PHARMACEUTICALS cost of manufacture and would not build unnecessary inventory .
Safety
We could not discuss process scalability without also mentioning safety , which is at the heart of everything we do .
As well as determining the compatibility of the synthetic routes with the equipment available , we also investigated experimentally in the laboratory , the routes with the greatest potential for commercialisation to understand any areas for concern . Although the second route - in grey - in Figure 2 is used industrially , we ruled out this pathway due to the low thermal onset temperature of the PCl 2 intermediate , coupled with the need to distill mid-process .
Thorough safety screening is paramount in determining if and how it is possible to scale a process , ensuring continuity of supply and most importantly , protecting the welfare of operators . While multi-tonne / year manufacturing has become routine for Phos Reagent , we continue to review protocols .
Supply chain
When selecting a scalable route , it is necessary to consider raw materials and whether the supply chain can support
Figure 1 - Chemical structure of RhodaPhos
Figure 2 ( below ) - Industrially used synthetic pathways to 2-cyanoethyl N , N , N ’, N ’ - tetraisopropylphosphorodiamidite
the volumes required as demand increases . Is the raw material widely available with multiple sources or are you limited to one supplier ? Concerns around security of supply , during and after the COVID pandemic , have been openly discussed .
We have seen some customers move towards Western suppliers of key raw materials as a result . As a large corporate entity , we benefit from a large sourcing team , which can build a robust supply chain . All of the raw material suppliers for Phos Reagent are based in the West , with our own production based in the UK .
Quality
Having a process that is scalable means factors which impact the quality and yield of the final material are well defined and measured as the process is transferred between equipment . This includes the measurement of intermediates and waste streams .
Taking the time to grow in volume with market need allows the team to reflect on the process and equipment . Business justification for investments can be gathered over time to ensure that resources are available where they are really needed . As Phos Reagent volumes have grown , we have invested in equipment to purify our crude material at larger scales and have grown the processing team , investing in training and increasing throughput of our high purity reagent .
Continuing innovation
While the start of the project lays the foundation for a safe , profitable and reproducible process , it is important to revisit existing processes , no matter how successful they are , to evaluate whether improvements can be made . These improvements may be driven by customers , sustainability initiatives , new developments , health and safety changes , or cost .
Since 2005 , our specification has gone through several iterations . As the market has grown , we have grown with it . Knowledge has evolved over time regarding impurity profiles and how these impact the downstream chemistry of oligonucleotides .
Having built a comprehensive understanding of potential impurities , we implement stringent controls to meet customer needs . Beyond customer driven changes , a team of researchers continue to improve Phos Reagent 18 years after first commercialisation .
Conclusion
Building a scalable process makes it possible for a fine chemical manufacturer to react to the market and be agile in responding to customers . The Solvay team has built and patented a process that has evolved both in terms of volume and customer requirements . We have safely transferred our process to full-scale manufacture this year , while maintaining the high level of purity expected by industry . ●
* - Rhoda Phos Reagent is a registered trademark of Solvay
References : 1 : M . Egli et al ., Nucleic Acid Res ., 2023 , 51 ( 6 ), 2524-2573 2 : T . C . Roberts et al ., Nat . Rev . Drug Discov ., 2020 , 19 , 673-694 3 : WO Patent WO2015 / 107110A1 , 2015 .
Dr Jade Markham
BUSINESS DEVELOPMENT MANAGER - PHOSPHORUS SPECIALTIES
SOLVAY k + 44 7436 250987 J jade . markham @ solvay . com j www . solvay . com
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