Integrated Continuous Pharmaceutical Technologies—A Review

Abstract

Innovation in the pharmaceutical industry has been limited for a long time to the research and development of new active compounds; meanwhile, the structure of the production, dominated by batchwise technologies, has not changed to date. As has already been demonstrated in several other industrial sectors, continuous manufacturing (CM) has many advantages over batch processes. Faster, cheaper, and more flexible production can be developed with a significantly higher level of quality assurance. In the recent years the main regulatory agencies recognized the need for a change in drug production and started to promote continuous technologies and encourage pharmaceutical companies to develop and adapt such processes. As a result, by today extensive research was conducted in the various fields of pharmaceutical technologies from drug substance to drug product manufacturing. Many publications deal with synthetic steps carried out in flow reactors and crystallizations implemented in a continuous manner, and on the formulation side continuous filtration, drying, granulation, and blending have all been studied to a lesser or greater extent. Moreover, besides the modification of these traditional processes to continuous operation, novel, intrinsically continuous technologies are being studied as well. In order to entirely exploit the advantages of CM, the mainly separately developed processes need to be integrated to form end-to-end systems from the raw materials to the final dosage forms. However, even the integration of two technological steps is a challenging task. The development of end-to-end systems requires deep process understanding and a holistic approach toward process development and optimization. The aim of this work is to give insight into the state-of-the-art and new directions in integrated continuous pharmaceutical technologies by critically reviewing the recent literature of the broad field.

Analysis of the Effects of Process Parameters on Start-Up Operation in Continuous Wet Granulation

“…Continuous manufacturing, where all unit operations are interconnected, offers flexibility in manufacturing scale by tuning running time, and enables production with smaller equipment. Researchers have discussed the benefits of continuous manufacturing from various perspectives, e.g., flexibility to demand change, less need for scale-up, and compatibility with process control [2,3].…”

Towards Continuous Primary Manufacturing Processes—Particle Design through Combined Crystallization and Particle Isolation

“…Upcoming challenges are the solid-liquid separation as well as washing and drying steps to meet specific product specifications regarding residual moisture and preservation of PSD [6]. Although pharmaceutical manufacturing has been traditionally employed in batch mode, continuous processes possess some crucial benefits, such as eliminating batch-to-batch-variability or reducing time-to-market due to an easier scale-up [7,8]. The overall goal is to create an end-to-end small-scale continuous manufacturing process for the typical API production scale of 250-1000 kg per Processes 2021, 9, 2187 2 of 17 year, starting from raw material treatment to final dosage form [9].…”

“…Thus, new challenges establish including the development of robust continuous synthesis, crystallization as well as product isolation and formulation in the pharmaceutical industry under defined product quality restrictions [5]. A number of recent review papers illustrate the fundamentals and challenges of individual unit operations (e.g., crystallization) [9,10] and also of combined and integrated processes [4,5,8].…”

Total Synthesis of Glipizide and Glibenclamide in Continuous Flow

“…Various multistep continuous flow synthetic procedures for active pharmaceutical ingredients (APIs) have been reported. [31][32][33][34][35][36][37][38][39] Herein, we take advantage of continuous flow chemistry technology to develop isocyanate free, rapid and efficient synthetic approaches towards glipizide 1 a and glibenclamide 1 b from commercially available chemicals. Due to the similarities in the chemical structures of the two drugs, a similar general synthetic approach can be used.…”

“…Furthermore, the technology also enables researchers to both evaluate and produce synthetic intermediates and products that would otherwise be inaccessible using conventional batch techniques. Various multistep continuous flow synthetic procedures for active pharmaceutical ingredients (APIs) have been reported [31–39] …”