Aggregation of therapeutic monoclonal antibodies due to thermal and air/liquid interfacial agitation stress: Occurrence, stability assessment strategies, aggregation mechanism, influencing factors, and ways to enhance stability.

Therapeutic proteins, such as monoclonal antibodies (mAbs) are known to undergo stability related issues during various stages of product life cycle resulting in the formation of aggregates and fragments. Aggregates of mAb might result in reduced therapeutic activity and could cause various adverse immunogenic responses. Sample containing mAb undergo aggregation due to various types of stress factors, and there is always a continuous interest among researchers and manufacturers to determine the effect of different factors on the stability of mAb. Thermal stress and air/liquid interfacial agitation stress are among two of the common stress factors to which samples containing mAb are exposed to during various stages. Initial part of this review articles aims to provide a generalized understanding of aggregation of mAb such as size ranges of aggregates, aggregate types, stress factors, analytical techniques, permissible aggregate limits, and stability assessment methods. This article further aims to explain different aspects associated with aggregation of mAb in liquid samples due to thermal and air/liquid interfacial agitation stress. Under each stress category, the occurrence of stress during product life cycle, type of aggregates formed, mechanism of aggregation, strategies used by various researchers to expose mAb containing samples to stress, different factors affecting aggregation, fate of aggregates in human body fluids, and strategies used to enhance mAb stability has been explained in detail. The authors hope that this article provides a detailed understanding about stability of mAb due to thermal and air/liquid interfacial stress with relevance to product life cycle from manufacturing to administration into patients.