On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system

Abstract

Pharmaceutical manufacturing typically uses batch processing at multiple locations. Disadvantages of this approach include long production times and the potential for supply chain disruptions. As a preliminary demonstration of an alternative approach, we report here the continuous-flow synthesis and formulation of active pharmaceutical ingredients in a compact, reconfigurable manufacturing platform. Continuous end-to-end synthesis in the refrigerator-sized [1.0 meter (width) × 0.7 meter (length) × 1.8 meter (height)] system produces sufficient quantities per day to supply hundreds to thousands of oral or topical liquid doses of diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride that meet U.S. Pharmacopeia standards. Underlying this flexible plug-and-play approach are substantial enabling advances in continuous-flow synthesis, complex multistep sequence telescoping, reaction engineering equipment, and real-time formulation.

Portable, On-Demand Biomolecular Manufacturing

“…Indeed, efforts in decentralizing pharmaceutical production summarized in recent reports send a powerful message that there is a clear global need for alternatives to centralized biomanufacturing. In one project (Adamo et al, 2016), researchers sought to alleviate drug storage or offer the means for quick reaction to epidemics by constructing a customized instrument (weighing 100 kg) for the chemistry-based production of pharmaceuticals. Another recent work (PerezPinera et al, 2016) described local biomanufacturing using a compact, microfluidic bioreactor housing genetically engineered yeast.…”

“…Building off of this foundation, the proposed use of FD-CF systems, with their long-term activity at room temperature (> 1 year) and ease of operation, could alleviate both the restrictions of live-cell biosynthesis and cold-chain distribution requirements (Pardee et al, 2014). Recent reports draw emphasis to a pressing need for the decentralization of therapeutic biomanufacturing, offering novel alternatives that, nonetheless, require expensive, large equipment and highly skilled operators or yet rely on production from living cells (Adamo et al, 2016;Perez-Pinera et al, 2016). Previous work has demonstrated protein production from lyophilized reactions, which strongly supports the notion of advancing this concept further, toward ondemand, local biomanufacturing (Salehi et al, 2016;Smith et al, 2014).…”

The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds

“…Neat or molten reagents led to higher reactivity and throughput in the multistep flow chemical preparation of Ibuprofen, 20,21 Rufinamide, 22 Aliskiren, 23,24 Lidocaine and Diazepam. 25 Complete removal of the solvent and introduction of a different one may be necessary in some cases, although only few continuous examples were described for such processes. During the synthesis of Oxomaritidine, the initially used THF had to be removed before the last steps.…”

“…28 In the synthesis of Lidocaine and Diazepam, separate pumps were used for the neat reagent and the solvent to avoid decomposition on standing. 25 On the other hand, the preliminary deprotonation occurring in the premixed solution of the benzimidazole substrate and the base was found beneficial for reaching appropriate regio-and chemoselectivity in an alkylation leading to Telmisartan. 30 When coupling the individually optimized steps during the synthesis of condensed benzothiazoles, significant differences were observed in the yields of the thiazole-formation step, depending on the premixing time.…”

“…66 More trivially, clogging can be hindered by employing wide bore channels or tubing, as well as applying agitation or sonic irradiation and controlling of fluid velocity. 25,27,67 If clogging is caused by the crystallization of low melting substances, the heating of the problematic areas is an effective method. 39 In the gas-liquid two phase flow during an ozonolysis leading to drug candidate OZ439, the evaporation of the liquid phase caused clogging.…”