Small-Scale Continuous Drug Product Manufacturing using Dropwise Additive Manufacturing and Three Phase Settling for Integration with Upstream Drug Substance Production

Abstract

The pharmaceutical industry has traditionally relied on mass manufacturing to make its products. This has created multiple problems in the drug supply network, including long production times, inflexible and sluggish manufacturing and lack of personalized dosing. The industry is gradually adapting to these challenges and is developing novel technologies to address them. Continuous manufacturing and 3D printing are two promising techniques that can revolutionize pharmaceutical manufacturing. However, most research studies into these methods tend to treat them separately. This study seeks to develop a new processing route to continuously integrate a 3D printing platform (Drop-on-Demand, DoD, printing) with crystallization that is generally the final step of the active ingredient manufacturing. Accomplishing this integration would enable harnessing the benefits of each method- personalized dosing of 3D printing and flexibility and speed of continuous manufacturing. A novel unit operation, three-phase settling (TPS), is developed to integrate DoD with the upstream crystallizer. To ensure on-spec production of each printed dosage, two process analytical technology tools are incorporated in the printer to monitor drug loading in manufactured drug products in real time. Experimental demonstration of this system is carried out via two case studies: the first study uses an active ingredient celecoxib to test the standalone operation of TPS; the second study demonstrates the operation of the integrated system (crystallizer - TPS - DoD) to continuously make drug products for the active ingredient- lomustine. A dissolution test is also performed on the manufactured and commercial lomustine drug products to compare their dissolution behavior.

Keywords: Additive manufacturing; Distributed manufacturing; MiniPharm; Miniaturized pharmaceutical manufacturing platform; Modular continuous manufacturing; Personalized dosing; Small-scale manufacturing; Three-phase settling.