(613d) Accelerated Reaction Development with Automated Transient Flow Experiments

Continuous manufacturing (CM) has been applied as an enabling technology in cases where precise control over reaction conditions and reduced equipment footprint facilitates the synthesis of key starting materials, drug substance intermediates, and APIs.

During lab-scale development, flow reaction parameters such as residence time and stoichiometry are typically explored using multiple steady-state experiments with the reaction sampled post start-up after waiting for equilibration. This extends lab time and unnecessarily consumes considerable amounts of high-value material. In contrast, transient flow experiments, in which reaction parameters are continuously manipulated in a controlled manner over the course of the run, enable sampling of multiple conditions within a single experiment. Depending on the residence times, variation rates, and sampling frequencies involved, transient experiments can provide improvements in time- and material-efficiency as well as data density compared to steady-state experiments.

In this talk, we describe how transient flow experiments combined with hardware automation were leveraged to accelerate flow reaction development at Amgen. In the first case study involving longer residence times, a single transient experiment enabled reaction characterization across the full residence time range of interest in one day, providing significant time and material savings. In the second case study, we demonstrate how the transient flow approach was extended from a single step to a multistep sequence involving the generation and consumption of a highly reactive intermediate.