Purification is the bottleneck in oligonucleotide manufacturing. Can it be reinvented from scratch?

For almost four decades, oligonucleotide purification has relied on technologies borrowed from biologics manufacturing. Reverse-phase chromatography, ion exchange chromatography, and ultrafiltration all work, but they were designed for proteins, not oligonucleotides. As demand for oligo therapeutics increases, purification is emerging as the true bottleneck to cost-effective, scalable manufacture.

Why purification matters more than ever

Purification decisions directly influence: 

• Batch turnaround time. 

• Process mass intensity (PMI).

• Solvent and/​or water consumption. 

• Labour costs.

• Critical quality attributes. 

• GMP compliance.

• Waste handling and disposal.

In many manufacturing workflows, purification consumes more resources than synthesis itself. Green manufacturing assessments frequently place PMI for oligonucleotide processes in the 3,000 to 7,000 range, with solvent-intensive synthesis and purification dominating that footprint. 

A typical oligonucleotide process can require around 1,500 kg of solvent for every kilogram of product. At a 20 kg batch scale, that equates to approximately 30 tonnes of solvent per batch. A similar demand for water for the aqueous based downstream purification processes is required. 

As a result, purification has become a defining constraint on cost, sustainability, and scalability. 

Are we using the right tools for oligonucleotides?

The honest answer is no. Much of today’s oligonucleotide manufacturing still relies on separation logic developed in the 1990s. While these approaches are proven, they were never designed to handle the unique impurity profiles, solvents, or throughput requirements of modern oligo modalities. 

As pipelines expand and batch sizes increase, this mismatch becomes harder to ignore. 

When synthesis decisions create purification pain

One reason purification remains inefficient is that it is often developed in isolation. Development teams naturally optimise synthesis for yield, speed, or novel chemistry, leaving downstream processing to manage whatever impurity profile results. 

Purification should not exist to fix synthesis. Instead, it should be treated as a core design constraint from the earliest stages of R&D. Decisions made upstream have a direct and lasting impact on solvent use, processing time, and overall manufacturing risk. 

Rethinking purification from first principles

Unlocking meaningful progress requires the oligonucleotide community to challenge long-held assumptions: 

• Does chromatography always need to be the primary separation step? 

• Could membranes or hybrid separations replace columns for certain chemistries? 

• Can process analytical technology reduce material volumes through real-time endpoint control? 

• Could machine learning be used to design more efficient purification gradients? 

• Can hybrid or alternative synthesis routes reduce the purification burden altogether?

These questions point towards a future where purification is smarter, more selective, and less resource intensive. 

Why manufacturing support accelerates purification innovation

Reinventing purification cannot happen in isolation or on paper alone. It requires access to environments where new ideas can be tested, refined, and scaled with confidence. 

That means practical testbeds where organisations can trial: 

• New separation media. 

• Novel solvent systems. 

• Membrane-based platforms.

• Continuous purification units. 

• Solvent recovery and recycling approaches. 

• Machine-learning-assisted impurity mapping. 

• Inline analytical and monitoring technologies.

In the UK, CPI provides scale-up and pilot environments that enable R&D teams to explore downstream purification strategies without the cost or risk of investing in new plant equipment. By combining oligonucleotide synthesis, analytical development, and purification optimisation in one place, CPI helps organisations reduce development risk and accelerate decision-making. 

The future is not a single platform

There is no single technology that will remove the purification bottleneck overnight. Instead, the future lies in a portfolio approach that applies the right tool to the right challenge: 

• Chromatography where high resolution is essential. 

• Membrane-based capture where selectivity allows. 

• Solvent recycling to reduce environmental and cost impact at scale. 

• PAT-guided decision-making to avoid over-processing. 

• Hybrid synthesis routes that minimise downstream purification demand. 

A new mindset for oligonucleotide manufacturing

If synthesis is where chemical innovation has flourished, purification is where manufacturing innovation must now catch up. 

Emerging oligo modalities, including shorter antisense oligonucleotides, modified backbones, ligation-based constructs, and enzymatically produced fragments, will demand new approaches to separation. Relying on recycled biologics strategies will increasingly limit progress. 

Organisations that treat oligonucleotide purification as a strategic advantage, rather than an operational necessity, will be best positioned to deliver cost-effective, scalable therapies. Those that collaborate with neutral partners equipped with synthesis, analytics, and downstream processing expertise will move faster and with greater confidence. 

The bottleneck is both technical and cultural in nature. Reinvent purification from first principles, and suddenly, much more becomes possible across oligonucleotide manufacturing. 

If you’re exploring new approaches to oligonucleotide purification or want to reduce cost, solvent use, and scale-up risk, CPI works with partners across synthesis, analytics, and downstream processing to accelerate innovation. Let’s innovate together.