Manufacturing of Oligonucleotides

Synthetic ONs have been explored for therapeutic and diagnostic purposes for more than two decades. These efforts have presently culminated into FDA approving two drug products with many ONs (c.100) currently undergoing clinical trials. In this article, we have tried to describe the potential sources and measures that can be taken to control oligonucleotide impurities from raw material, process, and equipment sources. Further, large-scale manufacturing equipment considerations and small-scale modeling approaches to develop each of the manufacturing process operations for large-scale manufacture have been described. Additionally, the related analytic tools that are involved in the development of processes and used to analyze ONs are also summarized in full detail. Finally, clinical development considerations based on regulatory guidance for ON programs have been described. Diligent management of manufacturing processes ensures robust scale-up processes, thereby building confidence in the quality of ON drugs manufactured and paving the way for future ON clinical applications.