Quality Management of Diastereomeric Impurity for Complex Peptide Manufacturing: A Case Study of Corticorelin Ovine

Diastereomeric impurities are ubiquitous in peptide synthesis and should be controlled with the highest degree of scrutiny in peptide API manufacturing. Diastereomeric impurity reference standards are normally prepared, and the corresponding analytical methods are developed to quantify the diastereomer impurities in the peptide product. This strategy suits the process development for short- to medium-sized peptide molecules containing no more than 15 amino acid residues. However, when the peptides of interest contain more amino acids, they will pose substantial challenges to the preparation of individual diastereomeric impurity reference standards and the development of corresponding analytical methods. In such cases, alternative strategies for controlling peptide diastereomeric impurities should be pursued to ensure the chiral integrity of the peptide product. A deuterated HCl (DCl) hydrolysis-based GC-MS (termed chiral amino acid analysis) strategy has been applied to manage diastereomeric impurity control in the development of a corticorelin ovine manufacturing process. Process optimization was accomplished on this basis.