Sustainability Challenges and Opportunities in Oligonucleotide Manufacturing.
Benjamin I Andrews, Firoz D Antia, Shawn B Brueggemeier, Louis J Diorazio, Stefan G Koenig, Michael E Kopach, Heewon Lee, Martin Olbrich, Anna L Watson
Author Information
Benjamin I Andrews: Chemical Development, GlaxoSmithKline, Stevenage SG1 2NY, United Kingdom. ORCID
Firoz D Antia: Biogen, Inc., Cambridge, Massachusetts 02142, United States.
Shawn B Brueggemeier: Bristol-Myers Squibb, New Brunswick, New Jersey 08901, United States.
Louis J Diorazio: Chemical Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield SK10 4TF, United Kingdom.
Stefan G Koenig: Genentech, Inc., A Member of the Roche Group, South San Francisco, California 94080, United States. ORCID
Michael E Kopach: Eli Lilly and Company, 1400 West Raymond Street, Indianapolis, Indiana 46285, United States.
Heewon Lee: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut 06877, United States.
Martin Olbrich: F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland.
Anna L Watson: Chemical Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield SK10 4TF, United Kingdom.
With a renewed and growing interest in therapeutic oligonucleotides across the pharmaceutical industry, pressure is increasing on drug developers to take more seriously the sustainability ramifications of this modality. With 12 oligonucleotide drugs reaching the market to date and hundreds more in clinical trials and preclinical development, the current state of the art in oligonucleotide production poses a waste and cost burden to manufacturers. Legacy technologies make use of large volumes of hazardous reagents and solvents, as well as energy-intensive processes in synthesis, purification, and isolation. In 2016, the American Chemical Society (ACS) Green Chemistry Institute Pharmaceutical Roundtable (GCIPR) identified the development of greener processes for oligonucleotide Active Pharmaceutical Ingredients (APIs) as a critical unmet need. As a result, the Roundtable formed a focus team with the remit of identifying green chemistry and engineering improvements that would make oligonucleotide production more sustainable. In this Perspective, we summarize the present challenges in oligonucleotide synthesis, purification, and isolation; highlight potential solutions; and encourage synergies between academia; contract research, development and manufacturing organizations; and the pharmaceutical industry. A critical part of our assessment includes Process Mass Intensity (PMI) data from multiple companies to provide preliminary baseline metrics for current oligonucleotide manufacturing processes.
