Benjamin I. Andrews, Fabienne Chapalain-Guyomard, Yan-Qiao Chen, Lukas Doulakas, Colm Duffy, Gresa Farmer, J. Gair Ford, Harper Kaminski, Francis Ring, Bradley D. Robertson, Muhid Shahid, Rohit Tiwari, Dale Turnacliff, Bastien Viverge, Martin Olbrich
{"title":"Considerations for Recycling of Acetonitrile in Oligonucleotide Synthesis","authors":"Benjamin I. Andrews, Fabienne Chapalain-Guyomard, Yan-Qiao Chen, Lukas Doulakas, Colm Duffy, Gresa Farmer, J. Gair Ford, Harper Kaminski, Francis Ring, Bradley D. Robertson, Muhid Shahid, Rohit Tiwari, Dale Turnacliff, Bastien Viverge, Martin Olbrich","doi":"10.1021/acs.oprd.6c00025","DOIUrl":null,"url":null,"abstract":"<p>Oligonucleotide therapeutics are expanding from rare\r\ndiseases to\r\nmore common conditions, leading to an increased demand for GMP-manufactured\r\noligonucleotides and consequently acetonitrile solvent. The acetonitrile\r\nsupply chain is volatile due to economic, regulatory, and environmental\r\nfactors. Shortages have been driven by production constraints, increased\r\ndemand, factory closures, natural disasters, and global crises. Key\r\ndisruptions include the 2008–2009 financial crisis, Hurricane\r\nIke, factory closures in China, and the COVID-19 pandemic. Addressing\r\nsupply chain security and environmental impact requires strategic\r\nplanning, implementation of recycling methods, and regulatory compliance.\r\nA comprehensive risk assessment process was designed by experts of\r\nthe European Pharma Oligonucleotide Consortium (EPOC) to evaluate\r\npotential contamination in acetonitrile recycled from oligonucleotide\r\nproduction. The severity and probability of contaminants were categorized\r\nas high or low based on their process impact and removal feasibility.\r\nThrough theoretical calculations and partial waste segregation assumptions,\r\nthe remaining volume and impact of various contaminants were quantified.\r\nDetailed evaluations and risk levels were provided for each contaminant.\r\nGiven this comprehensive risk assessment, recycling of acetonitrile\r\nfrom oligonucleotide synthesis is not only acceptable but also recommended\r\nbased on the ability to effectively mitigate potential contamination\r\nthrough meticulous risk evaluation based on theoretical calculations\r\nand supportive development data, partial waste segregation, and adequate\r\nspecification settings, thereby supporting sustainable growth in oligonucleotide\r\ntherapeutics. PREAMBLE: The European Pharma Oligonucleotide Consortium\r\n(EPOC) is a collaboration between multiple pharma companies with the\r\naim of sharing chemistry, manufacturing, and control (CMC) knowledge\r\nas well as strategies to enable harmonization of oligonucleotide development\r\nand commercialization. EPOC identifies areas for harmonization of\r\noligonucleotide CMC development and proposes solutions to influence\r\nthe external regulatory environment, expediting patient access to\r\nrevolutionary medicines.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 8","pages":"2119–2135"},"PeriodicalIF":3.3000,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Organic Process Research & Development","FirstCategoryId":"92","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.oprd.6c00025","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/7/24 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
引用次数: 0
Abstract
Oligonucleotide therapeutics are expanding from rare
diseases to
more common conditions, leading to an increased demand for GMP-manufactured
oligonucleotides and consequently acetonitrile solvent. The acetonitrile
supply chain is volatile due to economic, regulatory, and environmental
factors. Shortages have been driven by production constraints, increased
demand, factory closures, natural disasters, and global crises. Key
disruptions include the 2008–2009 financial crisis, Hurricane
Ike, factory closures in China, and the COVID-19 pandemic. Addressing
supply chain security and environmental impact requires strategic
planning, implementation of recycling methods, and regulatory compliance.
A comprehensive risk assessment process was designed by experts of
the European Pharma Oligonucleotide Consortium (EPOC) to evaluate
potential contamination in acetonitrile recycled from oligonucleotide
production. The severity and probability of contaminants were categorized
as high or low based on their process impact and removal feasibility.
Through theoretical calculations and partial waste segregation assumptions,
the remaining volume and impact of various contaminants were quantified.
Detailed evaluations and risk levels were provided for each contaminant.
Given this comprehensive risk assessment, recycling of acetonitrile
from oligonucleotide synthesis is not only acceptable but also recommended
based on the ability to effectively mitigate potential contamination
through meticulous risk evaluation based on theoretical calculations
and supportive development data, partial waste segregation, and adequate
specification settings, thereby supporting sustainable growth in oligonucleotide
therapeutics. PREAMBLE: The European Pharma Oligonucleotide Consortium
(EPOC) is a collaboration between multiple pharma companies with the
aim of sharing chemistry, manufacturing, and control (CMC) knowledge
as well as strategies to enable harmonization of oligonucleotide development
and commercialization. EPOC identifies areas for harmonization of
oligonucleotide CMC development and proposes solutions to influence
the external regulatory environment, expediting patient access to
revolutionary medicines.
期刊介绍：
The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.
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