(504d) Development of an Advanced API Manufacturing System

Active pharmaceutical ingredients (APIs) are traditionally synthesized via batch processing on an industrial scale, enabling the production of +500k metric tons of a given API per year. However, batch processing is a cumbersome, labor-intensive strategy that often involves iterative purification steps, large volumes of waste, and chemical variability between each API batch. Additionally, the cost of manufacturing and necessity of hands-on labor has culminated in complex logistical networks which span across multiple continents, requiring chain-of-custody documentation to ensure API synthesis meets FDA regulations. These inefficiencies have led to supply-chain delays for critical lifesaving drugs, a phenomenon exacerbated by SARS-CoV-2. Recently, a new and emerging advanced manufacturing strategy seeks to employ automated, continuous manufacturing systems for the production of drugs via flow chemistry. These Next-Gen systems can be configured for high throughput conversion of raw chemical feedstocks into packaged pharmaceutical drug formulations with on-line spectroscopic validation to ensure product purity.

This talk will highlight VCU's construction of a Next-Gen API synthesis module for the production of albuterol sulfate, a bronchodilator asthma drug found on the ASPR drug shortage list. The project is currently in year two in collaboration with Rutgers University. The continuous end-to-end manufacturing system will consist of Module 1: API synthesis (VCU), and Module 2: API formulation, fill-finish, and product packaging (Rutgers). Key engineering decisions will be highlighted including the incorporation of a tubular flow reactor to enable S_N2 amination, a catalytic packed bed reactor (PBR) for hydrogenation, and a series of purification submodules. Chemometric modeling is enabled by correlating off-line analytical characterization via high performance liquid chromatography (HPLC) to on-line nuclear magnetic resonance spectroscopy (¹H NMR) and in-line UV-Vis for purity and concentration evaluation. The final automated system will be monitored using process analytical technologies (PAT) to ensure product quality while facilitating the production of 120-1,200 packaged doses per hour. Ultimately, this Next-Gen strategy will help reduce API manufacturing costs and bolster America’s pharmaceutical supply chain resiliency.