Purification solutions in large-scale manufacturing of oligonucleotide APIs

Purification solutions in large-scale manufacturing of oligonucleotide APIs

With a significant increase in interest in oligonucleotide-based drugs over the past five years, the biopharmaceutical industry is challenged with meeting increased demand.

Originally used to treat rare illnesses, oligonucleotide-based drugs are now being developed to target more common diseases and wider patient populations. With the approval of the first-in-class siRNA for cholesterol reduction, the demand for oligonucleotide-based active pharmaceutical ingredients (APIs) has increased significantly. These treatments could be used to treat millions of patients per year, therefore there is a pressing need to optimise manufacturing processes to allow for larger batch sizes and support growth.

Challenges of large-scale oligonucleotide API production

It is vital for production processes to be as sustainable as possible. However, the current manufacturing process for oligonucleotide APIs involves high solvent consumption and generates a severe amount of waste – particularly during purification. This places strain on large-scale production of these new therapeutics, especially with the importance of green manufacturing being non-negotiable. The challenges of large-scale production of oligonucleotide APIs can be overcome by manufacturing partners through:

1. Reducing environmental impact by lessening solvent consumption and waste during purification
2. Improving efficiency with higher throughput and productivity to accelerate manufacturing
3. Increasing yield with target purity

Continuous innovation is crucial to optimise processes for higher product quality, cost efficiency, scale and sustainability, with the purification stage of production presenting hurdles to overcome.
In large-scale oligonucleotide manufacturing, purification is an essential step to guarantee the final product is pure and free of contaminants. The most efficient purification method is chromatography, but even this can result in high waste and material consumption, along with long running times in the manufacturing phase. Therefore, maximising yield and quality while ensuring sustainability is vital, as efficiency of processes and costs are factored into account while meeting industry standards.

Continuous chromatography: the solution

Continuous chromatography may offer a promising solution to the purification problem, due to its high productivity, improved selectivity and reduced costs. 

In large-scale production, continuous processes are particularly effective solutions to the challenges of maximising yield and quality while ensuring sustainability. For example, Bachem has implemented the first-of-its-kind Multicolumn Countercurrent Solvent Gradient Purification (MCSGP) system for center-cut purification on an industrial scale. 

This technology represents a major advancement in optimising the processing of oligonucleotides. MCSGP achieves higher capacity with lower solvent consumption and higher yield, as opposed to conventional single-column batch purification. MCSGP is cost-effective, scalable, and highly efficient; it is particularly effective in large-scale production, due to operating 24/7 through an automated process (reducing purification cycle times). And it is more sustainable, as it reduces solvent consumption and process mass intensity. 

Furthermore, the use of standard chromatographic conditions in MCSGP does not compromise the quality of the API, making it a technology that maximises the capacity, quality, and sustainability of the purification process.

Other API manufacturers will surely look to similar technologies in the near future to manage sustainability expectations and increasing demand. With research into oligonucleotide-based therapeutics intensifying, this demand is likely to increase, therefore production processes must be as robust as possible.