Modes of Degradation and Impurity Characterization in rhPTH (1-34) during Stability Studies

Unlike currently licensed therapies to manage osteoporosis, parathyroid hormone (PTH) and its analogs represent a new class of anabolic agents, which act primarily to inhibit bone resorption and remodeling. The hormone's recombinant form is a bioactive peptide, 1-34 residues, which is inherently very unstable. Prior understanding of the molecular degradation pathway will help in development of a process that will yield a better product with respect to its quality and stability. The current work focuses on detailed characterization of the product-related impurities generated during storage of recombinant human PTH. The study depicted the various routes through which the molecule can degrade during its shelf life. Through a combination of forced degradation and accelerated study, it was established that the impurities were generated owing to oxidation, deamidation, and peptide bond cleavage of/at various amino acid residues. Until this study, it was presumed that oxidation is the primary route of degradation in PTH and most of the published reports were on native (1-84) forms of the hormone. The present research confirms that the recombinant hormone (1-34) degraded not only because of oxidation but that deamidation and peptide bond cleavage are also prominent modes of degradation. Therefore, owing to the unstable nature of the molecule it is suggested that stringent conditions should be maintained during manufacturing to obtain a stable molecule with fewer impurities.