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

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...

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Published inOrganic process research & development Vol. 23; no. 5; pp. 870 - 881
Main Authors Reizman, Brandon J, Cole, Kevin P, Hess, Molly, Burt, Justin L, Maloney, Todd D, Johnson, Martin D, Laurila, Michael E, Cope, Richard F, Luciani, Carla V, Buser, Jonas Y, Campbell, Bradley M, Forst, Mindy B, Mitchell, David, Braden, Timothy M, Lippelt, Christopher K, Boukerche, Moussa, Starkey, Derek R, Miller, Richard D, Chen, Jing, Sun, Baoquan, Kwok, Martin, Zhang, Xin, Tadayon, Sam, Huang, Ping
Format Journal Article
LanguageEnglish
Published American Chemical Society 17.05.2019
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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.
AbstractList 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.
Author Zhang, Xin
Huang, Ping
Starkey, Derek R
Laurila, Michael E
Campbell, Bradley M
Hess, Molly
Lippelt, Christopher K
Sun, Baoquan
Johnson, Martin D
Luciani, Carla V
Forst, Mindy B
Kwok, Martin
Cole, Kevin P
Maloney, Todd D
Buser, Jonas Y
Braden, Timothy M
Miller, Richard D
Cope, Richard F
Mitchell, David
Reizman, Brandon J
Burt, Justin L
Boukerche, Moussa
Tadayon, Sam
Chen, Jing
AuthorAffiliation Small Molecule Design and Development
Shanghai SynTheAll Pharmaceutical Co., Ltd. (“STA”)
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