Angewandte
Chemie
DOI: 10.1002/anie.201305429
Continuous Drug Manufacturing
Hot Paper
End-to-End Continuous Manufacturing of Pharmaceuticals: Integrated
Synthesis, Purification, and Final Dosage Formation**
Salvatore Mascia, Patrick L. Heider, Haitao Zhang, Richard Lakerveld, Brahim Benyahia,
Paul I. Barton, Richard D. Braatz, Charles L. Cooney, James M. B. Evans, Timothy F. Jamison,
Klavs F. Jensen, Allan S. Myerson, and Bernhardt L. Trout*
For the past decade, the pharmaceutical industry has been
under pressure to improve efficiency, as rising costs outpaced
the development of new pharmaceuticals.[1] A growing
interest in green processes also highlights areas for possible
improvements in pharmaceutical synthesis and manufactur-
ing, where environmental impacts have been higher than for
other industries.[2] Continuous manufacturing has attracted
the attention of industry and academia alike by promising
lower costs, greater reliability and safety, better sustainability,
and novel pathways that are not otherwise accessible.[3]
Recent studies have demonstrated that economic savings
can be realized for certain cases by transforming a batch
production into a continuous process.[4] With existing batch-
based manufacturing methods, it can take up to 12 months
between the start of the first synthetic step and market release
of finished tablets,[5] which partially results from movement of
materials around and between facilities, and lengthy final-
product testing. This results in large and expensive invento-
ries, and shortages from manufacturing delays if the batch
fails during the final testing once the production has finished.
Continuous manufacturing allows faster response to changes
in demand; this permits a smaller inventory than for batch-
based manufacturing, which not only results in lower working
capital, but also decreases the stored amounts of potentially
hazardous intermediates, including high-potency active phar-
maceutical ingredients (API). Increasing the use of online
monitoring and control also reduces the burden of final
testing, which mirrors the online control present in other
continuous-manufacturing industries.[6] Simulations of pro-
cesses that include recycle loops demonstrated that improve-
ments in process yield and robustness can be achieved by
operating continuously.[7] In spite of these promising results,
there are still many hurdles to be overcome during the
implementation of continuous processes.[2b,8] These include
development of flow chemistry transformations, difficulties
with processing dry solids and solid-laden fluids, lack of
equipment at bench and pilot scale, development of control
methodologies to guarantee product quality, and breaks in the
process, especially between synthesis and formulation. Many
examples have been reported of continuous processes for
chemical synthesis in flow,[9] reactions with workup,[10] con-
tinuous crystallization,[10b,11] drying,[12] powder blending,[13]
and tableting;[13d,14] however, only few others have considered
multistep portions of a process.[9h,10b,13d,14c,15]
Herein, we present the first example of an end-to-end,
integrated continuous manufacturing plant for a pharmaceut-
ical product. Our plant starts from a chemical intermediate
and performs all the intermediate reactions, separations,
crystallizations, drying, and formulation, which results in
a formed final tablet in one tightly controlled process. This
provides a platform to test newly developed continuous
technologies within the context of a fully integrated produc-
tion system, and to investigate the system-wide performance
of multiple interconnected units. Herein, the key results of
operating the plant for runs of up to ten days are presented.
The ten-day period included start-up of the plant, stabiliza-
tion of key processes, and periods of end-to-end operation.
We specifically highlight areas where we took advantage of
continuous-flow features, and discuss techniques relevant to
continuous processes.
[*] S. Mascia, P. L. Heider, H. Zhang, R. Lakerveld, B. Benyahia,
P. I. Barton, R. D. Braatz, C. L. Cooney, J. M. B. Evans, K. F. Jensen,
A. S. Myerson, B. L. Trout
Department of Chemical Engineering
Massachusetts Institute of Technology (MIT), Cambridge (USA)
E-mail: trout@mit.edu
The target API is aliskiren hemifumarate (6; Scheme 1),
which is formulated as tablets containing 112 mg of the free
base form of aliskiren (5). The total throughput of the plant is
nominally 45 ghꢀ1 of 6, which corresponds to 2.7 ꢀ
106 tabletsyꢀ1. The throughput can be adjusted to values
between 20 ghꢀ1 and 100 ghꢀ1 by changing control setpoints
in the plant. The plant layout is compact, with a 2.4 ꢀ 7.3 m2
footprint, and the plant is entirely contained within enclo-
sures. The major unit operations in the plant are shown in
Figure 1. A more detailed diagram that includes the auto-
mated control loops used to ensure product quality is
provided in the Supporting Information (Figure S1). The
number of unit operations could be reduced from 21 for the
batch process to 14 for the continuous process, mainly
T. F. Jamison
Department of Chemistry, MIT (USA)
[**] We thank Novartis International AG for funding and supplying our
starting chemical intermediates. We would like to acknowledge the
contribution of the pilot plant team, including Soubir Basak, Erin
Bell, Stephen Born, Louis Buchbinder, Ellen Cappo, Corinne Car-
land, Alyssa N. D’Antonio, Joshua Dittrich, John Fisher, Megan A.
Foley, Ryan Hartman, Devin Hershey, Rachael Hogan, Bowen Huo,
Anjani Jha, Ashley S. King, Tushar Kulkarni, Timur Kurzej, Aaron
Lamoureux, Paul S. Madenjian, Sean Ogden, Ketan Pimparkar, Joel
Putnam, Anna Santiso, Jose C. Sepulveda, Min Su, Daniel Tam,
Mengying Tao, Kristen Talbot, Christopher J. Testa, Justin Quon,
Forrest Whitcher, and Aaron Wolfe.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!