Since opening a 20,000-sq-ft manufacturing facility in Europe last year, and with the acquisition of Belgian oligo producer RNA-TEC, IDT has significantly expanded its global production capacity for both RNA and DNA. Martin points to the technology shift at large genome centers away from traditional Sanger sequencing methods and to high-throughput next-gen sequencing as a key factor behind IDT’s expansion. “We have seen a lot of interest in highly modified, large-scale oligo preparations for next-gen sequencing applications; driven largely by that and by continued interest in the testing of oligos in vivo, we have doubled our large-scale synthesis and purification capacity.”
Another rapidly expanding area is the synthetic biology market and the demand for gene synthesis. “One of the biggest challenges in synthesizing genes is the assembly of complex fragments that may contain homopolymeric runs or heteropolymeric repeats,” for example, explains Martin.
“If we can push the envelope in synthesizing 400–500 base oligos, we would be able to “synthesize right through those difficult regions.” Producing a functional gene would then require combining only two or three large fragments. IDT currently offers its Ultramer oligos, which can extend up to 200 bases, and the company is working to produce oligos that are 300–400 bases in length.
As demand increases and production methods improve, the cost of synthesizing genes continues to drop and has dipped as low as $0.50/base pair in the marketplace. Martin predicts that declining costs will enable new types of projects that demand large numbers of synthetic genes. For example, a company that wants to improve the activity of a protein of interest would be able to “order the gene with a range of variants that yield amino acid substitutions at any position of interest, or a library of all possible variants, express them all, and test them functionally.”
Quality Up, Costs Down
Dr. Ackley reports that trends in the industry mirror the overall maturation of the oligo pipeline: as clinical candidates progress, GMP requirements become increasingly stringent. Dr. Ackley will speak at “TIDES” on analytical techniques the company has developed for characterizing impurities in oligo preparations. She is seeing a greater desire in the industry to understand what impurities are present in the API. Girindus is pursuing studies to characterize impurities in the raw materials used for oligo synthesis and correlating those to impurities detected in the final product.
Citing a common theme evident at the recent “BioEurope” conference, Rethage agrees that clients are seeking help in modeling the future commercial volume supply chain and cost of goods. Clients with early and mid-stage projects that are looking for funding or licensing partners want evidence—“credible numbers based on real experience”—that they will be able to bring down the cost of goods for APIs in the future.
“We are confident that our price/volume models for the future using new supply chains will be sustainable,” says Rethage. Avecia’s projections draw on its past experience producing its own amidites and leveraging its experience manufacturing a substantial project portfolio. The company has demonstrated, based on process validation experience and the use of statistical modeling in process development, that it can accelerate process validation and reduce the cost by as much as 80%, according to Rethage.
Avecia is investing in additional approaches to reduce costs associated with synthesis, primarily focusing on the installation of an Oracle enterprise resource planning system to increase standardization and automation of internal processes to achieve greater stability and predictability. Other ongoing investments include the implementation of the Pilgrim quality management system to improve and increase the reliability of regulatory compliance, of Corrective and Preventive Actions, audit, and training processes and reduced costs.
Biospring, a German CMO, also reports increased demand from the pharma sector for both DNA and RNA therapeutics, with an emphasis on intermediate- and large-scale quantities. The company is expanding its GMP production capacity by building a second facility at its existing corporate site, according to Hüseyin Aygün, Ph.D., CSO.
Commenting on overall trends in the oligo market sector, Dr. Aygün describes interest from European customers in projects focused on novel therapeutic applications for oligos. He also reports strong demand for better product characterization. In response, Biospring has initiated a program for sequencing highly modified oligos using MALDI mass spectrometry techniques, which are based on chemical rather than enzymatic fragmentation. MALDI-MS analysis is particularly useful for RNA, including sequencing of duplex RNA.
Defying the economic slowdown, oligo manufacturers are still seeing heavy demand for their products. This phenomenon is likely the result of a myriad of factors including:
- The number of ongoing oligo therapeutics programs more than doubled between 2003 (103) and 2009 (231).
- Collaborations with big pharma have created more funding for biotech oligo programs.
- The emerging synthetic biology field has created a demand for cutting-edge gene synthesis.
- The burgeoning diagnostics market is increasingly focused on oligo-based tests.
- As products progress through development, the need for large-scale production escalates.