Regulatory compliance mandates virus control in biomanufacturing processes. Central to that requirement are clearance and inactivation of potential viral contaminants in downstream processing. For inactivating and killing viruses, important technologies include high-temperature, short-term (HT/ST) and solvent/detergent (S/D) treatments of process streams. Virus removal can be effected through purification methods, typically using depth and tangential-flow filters and/or chromatographic columns.
The contributors to this featured report focus their discussions on such downstream operations. First, two consultants with Parexel (one of whom is a former FDA laboratory chief) provide an update on the Triton X-100 issue in Europe. Our second article reports on the results of a benchmarking survey by the BioPhorum Development Group’s viral clearance workstream. Over a dozen leading biopharmaceutical companies were asked about operating parameters they considered to present worst-case conditions. Finally, authors from Bristol Myers Squibb describe their study of a hollow-fiber nanofiltration method for clearance of viruses from antibody-derived molecules without Fc structural components that are required for protein A affinity capture chromatography.
Introduction: Viral Inactivation and Clearance in Downstream Processes
by Cheryl Scott
Triton X-100 Elimination: The Road Ahead for Viral Inactivation
Christiane Niederlaender and Kurt Brorson
Serving as the detergent in solvent/detergent (S/D) viral inactivation treatments for biologically derived pharmaceuticals, Triton X-100 surfactant is especially important to processing of blood plasma products. It also is used as an excipient in some product formulations and has been designated by the European Union as a substance of concern. Because of related reproductive and other toxicity considerations, companies are evaluating how to phase out their Triton X-100 use. In some cases, that will necessitate manufacturing process changes. The phase-out will affect medicinal products for European markets, depending on approval status and the point of manufacture at which they enter the European Union. Here, the authors discuss potential consequences of related EU regulations on two key industry sectors: plasma-derived products and biopharmaceuticals.
Worst-Case Conditions for Viral Clearance
Dhiral A. Shah, James Berrie, Jeremy Pike, Susan M. Liu, Sherrie Curtis, David Roush, Nuria DeMas, Atul Bhangale, and Nadine Hazelwood
Here, the BioPhorum Development Group’s viral clearance workstream reports on the results of a benchmarking survey involving over a dozen leading biopharmaceutical companies. Authors from Alexion, Bristol Myers Squibb, Genentech (Roche), Janssen, Lonza, Merck, Novartis, and Sanofi assess whether companies evaluate process parameters according to clinical trial stage or commercialization status of biological products in development. Although studies supporting biological license applications (BLAs) tend to be more conservative — testing more worst-case parameters overall — than those supporting investigational new drug (IND) applications, results indicate only minimal differences in how companies approach viral clearance studies throughout product development. The survey results revealed a strong consensus about how to approach studies for virus inactivation steps. Low temperature, minimum incubation time, and high pH were considered to present worst-case conditions for low pH inactivation. Low temperature, minimum incubation time, and low SD concentration were considered to be worst-case conditions for low pH and SD inactivation, respectively.
Hollow-Fiber Nanofiltration for Robust Viral Clearance of Non-MAb Biologics
Ji Zheng, Jessica A. Waller, Alice Butler, Erik Mertz,Valerie Brubaker, Daniel Strauss, and Sanchayita Ghose
A team at Bristol Myers Squibb worked with advice and assistance from Asahi Kasei Bioprocess America to study a hollow-fiber nanofiltration method for clearance of viruses from antibody-derived molecules without Fc structural components (which are required for protein A affinity capture chromatography). After reviewing the range of available virus filtration options, the team presents its reasoning for selecting a specific technology for a bispecific antibody (BsAb) candidate. With historical perspective and experimental results, they demonstrate optimal performance and robust clearance of minute virus of mice (MVM) from a BsAb under challenging conditions of high feed stream concentration, high volume throughput with low protein concentrations, and elevated conductivity conditions.
