Improving the efficiency and sustainability of the olpasiran drug substance process

Abstract: Olpasiran is a siRNA therapeutic that consists of a double-stranded oligonucleotide conjugated to a liver-targeting tri-N-acetylgalactosamine (GalNAc) ligand. Synthesis of this hybrid molecule comprises multiple complex steps: multistep batch manufacturing of a small molecule GalNAc ligand; solid-phase oligonucleotide synthesis (SPOS), including conjugation of the GalNAc ligand; and final downstream purification of the siRNA conjugate. At Amgen, synthetic process design is driven by green chemistry principles, and these principles were tightly integrated into the development of a process for multi-kilogram manufacturing of olpasiran. This presentation will discuss developments to both the GalNAc ligand synthesis and the conjugation process that enabled significant reductions in waste, solvent use, and hazardous reagents compared with the discovery route. These include 1) replacement of time- and solvent-intensive chromatographic purifications of GalNAc intermediates with robust precipitations, 2) replacement of a two-step process to a starting material with a catalytic one-pot process, enabling 81% reduction in step PMI, and 3) reduction of GalNAc equivalents and solvent volumes in the solid-phase conjugation step. These, and other, improvements resulted in scalable processes that have been demonstrated on >30 kg scale with corresponding reduction in E-factors (up to 37%). Overall, the optimized process will provide over 25% reduction in solvent and waste at peak production.