Small-Volume Continuous Manufacturing of Merestinib. Part 1. Process Development and Demonstration

Abstract

Development of a small volume continuous process that used a combination of batch and flow unit operations to manufacture the small molecule oncolytic candidate merestinib is described. Continuous processing was enabled following the identification and development of suitable chemical transformations and unit operations. Aspects of the nascent process control strategy were evaluated in the context of a 20 kg laboratory demonstration campaign, executed in walk-in fume hoods at a throughput of 5–10 kg of active pharmaceutical ingredient per day. The process comprised an automated Suzuki–Miyaura cross-coupling reaction, a nitro-group hydrogenolysis, a continuous amide bond formation, and a continuous deprotection. Three of the four steps were purified using mixed-suspension, mixed-product removal crystallizations. Process analytical technology enabled real-time or nearly real-time process diagnostics. Findings from the demonstration campaign informed a second process development cycle as well as decision making for what steps to implement using continuous processing in a proximate manufacturing campaign, which will be described in part 2 of this series.

Reactor design and selection for effective continuous manufacturing of pharmaceuticals

“…The lengths of these three reactors were 255, 53, and 153 m, with volumes of 12, 2.5, and 7.2 L, respectively. Accordingly, the reaction conditions were different, as described in Table 4 h [45][46][47]. It is important to note that the second PFR's coil diameter was smaller (< 10 cm) than the other two, and that it fit inside a 10 cm inner-diameter /1.2 m tall steam heating pipe.…”

Overcoming the Hurdles and Challenges Associated with Developing Continuous Industrial Processes

“…The necessity to carefully control the temperature of the reactor zone was additionally highlighted in a publication by Eli Lilly for the synthesis of Merestinib (Scheme 14). [ 25 ] One of the steps features an amide formation between two advanced reaction partners. Mixed anhydride formation of the acid substrate 42 with PivCl/NEt 3 led to excellent reactivity with the aniline partner ( 44 ).…”

Design Space Identification and Visualization for Continuous Pharmaceutical Manufacturing

“…The development of continuous separation processes as part of end-to-end CPM plants is essential for reaction effluent purification and crystallization prior to downstream unit operations. While some demonstrations of fully continuous plants (including synthesis, purification and drug product formulation) have been highlighted in the past decade [13][14][15], there is generally a lack of continuous separation process design in the literature in comparison to research efforts in flow synthesis [16], especially as part of integrated plants. That said, there have been investigations into the design, operation and optimization of isolated continuous pharmaceutical separation processes.…”

“…Adamo et al (2016) also demonstrated a compact, end-to-end production of multiple DPs with different APIs [13]. Monbaliu et al (2016) developed an automated system for the end-to-end CPM of lidocaine hydrochloride [20]; Cole et al (2019) described the end-to-end CPM of merestinib (a new biliary tract cancer drug) from synthesis to crystallization [14,15]. The above-mentioned demonstrations were implemented on pilot or production plant level.…”