On-Demand Continuous Manufacturing of Ciprofloxacin in Portable Plug-and-Play Factories: Implementation and In Situ Control of Downstream Production

Abstract

Traditional pharmaceutical manufacturing operates around a supply chain that is subject to complex logistics and is vulnerable to spikes in demand and interruptions. In this context, continuous pharmaceutical manufacturing in portable, refrigerator-sized factories is a promising solution with applications in battlefield medicine, pandemic response, and mitigation of local medical emergencies. A new iteration of the pharmacy on demand initiative is hereby presented, involving the development of equipment and processes for the manufacture of ciprofloxacin HCl with commercialization in mind. This article covers the implementation and the feedback control strategies for downstream manufacturing, as well as the results of the first end-to-end continuous manufacturing campaign. The results involve a significant leap from prior iterations, consistently attaining drug substance specifications in a fully automated process and with a 4-fold increase in the process throughput over the most recent iteration.

Towards 4th industrial revolution efficient and sustainable continuous flow manufacturing of active pharmaceutical ingredients

“…However, this can be achieved by final-product purification using techniques such as multicolumn chromatography catch-and-release chromatography, simulated moving bed (SMB), crystallisation, recrystallisation and centrifugal partition chromatography (CPC). 51,54–59 Adding to scalability concerns of some of these purification methodologies, these techniques have their drawbacks; crystallization and recrystallisation usually requires semi-batch processing, catch-and-release chromatography needs automated multiple columns switching and the SMB chromatography operation is technically complex and it uses expensive absorbents. 12,51,60 The application of various downstream continuous flow processing strategies examples are reviewed herein.…”

“…Capellades et al 58 demonstrated the implementation and in situ control of downstream production of ciprofloxacin in portable plug-and-play continuous flow platform. The work mainly focused on the implementation and in situ feedback control strategies for downstream manufacturing (Fig.…”

“…Such refrigerator-sized factories can potentially be used in battlefield medicine, pandemic response, and local medical emergency mitigation. 58 The purification and isolation of ciprofloxacin HCl into a powder was carried out in two modules, namely, workup and isolation and the processes involved in each module are summarised (Fig. 19A).…”

“…19A). 58 In the workup module (Fig. 15B), the first step involved crude ciprofloxacin HCl precipitation in the vessels WMX-1 and WMX-2.…”

Total Synthesis of Glipizide and Glibenclamide in Continuous Flow

“…Various multistep continuous flow synthetic procedures for active pharmaceutical ingredients (APIs) have been reported. [31][32][33][34][35][36][37][38][39] Herein, we take advantage of continuous flow chemistry technology to develop isocyanate free, rapid and efficient synthetic approaches towards glipizide 1 a and glibenclamide 1 b from commercially available chemicals. Due to the similarities in the chemical structures of the two drugs, a similar general synthetic approach can be used.…”