Scientists have potentially solved a major mystery in bioprocessing by uncovering a reason why cellular impurities can persist despite multiple attempts to remove them. The team from the University of Delaware discovered that host-cell proteins (HCPs), which are impurities produced by cells as a by-product of biopharmaceutical manufacturing, can get entangled in large aggregates.

According to Chase Herman, a PhD student who has just defended his thesis on this topic, large aggregates are typically treated as a different type of impurity than HCPs, and different techniques are used to remove them.

“Historically in monoclonal antibody processing, [aggregates and HCPs] are [regarded as] two different classes of impurities, which are typically [considered] different,” he says. “But one of the open problems in monoclonal antibody processing is that, despite the manufacturing technology being well established, we don’t understand why capture steps [only] reduce the concentrations of HCPs, but not the number of species.”

Large aggregates can include many HCP species

Herman and colleagues discovered that large aggregates could include many HCP species. This, he believes, could help to explain how HCPs can persist through the capture and polishing steps designed to remove them.

As part of his research, he also discovered that the number of large aggregates measured by size-exclusion chromatography could be used as a proxy for HCP persistence.

“Monitoring the clearance of what I [call] large aggregates, but high molecular weight content in general, could be a useful proxy for monitoring HCP concentration,” he points out. “It’s imperfect but can be useful because it’s relatively easy to assess high molecular weight content [using size-exclusion chromatography], but it’s much more laborious to assess HCP content using a standard technique like an ELISA assay or more sophisticated mass-spectrometry analysis.”

Herman believes his research could help industry make early-process development decisions, such as which resins should be used for HCP clearance. After defending his thesis, he will be moving to an industry position where he hopes to continue his work.

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