Speciality Chemicals Magazine October_November 2018

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API manufacturing: the benefits of continuous processing In this article, Mark Muldowney, head of technology and innovation at Sterling Pharma Solutions, discusses the challenges that companies must overcome in order to realise the benefits of continuous processing and what it could mean for the industry moving forward. In recent years, companies across the pharmaceutical industry have started to explore the use of continuous processing, specifically flow chemistry, in the manufacture of active pharmaceutical ingredients (APIs). This is primarily because of its potential to provide safer, faster and more sustainable manufacturing processes due to the increased control it gives operators over reaction parameters. However, before companies start investing in continuous processing, it’s important to assess its viability in terms of return on investment (ROI), its suitability for your product portfolio and availability of the required expertise. The current landscape Continuous processing is an alternative manufacturing method to traditional batch manufacturing. The flow reactors used in some continuous processing plants are a complex network of pipes with a small internal volumeto-surface-area ratio, allowing reactions to take place on a much smaller scale. While continuous processing has long been adopted in the production of commodity chemicals, the process is yet to be explored to a significant degree by the pharmaceutical industry. This might be because producing pharmaceuticals requires several more reaction and purification steps in order to reach the final result, which adds to the complexity of production. In addition, the regulatory landscape surrounding the production of pharmaceuticals is far stricter than the one surrounding commodity chemicals, not to mention that the adoption of continuous processing requires a shift in mindset for the pharmaceutical industry, which has been successfully using batch production for more than 100 years. Put simply, the adoption of continuous processing in the commodity chemical industry has been driven by the potential for cost savings, whereas for the pharmaceutical industry the focus needs to be on the ability to achieve improved reaction conditions and carry out reactions in a safer manner. Continuous processing in practice: the potential The chemical reactions in continuous flow processing take place in more compact reactors than in batch production. These reduced volumes allow the operator to gain greater
control over parameters such as concentration, temperature and pressure. This not only allows manufacturers to achieve previously unattainable conditions, but also mitigates the risk of handling hazardous chemicals that produce large volumes of unstable bi-products. In batch production, operators must wait until the entire process is complete before they can quench any unstable products, whereas in continuous processing this can happen in real-time, reducing the likelihood of adverse reactions. But these chemicals still need to be handled correctly and it is essential to have the right expertise in place. Used correctly, continuous processing could make handling hazardous chemicals much safer, but it can only be successful when combined with robust and scaleable chemistry, systematic process design and efficient process analytic technology (PAT). The process is also easily automated, leaving less room for human error. In addition, as a flow reactor runs uninterrupted until completion, there is less likelihood of quality variations and discrepancies in process reliability, which means less likelihood of costly batch dumping. As well as the quality assurance benefits, removing the need to stop production between batches can help to minimise labour. This, added to the fact that reactions can run 24/7, means there are also potentially significant savings to be made in terms of time. However, it is worth considering the impact this will have on internal operations. While time to market may be reduced for each API, turnaround times between projects may increase due to the need to thoroughly clean flow reactors to avoid cross contamination. The challenges Although the potential benefits are numerous, continuous processing is not a silver bullet. There are several challenges that pharmaceutical companies need to overcome in order for it to be a viable alternative to batch production. The biggest and most obvious barrier to implementing continuous processing is the upfront investment required to purchase the necessary equipment. While there are savings to be made by introducing less labour-intensive processes, the cost of flow equipment is high. This means that the decision to adopt this type of manufacturing often comes down to economic viability. Beyond the initial investment into laboratory equipment for proof-of-concept (POC) work, companies then need to invest in similar equipment that will allow them to scale-up for commercial manufacture. This usually means changing suppliers as many simply do not supply both smallscale lab and plant equipment, although the flow equipment can be stacked to allow commercial scale manufacturing. Product suitability is another important consideration as flow reactor pipes are more suited to certain types of APIs. The pipe network is designed to ensure adequate mixing of materials, but this can be problematic when handling solids. If a mixture precipitates out there is a high probability of blockages. This means operators have to dismantle their entire kit, which can have a knock-on impact on timelines. There is specific equipment designed to handle solids, which shakes to ensure continuous movement, but this machinery is more complex in nature than a simple flow reactor. The future: supply chain collaboration It is absolutely essential that companies invest time into understanding continuous processing before deciding to introduce new technologies. While there are huge potential benefits, companies need to build a good business case for adopting flow chemistry. The right expertise is as important as the correct equipment, which is leading to the formation of supply chain partnerships between drug developers and contract manufacturers. Such collaboration will allow the industry to successfully test the potential of continuous manufacturing, while mitigating risk and containing costs. £ CONTACT Mark Muldowney Head of Technology and Innovation Sterling Pharma Solutions www.sterlingpharmasolutions.com www.specchemonline.com
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Speciality Chemicals Magazine October_November 2018

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