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Small-volume continuous manufacturing of merestinib Part I: process development and demonstration Kevin Paul Cole, Brandon J. Reizman, Molly Hess, Jennifer McClary Groh, Michael E. Laurila, Richard F. Cope, Bradley M. Campbell, Mindy B Forst, Justin L. Burt, Todd D. Maloney, Martin D. Johnson, David Mitchell, Christopher S. Polster, Aurpon Mitra, Moussa Boukerche, Edward W. Conder, Timothy Braden, Richard D. Miller, Michael R. Heller, Joseph L. Phillips, and John R. Howell Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00441 • Publication Date (Web): 12 Mar 2019 Downloaded from http://pubs.acs.org on March 13, 2019
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Organic Process Research & Development
Small-volume continuous manufacturing of merestinib Part I: process development and demonstration Kevin P. Cole,‡* Brandon J. Reizman,‡* Molly Hess, Jennifer M. Groh, Michael E. Laurila, Richard F. Cope, Bradley M. Campbell, Mindy B. Forst, Justin Burt, Todd D. Maloney, Martin D. Johnson, David Mitchell, Christopher S. Polster, Aurpon Mitra, Moussa Boukerche, Edward W. Conder, Timothy M. Braden, Richard D. Miller, Michael R. Heller, Joseph L. Phillips, John R. Howell
AUTHOR ADDRESS
Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, IN 46285, USA
KEYWORDS
Merestinib, continuous processing, small volume continuous, continuous crystallization, flow chemistry
ABSTRACT
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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 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 which steps to implement using continuous processing in a proximate manufacturing campaign, which will be described in Part II of this series.
INTRODUCTION
The pharmaceutical industry and the U.S. Food and Drug Administration have recognized continuous manufacturing (CM) as an economically1 and environmentally2 transformative means of drug production.3,4,5 Applications of pharmaceutical CM have the potential to offer reduced variability upon process scale-up, greater flexibility in campaign sizing and location, and enhanced safety, greenness, and/or control of chemical operations. For drug substance (DS) manufacturing, efficiencies enabled by process intensification through CM can be maximized upon integration of multiple operations and synthetic steps in series.6 Such integrated continuous processes offer
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potential benefits to product quality assurance by allowing for extended, state-of-control process operation, and for intermediate material hold points to be shortened or eliminated.4 Recent examples from across industry and academia have highlighted technical achievements in the development and implementation of integrated continuous processes for pharmaceutical manufacturing. A team from the Massachusetts Institute of Technology (MIT) in collaboration with Novartis AG demonstrated the integration of continuous DS synthesis, drug product formulation, and tableting in the production of aliskiren hemifumarate at a throughput of approximately 1 kg/day.7,8 MIT has also demonstrated a modular approach to the on-demand continuous synthesis and purification of four DSs on a single platform, with capacity to generate 800 or more doses in a day.9 Companies such as Eli Lilly,10 GSK,11 Novartis,12 and Pfizer13 have invested in the construction of their own internal Current Good Manufacturing Practice (cGMP) facilities for continuous manufacturing. Our group previously disclosed a Small Volume Continuous (SVC) process for prexasertib that leveraged a series of eight continuous unit operations including multiple reaction steps, isolations, and PAT, to deliver 24 kg of DS under cGMP.14 These examples have illustrated a maturation of continuous flow technology that will soon enable the commercialization of fully continuous DS processes. As these processes advance through development, their acceptance will hinge upon development of a control strategy that delivers quality DS within the framework of CM. Such a control strategy would ideally leverage the strengths of CM while accounting for the challenges added by process intensification: fewer extended hold and/or isolation points, the added effect of dispersion on process upsets, overlapping transient (e.g. startup/shutdown) and state-of-control operations, and management of a richer set of process data. The risk of CM processes becoming overly specialized, to the point where only a
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handful of manufacturers have the capability to adhere to the control strategy, must be managed. In order to allow for faster responses to meet clinical and commercial drug demands, it is important to develop multiple manufacturing partners with the skillset of operating CM processes.15 Within this context, we present our experience in the development leading to a hybrid CM process for the Phase II oncolytic merestinib (LY2801653, 1, Figure 1).16 Our current projections for 1 put the peak demand for DS at
