Isoporous Organic Solvent Nanofitration Membranes to Enable High Value Manufacturing for Life Sciences (iOSN)

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Polymers are long molecules comprising repeated chemical units known as monomers. Some biopolymers, such as oligonucleotides (oligos) comprising a sequence of nucleotides, are used as therapeutic agents. Oligo medicines work by modulating the expression of proteins and the functioning of genes. There are now 10 approved oligo drugs on the market and many more in development, and there is a growing need for an efficient manufacturing technology to make these high value molecules. The exact order of the nucleotides in an oligo is absolutely crucial its function. Oligos are made industrially by sequential addition of monomers to growing oligos, taking care to remove residual, unreacted monomer before the next cycle, so that there are no errors in the sequence. This requires excellent separation at the end of each coupling cycle. A very effective way of doing this is to attach the growing oligo to a solid support, which is washed with clean solvents to remove residuals, before the next nucleotide is added - this is known as Solid Phase Synthesis (SPS). When oligo growth is complete, it is cleaved from the solid support. All other side chain protecting groups are then removed, and we proceed to test the purity of the final oligo - have all the required nucleotides been added? Often there are "missing" monomers because the reactions on the solid support did not go to completion, and it is typical to find 60-80% of the desired n-mer oligo, together with a "ladder" of n-1, n-2, n-3 mer shorter oligos which are missing 1, 2, 3 or more nucleotides. The ladder must be removed, and this requires extensive, and expensive, chromatography.Exactmer Limited, a UK Life Sciences business is commercialising a new technology platform, Nanostar Sieving, for large scale oligo synthesis. The key innovation is to use organic solvent nanofiltration (OSN) membranes to separate a growing oligo from unreacted monomers. This is carried out in the liquid phase and analysis is relatively straightforward. By connecting three growing oligos to a central hub molecule, a large nanostar complex is created, enhancing membrane retention and promoting efficient separation. Exactmer use Nanostar Sieving to produce oligos with unprecedented control over purity, and have recently entered into licensing and development agreements with several large pharma companies including Novartis and AstraZeneca.Exactmer has OSN membranes that work satisfactorily. They are crosslinked to make them stable in the organic solvent environment required for oligo synthesis, and are very robust. However, they have a wide distribution of pore sizes, and this means that the separation lacks efficiency, resulting in the need for multiple membrane stages to maintain a high yield, and a high volume of solvent to achieve the desired purity. In water treatment, molecular separation membranes have been designed that have an isoporous (single pore size) structure, through using micro-phase separations of block co-polymers. These membranes cannot yet be used in organic solvent systems, as there is no way currently to crosslink them. In this project the Future Leadership Fellow, Dr Zhiwei Jiang, intends to develop isoporous membranes for organic solvent use, and to apply these in oligo synthesis. To achieve this, he will work with two approaches, one based on creating new polymers which can be used to form membranes that can undergo etching and crosslinking; and a second approach in which a thin film separating layer is made on a support matrix by crosslinking, and then etched. This powerful combination of a dynamic growing high-tech business, a highly talented research engineer/scientist, unique membrane making facilities, and a crucial manufacturing need, offers a unique team well equipped to make a fundamental breakthrough in OSN membranes that will offer paradigm changing options to oligo synthesis and beyond.