Increasing Research and Development (R&D) costs, growing competition from generic manufacturers and dwindling market introduction rates for novel drug products bolster the efforts of pharmaceutical firms to secure competitiveness by investigating Continuous Pharmaceutical Manufacturing (CPM). The present paper explores the CPM of two key Active Pharmaceutical Ingredients (APIs), ibuprofen and artemisinin: cost savings and material efficiency benefits are evaluated for CPM vs. batch processing, with two continuous options for each API. Capital Expenditure (CapEx) savings of up to 57.0% and 19.6% and corresponding Operating Expenditure (OpEx) savings of up to 51.6% and 29.3% have been determined for ibuprofen and artemisinin, respectively. Total projected cost savings for a 20-year plant lifetime can reach 54.5% and 20.1%, respectively. Environmental (E)-factors (mass of waste generated per unit mass of product) of 43.4 (for ibuprofen) and 12.2 (for artemisinin) have been computed, indicating environmental and material efficiency advantages for these conceptual continuous pharmaceutical processes.

No abstract

Continuous Pharmaceutical Manufacturing (CPM) is a rapidly expanding research field with growing industrial importance: challenging the current batch production paradigm, it has a documented potential to deliver key cost, efficiency and environmental benefits. Ibuprofen, the potent painkiller, and artemisinin, a highly effective anti-malarial drug, have been identified as promising CPM candidates, and steady-state flowsheet models have been developed on the basis of published continuous organic synthesis pathways. Reactor design has been conducted using original kinetic parameter estimation results. A comparative economic analysis via published recoveries has computed performance indices which indicate that both CPM designs exhibit high economic potential, even if conservative profit and climate estimates are used to derive capital and operating costs. More detailed technoeconomic analyses can facilitate quicker CPM implementations.

Recent advances in pharmaceutical manufacturing technologies are showing the promise of continuous production: pharmaceutical firms currently rely on mature batch technology but increasingly evaluate the potential of Continuous Pharmaceutical Manufacturing (CPM). Continuous production methods have efficiency, cost, reliability and quality advantages: in this paper we evaluate and quantify these for the case of CPM of artemisinin, a key antimalarial Active Pharmaceutical Ingredient (API). Published reaction and unit operation data are analysed, static models are developed, and continuous plug flow reactors are designed for a reference case producing 100 kg of API per year. The small reactor volumes computed (19.72 mL and 78.72 mL) illustrate the capital expenditure and small footprint benefits of continuous manufacturing. Alternative CPM cases are also developed, whereby different continuous API recovery operations are evaluated in comparison to the base case; the latter employs a reported batch product recovery. Employing published solubility data as well as data estimated using the UNIFAC method, our systematic evaluation identifies ethanol (EtOH) and ethyl acetate (EtOAc) as promising candidate antisolvents for continuous crystallisation. For the same 100 kg per year production level of API, designs using continuous separation techniques can achieve significantly improved E-factor values (22.52 average) compared to the batch process (65.28), implying enhanced sustainability through reduced waste generation. This API of critical societal importance is a very promising candidate for CPM, with the future benefits of performing full analysis and technoeconomic optimisation evident.

Continuous Pharmaceutical Manufacturing (CPM) has recently emerged as a promising alternative to current batch production methods, which require significant expenditures in order to ensure product quality and process reliability. Advances in new continuous synthesis routes, demonstrations of full end-to-end continuous drug production and comparative technoeconomic analyses of potential cost advantages have all contributed to the advent of CPM and the strong interest of academic, corporate and regulatory beneficiaries. Continuous flow chemistry has been demonstrated for a variety of Active Pharmaceutical Ingredients (APIs), and there have been several landmark studies demonstrating practical CPM by illustrating the full design from raw materials to final product formulation. Fully continuous separations are critical to maximizing the CPM potential, but they are frequently not eludicated. This paper presents the formulation and solution of a nonlinear optimization problem for the CPM of ibuprofen. Adapting published continuous synthesis routes and experimental data, and considering reactor design, explicit mass transfer, thermodynamics via UNIFAC-estimated API solubilities, and cost estimation, optimal total costs have been determined for two solvents (toluene and n-hexane) at three different temperatures (25, 45 and 65 °C). The minimum total cost (728.5 × 103 GBP) is achieved for n-hexane use at 65 °C, while the minimum total cost for toluene is only marginally higher (761.4 × 103 GBP, also at 65 °C). With respect to the E-factor, a measure of design sustainability, the cases are comparable: the best E-factor (39.9) is obtained for the n-hexane at 65 °C, and the best E-factor for toluene is again close at 42.1 (for 65 °C). Given that the differences are small, the use of toluene at 65 °C is the preferable option, as this solvent is more environmentally benign than n-hexane and offers comparable performance.