Host cell proteins (HCPs) are a major constituent of the process-related impurities during biologics production.  The amount of residual HCP in the final drug product is a critical quality attribute due to its potential to affect both product safety and efficacy.  It is therefore a regulatory requirement to monitor the removal of HCPs during process development.  The downstream process for monoclonal antibodies (mAbs) typically uses multiple chromatography and filtration steps to remove HCPs to below acceptable levels.  However, for several mAbs it was found that specific HCPs known as lipases, despite being present at relatively low levels, were causing enzymatic degradation of polysorbates in the formulated drug product over time.  In addition to the possible immunogenicity of these residual lipases, polysorbate degradation can potentially lead to a reduced shelf life of the drug product due to increased aggregation and particle formation.  To overcome this issue, a focused effort has been made during downstream process development to track and remove these lipases, but that task is challenging as the lipases can associate or co-purify with the mAb and can be highly active even at sub-ppm levels.  Process development case studies for two mAbs will be presented to demonstrate the development and analytical strategies used to address lipase clearance.  Specifically, process parameters for different unit operations were investigated for their ability to remove lipases from the mAb process streams.  Clearance of lipases was monitored via multiple analytical assays to enable a detailed understanding of process performance as well as deliver robust, final processes.  The successes and challenges with lipase removal observed across the unit operations for the different mAbs will be highlighted along with the general strategy and approach used for tackling this downstream bioprocessing challenge.

Downstream process development strategy for reducing residual lipases in monoclonal antibody products

ACS Fall 2020 Virtual Meeting

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