Predicting Virus Filtration Performance with Virus Spike Characterization

E valuating a virus filter should, in theory, be a straightforward exercise. Membrane-based filtration is a robust virus-reduction technology that plays an important role in virus safety for most drug production processes. An appropriate virus filter for a given process is generally selected through preliminary testing with relevant drug feed material. Data acquired during such tests are used to determine hydraulic performance targets such as expected flow rates and total throughputs. A virus clearance evaluation study is then performed in which virus is added (" spiked ") into process fluid. Scaled-down studies sometimes referred to as virus validation measure the capability of miniature filtration devices to remove spiked virus. Ideally, during a scaled-down study, adding virus to a drug process solution does not perturb filtration, and a spiked process fluid flows across a filter at the same rate (or pressure) as does unspiked material. Unfortunately, in reality the virus spike frequently has detrimental effects on filter hydraulic performance, resulting in decreased fluid flow. Studies suggest that such filter membrane fouling is generally caused by impurities present in virus stocks rather than virus particles themselves (1–6). Spike-induced fouling may prevent achievement of throughput targets, resulting in studies being deemed unsuccessful even though virus reduction was satisfactory. Moreover, the presence of undefined impurities in a virus spike casts doubt on the integrity of a scaled-down model. The purpose of a clearance study is to accurately represent manufacturing, and this goal is subverted when virus spike impurities cause fouling that is not representative of the full-scale process. Here, we recount a virus clearance study in which challenges arose because of unpredicted hydraulic consequences of virus spiking. Fortunately, despite initial difficulties, throughput and virus removal targets were ultimately met thanks to implementation of a flexible spiking strategy. This success was made possible by cooperation among the drug producer, filter manufacturer, and contract testing laboratory specialists. We subsequently reflected upon the challenges encountered in an effort to understand and prevent them in the future. A follow-up collaborative study examined the root causes of spike-induced fouling and determined how they could have been prevented. We characterized our virus preparations in EMD MILLIPORE (WWW.MILLIPORE.COM)