Making a single cardiovascular drug for 300,000 NHS patients currently requires thousands of kilograms of chemical waste and costs up to £1,000 per gram. A UK consortium is now redesigning the manufacturing process for oligonucleotide drugs—short genetic sequences that treat conditions from heart disease to rare disorders—to slash that waste and cost. The problem is that the standard method, solid-phase synthesis, cannot scale beyond 20-kilogram batches, generates roughly 4,300 kilograms of waste for every kilogram of drug, and keeps prices prohibitive for large patient populations. The consortium’s Nanostar Sieving platform, a liquid-phase synthesis technology, already achieves 100-kilogram batches with high purity. This 24-month project aims to cut the process mass intensity by 40% relative to solid-phase synthesis, reduce the chemical building blocks needed to near-stoichiometric levels (under 1.1 equivalents per cycle), and integrate a solvent recycling loop with real-time quality monitoring. If successful, the work could make oligonucleotide therapies affordable and sustainable at ton-per-annum scale, enabling drugs like Inclisiran to reach hundreds of thousands of patients without the environmental burden of current manufacturing. The solvent recovery system will also be retrofitted into existing solid-phase synthesisers, extending efficiency gains across the industry.
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Oligonucleotides (oligos) are sequences of nucleotides monomers which usually contain between 15-25 nucleotides/ nucleotide-analogues, they offer promising treatment for a wide range of medical conditions. There are now 15 oligo drugs which have been approved between the EMA and FDA. In recent years, an **increasing number of oligos in clinical trials** have shown excellent results for diseases with large patient populations. For example, Inclisiran, an oligo developed for the treatment of cardiovascular disease (thousands of patients), was approved in Europe in 2020 and is available on the NHS since 2021\. It is estimated Inclisiran will treat 300,000 patients in the UK in the next three years. While Solid Phase Synthesis (SPS) is the dominant manufacturing process to produce oligos it presents several limitations. The main challenges comprise: **the lack of scalability** (~10-20kg batch sizes maximum), the **high costs** (£800-£1000/g of oligos) and the **heavy environmental burden** associated with the process (~4300kg/kg PMI). This creates a critical need for sustainable, ton-per-annum-scale oligo production routes to enable oligos to deliver patient benefits in large populations. The Grand Challenge 'GC3' consortium (comprising Novartis, AstraZeneca, Alnylam, Exactmer, CPI) is developing Nanostar Sieving, a **breakthrough new technology based on Liquid Phase Synthesis** (LPS) to manufacture oligos. For oligo manufacture, this platform is positioned to provide ease of scaling under GMP conditions (100kg/batch), with high crude purity oligos (70-90%) and use of similar phosphoramidite monomer equivalents (1.5 equivalents/cycle). Maximising Efficiency of Liquid-phase Oligo Synthesis (MELOS) is a UK based collaboration between Exactmer, Queen Mary University of London (QMUL), CPI and AstraZeneca, seeking to build on the success of GC3\. This 24-month project will focus on **a step change in the process efficiency and sustainability of the Nanostar Sieving platform** for the synthesis of oligos on large scale. The current chemistry will be further developed by using Nanostar hubs and monomers with better membrane selectivities and higher solubilities. Further step changes include integration of a solvent recycling loop within the Nanostar Sieving process, seeking a **reduction of 40% in the total Process Mass Intensity** (PMI) compared to SPS technology. A solvent drying device will allow in-process water removal that will reduce required phosphoramidites equivalents to close to stoichiometric (i.e., <1.1 equivalents). In-line, real-time analysis will be implemented to monitor the quality of the recycled solvent. Furthermore, this work is required to ensure the **highest quality of product is obtained with minimal environmental impact, and at reduced costs**. In addition to demonstrating the efficiency of the solvent recycling and drying device within the Nanostar Sieving technology, the consortium will also retrofit this device into a Solid Phase Synthesizer. Implementing solvent recovery through membrane separation will provide a competitive edge for CDMOs and other manufacturing sites offering this capability which will widen the impact of the project to existing manufacturing assets
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