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A portable drug factory


Producing drugs quickly with a portable device? This is what MIT researchers achieved, at the request of the US Department of Defense. The technologies developed to meet this requirement will revolutionise the pharmaceutical industry, and Jean-Christophe Monbaliu, researcher in organic chemistry at the University of Liège, took part in their development.


Imagine a portable production unit that can produce, in record time, thousands of drug doses in order to meet demand in conflict zones, during epidemics, or simply during a shortage. No, this is not the plot of an upcoming film. The pharmaceutical industry is about to undergo a major revolution for drug production, thanks to the efforts of a team of researchers from the Massachussetts Institute of Technology (MIT), where Jean-Christophe Monbaliu contributed as a postdoc. Working at the University of Liège since 2013 as an organic chemist, he created  the Center for Integrated Technology and Organic Synthesis (CiTOS). Ever since his PhD thesis, he has developed an interest in new ways to create matter. ‘What we currently use to produce pharmaceuticals, and what we have been using for centuries, are batch reactors,’ he explains. ‘These are macroscopic reactors, generally made of glass or metal, in which matter can be transformed – a typical example is the classic round-bottom glass flask found in laboratories. Images of this type of technology have been found dating as far back as Ancient Egypt.’ These macroscopic reactors, which we have been using for a long time, are inexpensive to maintain, and highly versatile since they are compatible with a wide range of chemical transformations. However, they also suffer from many drawbacks. ‘Using batch reactor processes often means having to manage of large inventories of chemical intermediates that may be toxic or explosive. As a result, the industrial risk is very high,’ adds Jean-Christophe Monbaliu. In addition, most of current drugs are manufactured according to multi-step processes, which accounts for long production times. In some cases, their production can take an entire year. As a result, this type of production is highly time, resource and workforce-demanding. Finally, the reactions taking place in batch reactors are not efficient. ‘The reaction does take place, but the reagent mix and heat transfer are not optimal,’ says Monbaliu. ‘Heat is transferred very slowly from the walls of the reactor to the reagents (or the other way around), which results in less successful reactions or contamination with side-products. This means that the drug produced at the end of the process has non-negligible variations in quality.’ In the case of reactions that produce heat, transferring the heat to the outside of the reactor can also be an issue. As the heat is not released from the reaction vessel, it accelerates the reaction, resulting in a runaway reaction which can eventually produce an explosion. 

batch mesoreactors

A mobile unit for emergency situations

With the limits of macroscopic batch reactors in mind, Jean-Christophe Monbaliu started investigating other technologies to transform chemicals during his several postdocs (Ghent University, University of Florida and then Massachusetts Institute of Technology). More specifically, he focused his work on a technology called microfluidics and continuous-flow processes. ‘Unlike batch processes, continuous-flow processes use micro- or mesoreactors. It's all about size,’ explains the chemist. ‘With micro- or mesofluidics, the processes involve specific reactors that can come in various shapes, but they all have one thing in common: they are made of channels, 100 to 1000 micrometres in diameter, through which reagents flow.’ Another difference with batch reactors is that micro- and mesofluidic reactors are fed with a continuous flow of reagents. The transformation occurs in the channels through which the reagents flow. This technology offers great advantages for transforming matter, as the mixing efficiency is excellent, and mixtures of chemicals get homogeneous much quicker than in batch; it also allows for very efficient control of how reagents interact and how heat is transferred.

device manufactrue pharmaceuticalsClearly, this technology offers obvious advantages in terms of reaction efficiency, but are these small reactors suitable for production? ‘Despite their small size, the reactors can quickly produce industrially viable quantities if they are operated continuously,’ explains Monbaliu. In addition, as only a small quantity of reagents is going through this type of reactor at any given time, safety is improved. ‘In the event of an explosion, the impact on the environment is much lower, with the same potential to produce large quantities,’ he continues. Their small size gives them another advantage: they can be moved when needed, acting as mobile production units.

During his postdoctoral fellowships, Jean-Christophe Monbaliu started studying chemical engineering and the application of microfluidics to organic chemistry. In 2012, he joined the famous Massachussetts Institute of Technology (MIT) in Cambridge, USA, taking part in the ‘Pharmacy on Demand’ project funded by the Defense Advanced Research Projects Agency (DARPA), an agency of the US Department of Defense. The project's goal was to provide a strategic advantage for national security by creating a mobile drug production unit. Quite a project! ‘This portable production unit enables the production of drugs in remote areas or conflict zones, or simply to meet a sudden increase in the demand on the market for a specific drug in case of an epidemic or a shortage,’ says Monbaliu. 

Drugs ready in 15 minutes!

When our young scientist started working on the project, studies had been published on applying microfluidics to organic chemistry and drug development, but none had led to the creation of such an advanced prototype. ‘The prototype we have developed can produce four very different drugs that are commonly used: an anxiolytic, an antidepressant, an antihistamine, and a local anaesthetic,’ reveals Monbaliu. ‘Beyond just producing these drugs, the unit purifies and formulates them.’ And all this in a device the size of a refrigerator! Put simply, raw reagents are introduced into the system, which produces a solution containing an active ingredient that can be directly injected into a patient's body. ‘We have pushed the boundaries in terms of microfluidics and flow chemistry, and created a very compact and fast production unit.’ The results of the study were published in Science (1).

Typically, producing these four drugs with classical batch reactors and strategies could take several days, in a best-case scenario. The prototype developed by Jean-Christophe Monbaliu and his colleagues reduces the reaction time to an incredible 15 to 30 minutes! This new technology should soon launch a revolution for the pharmaceutical industry, as well as other chemical industries. However, it is not expected to completely replace macroscopic batch reactors, but rather complement the toolkit for chemists. ‘Microfluidics can improve 50 to 60% of the reactions studied so far, but it isn't really beneficial for the rest,’ explains Monbaliu. ‘With this new technology, we can do what we've always been doing, only much better and more efficiently. We have more insight, more control and more safety.

A revolution at the speed of miniaturisation

This tool expands chemists' horizon, as it allows them to observe reaction conditions that were previously unattainable. ‘Since we have great control over what happens inside these microfluidic reactors, we can make the reactions more intense. We can turn the heat up and access unexplored conditions such as extreme temperature and pressure, with unpreceded accelerations of chemical reactions. The reagents flow quickly through the reactors, producing exactly the desired reaction and no secondary reactions,’ underlines Monbaliu.

Why did it take centuries before a new technology could overcome the shortcomings of batch reactors? Just like in computing, the state of the art had to evolve before the highly specific tools necessary for microfluidic processes could be implemented. For instance, etching microchannels requires advanced machining techniques, and these have become increasingly affordable starting about a decade ago. ‘The portable production unit built at MIT is based on a myriad of great technological achievements. This is true whether we're talking about engineering, chemistry, or the way in which multi-step processes are carried out,’ says Monbaliu.

multiflow continuous process

The unit will never be released on the market, but the technology that was developed to build it is partially marketed by an MIT start-up company. ‘This will be a boon for the pharmaceutical industry, and for all other areas of chemistry,’ he explains. ‘Since 2007, people have been realising that new technologies must be developed in order to produce drugs with much more flexibility. The development of continuous microfuidic processes is a priority for the pharmaceutical industry.’ These processes are faster, more efficient, and more compact, and they allow finer control while making it possible to respond to a suddenly increasing demand on the market; this makes microfluidics very attractive to drug manufacturers. ‘The technology could even be used to produce drugs for orphan diseases,’ predicts the chemist. ‘This is one of the ways forward at this point, since these drugs are very expensive to produce and the number of patients is so small that pharmaceutical companies are reluctant to invest.’ As a result, with this new technology, manufacturers might consider producing orphan drugs.

(1) A. Adamo, R. L. Beingessner, M. Behnam, J. Chen, T. F. Jamison, K. F. Jensen, J.-C. M. Monbaliu, A. S. Myerson, E. M. Revalor, D. R. Snead, T. Stelzer, N. Weeranoppanant, S. Y. Wong, P. Zhang. On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system. Science, 2016; 352 (6281): 61 DOI: 10.1126/science.aaf1337 

© Université de Liège - - September 28, 2020