Oligonucleotide production and development have continued to expand rapidly. A recent CRB report tells us that there will be a significant push for existing companies to enter the oligonucleotide market — whether startups, large pharma companies or CMOs — in the near future, with the majority planning for capital investment within the next four years. This data paints a picture of an industry where successful development has outstripped available production capacity.
The report also tells us that the sector continues to focus on the development of a diverse group of molecule types. However, public information indicates that 75% of the approved oligonucleotide therapies on the market today are either antisense (ASO) or siRNA technology.
As innovators, licensers and CMOs alike look to transition from adjacent industries or expand existing capacity to fill this need, there are two key facility considerations that will impact the CapEx business case initially and throughout the life of the facility.
Molecule type and facility throughput
ASO and siRNA represent two key molecule types, and they are largely similar in the synthesis operation. However, siRNA is a dual-stranded molecule where independently synthesized strands must be annealed together, often in a separate suite. Additional variations on these molecule types can increase purification suite time and the number of required process steps before the lyophilization (freeze-drying) operation that yields the final bulk drug substance. All of these variations can affect the throughput and flexibility of the facility.
Because of this, initial facility programming should take into account the intended molecule production goals of the facility. A facility designed to maximize throughput only for a simple ASO can require less capital investment but will suffer bottlenecks if it needs to pivot to support siRNA production or molecules requiring more complex purification.
The additional purification requirements of some molecules will also impact flammable buffer storage requirements, which with increasing scale, become more capital-intensive areas of the facility due to building and fire code requirements.
For multi-product facilities that require flexibility, a facility programming approach might consider a simple ASO and a more complicated siRNA molecule type as boundary cases for what the facility will produce. This can help create a phasing plan that balances initial capital investment against future throughput goals.
It is important to understand and articulate this vision for the facility at the programming phase, as it can help lead to more efficient overall use of capital via interior fit-out of shelled space versus a lower first cost exterior future build-out. Either approach should incorporate an expansion strategy that minimizes ongoing production downtime.
Planning for tomorrow
For a multi-product facility, it is important to keep a steady eye on the capabilities of the facility as new contracts fill the capacity. Even before large capital expansion plans are triggered, there are other facility planning considerations that can allow for incremental throughput gains.
For example, manufacturers may look to increase synthesis batch size by allowing for parallel synthesis columns to increase batch output. This strategy can further enhance a large batch campaign strategy that enables final bulk product lot pooling at the lyophilization operation, a common bottleneck due to the length of the freeze-drying process.
Especially within multi-product facilities, process characterization of purification is still handled carefully, with purification fractions often stored within cold rooms until they can be analyzed for potential inclusion in downstream batches. However, as companies look forward to performing more robust characterization of some products and readily improving online analytical capabilities, their plans may consider providing spaces for hold tanks that bypass the fraction storage and analysis step. This can free up overall facility time and reduce bottlenecks for fraction analysis, and storage for products that still require it.
As the oligonucleotide industry continues to gain momentum and take shape, it will be key that facilities continue to anticipate and plan for tomorrow as they build the capacity to meet today’s burgeoning demand.
