Physicochemical Stability of Monoclonal Antibodies

Monoclonal antibodies (mAbs) are subject to instability issues linked to their protein nature. In this work, we review the different mechanisms that can be linked to monoclonal antibodies instability, the parameters, and conditions affecting their stability (protein structure and concentration, temperature, interfaces, light exposure, excipients and contaminants, and agitation) and the different analytical methods used for appropriate physicochemical stability studies: physical stability assays (aggregation, fragmentation, and primary, secondary, and tertiary structure analysis), chemical stability assays and quantitative assays. Finally, data from different published stability studies of mAbs formulations, either in their reconstituted form, or in diluted ready to administer solutions, was compiled. Overall, the physicochemical stability of mAbs is linked to numerous factors such as formulation, environment, and manipulations, and must be thoroughly investigated using several complementary analytical techniques, each of which allowing specific characterization information to be harvested.

Many stability studies about commercially available mAbs have been published, independently or requested by the manufacturers. Those studies tend to show a prolonged physicochemical stability when compared to manufacturer recommendations, but many of them are limited in the performed assays. mAbs’ physicochemical stability is linked to numerous factors such as formulation, environment, manipulations, as well as their own structure. It must be thoroughly investigated using several complementary analytical assays, each of which allowing specific characterization information to be harvested, including but not limited to biologic potency assays, as inefficacy is not the only consequence of aggregation and degradation. Biological stability (preservation of the mAb’s efficacy) should be assessed (protein activity assay), even though by nature a higher variability of response is to be expected, questioning its relevance for the detection of small alterations or subvisible aggregates formation that are possibly responsible of increased immunogenicity. In parallel to potential physicochemical limitations, other long-term stability limitations must be analyzed. Microbiological stability (linked to container systems) and contamination risks should be assessed before usage.

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