A Greener Approach to Therapeutic RNA Production

Continued clinical success has transformed RNA from a promising modality into a rapidly expanding global therapeutic market. Valued at $10.9 billion in 2025, the field is projected to surpass $26 billion by 2035 as RNA-based medicines continue to advance across rare and high-prevalence diseases [1]. Within this growth, small interfering RNA (siRNA) therapeutics have become a leading segment, driven by improved delivery technologies, sustained clinical investment and their success in treating rare conditions.

As these modalities advance from early-stage programs to commercial production, the pharma industry faces mounting pressure to increase output efficiently and responsibly. Meeting rising demand will require manufacturing models that combine scalability with environmental stewardship, ensuring RNA therapeutics can be produced at the quality, speed and sustainability standards expected of modern pharmaceutical manufacturing.

The sustainability challenge of solid-phase oligonucleotide synthesis

Solid-phase oligonucleotide synthesis (SPOS) remains the established approach for producing RNA therapeutics, valued for its precision and reliability. The process enables stepwise construction of RNA sequences with well-controlled reaction chemistry and has supported much of the industry’s early clinical progress. For these reasons, SPOS continues to serve as the benchmark method for RNA manufacturing today.

However, its strengths come with notable challenges:

1. High solvent and reagent consumption
   SPOS relies on large volumes of organic solvents and reagents to drive stepwise synthesis, leading to significant consumption of chemicals and raw materials in each production cycle.
2. Significant chemical waste generation
   The process produces considerable quantities of hazardous waste that require complex handling, treatment and disposal systems.
3. Energy- and infrastructure-intensive operations
   Scaling SPOS demands specialized equipment and high energy input to manage solvent recovery, purification and process control. Expanding capacity to scale traditional RNA manufacturing also requires significant expenditure, exemplified by Agilent’s recent $725 million investment [2].

While SPOS will remain a reliable method for RNA synthesis, its heavy solvent use and cost required to expand infrastructure with scalability in mind highlight the need for more efficient and sustainable manufacturing approaches.

Enzymatic synthesis: A solution for a sustainable tomorrow

Enzymatic synthesis offers an innovative and environmentally responsible alternative to traditional chemical methods. Instead of using stepwise chemical coupling, enzymatic RNA synthesis employs specialized polymerases and ligases to assemble RNA strands in solution.

This approach offers several key advantages when considering sustainability:

• Cleaner chemistry
  Enzymatic synthesis operates under mild, water–based conditions, eliminating the need for harsh organic solvents and reducing chemical waste. By replacing stepwise chemical coupling with enzyme-catalyzed reactions, it creates a cleaner and safer manufacturing environment that reduces both material use and environmental burden.
• Process efficiency with uncompromised quality
  With fewer process steps and lower energy demands, enzymatic synthesis offers a simpler and more resource-efficient workflow that maintains product quality and consistency. These process efficiencies enable faster turnaround, reduced purification requirements and lower overall production costs within a greener manufacturing model.

As projects progress to commercial scale, these benefits become even more significant. Enzymatic synthesis can be scaled in solution without the fixed-bed limitations of solid-phase systems, allowing manufacturers to produce larger batches with consistent quality and less solvent use.

Collaboration for a responsible future

The future of RNA manufacturing will rely on practical solutions that make large-scale production cleaner, more efficient and easier to scale. As demand grows, collaboration between drug developers and partners such as Codexis, who provide scalable and sustainable enzymatic synthesis for therapeutic RNA, will be key to advancing manufacturing methods that balance performance and sustainability goals.

Codexis works with drug developers to help achieve these goals through the ECO Synthesis® Manufacturing Platform. This enzyme-enabled system replaces key chemical steps with biocatalytic reactions in a water-based solution, reducing solvent use and waste while maintaining product quality and process reliability. By combining enzyme engineering expertise with collaborative process development, Codexis supports the industry’s move toward scalable, sustainable RNA manufacturing.

References
1. PharmiWeb. RNA Therapeutics Market: A Detailed Analysis of Current Landscape, Future Prospects and Strategic Insights. Published 10 July 2025. Available at: https://www.pharmiweb.com/press-release/2025-07-10/rna-therapeutics-market-a-detailed-analysis-of-current-landscape-future-prospects-and-strategic-insights

2. Agilent Technologies Inc. (2023, January 10). Agilent investing $725 million to expand state-of-the-art manufacturing capacity for production of nucleic acid-based therapeutics