Considerations for Recycling of Acetonitrile in Oligonucleotide Synthesis

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.