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.

Eine Serie von Röhren: Ein kontinuierlicher Prozess für die Herstellung eines Medikaments aus chemischen Intermediaten wird beschrieben. Die Anlage im Pilotmaßstab nutzt viele Vorteile von Flussverfahren, um die aktiven pharmazeutischen Inhaltsstoffe und das Medikament in einem integrierten System herzustellen.

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.

• This is the pre-peer reviewed version of the article which has been pub- AbstractThe design of an effective plant-wide control strategy is a key challenge for the development of future continuous pharmaceutical processes. This paper 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.

Real-time control using process analytical technology (PAT) tools is required for the implementation of continuous crystallization within integrated continuous manufacturing (ICM) of pharmaceuticals. However, appropriate selection of PAT tools is challenging, and the design and operation of automated control loops for continuous crystallization within a continuous pharmaceutical process brings forward important questions. This paper discusses the process design and operation of a continuous reactive crystallization of aliskiren hemifumarate as part of an ICM pilot plant. Several PAT tools were used within automated control loops to satisfy specifications on the critical materials attributes of the crystallization process. The operational performance of the process was maintained for periods of time over 100 h. The purity of the targeted product exceeded 99%, and the process yield reached 91.4%.