Design and Commercialization of an End-to-End Continuous Pharmaceutical Production Process: A Pilot Plant Case Study

Abstract

The pharmaceutical industry faces multiple challenges (e.g., inefficient manufacturing techniques, quality control issues, and supply chain vulnerabilities) because of its current batch-wise approach to manufacturing. Recent regulatory support for continuous manufacturing and advances in continuous process technologies have caused an increase in interest from some drug manufacturers to modernize their production processes. However, many of these companies have focused on hybrid processes, where only certain steps are continuous, while others remain batch. Herein, the quality by design (QbD)-based design strategy and operation of an end-to-end integrated continuous manufacturing (ICM) pilot plant that produces both small-molecule active pharmaceutical ingredient (API) and oral solid dosages (OSDs) are discussed. Additionally, important quality and economic matters pertaining to scale-up and commercialization are addressed. ICM has significant benefits, including better quality control, increased supply chain flexibility, a lower capital investment (in the example provided, a ∼ 90% reduction), and lower operating costs (in the example provided, a 33.6% reduction for API and 29.4% reduction for tablets).

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

“…Industry has generally been slow to adopt flow technology due to the "like what you know, know what you like" sentiment and the initial costs of investing in the necessary equipment to replace well established and well optimised processes. Despite this, the pharmaceutical industry is beginning to take advantage of the benefits offered by continuous manufacturing [624][625][626]. Undoubtedly, there are processes currently being used within the flavour and fragrance industry for which flow would offer an attractive alternative with regards to both cost and green/ environmental implications.…”

“…In this example, the aluminium chloride was solubilised in the propionyl chloride (626) and streamed through a coil reactor at 87 °C along with the isobutylbenzene (620). The flow stream was then quenched with HCl to terminate the reaction and avoid clogging of the insoluble aluminium salts.…”

Continuous Isolation of Particles with Varying Aspect Ratios up to Thin Needles Achieving Free-Flowing Products

“…A second concept, the continuous rotary plate filter (CRPF) was invented as part of an integrated continuous manufacturing pilot plant of Continuus Pharmaceuticals. Recent studies showed the potential of combined filtration and washing in the CRPF as a part of an end-to-end continuous manufacturing process [10,[23][24][25][26].…”

Reactor design and selection for effective continuous manufacturing of pharmaceuticals

“…Motivated by the benefits shown in Fig. 1 [6][7][8][9][10], the pharmaceutical industry is transitioning to continuous processes, including end-to-end integrated continuous manufacturing (ICM) approaches [1,6,8,[10][11][12][13][14][15][16][17][18]. A first-of-its-kind research demonstration of an end-to-end ICM line was unveiled by MIT in 2011 [13].…”