By Mark Muldowney, Head of Innovation and Technology, Sterling Pharma Solutions
Over the last decade, pharmaceutical companies have started to explore the potential of continuous processing, specifically flow chemistry, for manufacturing active pharmaceutical ingredients (APIs). Despite its potential to offer safer, faster and more sustainable processes, the production method remains relatively untested by the industry. This is in part because manufacturing pharmaceuticals is far more complex than say, manufacturing commodity chemicals where continuous processing has been widely used for many years.
Producing pharmaceuticals requires a greater number of reaction and purification steps, meaning designing a suitable process is more complex. In addition, the regulatory requirements surround the manufacturing pharmaceuticals are generally far stricter than those surrounding commodity chemicals. This mean access to the right expertise is absolutely vital to success.
Before companies decide to explore continuous processing, it is essential that they take the time to weigh the potential benefits against the required investment. They should also consider the various challenges, such as product suitability and equipment availability. Assessing the viability is the first step to accessing the full potential of continuous processing, but what should companies be considering when choosing between continuous or batch production? And, what impact could successful implementation have on the industry as we move forward? In this blog our head of technology and innovation, Mark Muldowney, explores continues processing and the benefits and challenges it brings to API manufacturing.
What is continuous processing?
Continuous processing is essentially an alternative manufacturing method to batch production. A flow reactor is a complex network of pipes with a small internal volume to surface area ratio, meaning reactions run on a smaller scale over and over again until the entire volume of API is produced. This contrasts to traditional batch production, whereby a step-by-step approach is taken to manufacturing API in huge volumes.
Because it takes place on a smaller scale, continuous flow processing gives the operator greater control over parameters and can allow them to achieve conditions that were previously unattainable. This is also particularly useful when handling hazardous materials, not least because bi-products can be quenched in real time as opposed to at the end of a batch cycle.
Continuous processing also allows immediate immobilisation of any catalysts, meaning operators can limit the probability of any adverse reactions. However, these products still need to be handled with care making the right expertise essential.
Saving time and resource
By running the manufacturing process 24/7 until the project volume is complete, it is possible to maximise throughput and eliminate the labour and cost implications of starting up and shutting down production in between batches. This also means there is a reduced likelihood of any discrepancies in quality and process reliability, which means less chance of costly batch dumping should something go wrong. By running reactions on a smaller scale, you can reduce the amount of product you lose in the event of a pipe failure. This can mean huge savings in terms of money and raw materials.
However, although it is possible to reduce time to market by continuously running a start to finish process, there are other time implications associated with flow chemistry. For example, you will need to commission and set-up the correct equipment and once a project is complete you have to thoroughly clean your equipment to ensure no cross-contamination. This could mean dismantling your entire kit, which can have an impact on internal turnaround times between projects.
Equipment availability and ROI
It’s important to establish a good business case for implementing continuous flow processing. The upfront investment required to purchase equipment is substantial, with even small laboratory equipment costing in excess of £30K. You also have to consider how you will scale the process up.
Although scale-up may seem like a relatively straight forward process, it often means changing supplier for continuous flow equipment as there are few who manufacture both small-scale lab kit and plant equipment that can be stacked to cater for commercial manufacture. In addition, it is often best to use equipment made from the same materials to avoid altering reaction parameters. Consequently, sourcing the right equipment can be both time consuming and costly. So, the decision to implement continuous processing often depends on economic viability.
Continuous flow processing is also more suited to certain APIs than others. The nature of a flow reactor means it can be easily blocked by solids. If your solution precipitates out it could bring the process to a halt until the kit is dismantled and the blockage cleared.
There is kit specifically designed for the continuous flow manufacture of solid APIs that shakes throughout the process to ensure continual movement. However, it is more complex in nature than a simple flow reactor.
The current regulatory landscape surrounding the continuous manufacture of APIs is tenuous at best. Currently agencies such as the Food and Drug Administration (FDA) and the Medicine and Health Regulatory Agency (MHRA) do not specify how companies should manufacture APIs. Instead they provide guidance to ensure good manufacturing practice (GMP). As continuous flow processing remains relatively unexplored there is relatively limited guidance around the process.
This being said, as adoption grows, it is likely that stricter guidance will be enforced surrounding its use. This, in addition to the upfront investment, means that many companies are reluctant to dedicate the time, resource and funding until the landscape is clearer.
Collaboration across the supply chain
There are many factors to consider when deciding whether to implement continuous flow processing. Companies should carefully assess the suitability in relation to their product portfolio, as well as the business case for using this type of technology. In addition to the right equipment, this type of manufacture can only be successful when supported by robust and scalable chemistry, systematic process design and efficient process analytical technology (PAT). Success is simply not viable without a skilled team.
Given the investment and the expertise required to be successful, outsourcing and strategic supply chain partnerships are becoming increasingly popular. This type of collaboration can allow companies to mitigate risk, contain costs and access expertise they may not have in-house, while they explore the viability of the process.
For more information, or to speak to a member of the Sterling team, please get in touch.