In a typical monoclonal antibody process (mAb), process-related impurities (e.g., host cell proteins (HCP) and residual DNA) are well controlled due to the specificity of Protein A chromatography and other well-defined downstream unit operations.<br/>To further reduce HCP, the protein A immobilization can be exploited by exposing the bound mAb to various washing additives to disrupt the protein-protein interactions. HCP content is typically reduced from &gt;500,000 ng/mg to &lt;1000 ng/mg in this single-step.<br/>For non-antibody processes, the commercial use of custom affinity ligands is not typically used in early phase development. Due to significant development time and a high cost of goods of custom affinity resins, conventional chromatography techniques (CEX, HIC, and Mixed-mode) are typically employed to purify the target protein from process-related impurities.<br/>In this case study, host cell protein reduction challenges were encountered with a recombinant protein conjugate expressed in CHO cells. A baseline process using conventional chromatography and filtration techniques was rapidly developed to support Toxicology and Phase 1 production. However, HCP levels of 10,000-20,000 ng/mg were measured at the intermediate stage (pre-conjugation) of the process. Here we discuss the systematic approach to reduce HCP levels to within specification using strategies amenable to manufacturing.

Host cell protein challenges in the downstream process development of non-antibody processes

ACS Spring 2022

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