As part of the initiative, the FDA encouraged pharmaceutical manufacturers to abandon their conservatism and to seek alternatives to traditional large vessel, batch processing which, although responsible for the successful production of quality pharmaceuticals, has its disadvantages. These disadvantages include, the production of large quantities of unwanted byproducts, heavy use of energy resources, inefficiency, and excessive use of starting materials, such as solvents and catalysts.
Consequently, alternative solutions were sought and attention turned to a technology that was once only used in R&D laboratories and for small-scale production — microreactor technology (MRT).MRT is based on continuous flow chemistry through reactors with a typical height or width of < 1 mm, but with lengths of 1 cm–1 m. Chemical reactions occur continuously through these tiny microstructures to yield thousands of kilograms of product per hour, thus making the technology suitable for large-scale, commercial production.
Although microreactors are thousands of times smaller than their traditional batch counterparts, they fundamental benefits, including selectivity, reliability, rapid mixing, effective heat exchange, minimal reagent and solvent volumes, speed, safety, easy process control and automation, simple scale-up, improved sustainability, reduced waste, and cost-effectiveness. MRT also allows manufacturers to undertake certain, often hazardous, reactions that were not possible in a batch reactor.
Consistently under pressure to reduce costs, improve efficiency, reduce environmental damage and to remain competitive, and in line with the FDA's guidance, an increasing number of pharmaceutical and chemical manufacturers are looking to the continuous, intensified manufacturing processes offered by MRT as a way to achieve some of these aims.
Is the pharma industry ready for it?
"The concept that MRT is suitable for large-scale production has been known for some time, the problem has been the availability of high quality, commercial equipment. I believe the equipment that is now becoming available is making the large-scale applications develop," says Paul Watts, Chief Technology Officer at Chemtrix BV. Sergio Pissavini, Business Director of Reactor Technologies at Corning, agrees: "Our company has decades of experience in the chemical industry, but it was evident that the pharmaceutical industry was becoming more and more interested in MRT for fine chemical and pharmaceutical production. The focus, however, was no longer on small-scale production, but the industry began to understand the benefits that this technology had to offer for high volume business and industrial-scale production. As such, we too turned our attention to pharmaceutical manufacture and concentrated some of our technology investments on MRT for pilot right through to commercial-scale pharmaceutical production."
"Perception relating to MRT and its use in full-scale manufacturing has been quite negative, but I do think that some of the technologies on the market in previous years were not ready to be used for continuous, large-scale processing and so perception has been informed by failed early-stage trials," admits Sophie Walton, Business Manager at the Centre for Process Innovation (CPI) UK. "I think there has also been a lack of understanding of the skill-set needed and the volume of work required to fit complex chemical reactions to MRT to really reap the rewards. Quite often we still see people trying to fit chemistry to these reactors without knowledge of the calorimetry or the kinetics of the reaction, and frequently we see customers who don't really understand the reaction chemistry — usually because the chemistry has been run for so long in the plant that they know what they have to do to achieve compliance on a batch without understanding why they do that in terms of the chemistry," she adds. According to Walton, a common misconception amongst manufacturers is that raised reaction temperatures leads to more side reactions and byproducts. "We know that in most cases this doesn't happen because of the greatly reduced residence time within the reactors," she explains.