Nanoparticulate Impurities Isolated from Pharmaceutical-Grade Sucrose Are a Potential Threat to Protein Stability.

Purpose: To investigate the effect of nanoparticulate impurities (NPIs) isolated from pharmaceutical-grade sucrose, on the stability of monoclonal antibodies (mAbs).

Methods: NPIs were purified from pharmaceutical-grade sucrose and spiked into trastuzumab, rituximab, infliximab, and cetuximab formulations. The stability of the mAbs as a function of storage time, temperature, and NPI concentration was assessed by visual inspection, flow-imaging microscopy, nanoparticle tracking analysis, size-exclusion chromatography, capillary isoelectric focusing, and intrinsic differential scanning fluorimetry.

Results: NPIs negatively affected the stability of all mAbs, albeit it to different extents. After spiking with NPIs, trastuzumab formulations showed high numbers of μm-sized particles and turbidity, rituximab and cetuximab formulations contained high numbers of nm-sized particles, while infliximab formed nm- and μm-sized particles, and showed turbidity. Low-molecular-weight species were observed for rituximab and infliximab, whereas high-molecular-weight species were detected for cetuximab. Whereas the stability of trastuzumab and infliximab formulations was affected directly after spiking NPIs, degradation of rituximab and cetuximab was observed only after 14 weeks at elevated temperatures. Moreover, the stability of rituximab and infliximab was affected by NPI concentrations that are potentially present in final drug products.

Conclusions: The presence of sucrose-derived NPIs in (bio-)pharmaceutical formulations may pose a threat to the stability of mAbs.