Today’s pharmaceutical medicines (drugs) are produced through a number of process steps; in average over all processes being 8. Continuous-flow processing is a disruptive technology approach and thus, analogous to the automation lines of industry in car and electronics manufacturing, can intensify those pharmaceutical production processes. This intensification leads to faster, safer, more economic and environmentally friendly processes (eg less waste, higher quality product). While continuous-flow intensification for single steps has been reported as well as a multi-step continuous-flow manufacture at laboratory stage, demonstration of both combined achievements at production stage is still rare, i.e. end-to-end pharmaceutical production in practice is lacking.
The project PICASCO made a major step to close that gap, and developed a pilot plant, which paves the way toward industrial transformation in drug manufacture. Thus it provided an essential missing link for further commercialisation of continuous-flow. On top of that, all the individual processes were highly intensified, and also, and even more notably, the process as a whole by solvent-free processing, breaking the dogma that solvents are needed as reaction medium to disperse reactants and control process parameters.
This was demonstrated for the anti-epilepsy, blockbuster drug rufinamide (brand name Banzel). The pilot manufacture was made in an industrial environment, to ensure a Technology Readiness Level of 6 (following the CloudWATCH2 assessment used for EC project evaluation). That means that the project result is readily transferable to industrial use. The industrial environment has been provided by MicroInnova Company, Allerheiligen, Austria which received the “Process Intensification Award for Industrial Innovation 2015” from the European Federation for Chemical Engineering (EFCE). The process development was made at Eindhoven University of Technology, the Netherlands. To a part, industrially available reactors were taken, thus commercial equipment with proven documentation.
Due to the high intensification achieved, the pilot plant takes just a footprint of 3 m2 (typical pharmaceutical plants may have 10 m2 or more), while achieving a productivity of 47 g/h or >400 kg/year. As a rufinamide tablet contains 200 mg, this is equivalent to producing 2 million tablets per year. That pilot productivity is 7 times higher as compared to laboratory performance, which were achieved in the EC research excellence grant “ERC Advanced”. Thus, this proves that its key concept, ‘Novel Process Windows’ (unseen process conditions with large potential) have been made ready for transfer into industrial practice. As (small) compromise to reaching the new industrial scale of productivity, energy consumption and temperatures had to be set slightly higher than given for the laboratory.
The project also demonstrated economic viability: cash-flow scenarios show how long it takes until the capital investment for the chemical plant is paid off (break-even) and starts to make profit. It was found that both break-even (4 years) and profit of the chemical plant are within economic margins, in which business managers at pharmaceutical companies decide for acquisition of a new plant.
The techno-economic direction was critically followed and advised by an Industrial User Club, including world leaders in the fields of continuous-flow equipment and pharmaceutical manufacturing: HNP Mikrosysteme GmbH, GlaxoSmithKline - GSK, Chemtrix BV, Patheon - part of Thermo Fisher Scientific, Kobelco - Kobe Steel LTD, and Corning SAS. A business case study, developed by a business consulting company (ttopstart, now PNO Consultants) shows up the next steps to commercial implementation, by giving a business development plan. It also includes to avoid possible patent bottlenecks (freedom-to-operate), regulatory demands, IP strategy, market survey, business pitch, and commercialization/partnering strategy.
