Solid phase synthesis is the gold standard in oligonucleotide development and manufacturing for many reasons. It is well understood, easily scalable (at least to mol scale), and reliable with short development times. There are a plethora of automated instrumentation, solid supports, and human expertise available. For the industry’s historical 20-30-mer products, solid phase fits like a glove. However, solid phase is not without its warts. It involves costly reagents, generates significant waste – especially at large scale – and faces limitations in producing long or modified oligonucleotides. Yields are as low as 50% with process mass intensity (PMI) as high as 5000 per kg of oligo. In the final article in our WHAT’S NEXT IN OLIGO MANUFACTURING series, we look at new approaches that are seeking to solve these manufacturing challenges of the future.

While the low yields and high PMI of solid phase have been acceptable to produce limited amounts of rare disease oligotherapeutics and clinical material, Big Pharma and the wider industry increasingly do not necessarily see solid phase as a sustainable method of manufacturing commercial scale oligos for broad diseases, for which multi-metric tons may be required. Traditional legacy process by Letsinger and Khorana are now being entirely revisited by radically different enzymatic, biocatalytic and other liquid phase approaches, borne from the experiences of PCR and genome sequencing methods. Liquid-phase enzymatic and biocatalytic synthesis offer intriguing alternatives by leveraging the precision and mild conditions of enzymes, enabling the production of high-quality oligonucleotides with reduced environmental impact.

The trend toward greener and more cost-effective synthesis methods has spurred the development of these innovative technologies that enhance yield, purity, and scalability. Thus, suppliers, CDMOs and oligo drug innovators should all be aware of the alternative technologies available for the future. 

Emerging Oligosynthesis Technologies

Below is a list of some emerging liquid-phase enzymatic and biocatalytic technologies for oligonucleotide synthesis, along with brief descriptions and the organizations pioneering them:

This overview demonstrates the depth of disruptive technologies coming to oligonucleotide manufacturing technology platforms. Many of these next-generation technologies have already exhibited the potential of lower costs, simple fast reactions at room temperatures, lower solvent consumption, long chain synthesis, higher purity with reduced downstream purification requirement, higher yield, and a much lower environmental footprint. Most importantly, the liquid phase enzymatic methods can be scaled to produce the metric tons of oligos which would be required should oligos succeed with entry into broad disease indications. Although most of these technologies are in validation stage pending further scale-up studies, recent partnership involvements of Big Pharma such as Astra Zeneca, GSK, Novartis, Biogen, and Roche may encourage a more rapid adoption of these technologies than expected.

A 2023 TIDES survey of 110 oligo manufacturing industry respondents by Asahi Kasei reveal that 71% believe enzymatic methods will dominate by next decade. Therefore, this potential transformation in oligo manufacturing presents a rare opportunity for new, small and emerging equipment vendors, materials suppliers, CDMOs and CROs for entry into a billion-dollar market. Thorough technical and market knowledge is recommended to consider prior to collaboration, investment and go-to-market strategies; but, in fact, the timing is ideal right now for such considerations.

In a 2023 TIDES survey, 71% of respondents believed that enzymatic methods will dominate oligosynthesis within the next decade.

Despite this promise, it is our belief that solid phase synthesis will hardly disappear; after all, as described, it is a reliable, go-to approach for early-stage development. Further, the economics of solid phase may still make sense in the future for orphan indications which may only require kg annual quantities when commercialized. Even in broad disease indications, solid phase could be applied at development stage, and perhaps even early clinical phases; however, to truly enable metric ton-scale production, it is clear that a transition to more cost-effective manufacturing methods will need to be considered. 

Considerations for Oligo Suppliers and CDMOs

Established oligo manufacturers and suppliers should therefore consider the following to better prepare for a future that extends beyond solid phase:

  • Detailed new technology evaluations for partner identification or in-house development
  • Business potential, collaboration, licensing or acquisition roadmap
  • Scale up, modelling and specification of liquid phase technologies
  • Green chemistry workflow, solvent usage and PMI calculations and planning
  • Understanding of new critical process parameters, quality attributes and regulatory requirements
  • Identification and qualification of new enzymes and materials suppliers
  • Leveraging and retraining of existing workforce
  • Expansion or retrofitting of existing facilities, equipment design and downstream purification
  • Use of AI to accelerate liquid phase process development
  • Value propositions and market messaging to differentiate and attract clients

Adoption of these new technology platforms is already happening through several startups, consortiums and big players with wider adoption anticipated following scale-up proofs.

Read our previous article, “What’s Next in Oligo Manufacturing: Conjugates and Lipid Nanoparticles for Drug Delivery“.

To Summarize:

Solid phase synthesis is the current gold standard in oligonucleotide development and manufacturing. While it may very well remain the standard in early-stage development, it is also true that oligo therapeutics are now in development for broad disease indications. This will necessarily require larger scales of API production for commercialization in the future – potentially into the metric ton scale. At this level, together with sustainability initiatives undertaken by many Big Pharmas, the industry’s interest in next-gen liquid phase and enzymatic synthesis solutions will continue to rise. Suppliers and CDMOs should keep abreast of the competitive landscape in this emerging field and consider partnerships and investments that may help them catch this future wave.  

Are you interested in custom market research services to gain deeper insights into future oligonucleotide starting materials and other manufacturing trends? Reach out for a consultation.

References:

  1. Moody, E., Obexer, R., Nickl, F., Spiess, R., & Lovelock, S. (2023). An Enzyme Cascade Enables Production of Therapeutic Oligonucleotides in a Single Operation. Science. https://doi.org/10.1126/science.add5892
  2. Tia Byer,  April 2022,  Sustainable Synthesis of Therapeutic Oligonucleotides, Biologics Oxford Global
  3. https://www.pharmaceutical-technology.com/sponsored/oligonucleotides-overcoming-sustainability-challenges-with-manufacturing/
  4. https://exactmer.com/oligonucleotide-synthesis/
  5. https://wyss.harvard.edu/technology/controlled-enzymatic-rna-oligonucleotide-synthesis/
  6. The ECO Synthesis™ Platform & The Future of RNAi Therapeutics Manufacturing Virtual Key Opinion Leader Event, December 8, 2023, Codexis
  7. Helen Albert  June 2023,  Biocatalytic process shows promise for large-scale medicinal oligonucleotide production, Chemistry World News
  8. Ajinomoto BioPharma Services, From Research To Commercial Quantities:A Seamless Supply Of Oligonucleotides
  9. October 2023, Evonetix Places First DNA Synthesis Development Platform at Imperial College London – European Pharmaceutical Manufacturer