Growing a resilient oligonucleotide ecosystem: From innovation to industrialisation

At CPI’s recent Oligonucleotide Manufacturing Symposium, we brought together academics, developers, manufacturers and policy makers from across the ecosystem to explore the evolving challenges, and immense opportunities, in oligonucleotide development and manufacture. Here are some of the key themes that emerged.

Scaling up to meet growing demand

The demand for oligonucleotide-based therapies has surged in recent years, with over a dozen major pharmaceutical companies now incorporating these genetic medicines into their strategic portfolios. However, scaling up production to meet this demand presents significant challenges. Traditional solid-phase synthesis methods are reaching their limits in terms of batch size and efficiency. Innovative approaches, such as hybrid enzymatic synthesis, are being explored to overcome these limitations and enhance scalability. 

One of the key drivers of change in oligonucleotide manufacturing is the shift in therapeutic focus. While oligos were initially developed to treat rare diseases with small patient populations, they are now showing promise for more widespread conditions such as hepatitis. As the potential applications grow, so too does the need to produce far greater volumes of material. Moving from gram-scale to tonne-scale production transforms scale-up from a purely technical hurdle into a complex, strategic challenge that spans process innovation, supply chain planning and regulatory readiness. 

UK-based manufacturing facilities

CPI’s Medicines Manufacturing Innovation Centre was designed to help bridge the gap between innovation and commercialisation of transformative manufacturing processes for the pharmaceutical industry. In Autumn 2025, we’ll achieve a major milestone with GMP manufacture of oligonucleotides in our cleanroom facilities. 

We identified almost immediately that demand for our oligonucleotide cleanroom facilities would quickly outpace supply. That’s why we’re building the Oligonucleotides Manufacturing Innovation Centre (OMICE), currently under construction and set to be completed in late 2026. This new facility will help to de-risk and accelerate oligonucleotide scale-up while enabling the UK to stay globally competitive in this emerging field. 

Upskilling the workforce of the future

With novel technologies comes the need for a highly skilled workforce capable of operating, optimising, and evolving them. This isn’t just about process engineers and analytical scientists, it’s about chemists, molecular biologists, quality professionals and equipment designers working together as interdisciplinary teams. 

To help address this need, we’ve developed an Oligonucleotides Training Academy in collaboration with the University of Strathclyde, which was launched at the event. From foundational theory to advanced one-to-one sessions, we aim to equip early-career scientists and transitioning professionals for work with cutting-edge oligo technologies. 

Panel discussions throughout the symposium highlighted the acute shortage of oligonucleotide chemists and the need to attract more chemical engineers, analysts and technicians into the field. The goal is to build a future-ready workforce that understands not only the science of oligonucleotides but also the complex interplay between chemistry, process engineering, regulation, and manufacturing. As one panel speaker noted, ​“good oligo chemists are like unicorns” and that needs to change. 

Driving efficiency through technology and data

Traditional solid-phase oligonucleotide synthesis (SPOS) remains the industry workhorse, offering rapid and robust synthesis cycles. But it has drawbacks. Manufacturing 1 kg of oligo API can require up to 4,000 kg of raw materials, largely due to reagent excess and solvent washes and the need for chromatographic purification. Reducing this Process Mass Intensity (PMI) is essential for sustainability and cost control. 

Improving efficiency in oligo production isn’t just about doing things faster, it’s about doing them smarter. Several presentations demonstrated how better data, smarter control, and predictive technologies are transforming manufacturing. 

CPI and Intellegens demonstrated how machine learning is transforming process development. By using Alchemite™, a model trained on synthesis data, the team can predict optimal conditions for yield, purity, and impurity control. One case study showed a 30% reduction in cost of goods and >99% purity — a powerful proof of concept for AI-assisted scale-up. 

Similarly, AstraZeneca shared their success using in-line mid-IR spectroscopy to monitor key synthesis reactions. This allowed for precise real-time adjustments to detritylation and related washing steps, resulting in a 27% reduction in DCA usage, 33% less MeCN, and better impurity control. The shift from manual, offline analysis to real-time feedback is helping remove uncertainty and reduce development time from months to days. 

GSK presented a bold new approach using enzymatic templated ligation to assemble single-stranded oligos from short fragments. This aqueous, chromatography-free process achieved >99% API purity and up to 70% overall yield — demonstrating significant environmental and cost advantages over traditional SPOS. 

Agilent’s presentation reminded us that great analytical tools are only as good as the people who know how to use them. Richard Blankley, Biopharma Application Specialist showed that when quality control and LC-MS are applied thoughtfully, they not only accelerate decision-making but also future-proof manufacturing platforms. 

Balancing cost, sustainability and quality

Sustainability was a recurring theme, although some speakers noted a shift in industry priorities from environmental impact to economics. As one participant put it: ​“Cost is the one thing everyone agrees on.” Reducing cost per dose or per treatment is now driving decisions on platform choice and process design. 

That said, sustainability isn’t off the table. Process intensification — through reduced solvent use, improved yields, and removal of unnecessary steps — is still seen as a route to both greener and cheaper manufacturing. And initiatives like benchmarking process mass intensity are helping to quantify where improvements can be made. 

The use of in-line PAT tools, solvent recycling, and machine learning-driven optimisation is helping reduce waste and energy usage across the board. Notably, AstraZeneca’s inline near-IR monitoring during ultrafiltration/​diafiltration (UFDF) led to an 83% reduction in diafiltration time and a 64% drop in the stage PMI. 

A key takeaway: process changes upstream can affect purification downstream. Developers must consider the full lifecycle of the process and explore where decoupling synthesis from purification might unlock efficiencies. 

Collaborating to build a resilient ecosystem

Perhaps the most encouraging insight from the symposium was the strong sense of community. Oligonucleotide manufacturing remains a relatively small field and events like this play a vital role in strengthening collaboration and sharing lessons learned. 

We also discussed how CPI can support the sector beyond technology: by feeding into policy discussions, guiding investment priorities and enabling standardisation in areas like analytics, quality and regulatory compliance. Initiatives like the Oligonucleotide Manufacturing Innovation Centre and our training academy are examples of the UK’s commitment to securing a leadership position in oligonucleotide therapeutics. With increasing government attention on this emerging field, we’re working to present a coordinated and capable UK ecosystem that can compete effectively in the global market. 

Looking ahead

The oligonucleotide sector is evolving rapidly, and its impact on human health could be transformative. But realising this potential requires a coordinated ecosystem where manufacturers, developers, researchers and regulators all play their part. 

At CPI, we’re proud to help drive this transformation. If you’re developing an oligo product or platform and want to accelerate your progress, we’d love to hear from you. 

Let’s build the future of oligonucleotide therapeutics, together.