Built to scale : Increasing raw material production with growing oligonucleotide demand
Dr Jade Markham and Peter Thornton of Solvay discuss designing a scalable process to meet market demands for a key raw material
Interest in and investment into the use of antisense oligonucleotides for therapeutics continue to grow . As of 2023 , there are 18 FDA-approved nucleic acid based treatments , including inclisiran , a treatment for high cholesterol , and nusinersen , a therapeutic for spinal muscular atrophy - with a vast number of other candidates in development . 1 As the oligonucleotide market grows , so does the demand for key raw materials .
Oligonucleotides are short , single- or double-stranded DNA or RNA molecules , which are typically synthesised in a synthetic cycle using natural and unnatural nucleosides functionalised with a phosphoramidite moiety . This moiety aids selectivity and the rate of formation of internucleosidic linkages . The phosphoramidite reagent of interest here is 2-cyanoethyl N , N , N ’, N ’ - tetraisopropylphosphorodiamidite , also known by the trade name , Rhodaphos Phos Reagent * ( Figure 1 ).
The life science industry has been researching therapeutic oligonucleotides for decades , with great expectations of what a breakthrough would mean for personal and precision healthcare . 2 Solvay began the development of Phos Reagent in the early 2000s . Although the outlook on volume and likelihood of fruition was uncertain at the time , the research and innovation team chose to plan for the future and design a process that was built to scale .
Part of the Phos Reagent processing team . ( L-R : Ross Egan , Ayisha Ali and Peter Thornton )
Considering the scalability of a manufacturing process reduces the risk to time , finances and resources and ensures that you can deliver your customers ’ expectations on volumes , lead time and quality . In this article , we briefly describe the key considerations for designing a scalable manufacturing process and its benefits , with reference to our approach with Phos Reagent . 3
Choosing the right synthetic route
Making major process changes to meet increased volume demands and / or transfer to fundamentally different equipment is hard to do mid-manufacture , especially with the pressures to meet customer demand and business expectations . Selecting a synthetic route in consultation with a team of colleagues at the beginning of a project with future volume possibilities in mind is how we began .
Amongst other synthetic avenues considered , there are two known industrial routes to Phos Reagent ( Figure 2 ). We selected the top route ( in black ) as our pathway of choice , a route we patented in 2015.3
This route does not require purification steps mid-process and is essentially a one-pot process , limited only by the scale of the reactor . At project inception , it was determined that this route could translate to the equipment already available at the Solvay plant in Oldbury , UK , in terms of small and large pilot plant reactors and on to full-scale manufacture .
This proved to be a correct assumption because , from our initial commercialisation in 2005 in the smallest pilot plant reactor , we now produce at full manufacturing scale . It is also important to note that this means that if the market turned and volume demands were to drop , we can scale back while still having control of the
28 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981