An automated modular assembly line for drugs in a miniaturized plant

Abstract

Modular assembly line: a promising approach to reduce drug shortages, assure quality, and improve affordability.

Impurity incorporation in solution crystallization: diagnosis, prevention, and control

“…[26][27][28][29][30] Consequently, most recent examples of end-to-end synthetic pharmaceutical manufacturing involve a number of crystallization steps where the main role is to purify an intermediate product, limiting the accumulation of impurities along the main process stream. 25,26,[31][32][33][34][35][36][37][38] Despite the widespread use of these purification steps, our understanding of how impurities incorporate in crystals is far behind, current models for predicting purity in solution crystallization are limited to a narrow design space, 25,28 and process design is still largely based on extensive solvent screenings and trial and error. 24,26,[38][39][40][41] This is, in part, due to the number and complexity of mechanisms by which impurities incorporate in growing crystals, and the limited understanding of kineticdriven interactions between impurities and solute molecules in the crystal-solution interphase.…”

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].…”

“…A first-of-its-kind research demonstration of an end-to-end ICM line was unveiled by MIT in 2011 [ 13 ]. The model drug was aliskiren hemifumarate, and the throughput of the process was 45 g/h, with a residence time of 47 h. Subsequently, the first commercial-setting end-to-end ICM pilot plant was reported by CONTINUUS Pharmaceuticals in 2019 [ 12 ]. The throughput of the process was 4800 tablets per hour, or 40.3 × 10 6 tablets per year, with a total residence time of <30 h. There are examples of continuously manufactured drug products that have been approved in the US (e.g., Orkambi, Symdeko and Trikafta by Vertex, Prezista by Johnson & Johnson, Verzenio by Eli Lilly, Daurismo by Pfizer), in the EU (e.g., Orkambi and Symkevi by Vertex, Prezista by Johnson & Johnson, Verzenios by Eli Lilly), and in Japan (e.g., Tramacet by Johnson & Johnson, Verzenio by Eli Lilly), as well as drugs that are under development [ 12 , 16 , 19 ].…”

Multi‐Step Synthesis of Miltefosine: Integration of Flow Chemistry with Continuous Mechanochemistry

“…A few of the most advanced examples include; the flow synthesis of quinolone antibiotic ciprofloxacin, [7] end‐to‐end manufacturing process for aliskiren hemifumarate [8] solid‐supported synthesis of imatinib [9] development of a single dedicated platform for the multiple drug molecules [10] flow synthesis of rolipram using heterogeneous catalyst [11] four‐step continuous flow process for antihistamines from bulk alcohols, [12] seven‐step continuous flow synthesis of linezolid molecule [13] and continuous flow synthesis and purification of ibuprofen [14] . The development and operation of fully automated pilot plant enables efficient and end‐to‐end integrated continuous manufacturing of the pharmaceutical product and small drug molecules, [15–17] including continuous solvent recovery for sustainable manufacturing [18] Recently, Kappe et al. has developed a real‐time analysis platform and fully integrated multistep synthesis of an active pharmaceutical ingredient, mesalazine [19] …”