Small-Volume Continuous Manufacturing of Merestinib. Part 2. Technology Transfer and cGMP Manufacturing

Abstract

Technology transfer of a small volume continuous (SVC) process and Current Good Manufacturing Practices (cGMP) manufacturing of merestinib are described. A hybrid batch-SVC campaign was completed at a contract manufacturing organization under cGMP. The decision process by which unit operations were selected for implementation in flow for the cGMP campaign is discussed. The hybrid process comprised a Suzuki–Miyaura cross-coupling reaction, a nitro-group hydrogenolysis, a continuous amide bond formation, and a continuous deprotection. A continuous crystallization using two mixed suspension, mixed product removal (MSMPR) crystallizers and a filtration with in situ dissolution were employed for purification between the two SVC steps. Impurity levels were monitored using both online process analytical technology (PAT) and offline measurements. The continuous processing steps operated uninterrupted for 18 days to yield the drug substance in solution at a throughput of 12.5 kg/day. Crystallization in batch mode afforded 183 kg of the drug substance in specification. Success of the campaign was attributed to robustness of the control strategy and to the multiyear partnership in continuous manufacturing between the development organization and the contract manufacturer. Key learnings are offered from the perspectives of both the development organization and the contract manufacturer.

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.…”

Improved Synthesis of Bioactive Molecules Through Flow Chemistry

“…The advantages of continuous API manufacturing range from increasing flexibility to produce smaller annual volumes of targeted therapies for smaller patient populations, increasing worker health and safety, improving product quality, higher pressure capabilities, a wider temperature operating window as well as reducing development costs for new medicines, decreasing cycle time, decreasing environmental impact, and decreasing costs of manufacture. Besides, it is already well known that making a combination between flow with chemo-or biocatalysis greatly improves the contributions with lower environmental impact and higher safety [26,27,[29][30][31].…”

Continuous Flow Synthesis of Anticancer Drugs

“…Due to the low oral bioavailability, the drug is administered via infusion [46,76,77]. To render the drug more water-soluble, a semi-continuous process was targeted by a team from Eli Lilly to produce the required monolactate salt of 28 [78].…”