Quality by Design Considerations for Drop-on-Demand Point-of-Care Pharmaceutical Manufacturing of Precision Medicine

Abstract

Distributed and point-of-care (POC) manufacturing facilities enable an agile pharmaceutical production paradigm that can respond to localized needs, providing personalized and precision medicine. These capabilities are critical for narrow therapeutic index drugs and pediatric or geriatric dosing, among other specialized needs. Advanced additive manufacturing, 3D printing, and drop-on-demand (DoD) dispensing technologies have begun expanding into pharmaceutical production. We employed a quality by design (QbD) framework to identify critical quality attributes (CQAs), critical material attributes (CMAs), and critical process parameters (CPPs) of a pharmaceutical manufacturing framework that encompasses the production of active pharmaceutical ingredient (API) ‘inks’ at a centralized facility, which are distributed to POC sites for DoD dispensing into/onto delivery vehicles (e.g., orodispersible films, capsules, single liquid dose vials). QbD considerations and cause-and-effect analyses identified the dispensed API quantity and solid state form (CQAs), as well as nozzle diameter, system pressure channel, and number of drops dispensed (CPPs) for detailed investigation. Final assay quantification and content uniformity CQAs were measured from demonstrative levothyroxine sodium single-dose liquid vials of glycerin/water, meeting standard acceptance values. Each POC facility is unlikely to maintain full quality control laboratory capabilities, requiring development of appropriate atline or inline methods to ensure quality control. We developed control strategies, including, atline UV-Vis verification of the API ink prior to dispensing, inline drop counting during dispensing, intermediate atline dispensed volume checks, and offline batch confirmation by LC-MS/MS following production.