Towards a mobile drugs lab

(De "Horizons" no 108 mars 2016)

Producing pharmaceutical agents continues to be a cumbersome process, like a relay race over hurdles. Production takes place in a long chain of individual steps. One stirrer tank after the next has to be filled, one chemical reaction started after another. Sometimes, these individual steps even take place at different sites, which means production takes even longer still.

But all this could soon change. Because the batch processes that are still the norm are due to be replaced by more modern methods. "Continuous manufacturing" is the magic formula. From now on, production is to become a seamless procedure.

In a long, single stream of reactions, the initial substances are added bit by bit. Control measurements and regular feedback ensure things don't get out of hand. The motivation behind all this is simple. Pharmaceutical companies could be able to develop and produce drugs quicker by using 'flow chemistry', as the procedure is called. It would also require less energy and a smaller volume of starting substances. Altogether, it's claimed that costs could be reduced by up to 30 percent. Several companies are now working on bringing these new production techniques onto the market – from Pfizer and GlaxoSmithKline to Novartis and Lonza.

Flowing fully from start to finish

Researchers at the Massachusetts Institute of Technology (MIT) and Novartis set themselves an ambitious goal back in 2007. Together, they wanted to develop the first-ever drugs production factory to be fully devoted to continuous manufacturing. In 2012, an experimental plant was completed at MIT. All steps were fully integrated, from the chemistry to the cleaning and the coating of the tablets. Team leader Bernhard Trout from MIT is firmly convinced of the potential of this concept. "We can produce any drug, and do it more efficiently and with less waste", he claims. That experimental plant at MIT is currently being used as a model for developing viable industrial plants for drugs production. And the MIT spin-off 'Continuous Pharmaceuticals' in the USA is working on this too.

More efficient production needed

The oil industry has already demonstrated the benefits of continuous manufacturing. The techniques have been used in oil refineries for decades now – notably for the production of synthetic materials. Ten years ago, the idea was taken up by other sectors. Dwindling profits and greater competition in the pharmaceutical industry helped to raise awareness of a need to make production more efficient and more flexible.

Flow chemistry isn't just limited to pharmaceuticals. "There's no limit to the spectrum of products that can use it", explains Roger Marti, a chemist at the School of Engineering and Architecture in Fribourg. You can produce both basic chemicals and complex fine chemicals on a large scale. Even polymers and nanoparticles are possible.

Indispensable miniaturisation

In order to apply continuous manufacturing to drugs production, reaction systems had to be miniaturised, because in the pharmaceutical industry, especially at the development stage, the volumes involved are much smaller than in the oil industry. "From a chemistry perspective, miniaturisation also has its advantages", says Marti. "For example, reactions can be carried out at higher temperatures than used to be the case".

So researchers have designed special little pipes and micro-reactors in which the reactions take place, and which are often made of steel, glass or plastic. And they didn't just design new reaction vessels, but​​​ also new components for mixing or heating substances, because when shrunk down to a mini-format, standard components could fail.

Assembling micro-reactors

One typical example of this miniaturisation is the FlowPlate MicroReactor developed by Lonza. These micro-reactors are made in four different sizes, allowing a flow volume of between just a few millilitres and half a litre per minute. They can be combined in a modular system, meaning they can be adjusted to different volume requirements. According to Lonza, they can be used to develop new chemical processes in the lab and then afterwards transform them into a production line.

Lonza says the modular design saves space and can lower production costs. Furthermore, it offers secure reaction conditions, even for highly reactive or poisonous starting substances. The process yield could conceivably be increased, says Lonza, if quick mixing processes, efficient heat exchange and precisely controlled reaction times could be integrated. Lonza has already tested different reaction types successfully: liquids with each other, liquids with gases, oxidation, and with bromine or chlorine, for example.

Standardised container modules

Industry relies on modular systems. If pharmaceutical companies want to make use of continuous manufacturing on a large scale, they will find it advantageous to employ modules in which chemical substances can be produced for a broad variety of active agents. This would also speed up supply. For this, they need flexible units that can facilitate the transfer of laboratory processes to the pilot and production phases. This can mean a leap from just a few millilitres to several cubic metres per year.

This is why the EU research project 'F3 Factory' developed practical modules oriented to the standardised size of containers: six metres long and 2.4 metres high and wide. Forty modules can fit into a single container. In this research project, for example, such modules were used to produce chemical intermediates for a test drug to treat cancer.

The EU project was run by a large consortium from 2009 to 2013, and its modules are now being further refined at the INVITE research centre in Leverkusen, run jointly by Bayer Technology Services and the Technical University of Dortmund. Lots of minor changes are being made there. They're working on the regulation technology and on preparing the active ingredients for the drugs. "Our centre isn't called 'INVITE' for nothing", says Thomas Bieringer, a former managing director of INVITE. "We are a public-private partnership, and we invite external partners to develop and try out new continuous procedures".

Tricky crystals

Several obstacles still have to be tackled. "Some of the chemical processes can block the reaction channels", says Bieringer. This can happen when the chemical reactions produce solid substances. Then the researchers have to try and alter the reaction conditions – such as by employing feedback loops. If this works, then they will be able to recognise the danger of a blockage in good time and prevent it.

Flow chemistry's full potential for the pharmaceutical industry is yet to be realised. Scientists in various places are working on adding crystallisation to continuous production processes, which would help them to produce drugs in tablet form. But they also have to make these new processes safe enough for them to be accepted by the authorities. And all this will take time. But it could soon become normal for the tablets on our bedside table to be made in a mini-refinery.

Sven Titz is a science journalist. He lives in Berlin and writes regularly for Neue Zürcher Zeitung, Tagesspiegel and Welt der Physik.