Navigating the Next Era of RNA Manufacturing

According to Britton Jimenez, from Codexis, the future of RNA therapeutics lies beyond traditional synthesis and requires a shift in manufacturing strategy toward advanced and agile platforms and sourcing.

The evolution of RNAi therapeutics is at a critical juncture; while the historic success of COVID-19 messenger RNA (mRNA) vaccines proved the viability of nucleic acid platforms, the next generation of RNA interference (RNAi), antisense oligonucleotides (ASOs), and guide RNAs is pushing the boundaries of traditional manufacturing infrastructure. As these novel modalities transition from niche orphan indications to broader applications for chronic conditions, developers must rethink their operational, technical, and supply chain strategies. One of the most pressing concerns is achieving sustainable scalability — ensuring that manufacturing processes can meet growing demand without compromising environmental or operational efficiency. This includes improving raw material utilization and minimizing waste.

To find out more about how advanced materials science and biocatalysis are reshaping the manufacturing landscape, The Pharma Navigator sat down with Britton Jimenez, SVP Sales and Marketing, Codexis.

Overcoming the Limits of Solid-Phase Oligonucleotide Synthesis

TPN: Could you highlight any specific trends that are having a significant impact on the bio/pharma outsourcing market?

Jimenez: The success of RNAi therapeutics, including siRNA, in treating niche patient populations is now paving the way for this modality to expand into chronic conditions which impact large patient segments, such as cardiovascular disease and cancer. This shift is prompting manufacturers and innovators to reassess traditional methods like solid-phase oligonucleotide synthesis (SPOS), seeking scalable, efficient, and sustainable alternatives that can meet the demands of high-volume production. Adjacent RNA modalities, including guide RNAs and antisense oligonucleotides (ASOs), are also gaining attention as part of this evolution. Among the promising approaches is the ligation-based method for oligonucleotide synthesis, offering advantages in scalability, sustainability and process efficiency. Leaders in the industry like Lilly have successfully adopted ligation for assets at scale and are investing heavily in ligation strategies.

The Economic Imperative for High-Purity Alternatives

TPN: How is the push for greater cost efficiency and affordability, reshaping the bio/pharma outsourcing landscape?

Jimenez: The push to expand RNA therapeutics to prevalent patient populations is driving innovation in manufacturing, particularly in exploring alternatives to solid-phase oligonucleotide synthesis (SPOS). As demand grows, sustainable scalability has become a critical concern, prompting the industry to seek methods that can support higher production volumes without compromising environmental, operational efficiency while maintaining similar or better economics.

Equally important is the issue of quality — low purity in oligonucleotide synthesis not only reduces yield but also significantly increases production costs, making high-quality output essential for both economic and therapeutic success. Alternative manufacturing methods using enzymatic synthesis like the Codexis’ ECO Synthesis® Manufacturing Platform, are gaining traction for ligation-based and fully sequential oligonucleotide synthesis for scalable RNA manufacturing services.

Scaling Next-Gen Modalities Responsibly

TPN: As next-generation therapies become more prevalent, what specific technological and logistical challenges will CROs and CDMOs need to address to scale production and ensure quality and compliance?

Jimenez: Capital expenditure (CapEx) is a critical factor, especially when comparing the high costs of infrastructure and operating solid-phase oligonucleotide synthesis (SPOS) facilities versus more cost-effective enzymatic alternatives. Enzymatic synthesis infrastructure requires a much smaller footprint and a workflow that can fit into existing buildings sometimes with equipment that’s already on-site. Additionally, quality control becomes increasingly vital; low purity in oligonucleotide synthesis can lead to reduced yields and significantly higher production costs, making robust quality assurance systems essential for economic viability and regulatory compliance.

The ECO Synthesis Manufacturing Platform empowers RNA therapeutic developers to scale sustainably — delivering high-quality RNA with minimal purification steps, reducing solvent use through water-based processing, and enabling larger batch sizes that minimize production runs and infrastructure investment.

The Architecture of the Ballroom Facility

TPN: What is the future of the traditional ‘one line, one product’ manufacturing model, and how will contract organizations adapt to a more agile, multi-product environment?

Jimenez: Traditional one line, one product manufacturing models experience pressure from a change in emerging trends such as: smaller batch sizes for cell and gene therapies, pipeline diversity as companies develop different modalities, speed to market and cost efficiency.

Smaller, more flexible ‘ballroom’ type cleanrooms with plug and play equipment, electronic batch records, and single use technologies that eliminate cleaning validation and reduce changeover will replace one line, one product plants.

In the future, hybrid models will dominate with some dedicated lines for high volume products along with a mix of more flexible suites for niche or emerging therapies, while digital twins and smart manufacturing will further enable real time optimization. Codexis is in a strong position to take advantage of this trend as the ECO Synthesis Manufacturing Platform is designed to work in a manufacturing footprint that is 5–10 times smaller than traditional chemical synthesis.

Streamlining Development Through Machine Learning

TPN: How are advancements in AI and automation being leveraged by biopharma companies and their outsourcing partners to improve R&D, manufacturing, and supply chain efficiency?

Jimenez: Advances in AI and automation are reshaping how biopharmaceutical companies and their manufacturing partners approach process development, production, and supply chain optimization. Codexis has long applied machine learning, bioinformatics, and advanced laboratory workflows through its proprietary CodeEvolver® Technology and ECO Synthesis Manufacturing Platform that enable more efficient and scalable manufacturing across pharmaceutical and RNAi therapeutic applications through engineered enzymes.

In RNAi manufacturing, these capabilities help streamline dsRNA ligase screening by rapidly identifying optimal enzyme and fragment combinations for specific siRNA constructs. The result is fewer experimental iterations, faster decision-making, and greater confidence in downstream manufacturing processes. For example, with ligase selection achievable in as little as three weeks, AI-enabled approaches are helping accelerate development timelines while improving precision in RNA manufacturing.

Reinforcing Supply Chain Resiliency and Geopolitical Agility

TPN: With an increasing focus on supply chain security and geopolitical tensions, what strategies can service providers employ to mitigate risks associated with international outsourcing?

Jimenez: Pharma companies have used a variety of supply chain and business continuity strategies for quite some time, including multi-sourcing from different internal and external sites in different jurisdictions or holding of strategic inventories. Service providers have historically played a role in these strategies, by being one of the sites the bio/pharma company would utilize as it diversifies its jurisdictions.

In the current landscape CDMOs may need to adopt those same strategies in their own network, such as having sites in different jurisdictions that they can offer to their clients while also having multi-source options for raw materials.

To align with these strategies Codexis is building a vertically integrated US based supply chain by adding a cGMP manufacturing facility to its multi-building presence in Northern California. The ECO GMP Manufacturing Center will open late 2027 and will support kilo scale and beyond for Phase I and Phase II clinical supply needs. This presence gives partners direct access to proprietary innovation across our RNAi and pharma biocatalysis workflows.

Quality and Regulatory Challenges for Emerging Technologies

TPN: With growing demand for RNAi therapies and a shift towards broader indications, how is that changing expectations for innovators and manufacturing partners?

Jimenez: The rapid growth of RNAi therapeutics and expansion into larger patient populations are raising the bar for both innovators and manufacturing partners. Beyond simply increasing capacity, the industry is focused on developing manufacturing platforms that can deliver consistent quality, robust supply chains, and cost-effective scalability as RNAi medicines move into more prevalent disease areas.

Enzymatic manufacturing approaches are gaining increased attention because they offer a path to improved process efficiency and scalability while supporting the high-quality standards required for commercial RNA therapeutics. At Codexis, we view this evolution as extending beyond manufacturing throughput to encompass greater control over product quality attributes. One area of growing industry interest is stereochemical control, where the ability to precisely define phosphorothioate stereochemistry could help improve consistency, therapeutic potency, and manufacturability for next-generation oligonucleotide therapeutics.

The regulatory community is also actively engaging with these innovations. In August 2024, the FDA accepted Codexis' ECO Synthesis® Manufacturing Platform into its Emerging Technology Program, reflecting the agency's interest in technologies that have the potential to advance RNA therapeutic manufacturing. As RNAi medicines continue to expand into broader indications, success will increasingly depend on manufacturing platforms that can seamlessly scale while meeting evolving expectations for quality, reproducibility, and regulatory readiness.

Reference:

1: Alnylam Pharmaceuticals, “Alnylam to Invest $250 Million to Add Enzymatic Ligation Platform to U.S. Manufacturing Facility to Meet Growing Global Demand for RNAi Therapeutics,” December 17, 2025, https://investors.alnylam.com/press-release?id=29466.

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