Enhanced product understanding in the QbD paradigm: linkage between charge heterogeneity and stability of monoclonal antibody therapeutic products

Abstract BACKGROUND Product stability is a major concern during production of biotherapeutic products, including the monoclonal antibody (mAbs) products. A deeper understanding of the underlying mechanisms is encouraged in the Quality by Design (QbD) paradigm. This paper presents results from an investigation aimed at elucidation of the impact of product heterogeneity (charged variants) on mAb stability. RESULTS Samples exhibiting a wide variability in levels and distribution of charge variants and aggregates were generated using ion exchange and hydrophobic interaction chromatography. Both size based (fragments and aggregates) and charge based (basic and acidic variants) heterogeneities were monitored using analytical size exclusion chromatography and cation exchange chromatography, respectively. Partial least square (PLS) analysis was performed to correlate size heterogeneity with charge heterogeneity. It was found that presence of certain charge variants dominates degradation of mAb. Each high molecular weight specie is primarily influenced by a subset of charge heterogeneities and at times presence of other size heterogeneities. The resulting PLS models yielded satisfactory values for the regression coefficient as well as for predictability confirming the statistical relevance of the conclusions. CONCLUSIONS The results presented in this study provide a novel insight into the impact of mAb charge and size heterogeneity on product stability. This knowledge can be used during process design so as to enhance stability of the biotherapeutic. This is the first investigation that relates charge heterogeneity to mAb stability. © 2018 Society of Chemical Industry