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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 ...

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 mak...

Continued emphasis in the pharmaceutical industry toward development of hybrid and continuous processes has led to a resurgence in process analytical technologies. The need to consistently and rapidly monitor the quality of material being made from these processes is a significant challenge that requires integrated, online analytics. Often the most challenging aspect of implementing real-time monitoring is ensuring that the analytical instrumentation is receiving a representative sample from the process. The Small Molecule Design and Development organization at Eli Lilly and Company has developed a highly adaptable process-to-analytics interface that has been broadly implemented across the development portfolio. The automated sample carts use only gravity and low-pressure nitrogen to obtain representative process samples, typically on the order of 0.3–6 mL. Subsequent sample preparation operations including quenching, derivatization, and most commonly dilution (10–250× is customary, but not restrictive) i...

A new synthesis of a key indazole-containing building block for the MET kinase inhibitor merestinib was designed and demonstrated. Crucial to the successful construction of the challenging indazole is an SNAr reaction, which forges the heterocyclic ring. Continuous processing was applied to two of the five steps: nitration of a benzaldehyde and high-temperature hydrolysis of an aniline to phenol. Compared to a highly developed historical route, the new route shows clear benefits in terms of product quality and potentially manufacturability and robustness.

An NH4Cl-catalyzed ethoxy ethyl deprotection was developed for the synthesis of merestinib, a MET inhibitor. Alternative reactor technologies using temperatures above the solvent boiling point are combined with this mild catalyst to promote the deprotection reaction. The reaction is optimized for flow and has been used to synthesize over 100 kg of the target compound. The generality of the reaction conditions is also demonstrated with other compounds and protecting groups.

The IQ Consortium reports on the current state of process analytical technology (PAT) for active pharmaceutical ingredient (API) manufacturing in branded pharmaceutical companies. The article describes the application of PAT in manufacturing and provides representative examples in four common pharmaceutical unit operations: reaction and workup, crystallization, drying, and milling.