Advanced Continuous Flow Platform for On‐Demand Pharmaceutical Manufacturing

Abstract

As a demonstration of an alternative to the challenges faced with batch pharmaceutical manufacturing including the large production footprint and lengthy time-scale, we previously reported a refrigerator-sized continuous flow system for the on-demand production of essential medicines. Building on this technology, herein we report a second-generation, reconfigurable and 25 % smaller (by volume) continuous flow pharmaceutical manufacturing platform featuring advances in reaction and purification equipment. Consisting of two compact [0.7 (L)×0.5 (D)×1.3 m (H)] stand-alone units for synthesis and purification/formulation processes, the capabilities of this automated system are demonstrated with the synthesis of nicardipine hydrochloride and the production of concentrated liquid doses of ciprofloxacin hydrochloride, neostigmine methylsulfate and rufinamide that meet US Pharmacopeia standards.

Continuous manufacturing – the Green Chemistry promise?

“…179 cessing capabilities. 180 For the synthesis unit, this was achieved through the use of modified compact Milligat pumps (21 pumps), a bookshelf reactor holding bay (12 reactors), and greatly simplified control unit that is run off LabVIEW. Liquidliquid separators and in-line evaporators were added as additional unit operations.…”

“…Units designed for the pharmacy on demand initiative, phase two. Reprinted with permission from Wiley & Sons 180. …”

Experimental methods in chemical engineering: Micro‐reactors

“…However, Pashkova and Greiner report that continuous unit operations can also increase overall process complexity with additional costs, particularly during start‐up and changeover stages. This complexity may, or may not, impede flexibility in producing smaller annual volumes of several different personalized therapeutics. Continuous processing can thus reduce costs and improve product quality; however, the resulting technical‐economic analysis is specific to the chemical synthesis and company's assets.…”

“…Continuous flow technology has entered fine chemical and pharmaceutical laboratories with systems from Syrris, Uniqsis, ThalesNano, Vapourtec, Ehrfeld Mikrotechnik, FutureChemistry, Fraunhofer Institute for Microengineering and Microsystems, Chemtrix, and Corning. Compounds synthesized with continuous flow technology comprising multi‐step reactions and purification include the following: nitroethanol (∼21 g/h) by Lonza‐Novartis; aliskiren hemifumarate and other active pharmaceutical ingredients (∼45 g/h) at the Novartis‐MIT center; artemisinin‐derived medicines (∼3.4 mmol/h) at the Max‐Planck Institute; and the cGMP synthesis of prexasertib monolactate monohydrate (∼125 g/h) by Eli Lilly . Eli Lilly, Vertex, Pfizer, Novartis, Johnson & Johnson, Amgen, and GSK are among those that have made significant research and development investments in small‐scale continuous processing, however, commercial syntheses using intensified/miniaturized continuous flow technology throughout the entire plant remain limited in part due to lack of information and technology.…”

Continuous Flow Organic Chemistry: Successes and Pitfalls at the Interface with Current Societal Challenges

“…It is also worth mentioning that in the last two years a considerable increase in complexity in continuous flow processes has been observed, especially for applications toward active pharmaceuticals. Flow chemistry has rapidly evolved from single step reactions to fully integrated multistep processes, sometimes including advanced downstream purification and formulation …”