Viral clearance and inactivation by the bulk protein purification process are critical components of the overall strategy to ensure the safety of therapeutic proteins derived from mammalian cell culture. A mechanistic understanding of the factors that influence viral clearance and inactivation are essential for ensuring that adventitious agent control is conserved as downstream unit operations are refined and implemented.
A recognition of the critical nature of viral clearance and opportunities for improvement led to the initiation of the Viral Clearance Symposia Series in 2009. The meeting brought together industry and regulatory agency representatives for a critical evaluation of viral clearance practices. The focus of that first meeting, held in Indianapolis, IN, was to review the current state of viral clearance for specific unit operations, to discuss lessons learned, and to chart a course to experimentally address the gaps (1).
There have been three subsequent meetings. The 2nd Viral Clearance Symposium was held in 2011 in South San Francisco, CA. Topics included a discussion of an integrated adventitious agent control strategy and associated risk assessment, quality by design (QbD) approaches to viral clearance, and critical assessments of existing and emerging technologies. Proceedings from the 2nd Viral Clearance Symposium were published in a total of 11 articles in the PDA Journal (Vol. 68) in early 2014.
The 3rd Viral Clearance Symposium was held in 2013 in Princeton, NJ. The meeting included discussions on addressing gaps in traditional unit operations, new approaches to viral inactivation and clearance, and the impact of impurities on membrane adsorbers. Proceedings from the 3rd Viral Clearance Symposium were published in a total of eight articles in the PDA Journal (Vol. 69) in early 2015.
Recently, the 4th Viral Clearance Symposium was held October 2015 in Cambridge, MA. The meeting included discussions on viral inactivation and removal by purification unit operations such as low pH and detergent viral inactivation, viral filtration, Protein A chromatography, mixed-mode chromatography, hydroxyapatite chromatography, depth filters, and membrane adsorbers. In addition, a broad range of viral clearance topics including integration of an overall clearance strategy, generic virus clearance claims, QbD studies for viral risk mitigation, viral preparations, and viral spiking methods were discussed.
Some key highlights of the 4th Viral Clearance Symposium include significant progress on the following topics: further understanding of data and practices for ensuring the viral clearance of cycled reins; the viral clearance obtained with cycled Protein A and ion exchange resins was typically similar to that of new resins; and discussion of column performance indicators including yield, impurity removal, and pressure drop as potential surrogate indicators of column viral clearance.
Other key highlights include the observation that traditional and alternative detergents appear effective for inactivation of enveloped viruses over a wide range of operating conditions. In addition, mixed-mode chromatography resins appear to provide robust mouse minute virus (MMV) and murine leukemia virus (MuLV) clearance over a wide range of operating conditions.
In this issue of the PDA Journal, the summarized findings and next steps from the 2015 4th Viral Clearance Symposium are presented.
- © PDA, Inc. 2016
