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Design of a Continuous Solvent Recovery System for End-to-End Integrated Continuous Manufacturing (ICM) of Pharmaceuticals

Authors
Brianna T. Shores, Peter E. Sieg, Ana T. Nicosia, Chuntian Hu, Stephen C. Born, Khrystyna Shvedova, Ridade Sayin, Christopher J. Testa, Wei Wu, Design of a Continuous Solvent Recovery System for End-to-End Integrated Continuous Manufacturing (ICM) of Pharmaceuticals, Sukumar Ramanujam, Design of a Continuous Solvent Recovery System for End-to-End Integrated Continuous Manufacturing (ICM) of Pharmaceuticals

Introduction

Disadvantages of the “batch” paradigm of pharmaceutical manufacturing include long drug lead times, large plant footprints, high costs, and issues with quality. Consequences of these shortcomings include drug shortages, of which more than half arise from quality issues. As current pharmaceutical manufacturing operates at 2−3σ quality (∼6.7−30.9% defects, i.e., failed/rejected products), there is still much work that is required to achieve 6σ quality (∼0.0003% defects), which has long been the quality target in other industries, such as electronics, semiconductors, and automotive. This quality deficit, along with the aforementioned limitations of batch manufacturing, has motivated industry leaders to reexamine the way that pharmaceuticals are produced. As a result, the pharmaceutical industry is transitioning from traditional batch processes to continuous ones, including end-to-end integrated continuous manufacturing (ICM) approaches. The first-of-kind research demonstration of ICM (the model drug was aliskiren hemifumarate) was unveiled at MIT in 2011, with an active pharmaceutical ingredient (API) throughput of 45 g/h. Similarly, the first fully automated end-to-end commercial-setting ICM pilot plant was reported by CONTINUUS Pharmaceuticals in 2019, and the throughput reached 4800 tablets/h with a total residence time of <30 h. As the pharmaceutical industry is relatively solvent intensive, solvent recovery is critical to achieve the goal of sustainable processing. Solvent recovery is defined as the process of extracting useful materials from waste or byproduct solvents during the manufacturing process. These recovered chemicals can then be reused in the manufacturing process, which greatly reduces the need for new solvents and decreases waste significantly. The types of solvent that can be recovered include aliphatic solvents, aromatic solvents, halogenated hydrocarbons, alcohols, ketones, esters, etc. Common solvent recovery methods include distillation, membrane separation, liquid−liquid extraction, thin-film evaporation, and chemical extraction. Distillation is a process used to separate components in a mixture by vaporization followed by condensation. It takes advantage of concentration differences of components in the vapor and liquid phases. Distillation has been widely used in industry (90−95% of all industrial separations) because it is fast and very effective and efficient. However, its disadvantages are also important to consider, such as high costs, operational hazards, and the potential environmental impact. Various factors, such as feed composition, reflux ratio, liquid and vapor flow conditions (e.g., foaming, entrainment, weeping/dumping, and flooding), and the state of trays and packings (e.g., fouling, wear and tear, corrosion), could influence the performance of a distillation column. The feed composition has a direct impact on the number of plates necessary for effective separation as well as feed tray location. Some solvent mixtures can be very energy-intensive or difficult to separate if an azeotrope forms or boiling points are close. Also, risks of impurity enrichment and fouling are other challenges for solvent recovery through distillation in the pharmaceutical industry. In the present study, a continuous solvent recovery system for a two-solvent system (Solvent 1 and Solvent 2) was designed for an end-to-end ICM pilot plant. The reliability of the experimental setup for the vapor−liquid equilibrium (VLE) measurements was assessed and substantiated using ethanol-cyclohexane as a model system. The VLE data for the Solvent 1−Solvent 2 binary system are provided and have been used for the design of the distillation columns. In addition, the purities and recovery yields of Solvent 1 and Solvent 2 and the impact of the solvent recovery system on waste reduction are discussed.

Abstract

Disadvantages of the traditional discontinuous batch process have encouraged the pharmaceutical industry to explore continuous manufacturing, including end-to-end approaches, such as integrated continuous manufacturing (ICM). As the pharmaceutical industry is relatively solvent intensive, recovering solvent is necessary to achieve the goal of sustainable manufacturing. A simple vapor-liquid equilibrium (VLE) setup was designed and the reliability was assessed, from which the VLE data of a two-solvent system was obtained and, accordingly, the distillation columns were designed. The recovered solvent purities were > 99.9 wt% for the first solvent (Solvent 1) and > 99.8 wt% for the second solvent (Solvent 2), and the recovery yields were 94.9% and 98.3 %, respectively. From the E-factor analysis, there was approximately 30% less waste generated in the ICM process, compared to a corresponding batch process. After integrating the Solvent Recovery system, E-factors for both batch and ICM processes decreased significantly, from 1.63 to 0.29 and from 0.77 to 0.21, respectively.

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