Continuous manufacturing processes
Present situation worldwide and in Switzerland
Pharmaceutical products are traditionally produced in batch mode, which remains the dominant production technique: defined materials are processed for a defined period of time before being released as a production unit (batch). This usually involves several separate and consecutive processes. Products are analysed off-line and released for further processing. In recent times, “continuous manufacturing” has gained ground. Materials undergo all process steps in a single flow: materials are added and finished products are released on a continuous basis. Product release takes place in real time based on on-line and in-line process analytics and control algorithms.
Compared to batch production, the continuous approach presents several benefits: safer and more cost-effective production on highly specific and customised systems, shorter time to market, smaller and thus more environmentally friendly production facilities, lower requirements in terms of scaling and maintenance as well as the possibility of “auto- tuning”. Integrated real-time quality control, a fundamental prerequisite for continuous manufacturing, is another major advantage. Continuous manufacturing production facilities are flexible platforms: new processes can be developed faster on existing continuous manufacturing lines, as the same lines can be used for process development and for production. This makes it possible to massively reduce costs and time required for scaling. In addition, the range of chemical solutions expands: since reaction volumes are smaller, it becomes possible to apply more “risky” exothermic reaction steps or higher pressure, enabling the synthesis of new molecules. It is furthermore possible to vary the production volume as needed on a continuous scale. Such platforms are also better suited for implementing customised medication-based patient solutions.
A key obstacle facing continuous manufacturing concepts was the lack of regulatory framework for this new production paradigm. In recent years, under the leadership of the US Food and Drug Administration (FDA), many uncertainties have been removed, greatly boosting research and testing activities in the field of continuous manufacturing. Many equipment manufacturers have also undertaken major steps toward developing continuous manufacturing solutions. Several companies now also provide solutions for process monitoring and analysis as well as integrated process control platforms. New manufacturers have recently entered the market, leading to more competitive and better solutions for industry.
Large pharmaceutical companies are leading the way in implementing this new paradigm. Yet SMEs have also begun to assess the opportunities and benefits of continuous manufacturing. In the meantime, products developed specifically for continuous manufacturing have received regulatory approval, e.g. Orkambi by Vertex Pharmaceuticals. Recently, a switch from batch to continuous manufacturing was approved for the first time. Close collaborations between academic institutions and industrial partners, such as the Novartis-MIT Centre for Continuous Manufacturing, are also increasing in number.
Implications for Switzerland
Switzerland is well positioned, although application is largely limited to large producers. Key aspects to be considered are concept development, equipment and automation. There is room for improvement as regards cooperation with Swiss institutions of higher education on concept development: such endeavours often fail due to intellectual property issues. There are also opportunities for collaboration with niche suppliers on the development and application of technical equipment with subsequent commercialisation by the industrial partner. Expanding activities in the field of continuous manufacturing should prove significant for Switzerland, as the emerging shift in paradigm can only be accelerated by further innovation. This also creates opportunities for smaller academic and private sector players.