The FDA's Process Analytical Technology (PAT) Initiative1 was launched some years ago "to support innovation and efficiency in pharmaceutical development, manufacturing, and quality
assurance", to "design and develop processes that can consistently ensure a predefined quality at the end of the manufacturing
process." Sets of guidelines were laid out as part of the PAT framework, offering advice to manufacturers on how to make their
processes more efficient. These included:
Image supplied by Corning SAS
- Reduce production cycle times by using on-, in-, and/or at-line measurements and controls.
- Prevent rejects, scrap, and re-processing.
- Real time release.
- Increase automation to improve operator safety and reduce human errors.
- Improve energy and material use and increase capacity.
- Facilitate continuous processing to improve efficiency and manage variability; for example, by using dedicated small-scale
equipment (to eliminate certain scale-up issues).
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."
A large portion of pharma manufacturers remain to be convinced by MRT and its place in large-scale processing. This scepticism
can, however, be primarily attributed to the lack of availability of the technology; MRT has only very recently been made
available for the production of vast quantities of pharmaceuticals. In fact, industry experts began to realise the benefits
of the technology in this setting approximately 4 years ago, making it a relative newcomer in the pharma manufacturing circuit.
"MRT has completely changed the way that industrial pharmaceutical processing takes place; it requires a shift in methods
and in thinking. It is for this reason that we delayed introducing our MRT to the market. We needed the market to be ready
for it," says Pissavini. Corning began commercializing its MRT less than 2 years ago and Pissavini confirms that European
interest was very strong to begin with, while the North American, Indian and Japanese markets are now slowly following suit.
Conversely, microbioreactor manufacturer, Applikon Biotechnology, has witnessed a different geographical trend. "Our users
in the US are more open to new technologies, whereas in Europe, the users want to test the systems and see more proof that
it really works," admits Erik Kakes, International Sales & Marketing Director at Applikon. Sidebar 1 explains the benefits of MRT in biotechnological applications.
Sidebar 1: MRT in biotechnological applications
"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.