complexity Bioprocessing Feature Asahi Kasei Bioprocess America provides custom equipment supporting the automated use of Planova™ filters. Continued from page 1

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