(188bh) Viral Filter Fouling By Monoclonal Antibody Under Seemingly Mild Oxidizing Conditions

The downstream manufacturing process for monoclonal antibodies (mAbs) consists of a series of chromatography and filtration steps to provide sufficient product quality and desired concentration of the drug substance. The expectation for mAbs derived from mammalian cell lines is that the process demonstrates a certain level of viral clearance to provide adequate safety for patients and satisfy regulatory requirements. To meet this expectation, a viral filtration step is typically included as one of the steps in the downstream process to help demonstrate sufficient virus removal. The viral filtration step consists of filtering the mAb product under constant pressure through a nanofilter with pore sizes large enough to allow the mAb to pass through the filter while retaining any viruses. These filters are one of the more expensive consumables in downstream processing, so it is desired to have a high throughput to minimize both cost of goods and processing time for producing a batch. For one recent mAb, obtaining a sufficiently high viral filtration throughput was a challenge that needed to be addressed prior to clinical manufacturing. Parameters such as pH, conductivity, mAb concentration, and pre-filter were first investigated using small-scale experiments controlled with compressed air, but results gave only marginal improvements in throughput over the baseline process. It was then discovered using compressed nitrogen to drive the filtration could improve the throughput more than 2.8x over using compressed air for the same process condition. It is hypothesized that, unlike for previously developed mAbs, holding this particular mAb under modest air pressure for a few hours resulted in some type of oxidation that led to fouling of the viral filter. This finding allowed the viral filtration step to be successfully run for viral clearance studies as well as successfully scaled-up for clinical manufacturing.