Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions

被引：211

作者：

Cole, Kevin P. ^{[1
]}

Groh, Jennifer McClary ^{[1
]}

Johnson, Martin D. ^{[1
]}

Burcham, Christopher L. ^{[1
]}

Campbell, Bradley M. ^{[1
]}

Diseroad, William D. ^{[2
]}

Heller, Michael R. ^{[1
]}

Howell, John R. ^{[1
]}

Kallman, Neil J. ^{[1
]}

Koenig, Thomas M. ^{[3
]}

May, Scott A. ^{[1
]}

Miller, Richard D. ^{[1
]}

Mitchell, David ^{[1
]}

Myers, David P. ^{[1
]}

Myers, Steven S. ^{[1
]}

Phillips, Joseph L. ^{[1
]}

Polster, Christopher S. ^{[1
]}

White, Timothy D. ^{[1
]}

Cashman, Jim ^{[4
]}

Hurley, Declan ^{[5
]}

Moylan, Robert ^{[5
]}

Sheehan, Paul ^{[5
]}

Spencer, Richard D. ^{[6
]}

Desmond, Kenneth ^{[7
]}

Desmond, Paul ^{[7
]}

Gowran, Olivia ^{[7
]}

机构：

[1] Eli Lilly & Co, Lilly Res Labs, Small Mol Design & Dev, Indianapolis, IN 46285 USA

[2] Eli Lilly & Co, Tech Serv Mfg Sci, Indianapolis, IN 46285 USA

[3] Eli Lilly & Co, Tech Serv Mfg Sci, Greenfield, IN 46140 USA

[4] Eli Lilly & Co, Qual Assurance, Kinsale, Cork, Ireland

[5] Eli Lilly & Co, Tech Serv Mfg Sci, Kinsale, Cork, Ireland

[6] Eli Lilly & Co, Proc Engn, Kinsale, Cork, Ireland

[7] Eli Lilly & Co, Qual Control, Kinsale, Cork, Ireland

来源：

SCIENCE | 2017年 / 356卷 / 6343期

关键词：

PHARMACEUTICALS; PURIFICATION;

D O I：

10.1126/science.aan0745

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufacturing to transition from a traditional batch paradigm to more flexible continuous processing. Here we report the development of a multistep continuous-flow CGMP (current good manufacturing practices) process that produced 24 kilograms of prexasertib monolactate monohydrate suitable for use in human clinical trials. Eight continuous unit operations were conducted to produce the target at roughly 3 kilograms per day using small continuous reactors, extractors, evaporators, crystallizers, and filters in laboratory fume hoods. Success was enabled by advances in chemistry, engineering, analytical science, process modeling, and equipment design. Substantial technical and business drivers were identified, which merited the continuous process. The continuous process afforded improved performance and safety relative to batch processes and also improved containment of a highly potent compound.

引用

页码：1144 / 1150

页数：7

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