A series of tubes: The continuous manufacture of a finished drug product starting from chemical intermediates is reported. The continuous pilot-scale plant used a novel route that incorporated many advantages of continuous-flow processes to produce active pharmaceutical ingredients and the drug product in one integrated system.

The development and operation of the synthesis and workup steps of a fully integrated, continuous manufacturing plant for synthesizing aliskiren, a small molecule pharmaceutical, are presented. The plant started with advanced intermediates, two synthetic steps away from the final active pharmaceutical ingredient, and ended with finished tablets. The entire process was run on several occasions, with the data presented herein corresponding to a 240 h run at a nominal throughput of 41 g h^–1 of aliskiren. The first reaction was performed solvent-free in a molten condition at a high temperature, achieving high yields (90%) and avoiding solid handling and a long residence time (due to higher concentrations compared to dilute conditions when run at lower temperatures in a solvent). The resulting stream was worked-up inline using liquid–liquid extraction with membrane-based separators that were scaled-up from microfluidic designs. The second reaction involved a Boc deprotection, using aqueous HCl that was rapidly quenched with aqueous NaOH using an inline pH measurement to control NaOH addition. The reaction maintained high yields (90–95%) under closed-loop control despite process disturbances.

The design of an effective plant‐wide control strategy is a key challenge for the development of future continuous pharmaceutical processes. This article presents a case study for the design of a plant‐wide control structure for a system inspired by an end‐to‐end continuous pharmaceutical pilot plant. A hierarchical decomposition strategy is used to classify control objectives. A plant‐wide dynamic model of the process is used to generate parametric sensitivities, which provide a basis for the synthesis of control loops. Simulations for selected disturbances illustrate that the critical quality attributes (CQAs) of the final product can be kept close to specification in the presence of significant and persistent disturbances. Furthermore, it is illustrated how selected CQAs of the final product can be brought simultaneously to a new setpoint while maintaining the remaining CQAs at a constant value during this transition. The latter result shows flexibility to control CQAs independently of each other. © 2013 American Institute of Chemical Engineers AIChE J, 59: 3671–3685, 2013

Continuous manufacturing offers potential opportunities for the improved manufacturing of pharmaceutical products. A key challenge is the development of an appropriate control strategy. The experimental application of an automated control strategy is presented for an end-to-end continuous pharmaceutical pilot plant. The process starts from an advanced intermediate compound and finishes with the tablet formation steps. The focus of the experimental results is on the design and performance of the control loops needed to produce a slurry of an active pharmaceutical ingredient and a solvent with specified material properties. The results demonstrate that automated control can successfully keep critical material attributes close to the desired set points for a sustained period of operation. This work aims to contribute to the development of future continuous pharmaceutical processes by providing a realistic case study of automated control of an integrated, continuous, pharmaceutical pilot plant.