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The proteinaceous nature of monoclonal antibodies (mAbs) makes them highly sensitive towards various physical and chemical conditions, thus leading to instabilities which are classified as physical and chemical instabilities. In this review, we are discussing in detail about the physical instability of mAbs because a large number of articles previously published are solely focusing on the chemical aspect of the instability with little coverage on the physical side. The physical instabilities of mAbs are classified into denaturation and aggregation (precipitation, visible and subvisible particles). The mechanism involved in their formation is discussed in the article along with the pathways correlating the denaturation of mAb or formation of aggregates to immunogenicity. Further equations like Gibbs-Helmholtz involved in the detection and quantification of denaturation are discussed along with various factors causing the denaturation. Moreover, questions related to aggregation like the types of aggregates and the pathway involved in their formation are answered in this article. Factors influencing the physical stability of the mAbs by causing denaturation or formation of aggregates involving the structure of protein, concentration of mAbs, pH of the protein and the formulations, excipients involved in the formulations, salts added to the formulations, storage temperature, light and UV radiation exposure and processing factors are mentioned in this article. Finally, the analytical approaches used for detecting and quantifying the physical instability of mAbs at all levels of structural conformation like far and near UV, infrared spectroscopy, capillary electrophoresis, LC-MS, micro flow imagining, circular dichroism and peptide mapping are discussed.

Drugs that are procured from living cells and are used to treat acute and chronic diseases are called biologics, whereas biosimilars are the drugs which are highly similar but not identical to the original reference product. The main advantage of these drugs is that they are highly targeted with great therapeutic activity and can be used for multiple indications. Despite all the advantages biologics are still extremely costly. The main purpose of developing and introducing biosimilars was and is to increase market competition leading to a decrease in the cost of the biologics. However, until now the cost of the treatment has not decreased in the US market because there are many barriers to the entry of biosimilar in the US market which are discussed in this article. In this article, we argue that the barrier or hurdle in the US market entry of the biosimilars is not only limited to patent protection or exclusivity but other less discussed barriers are also there which are to be discussed. Due to these barriers till June 10, 2020, only 9 biosimilars are available commercially in the US market out of the 27 biosimilars approved for marketing by the U.S. Food and Drug Administration (FDA). We argue that the introduction of these biosimilars in the US market is essential for increasing market competition and thus decreasing the overall treatment cost for both the government and the payers. In this article, we are also providing perspective on the possible solutions to reduce these barriers and to encourage the entry of biosimilar in the US market.

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