The commercial-scale production of oligonucleotides.

Progress in the field of oligonucleotide therapeutics has required commercial-scale production of oligonucleotides from multigram to multikilogram. The demand for large quantities of oligonucleotides has been met to date by the scaling-up of solid-phase syntheses. The synthesis of oligonucleotide phosphorothioates can be routinely carried out at scales of 10 to 100 mmol, with a cost of less than US $300 per gram and currently available cGMP facilities are able to produce 10 to 100 kg of oligonucleotides annually. Further developments on increasing scale and purity, as well as reducing cost, will rely on the invention of novel reagents and processes. The recent progress and challenges in the commercial-scale production of oligonucleotides are discussed herein.