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Over the past two decades, more than $22B of direct investment fueled the rapid growth of the oligonucleotide therapeutic market. To illustrate, in 2019, 163 companies were actively working on 542 therapeutic projects, and 85% of the top 20 pharmaceutical companies had oligonucleotide therapeutic deals.
This fast-growing market, with close to 100 mid- to late-phase projects, some of which may require hundreds or even thousands of kilograms of product, is igniting urgency in companies to secure a stable supply of oligonucleotide active pharmaceutical ingredient (API) in preparation for drug approval.
Ionis Pharmaceuticals is a key player and innovator in RNA-targeted therapeutics with an expanding, diverse, and mature pipeline i.e., 40+ first-in-class or best-in-class medicines to meet unmet needs, targeting a broad range of diseases from the ultra-rare affecting a handful of patients to diseases affecting millions of patients.
“People get hung up on scaling oligonucleotide production, but it has already been solved using technology from Cytiva (formerly part of GE Healthcare Life Sciences). We (Ionis) surpassed the 500–1000 mmol scale, that some refer to as large-scale, decades ago. We now consider lot sizes under 10 kg as small scale,” says Max Moore, Executive Director of manufacturing and operations at Ionis.
As the process steward for oligonucleotide production for Ionis products, their partners, and contract manufacturing organizations (CMOs) around the globe, Moore’s department manufactures APIs, educates newcomers to the field, and leads process transfers. To date, Moore’s team has successfully completed approximately 30 technology transfers for R&D and commercialization to almost every global major pharma and CMO. At the heart of the transfer is the synthesis operation that includes 200 chemical transformations that occur over eight hours.
A typical technology transfer starts with an equipment review to ensure partners have the Cytiva equipment in place. This makes transfer of the synthesis methods effortless using UNICORN software, which becomes a common language between sites.
Flow-Through Solid-Phase Synthesis Technology
Cytiva designed synthesizers that use flow-through solid-phase synthesis technology with linear scalability almost 30 years ago. Revolutionary at the time, the technology made kilogram-scale production of oligonucleotides a reality.
Solid-phase flow-through synthesis is highly scalable. Coupling reactions are greater than 98% efficient across manufacturing scales, and the technology provides control of reactions by precisely controlling reagent delivery times and volumes.
Over time, collaborative efforts between Ionis’ and Cytiva’s engineers incrementally improved the synthesizer design, both at the research and the production scales. For example, an optional heat exchanger was added to modulate the temperature of the reactions, and software was created to adjust the column volume to the bed height and reduce solvent use. Today, these options are openly offered to the industry at large.
“For process development, we conduct small-scale syntheses in the laboratory,” says Moore. “Once we have confidence in the process parameters, we apply them directly to our production-scale synthesizer without any pilot-scale syntheses.” The field-tested components and software have the ability to produce milligrams to metric tons annually with the benefit of being able to opt out of pilot-scale confirmation work.
In 2010, Moore’s then staff of seven, produced 70 kg of a single compound and 20 kg of 10 compounds of various chemistries. “In a properly engineered plant, you can also use the technology to produce 50 or more lots of 5–10 kg per year or 1,000s of kgs of a single
compound depending on commercial or clinical needs,” adds Moore.
The high yields and purities achieved with automated solid-phase synthesis have set a precedent of performance that has yet to be matched by other approaches. Tens, if not hundreds of millions of dollars have been invested to develop solution-phase synthesis without success.
“We figured out how to make solution-phase chemistry work at Ionis, it is just not cheaper or faster. People pursuing solution-phase synthesis assume there is a problem with solid-phase, more specifically, that the technology cannot be used to produce metric tons of oligonucleotides at an affordable cost. Solid-phase is scalable and efficient; we can control each reaction with precision via temperature, reagent volume, and contact time,” emphasizes Moore.
Establishing a Commercial Process
Prior to process performance qualification (PPQ), appropriate parameter set points and ranges must be established to ensure a commercial process that can consistently produce a product that meets the strict specifications required by global regulatory bodies. This can mean spending several years in the laboratory, a costly endeavor involvinging complex experiments to understand scaleup and parameter interactions.
Moore conducts pre-PPQ work at small scale to establish setpoints and proven acceptable ranges (PARs) for synthesis parameters. Once PARs for synthesis parameters are established, the process goes directly to production. For one compound, Ionis used data generated in-house and at two CMOs to establish ranges, demonstrating the utility of common software and hardware to quickly investigate any differences in results.
“Our confidence in Cytiva’s equipment and our chemistry has allowed us to reduce PPQ effort by orders of magnitude,” says Moore. “We can do the work in under a year or even months by leveraging platform experience to reduce experimental workload.”
Field-Tested Hardware and Control Software
The strength of this synthesis platform are in both the software and hardware. Unstable software can contribute to batch losses that are expensive both from a raw material perspective and also because a deviation in a GMP environment must be investigated even if there is no product loss. Such investigations are an expensive undertaking.
“We do R&D to reduce costs and increase purity and yield; we do not want to think about hardware and software, and certainly do not want to use unstable software. Having Cytiva equipment installed at our facility and at our partner’s facility is a critical part of our business,” inserts Moore.
Ionis has conducted hundreds of GMP syntheses without rejecting a batch due to equipment malfunction. The tested and predictable software simplifies transferring and scaling support with the goal of shortening time to market.
Other aspects to take into consideration when scaling up include the significant increase in material consumption and the stability of the supply chain. Inadequate quantities or untimely access to raw materials can be calamitous. Other factors include raw material variability and the range of acceptable variations in the process parameters.
Supply chain stability is critical. Being single-sourced for critical raw and starting materials is a precarious position when supplying important pharmaceutical drugs. Ionis is able to use Cytiva’s research tools to develop supply chain processes and new chemicals at their vendors through collaborative R&D agreements, which brings more stability to their processes.
Optimum Manufacturing Planning
Recommendations vary in terms of doing smaller, faster, continuous batches versus larger, infrequent batches due to the speed of qualitative feedback on batch completion, binding capital, and hours invested.
That is why it is critical to have access to equipment that opens the door to many options, where the developer’s manufacturing and financial requirements define the scale and capacity, not the equipment.
For more information visit Ionispharma.com.
For more information visit cytiva.com.