Green manufacturing in pharma: Sustainable oligonucleotide production on an industrial scale

Oligonucleotides are at the forefront of modern medicine, and have emerged as powerful tools in treating diseases in recent years. Oligonucleotides – short DNA or RNA molecules that host a range of applications in genetic testing, research, and forensics – have seen a marked growth in significance as therapeutics. As their clinical application widens, methods of production must be robust to ensure demand is met.

Demand for oligonucleotides in medicines is steadily increasing, with pressing need for an eco-friendly manufacturing process which satisfies green manufacturing standards without compromising yield or process efficiency. Thus, the responsibility lies with manufacturers to ensure end users receive their medications, while striving for sustainable production methods.

The importance of sustainable oligonucleotide synthesis 

The need for sustainability in oligonucleotide manufacturing is increasing rapidly, driven by the growing use of these therapeutics to treat a diverse variety of conditions. With the oligonucleotide and peptide therapeutics market projected to grow at an annual rate of 17.5% through 2030, the industry faces significant challenges such as high production costs, waste, and energy-intensive processes.

With new oligonucleotide-based drugs being approved for development on a regular basis, the need for affordable and eco-friendly methods of production becomes more urgent.

The benefits of green manufacturing are twofold: sustainable practices help reduce environmental impact, but also address economic and regulatory demands, leading to improved efficiency and accountability. 

What steps can pharmaceutical manufacturers take to improve sustainability? 

Advancements in green manufacturing technology by innovators have seen sustainable production become widely accessible across the pharmaceutical industry. By prioritising cutting waste, promoting recycling, process efficiency, and innovation of synthesis methods, manufacturers can reduce both their environmental footprint and production costs.

1. Reducing waste and boosting recycling

The purification process in manufacturing oligonucleotides can be a costly process. It can produce high levels of waste and detrimental environmental impacts if not carried out in line with the latest technological developments to mitigate these effects. 

Techniques such as Multicolumn Countercurrent Solvent Gradient Purification (MCSGP), developed by Bachem, mark a major advancement in sustainable production. By continuously recycling mixed fractions, solvent consumption can be reduced by over 30% in comparison with traditional batch methods. Being a fully automated system, MCSGP not only enhances sustainability but also increases efficiency, delivering on average 10% higher product yield and purity while potentially cutting cycle times by 70%. Originally developed for peptides, this technology has now been successfully scaled for oligonucleotide manufacturing, offering a less wasteful and more cost-effective solution to previous purification methods.

1. Optimise production to maximise yield and quality 

Maximising both yield and quality is essential for sustainable oligonucleotide production. Continuous chromatography techniques like MCSGP generally offer higher capacity and yield, while cutting down on solvent use compared to traditional batch purification methods.

These automated systems, which operate around the clock, can significantly shorten purification cycle times. This method not only boosts efficiency but also promotes sustainability by reducing Process Mass Intensity (PMI). Notably, these advanced purification technologies maintain or even increase the quality of active pharmaceutical ingredients (APIs), proving that increased productivity and sustainability can still be achieved in large-scale oligonucleotide manufacturing.

1. Achieve lower PMI with alternative synthesis methods

Process Mass Intensity is a key metric in measuring sustainability in oligonucleotide manufacturing, calculating the total mass of materials used per mass of product. This is vital in pinpointing areas for optimisation, with traditional synthesis methods often resulting in a PMI of 4300 kg of waste per kilogram of API for a 20-building block oligonucleotide – a significant amount of waste when replicated on a large scale.

To tackle this issue, new techniques like one-pot liquid-phase oligonucleotide synthesis are being explored. This hybrid approach combines the advantages of both solution-phase and solid-phase synthesis; instead of solid-phase resins, liquid anchor molecules or "tags" are used, enabling efficient separation of products from byproducts while yielding higher volumes.

By significantly cutting down on solvent usage—one of the primary contributors to high PMI—this method minimises the need for excessive washing steps, potentially reducing the PMI from solvents by half.

1. Improve production capacity by scaling up your operation

Dedication to innovation must be implemented across each step of the manufacturing process, to ensure efficiency improves as a whole. To scale oligonucleotide production sustainably, Bachem has established large-scale oligonucleotide synthesiser within the synthesis stage, customised with advanced process control and crude API purity enhancements. In the cleavage and deprotection phase, these automated systems can significantly enhance both production safety and efficiency, again reducing waste.

Manufacturing product on a large scale sees numerous advantages, in comparison to small-batch production processes. Yield and purity are significantly improved as a result, while solvent consumption is reduced and process mass intensity is lowered. Meanwhile core competencies in lyophilization and clean room operations ensure a streamlined, high-quality isolation process, preventing bottlenecks.

1. Promoting worker-level innovation

Promoting sustainability begins at a grassroots level. By actively engaging the workforce in sustainable innovation, industry leaders can levy collective expertise and experience to drive technological advancements, and improve processes from the ground upwards. As a result, manufacturers can better deliver products and services, while navigating the evolving landscape of sustainable manufacturing as an organisation.

This culture of continuous improvement improves efficiency, by optimising business processes, and identifying advanced manufacturing technologies in collaboration with those that use them. 

With the application of oligonucleotide-based therapeutic drugs continuing to expand, it is vital that manufacturers modernise production processes as a matter of urgency, in order to meet demand and ensure end users have access to medication.

As processes continue to improve with technological advancements, manufacturers should look to continuously evaluate and upscale their operation, with technology evolving at a rapid pace. It is their responsibility to ensure that environmental standards are met and exceeded, delivering their services at optimum efficiency, while not at the expense of the climate.