Continuous Manufacture of Hydroxychloroquine Sulfate Drug Products via Hot Melt Extrusion Technology to Meet Increased Demand During a Global Pandemic: From Bench to Pilot Scale.

de Margerie, Victoire; McConville, Christopher; Dadou, Suha M; Li, Shu; Boulet, Pascal; Aranda, Lionel; Walker, Andrew; Mohylyuk, Valentyn; Jones, David S; Murray, Brian; Andrews, Gavin P

Duringpandemics and global crises, drug shortages becomecritical as a result of increased demand, shortagesin personnel and lockdownrestrictionsthatdisruptthe supply chain. The pharmaceutical industry is therefore moving towardscontinuous manufacturing instead of conventional batch manufacturing involving numerous steps, that normally occur at different sites. In order to validatethe use of large-scale industrial processes, feasibility studiesneed to be performed usingsmall-scale laboratory equipment.To that end, the scale-up ofa continuousprocess and its effect on the critical quality attributes (CQAs) of the end product were investigatedin this work. Hydroxychloroquine Sulphate (HCQS) was used as the model drug,Soluplus® asa modelpolymeric carrier and both horizontal and vertical twin screw extruders used to undertake this hot melt extrusion (HME) study.Seven formulations were processed using a small-scale horizontal extruder and a pilot-scale vertical extruder at various drug loadings, temperature profiles and screw speeds. When utilising a horizontal extruder, formulations with the highest drug loadandprocessed at the lowest screw speed and temperature had the highest crystallinity with higher drug release rates.Upon scale-up to a vertical extruder, the crystallinity of the HCQS was significantly reduced, with less variation in both crystallinity and release profile across the different extrudates. This study demonstrates improved robustness with the pilot-scale vertical extruder compared to lab-scale horizontal extruder. The reduced variation with the vertical extruder will allow for short increases in production rate, with minimum impact on the CQAs of the final product enabling high-performance continuous manufacturing with minimum waste of raw materials. Finally, this research provides valuable information for thepharmaceutical industry in accessing continuous technologies for the manufacture of pharmaceutical products, allowing for efficient utilisation of resources upon scale-up and mass production during global pandemics and drug shortages.