Abstract
Processing equipment involving grinding of two solid surfaces has been demonstrated to induce subvisible particle (SvP) formation in monoclonal antibody (mAb) drug product manufacturing processes. This study elucidated potential stress types associated with grinding action to identify the stress mechanism responsible for SvP formation. Several potential stress types can be associated with the grinding action, including interfacial stresses (air-liquid and liquid-solid), hydraulic/mechanical shear stress, cavitation, nucleation of stressed protein molecules, and localized thermal stress. More than one stress type can synergically impact mAb product quality, making it challenging to determine the primary mode of stress. Our strategy was to assess and rule out some stress types through platform knowledge, rational judgments or via small-scale models, for example, rheometer/rotator-stator homogenizer for hydraulic/mechanical shear stress, sonicator for cavitation, etc. These models may not provide direct evidence but can offer rational correlations. Cavitation, as demonstrated by sonication, proved to be quite detrimental to mAb molecules in forming not just SvPs but also soluble high molecular-weight species (HMWs) as well as low molecular-weight species (LMWs). This outcome was not consistent with that of grinding mAbs between the impeller and the drive unit of a bottom-mounted mixer or between the piston and the housing of a rotary piston pump, both of which formed only SVPs without obvious HMWs and LMWs. In addition, a p-nitrophenol model suggested that cavitation in the bottom-mounted mixer is barely detectable. We attributed the grinding induced, localized thermal effect to be the primary stress to SvP formation based on a high-temperature, spray-drying model. The heat effect of spray drying also caused SvPs, in the absence of significant HMWS and LMWS in spray-dried mAb powders. This investigation provides a mechanistic understanding of the underlying stress mechanism leading to mAb SvP formation as the result of drug product processing involving grinding of solid surfaces.
- Received June 15, 2017.
- Accepted October 11, 2017.
- Copyright © 2017, Parenteral Drug Association
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