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Development of a modified process to tackle the challenge of producing therapeutic oligonucleotides at scale.
Manufacturing oligonucleotide medicines
Dr Barrie Cassey, Medicines Manufacturing Technology Lead, CPI.
“The knowledge input from our pharma partners is as important as their financial support. At team meetings, whenever I have a question on the manufacturing process, there will be somebody in the room who has an answer.”
Dr Barrie Cassey is the Medicines Manufacturing Technology Lead at CPI, a technology innovation catalyst which is part of the High Value Manufacturing Catapult. CPI accelerates the development, scale-up and commercialisation of advanced technology and sustainable manufacturing solutions by working with industry, academia, government, entrepreneurs, and the investment community.
Therapeutic oligonucleotides, a relatively new class of medicines made from short strands of DNA or RNA, demonstrate significant potential to operate against ‘undruggable’ disease targets where, to date, other medicines cannot. Oligonucleotide medicines work by interfering with gene expression and have shown success in the treatment of rare diseases. As such, researchers are now exploring the potential of these therapeutics to treat chronic diseases that affect much larger patient populations, such as heart disease and cancer.
The current manufacturing process, known as solid phase synthesis, is expensive and inefficient. The method assembles the oligonucleotide by anchoring one end to a solid support packed in a column, adds monomers sequentially to extend the chain, and then flushes away unused monomers before preparing for the next round of synthesis. The product is then cleaved from the support and purified. This method was originally developed for laboratory use and uses solvents which are environmentally harmful and in limited supply globally. Consequentially, the current manufacturing process is not scalable and unable to provide the quantities of oligonucleotides that will be required to meet the predicted global demand.
One of the Government’s Grand Challenges for the life sciences was to identify a scalable and more cost-effective medicines manufacturing process for therapeutic oligonucleotides. Working alongside AstraZeneca, Novartis, Alnylam and UK Research and Innovation, CPI has adapted a novel process developed by Exactmer, a spin-out company from Imperial College London, to create a scalable solution phase manufacturing method.
In the modified process, the oligonucleotide polymer chains are extended on a support in solution, and the growing chains filtered from the unused monomers through nanofiltration before the next monomer addition step. The product is then split from the support prior to further purification. The modified process requires less solvent, and, since it is not constrained by column size, allows manufacture at scale.