Image supplied by Corning SAS

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:

• 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."

Sidebar 1: MRT in biotechnological applications

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.

"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.

Hampered by regulations

Any desire for new technology and innovation in the pharmaceutical industry will, however, always be slightly dampened by regulations, compliance procedures and cost. Irrespective of whether a company believes in a new advance in pharmaceutical manufacturing or not, the benefits need to be proven beyond doubt before investments of money and time can be made.

"The pharmaceutical landscape is a highly regulated market with many stakeholders, which makes it difficult and time-consuming to introduce a new production technology," acknowledges Andreas Weiler, Global Business Director at SAFC. "Although, when the top fine chemical companies started to explore and market this technology, the perception began to change," he adds. This is evidenced by the many big names in pharma that have openly placed their trust in MRT, including Schering-Plough, sanofi aventis, Roche, GlaxoSmithKline, Novartis and AstraZeneca.

"Perception is gradually changing; we know of many large pharma projects currently underway in MRT. Many companies who do not have projects in this area are coming forward and speaking with CPI to see if they can tap into the knowledge and resource that we have, so they can effectively 'catch up' with some of the companies that are way out in front in this form of pharmaceutical manufacturing," says Walton.

Advantages of MRT

It is clear that the pharmaceutical industry is beginning to understand that there may be a place for this exciting technology in their manufacturing facilities, but MRT will not only require a change in thinking and processes; a significant investment of time and money will also be necessary. Furthermore, not all reactions that are conducted in traditional large vessels can be done in microreactors, although it is now thought that this relates to a minority of reactions. So why should pharmaceutical manufacturers take the plunge?

Flexible

"One of the major benefits of MRT when compared with some other continuous technologies, such as the spinning disk, is its flexibility. For instance, you can run many different reactions on one reactor system, which was a common argument previously held as a good justification for batch reactors," says Walton. "Not only can you perform more than one reaction in one system, but there is less restriction on minimum fill volumes and you can ramp up your manufacturing quantity easily by scaling out the technology and adding units operating in parallel," she adds. Pissavini agrees, confirming that a reactor can be customized for a specific reaction, thus customers do not need to adapt the chemistry for the equipment. "Flexibility is a real advantage of MRT," he says. "You can first test a reaction in a small structure and then add several lines in parallel to your industrial process, thus you can very easily increase the volume of your structure, yet you do not have the risk of loss of quality that you do if , for example, you were increasing a 200 L batch to a 1000 L."

Sidebar 2: Selective nitration in a microreactor under cGMP conditions — A case study2

Indeed, the successful production of vast quantities of material through industrial-scale operation of a hazardous nitration reaction using MRT was something of a turning point for the technology and provided strong evidence in support of the technology's flexibility, efficiency and safety.

Safe

"The internal volume of the microreactors is tiny compared with batch reactors; hence reactions that are highly explosive on a large scale can be safely conducted in continuous flow reactors because of the very good heat transfer. An example here is the synthesis of nitroglycerine by Xian in China," says Watts. "The rapid dissipation of heat during a reaction conducted in a microreactor, coupled with the low reactor hold-up time and real-time in situ analytical evaluation of reactions, all add to the safety of these devices," he adds.

Improved efficiency, higher yields, greater reliability, less waste; all descriptive of MRT processing reactions, when compared with the traditional, batch method. It is, therefore, no surprise that this technology, although requiring an initial financial and time-intensive investment, is undoubtedly viewed as the more cost-effective option.

Reliable and efficient

The author says...

According to Watts, the vast majority of scientific literature shows that reactions conducted in MRT give the desired product in higher yield and higher purity compared with batch reactions. "Meanwhile, the time to development of new products 'from scratch' is much shorter and clearly time savings means money savings," he remarks. "Once the manufacturing process has been defined, you can move from the lab right to commercial launch within 6 months with MRT if a company so wished. With traditional technology, it could take 2 years to move the processing from the laboratory to industrial scale. Time has a value in the market," asserts Pissavini.

Walton agrees that the potential for cost reduction with MRT, because of the increased efficiency, decreased demand for energy, infrastructure, space and, in some instances, a decrease in the number of operators required for each shift, is a major attraction. According to Walton, at CPI, they have witnessed many instances of improved yields, better product conformity, fewer 'batch' failures and an ability to handle some chemistries that carry significant financial risk in a batch. "There is also less leakage; with each reactor only containing substance in the millilitre range, you never really waste much product," adds Pissavini.

Kind to the environment

The pressure to reduce costs and increase efficiency is permanently etched on the target list of all pharmaceutical manufacturers but now, so too, is the pressure to reduce environmental impact. For today's pharmaceutical manufacturer to remain competitive in a highly competitive market, they must seek to develop more intensified, safe, yet environmentally-friendly processes.

"MRT can definitely contribute to greener manufacturing," confirms Walton. "Energy input is greatly reduced as you are effectively heating a narrow channel rather than a large, stirred tank that holds, for example, 30000 L," she adds.

"Less byproducts also equals less waste," says Weiler. "The great heat transfer rate also allows some reactions to be performed without solvents. Further, many processes that are carried out in a batch reactor must be done at a temperature of –70 °C to control the reaction; similar reactions can be done at 0 °C or even at room temperature in combination with shortened contact times, which saves a lot of energy," he adds.

In addition, it is very common in batch reactions to require excess chemical reagents to complete a reaction. "This is not frequently needed in MRT and one can use stoichiometric quantities of reagents. This clearly improves the environmental efficiency of the process," explains Watts. "However, I feel that one also needs to consider the process as a whole; frequently larger volumes of solvent are used in purifications than in the reactions themselves. If one can reduce the amount of waste in a reaction mixture, it simplifies the purification overall," he adds.

"There are massive health and safety benefits too — as the inventory of chemical reacting in a microreactor channel at any one time is so small when compared with traditional systems and inventories," explains Walton. She also highlights the energy and infrastructure savings associated with MRT because of the small size of the equipment and the reduced amount of cleaning agents required.

Broad applications

Although it is known that not all processing reactions that can be performed in batch systems can also be conducted in microreactors, the number of reactions that this applies to is lessening. "Years ago, only around 20–30% of reactions would work with MRT. Today, we believe that more than 60% could be accessible to this technology," insists Pissavini. "We are currently performing hydrogenation reactions on behalf of a customer with MRT," he adds.

"In the past, continuous flow processing was mainly used for the production of commodity, bulk chemicals, such as ethylene, styrene, ethylene oxide, monomers, and so on in metre-wide diameter channels," says Weiler. He explains that it is now possible to perform complex chemical reactions, particularly two-stage reactions, in an efficient manner inside these tiny reactors because of the following innovations:

• The change in tube diameter (from several metres to 10 microns).
• Different geometries can be used in the mixing zones to support the desired reaction.
• Different materials are used, such as glass, stainless steel, hastelloy, which allow a broader variety of chemical reactions.

Will all manufacturers adopt MRT soon?

With all of the promise that this technology holds, is it a matter of time before all pharmaceutical manufacturers adopt MRT for continuous, large-scale processing?

"I don't believe so; there are many instances where a smaller scale, batch reactor will perform perfectly well on a family of chemistries that a company may be performing and, in these instances, it makes no sense to change for the sake of change," says Walton. Weiler agrees, "Whether a manufacturer opts to install MRT or not will depend on the kind of reactions they have to conduct. Most of the classical, small organic API manufacturers will adopt this technology for some of their reactions. But it is important to note MRT will not replace the classical batch approach; perhaps up to 10% of all reactions will be performed continuously," he predicts.

In contrast, Watts believes that the adoption of MRT by the majority of pharmaceutical manufacturers is inevitable. "In reality, a lot is already happening, but unfortunately members of the industry do not always publish what they are doing. From the published developments that I have read, however, it is clear that things are happening," he says.

"If researchers and universities begin using this technology more and start thinking of reactions as continuous processes, then we will probably see a steady increase over the next couple of years," admits Weiler. "The pharmaceutical market is highly confidential until drug filing, so there might already be pharmaceuticals in the pipeline, created using promising continuous reactions that we just don't know about," he adds.

Sidebar 3: How Centre for Process Innovation (CPI) UK partners with industry to promote MRT

Room for improvement

Although MRT use in the large-scale, industrial processing of pharmaceuticals is expected to rise, research is still ongoing on the improvement and refinement of this technology. "Materials are continuously being improved; the channel size and the geometry, for example," Weiler advises. "The development of pulsation-free pumps is also an area where a lot of investment is being made. Hopefully we will also see more user-friendly and cheaper kits, such as all-in-one solutions with MR, pumps and temperature control devices, including training platforms. Currently, a lot of MRT knowledge is covered by confidentiality and it is not easy for students or researchers to be trained in the technology," admits Weiler. According to Watts, modifications such as downstream separation, in-line analytical inspection for quality control, and full integration into one continuous process will enhance the attractiveness of MRT to pharmaceutical manufacturers.

Overall, Weiler believes that, if researchers and engineers start to think of processes as 'continuous' processes at the early stages of the pharmaceutical process, this will clearly improve the time-to-market for new products. "We will see improved selectivity and more reliability leading to less negative scale-up effects," he says.

"Industry is already making a good start in trialling MRT; however, we would like to see a greater success rate in these trials, as we have heard rumours within industry of some disappointing results with continuous processing, which we think could have been avoided had the right approach been taken," comments Walton. She advises that companies must use the right support from contractors and reactor manufacturers when trialling the new technology, "this is the key to success in many instances," she explains. She also insists that companies should not expect to have all the right skills in-house. "Quite often, collaborating with companies with a proven track record of implementation increases the success rate greatly. We know that in industries such as the pharmaceutical industry, collaboration on cutting-edge chemistry can be hard for the intellectual property owner to come to terms with. But we believe it really is the key to success, so long as the correct partners are selected for the collaboration," she emphasizes.

In summary

MRT offers pharmaceutical manufacturers clear benefits. Continuous processing is associated with a number of advantages compared with traditional batch reactions, including enhanced safety, efficiency, cost-effectiveness, waste and reagent-use minimization, greater speed-to-market, to name but a few. However, with the benefits of the technology in a pharmaceutical setting only recently being realized, it will be some time before use becomes more widespread. And although MRT will never fully replace batch processing for large-scale manufacturing, the clear benefits and the expanded number of reactions that can occur with the technology certainly make it appealing.

As companies continue to feel the pressure to reduce costs, increase efficiency, alter infrastructure, and increase their portfolio, whilst being kind to the environment, we expect MRT to appear on the radars of most commercial-scale pharmaceutical manufacturers. As more data become available, demonstrating the benefits of this exciting technology in the manufacture of pharmaceuticals, and as the dynamics of the pharmaceutical market continue to change, veering towards more complex molecules and personalized medicine, the widespread adoption of MRT will be inevitable.

"The future lies in all processes being physically connected," concludes Pissavini.

Fedra Pavlou is Editor-in-Chief of Pharmaceutical Technology Europe.

References

1. FDA Guidance for Industry: PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance (September 2004). www.fda.gov

2. S. Braune et al., Chemistry Today, 27(1), 1–4 (2009).

Contributors

Sergio Pissavini, PhD is Business Director Reactor Technologies at Corning SAS, France. pissavinis@corning.com

Erik Kakes is International Sales & Marketing Director, Applikon Biotechnology BV, The Netherlands. e.kakes@applikon-biotechnology.com

Sophie Walton is Business Manager at the Centre for Process Innovation in the UK. Sophie.Walton@uk-cpi.com

Paul Watts, PhD is Chief Technology Officer at Chemtrix BV, The Netherlands P.Watts@hull.ac.uk

Andreas Weiler, PhD is Global Business Director at SAFC, Switzerland. Andreas.Weiler@sial.com

Chemtrix BV

Applikon Biotechnology BV

Corning SAS

AM Technology