Development of an Advanced Manufacturing Technology for Continuous Drug Substance Production.

We describe the early conceptual development of a candidate advanced manufacturing technology (AMT) which enables 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 candidate AMT system is currently under construction for the automated production of +2,000 mg/h of albuterol sulfate via a new synthetic pathway with a 78.4% solution yield when operating at a 1.0 mL/min flow rate basis. Additionally, system throughput can be scaled 10-fold with minor modifications. The authors plan to apply for AMT approval of this technology under the FDA's new AMT designation program. Key engineering design strategies are highlighted for successful translation of traditional batch synthetic methods toward continuous manufacturing, with an emphasis placed on process intensification via rational synthon selection, the introduction of continuous flow technologies, incorporation of in-line process analytical technologies (PAT), and system scale-up within a larger production facility. Analytical characterization via high-performance liquid chromatography (HPLC), LC mass spectrometry (LC-MS), gas chromatography-flame ionization detection (GC-FID), and in-line nuclear magnetic resonance spectroscopy (NMR) are utilized to assess composition and purity throughout the process. The results presented herein enable scale-up of an automated continuous manufacturing system as it provides a means of exceeding batch efficiency during the production of liquid drug formulations; a strategy which can reduce capital costs, eliminate drug shortages, and strengthen America's pharmaceutical supply chain resiliency.