(189d) Development of a Modular, Continuous, End-to-End Albuterol Manufacturing Plant

Conventional pharmaceutical manufacturing involves an iterative series of batch processing steps to synthesize and purify active pharmaceutical ingredients (APIs). During batch API synthesis, pharmaceutical synthons are repetitively reacted, separated, purified, redissolved, and monitored via chain-of-custody documentation to ensure product quality between each batch. This labor-intensive process generates large amounts of waste, necessitates large scale-up vessels which increase safety concerns, complicates logistics, and increases capital costs. These inefficiencies have reduced America’s economic competitiveness in the pharmaceutical industry and has resulted in the offshoring of API manufacturing – a trend which has exacerbated supply-chain delays for lifesaving medicines. A competitive alternative methodology seeks to continuously manufacture APIs on a smaller, modular scale via continuous flow chemistry to facilitate high throughput conversion of API reactants into packaged pharmaceutical formulations – all within a single, streamlined, end-to-end process.

This talk explores VCU’s ongoing development of a modular, continuous, end-to-end manufacturing plant for the synthesis of albuterol sulfate, a bronchodilator used for the treatment of asthma, and an API currently listed on the FDA’s drug shortage list. The final automated system will be monitored using in-line process analytical technologies (PAT) to ensure product quality and facilitate the production of 120-1,200 packaged doses per hour. Key engineering design decisions necessary for successful translation of batch synthesis towards continuous manufacturing will be highlighted, with emphasis placed on model-based systems engineering (MBSE), statistical design of experiments (DOE), process intensification via rational synthon selection, the introduction of packed bed catalytic reactors, and operation under non-equilibrium conditions in flow. Analytical characterization via high performance liquid chromatography (HPLC), LC mass spectrometry (LC-MS), nuclear magnetic resonance (NMR), and spectroscopy (Raman, IR, UV-Vis) are employed to monitor albuterol synthesis in batch versus flow. The results presented herein validates the application of continuous end-to-end manufacturing as a means of exceeding batch efficiency during the production of liquid drug formulations; a strategy which can reduce capital costs and bolster America’s pharmaceutical supply chain resiliency.