A Continuous Process for Manufacturing Apremilast. Part II: Process Characterization to Establish a Parametric Control Strategy

Abstract

This is Part II of a series on the development and characterization of an integrated continuous manufacturing (CM) process developed for the penultimate step in the synthesis of the drug substance Apremilast (Otezla). Part I gives the development history and highlights the achieved process intensification. Here, we describe the process characterization (PC) undertaken. In doing so, we point out aspects of characterization that are unique to an integrated CM process and give our strategy for navigating PC in this scenario. Moreover, we provide data that support a robust control strategy which relies on parametric control only (i.e., no inprocess controls) followed by batch release of the produced Apremilast drug substance intermediate. Such a control strategy is advantageous as it minimizes divert-to-waste loss and operational costs.

PAT-Enabled Automated Feedforward Control: An Application to the Continuous Manufacture of Apremilast

“…The IR concentration PLS model was built by using Mettler-Toledo iC Quant software with off-line test samples. For compound characterization, please refer to our previous publications. , …”

“…In this manuscript, we report the development of a closed-loop control system applied to a small-scale replication of a continuous manufacturing process for the synthesis of apremilast, the drug substance for the commercial product Otezla. , In doing so, we provide proof-of-concept for a feedforward control strategy, implemented in the lab to maintain near optimal operation of the plug flow reactor without human intervention despite disturbances in the feed tank compositions.…”

“…Apremilast is a first-in-class small molecule selective phosphodiesterase 4 (PDE4) inhibitor for the treatment of inflammatory diseases, such as psoriatic arthritis, plague psoriasis, and Beç̧̧het’s disease. , With the aim to create an alternative manufacturing configuration with a significantly smaller physical and environmental footprint, a CM process was developed for the penultimate step in the apremilast synthesis that greatly reduced the number of unit operations (Figure ). ,, …”

“…While conducting process characterization (PC) for this CM process, we observed the isolated solid apremilast consistently had the purity greater than 99.9 LCAP (liquid chromatography area percentage, full integration) even with wide variations of the process parameters . This robustness was largely due to an effective crystallization process, which rejected leftover starting materials, intermediates, and raw-material-derived as well as process-derived impurities.…”

“…The data in Figure indicates that variations to the reaction process parameters do indeed result in meaningful variations in product assay yields through the reaction (87–99%, not shown in figure) as reflected in the product LCAPs (88–98%, with full impurity profile integration) of the crude reaction stream while the purity of the solid isolated apremilast remains largely unperturbed. These results enabled the proposal of a parametric control strategy (i.e., no analytical in-process controls) with the process parameters allowed to vary across relatively wide proven acceptable ranges (PARs) without triggering a deviation and/or divert to waste . Such a control strategy is beneficial from a simplicity-of-operations standpoint, as the process can be expected to run for a significant duration, producing quality material without human intervention.…”