The difficulty of maintaining viral safety while expediting 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 exclusively or primarily to remove viruses. These are low pH virus 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 downstream 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 significant 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 collaboration, 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 information,” 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 filtration 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 continuous 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 continuous 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.”