(613e) Process Modeling, Simulation and Technoeconomic Evaluation of Batch Vs. Continuous Pharmaceutical Manufacturing (CPM) of Cephalexin

Continuous Pharmaceutical Manufacturing (CPM) has been recognized as an increasingly promising multidisciplinary research domain, addressing the significant obstacles hampering sustainable profitability (increasing R&D costs, globalized competition, licensing protocols, legal and regulatory landscape changes). Introducing a viable alternative to traditional batch production processes, CPM has an expanding potential capable of achieving lower costs (Schaber et al., 2011), higher yields, more economical heat and solvent use, high mass transfer rates, rapid scalability and elimination of intermediate storage (Calabrese and Pissavini, 2011). The technical viability and process efficiency of CPM prototypes must be investigated in silico, to ensure successful pilot-scale efforts (Mascia et al., 2013) and reliable production-scale implementations keenly pursued by pharma corporations (Badman et al., 2019).

Organic flow synthesis literature contains a wide range of Active Pharmaceutical Ingredients (APIs) whose production is demonstrated in continuous mode at laboratory scale, with subsequent studies exploring technical viability and economic feasibility, e.g. ibuprofen and artemisinin (Jolliffe & Gerogiorgis, 2015), as well as diphenhydramine (Diab & Gerogiorgis, 2017). Systematic flowsheet synthesis, process modelling and simulation are key for assessment of CPM potential, and widely applied in case studies (Gernaey et al., 2012; Sen et al., 2013, Rogers & Ierapetritou, 2015).

The present paper focuses on a plantwide process modeling and simulation study for the production of cephalexin: this broad-spectrum antibiotic prescribed for chest, skin and other bacterial infections has an annual production of ca. 30 thousand tons and sales of USD 15 billion. Cephalexin can be synthesized from phenylglycine methyl ester (PGME, acyl donor) and 7-aminodesacetoxycephalosporanic acid (7-ADCA, β-lactam nucleophile), and this synthesis is catalysed by penicillin acylase (PA) (Vobecka et al., 2020).

Our process models portray both batch and continuous production modes, on the basis of published organic synthesis precedents (Schroën et al., 2001; Illanes et al., 2007; Vobecká et al., 2020), which have demonstrated that this economically and societally important API can be produced using Plug Flow Reactors (PFRs) and suitable separations. Here, we consider employing the enzymatic reaction synthesis in combination with an aqueous two-phase system (ATPS) consisting of PEG4000 water and dipotassium hydrogen phosphate (K2HPO4) for cephalexin purification in situ.

Process modelling and steady-state simulations have been conducted toward process design for the respective CPM routes, with reactor design completed on the basis of published kinetic expressions, and separator design on the basis of rigorous thermodynamic property estimation. Economic evaluations of both batch and continuous plant operation ventures are performed on the basis of plantwide mass balances, to quantitatively evaluate production-scale cephalexin process viability.

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