Report from Europe

Continuous processing in pharmaceutical production has been making only small inroads into Europe's drug sector, which continues to be dominated by batch-manufacturing systems. However, the introduction of continuous technologies is gaining momentum in the region primarily due to R&D schemes backed by public-sector funds. Attention is shifting from relatively small-scale continuous processes, particularly in areas such as tableting and coatings, to concepts in which the production of intermediates or even of the whole drug is transferred from batch to continuous manufacturing.

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"The uptake of continuous technologies has been relatively slow because it requires a complete rethink of the whole production process," says Paul Hodges, chairman of NiTech, an Edinburgh-based startup in continuous-flow technology, who also runs the chemicals consultancy International eChem, London.

"To gain the full benefits of continuous processing, plants and their adjacent facilities need to be redesigned, otherwise the big advantages of lower capital costs will not be realized," he explains. "In comparison to batch production equipment, the continuous-manufacturing unit is much smaller but also much less space is needed for storage and logistics."

The largest European R&D scheme in continuous processing in pharmaceuticals and chemicals is a four-year €30 million (approximately US$39 million) public–private project in Leverkusen, Germany, called the Flexible, Fast and Future (F3) Factory. The project is backed by the EU and 25 other partners, including Bayer, AstraZeneca, and Proctor & Gamble.

Among other smaller, mostly national R&D projects covering continuous processing is La Maison Europeenne des Procedes Innovants (MEPI) in Toulouse, France.

The F3 Factory scheme is developing "smart-scale" plants consisting of individual modules that can be assembled in container frames in central workshops. They will then be transported to production sites to be connected together to form a single plant.

The partners in the project believe that the modular system eliminates many scale-up problems because the design of the equipment in each module for commercial production will be similar to that used during the laboratory development stages.

"The F3 project is so important because it provides an opportunity for a complete redesign of the process engineering in plants so that they can be switched to a total continuous system for the production of pharmaceuticals and certain chemicals," says Hodges. "Instead of adopting the traditional evolutionary strategy of incremental improvements to processes, this is taking a revolutionary approach."

AstraZeneca is using the F3 scheme to develop a continuous-manufacturing system for making a range of pharmaceutical intermediates through to the final synthesis stage of active ingredient production.

The company believes that a continuous processing capability in the production of new materials in the 10- to 100-L scale for toxicological studies will result in the quicker assessment of new compounds, more flexibility, and lower costs than traditional batch-processing equipment.

A case study, headed by Bayer Technology Service, the engineering arm of the Bayer group, which is coordinating the F3 project, found considerable cost reductions in the modular approach to pharmaceutical intermediates production.

Transforming a batch to a continuous process could achieve 10 to 25% cuts in operating costs and around 20% in investment costs, according to the study. But if the shift to continuous production also involves fewer processing steps, the total reduction in costs could be as high as 60%.

In a partnership with Technische Universitat (TU) Dortmund, which has one of the biggest chemical engineering departments in Europe, Bayer has just opened with the help of German government funds, a research center in Leverkusen called INVITE for the testing of modular processes.

"In the initial stages of development the modular methodology has shown itself to have clear chemical as well as cost advantages because it provides more efficient reactions with more effective heat exchange and better control," says Wolfgang Plischke, management board member at Bayer responsible for innovation, technology, and environment. "Now we need to standardize the equipment and its components so that the system can be used widely."

Standardization could be a complex, lengthy procedure because of the necessity to involve both drug and other manufacturing companies and equipment makers. Continuous processing may take several more years to become firmly established in Europe's pharmaceuticals sector but at least it now has a technological platform for its advancement in the region.

Sean Milmo is a freelance writer based in Essex, UK