Entirely Liquid Phase Oligo Manufacture Using Nanostar Sieving Membranes

Andrew Livingston is a professor of chemical engineering at Queen Mary University of London, with a background in industry and academia, including a PhD and positions at Imperial College and Queen Mary University. His presentation focused on a collaborative project between his lab at Queen Mary, his company Exactmer, Novartis, AstraZeneca, and Alnylam, and mediated through the Medicines Manufacture Centre at CPI. 

His research group focuses on creating membranes for molecular separation and new chemical processing strategies, particularly in producing oligonucleotides. Livingston is also the CEO of Exactmer Limited, a startup from his research group, which collaborates with major pharmaceutical companies on scaling up the manufacturing of therapeutic oligonucleotides. 

Queen Mary and Exactmer are responsible for the Nanostar Sieving Technology Platform. They use membranes which are stable in organic solvents which can allow small molecules to pass through while sieving out large molecules. These membranes can then be used to synthesize oligonucleotides in a scalable, liquid-phase process, reducing solvent use and aiming for high purity. 

Here, oligo synthesis starts with a large ‘hub molecule’ with multiple points. This hub is unable to pass through the membrane. Monomers can then be washed over the hub and pass through the membrane one by one, growing the polymers on the hub. Once all the monomers have been added, the hub can be cleaved off leaving you with the finished oligos. 

Due to the fact that their membranes are stable in organic solvents, their platform is able to provides entirely liquid-phase synthesis. Unlike semi-liquid phase processes, this avoids the use of crystallisation, precipitation, or solid-phase beads, ensuring that the entire synthesis remains in a liquid phase. This approach aims for high purity and reduced solvent use, making it a scalable and efficient method for synthesising oligonucleotides. 

Exactmer uses its technology to develop large-scale oligonucleotide manufacturing, targeting batch sizes of 100 kg. This presentation takes us through the challenges and solutions that the team need to deal in large-scale oligonucleotide manufacturing, ensuring selectivity and avoiding fouling, and scaled up the membrane manufacturing process. 

Livingston concludes the talk by explaining Exactmer’s plans to manufacture polymers commercially, develop alternative oligonucleotide chemistries, and improve process efficiency, with GMP-capable synthesizers in development.