Process Development/Flow Chemistry

the required skillsets (of chemists, analysts, chemical engineers, QA staff, etc.) will be batch- centric! Alongside the mind-set change needed when performing retrosynthetic and process design, implementation of continuous flow processes relies on successful partnership with multi-disciplinary teams. Building a team of chemists and chemical engineers, who work closely together from the lab development stage right through to scale-up mitigates the risks with movement towards manufacture, ensuring the design of a robust and scalable process. Building networks with

academic groups and equipment manufacturers will undoubtedly advance flow capabilities within any CDMO, including Almac. Academic collaborations are essential to securing a pipeline of competent, expertly trained flow chemists with a crucial understanding of industry requirements. It is critical for academic institutions and industry to engage with each other to tailor undergraduate chemistry courses to ensure that continuous flow is a core discipline (akin to that of biocatalysis, for example). To this end, Almac has built collaborations within the island of Ireland to support its manufacturing sites in Northern Ireland and in the Republic of Ireland at Queens University Belfast and University College Dublin. The so-called CDMO ‘cultural change’ will be accelerated if students are already exposed to new technologies and novel strategies for synthesis,

building a deep understanding of the core principles. Collaborations with flow equipment manufacturers also facilitates rapid development of flow processes through tapping into their expertise and identifying suitable engineering partners to translate lab processes to manufacturing.

Almac’s platform technology

With the adoption of flow chemistry increasing at research- scale, industry expects that continuous flow offerings available from the innovator should be scalable at the selected CDMO site(s). Since flow chemistry is not ‘one thing’ and no one tool addresses all needs / chemical space, CDMOs are developing a toolbox approach with modular, flexible skids to meet their clients’ needs. Identifying processes where flow can be utilized as an enabling technology to add value for clients is a key strategy for Almac, based on in-house expertise and partnering with equipment experts like Chemtrix. Specializing in key areas of flow chemistry is not only advantageous for hardware selection, but is also beneficial for expertise development and debottlenecking within a CDMO. With this in mind, Almac has, and will continue to, focus on flow platforms for high-pressure hydrogenation, cryogenic, high energy and photo-redox chemistries. Almac’s flow chemistry department have implemented

a four-stage project workflow to ensure successful delivery of projects for clients in acceptable timelines, with minimized risk and at competitive prices. These defined stages that ensure the development of robust, safe and scalable processes for multi- kilo to tonne-scale manufacture (Figure 3).

Future outlook

Flow chemistry at Almac and equipment manufacture at Chemtrix is not adventitious, offering clients the best available technology to meet the demanding processing needs of today whilst securing supply for the future. Continuous flow technology is being utilized at Almac to expedite the development of processes where the target chemistry is inherently difficult to scale in batch, with the synthesis of novel / highly valuable functional group interchanges using high energy and pressure, oxidation and photochemical transformations central to this.

Identifying opportunities to effectively implement the technology for appropriate chemical transformations is only part of the solution: access to modular, multi-purpose flow rig(s) is key to bringing about success as a CDMO. Through continued collaboration with academic and industrial partners, the technology will continue to grow within the pharmaceutical, specialities, agrochemical and flavour and fragrance (F&F) industries. The time is now to change and flow into the future!

Authors: Tom Moody1,2, Megan Smyth1, Scott Wharry1 and Charlotte Wiles3 1 Almac Sciences, 20 Seagoe Industrial Estate, Seagoe Road, Craigavon, BT63 5QD, Northern Ireland, UK 2 Arran Chemical Company, Monklands Industrial Estate, Athlone, Co. Roscommon, Ireland www.arranchemical. ie

3 Chemtrix BV., Galvaniweg 8a, 6101 XH Echt, The Netherlands www.chemtrix. com

REFERENCES 1. Baumann, M.; Moody, T. S.; Smyth, M.; Wharry, S.; Org. Process Res. Dev., 2020, Article ASAP; DOI: 10.1021/acs. oprd.9b00524. 2(a). Gobert, S. R. L.; Kuhn, S.; Braeken, L.; Thomassen, L. C. J., Org. Process Res. Dev. 2017, 21, 531− 542. (b) Britton, J.; Raston, C. L., Chem. Soc. Rev. 2017, 46, 1250−1271. (c) Shukla, C. A.; Kulkarni, A. A., Beilstein J. Org. Chem. 2017, 13, 960−987. (d) Hartman, R. L.; McMullen, J. P.; Jensen, K. F., Angew. Chem., Int. Ed. 2011, 50 (33), 7502−7519. 3a). information/search-fda-guidance- documents/quality-considerations- continuous-manufacturing (b)S. L. Lee,T. F. O’Connor,X. Yang, C. N. Cruz, S. Chatterjee, R. D. Madurawe, C. M. V. Moore, L. X. Yu &J. Woodcock, J Pharm Innov. (2015) 10:191–199. 4.Rivera, N. R.; Kassim, B.; Grogorov, P.; Wang, H.; Armenante, M; Bu, X.; Lekhal, A.; Variankaval, N.; Org. Process Res. Dev., 2019, 23, 11, 2556-2561 5.(a) Ley, S.V.; Fitzpatrick, D. E.; Ingham, R. J.; Myers, R. M.; Angew. Chem. Int. Ed., 2015, 54, 3449-3496; (b) Price, G. A.; Mallik, D., Organ, M. G.; J. Flow Chem., 2017, 7, 82-86.

Figure 3: Almac’s four stages of flow chemistry process development from POC to full-scale manufacture 34 Autumn 2020 Autumn 2020 35

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