Sampling and Analysis in Flow: The Keys to Smarter, More Controllable, and Sustainable Fine‐Chemical Manufacturing

Abstract

Process analytical technology (PAT) is a system designed to help chemists better understand and control manufacturing processes. PAT systems operate through the combination of analytical devices, reactor control elements, and mathematical models to ensure the quality of the final product through a quality by design (QbD) approach. The expansion of continuous manufacturing in the pharmaceutical and fine‐chemical industry requires the development of PAT tools suitable for continuous operation in the environment of flow reactors. This requires innovative approaches to sampling and analysis from flowing media to maintain the integrity of the reactor content and the analyte of interest. The following Review discusses examples of PAT tools implemented in flow chemistry for the preparation of small organic molecules, and applications of self‐optimization tools.

The role of PAT in the development of telescoped continuous flow processes

“…Recognising the role that continuous manufacturing is playing in manufacturing of APIs, the US Food and Drug Administration (USFDA) and European Medicine Association have encouraged pharmaceutical companies to develop new manufacturing methods which incorporate a quality-bydesign approach (QbD), which is reinforced using PAT. 5 QbD was first developed by Juran, who championed that quality should be designed into the route to a product as early as its initial discovery, as many quality issues can be related back to the design of the particular product itself. 7,8 Since its inception, many pharmaceutical companies, and indeed academic researchers, have developed new and improved synthetic routes using this QbD approach.…”

“…Furthermore, it is crucial to recognise the difference in the sampling methods of each piece of analytical equipment. Various sampling methods are listed below: [1][2][3][4][5][6]18 • In-line: this sampling technique involves analytical methods capable of recording rapid or relatively fast measurements such as an in-line IR spectroscopy probe. It involves a flow-through cell or a submerged detection probe within the cell that is placed in-line with the flow of material through the system.…”

Non-fouling flow reactors for nanomaterial synthesis

“…or a reduced precursor conversion, can be enabled via process analytical technology that is well established for fine chemical production in flow reactors. [216][217][218]…”

Online and In Situ Monitoring of the Exchange, Transmetalation, and Cross-Coupling of a Negishi Reaction

“…1−4 These tools are capable of collecting measurements with minimal analyst intervention by often functioning either online or in situ. 5 Kinetic data acquired allow the relationship between yield and reaction variables such as time, temperature, and stoichiometry to be delineated. The utility of PAT is exemplified when used to measure both the formation and consumption of unstable intermediates over the course of a multistep reaction.…”

“…Monitoring changes in the concentrations of starting materials, intermediates, and products in real time provides invaluable information to increase process understanding. Process analytical technology (PAT) tools provide a means to obtain temporal information related to the reaction’s progress. − These tools are capable of collecting measurements with minimal analyst intervention by often functioning either online or in situ . Kinetic data acquired allow the relationship between yield and reaction variables such as time, temperature, and stoichiometry to be delineated.…”