Process Development of a Macrocyclic Peptide Inhibitor of PD-L1

This
article outlines the process development leading
to the manufacture
of 800 g of BMS-986189, a macrocyclic peptide active pharmaceutical
ingredient. Multiple N-methylated unnatural amino acids posed challenges
to manufacturing due to the lability of the peptide to cleavage during
global side chain deprotection and precipitation steps. These issues
were exacerbated upon scale-up, resulting in severe yield loss and
necessitating careful impurity identification, understanding the root
cause of impurity formation, and process optimization to deliver a
scalable synthesis. A systematic study of macrocyclization with its
dependence on concentration and pH is presented. In addition, a side
chain protected peptide synthesis is discussed where the macrocyclic
protected peptide is extremely labile to hydrolysis. A computational
study explains the root cause of the increased lability of macrocyclic
peptide over linear peptide to hydrolysis. A process solution involving
the use of labile protecting groups is discussed. Overall, the article
highlights the advancements achieved to enable scalable synthesis
of an unusually labile macrocyclic peptide by solid-phase peptide
synthesis. The sustainability metric indicates the final preparative
chromatography drives a significant fraction of a high process mass
intensity (PMI).