Comparison of Structurally Related Impurity Profiles in Teriparatide From Synthetic and Recombinant DNA Origin Using Liquid Chromatography–High Resolution Mass Spectrometry

RATIONALE: Teriparatide (TPT) is a synthetic peptide primarily used in the clinical treatment of osteoporosis, with its reference materials available from both synthetic and recombinant DNA origin used for generic drug preparations. Considering the potential toxicological effects of structurally related impurities, systematic characterisation of the impurity profiles of TPT reference materials arising from different synthetic sources is essential for regulatory evaluations of generic drugs' safety and efficacy. METHODS: One commercially available chemical synthesis material and two recombinant synthesis pharmacopoeia reference standards were used to investigate the TPT impurity profiles in this study. Separation for the structurally related impurities was achieved via liquid chromatography, and mass spectrometry analysis was conducted by electro-spray ionization linear quadrupole ion trap-Orbitrap mass spectrometry. Subsequently, external standard method and four quantitative scenarios were adopted to achieve an accurate quantification of structurally related impurities in the TPT study materials. RESULTS: Distinct impurity profiles were observed in the TPT study materials from different synthetic sources. One isomer and three oxidation impurities were found co-existing in all the study materials. Six amino acid deletion impurities were specifically observed and identified in chemically synthetic TPT material. Among these detected impurities, eight impurities were newly characterized in addition to the previous studies. CONCLUSIONS: A liquid chromatography-high resolution mass spectrometry-based method was developed for the identification and quantification of structurally related impurities in three TPT study materials from different synthetic sources. Characterization of these TPT impurity profiles highlights the necessity of synthetic source-specific impurity monitoring for TPT production and contributes to enhanced regulatory evaluation of generic peptide drugs.