ABSTRACT
Schellekens (2005) pointed out that small-molecule drug products tend to follow Arrhenius behavior (i.e., thermally dependent molecular motion) and thus have predictable stability based on acceleration studies. In contrast, the activity and biological function of proteins are highly dependent on their unique spatial conformation, which is the reason why biologics are much less stable than small-molecule compounds. First, proteins may shift between several related structures, in conformational changes, usually induced by the binding of a substrate molecule to an enzyme’s active site, or the physical region of the protein that participates in chemical catalysis. Second, many environmental factors such as temperature, pH, pressure, concentrated in organic salt or organic solvent will cause proteins lose their tertiary and secondary structure in a process called denaturation. Third, enzymolysis and hydrolysis will lead to protein degradation and the loss of their functions. Accordingly, slight variations in the manufacturing process may affect protein stability and efficacy of the biopharmaceuticals. Thus, stability profiles of the biosimilar product and the reference biological products need to be studied by placing the product under stressed conditions. The rate of degradation and degradation profiles (oxidation, deamidation, aggregation, and other degradation reactions) should be compared. If unknown degradation species are detected, they need to be studied to determine if they affect safety and efficacy. If differences in product purities and stability profiles are present between the biosimilar product and the reference biological products, these differences need to be justified using scientific knowledge or pre-clinical or clinical data.
