Industry Insights with… Rory MacDonald
Welcome to the latest blog in our Industry Insights series, where we ask our experts to share their in-depth expertise on topics within the pharmaceutical industry. In this instalment, we asked our Lead Chemical Engineer, Rory MacDonald, to share his knowledge on seminal developments in continuous manufacturing technology and what they mean for the future of the field.
What do you need to take into consideration when choosing between batch and continuous manufacturing?
The batch method is a well-established step-by-step approach to manufacturing that chemists are familiar and comfortable with. Continuous manufacturing is comparatively new within the pharmaceutical industry but has been the trusted approach favoured across other industries for many decades. It is worth noting that, as a CDMO, it is our responsibility to remain entirely impartial in terms of which process is best for a given reaction. Batch manufacturing is often an excellent choice for slow or simple reactions, and I believe it will always have a place in the industry. The latest advances in continuous manufacturing, however, offer numerous benefits in many situations, and can unlock the ability to utilise new synthetic routes.
What are the main advantages associated with continuous manufacturing technology for the pharmaceutical industry?
There are a few key benefits that continuous manufacturing offers in the pharmaceutical space. Firstly, there is increased safety at scale – which, from my perspective as lead chemical engineer, is paramount. Continuous manufacturing means that solvents and reagents are trickled through a reactor with smaller quantities being present at any one time than in a batch process of equivalent scale, reducing the risk associated with using hazardous solvents and reagents. Another key improvement over batch is that the technology can allow you to access much more challenging reaction conditions and novel synthesis routes. Additionally, a continuous process lends itself to continuous monitoring, which can contribute to increased assurance of product quality.
Finally, continuous manufacturing can often eliminate the need for a completely new process to accommodate scaled-up production – you can simply run the same process for longer. If demand goes up significantly, you can also scale-out and devote more reactors to manufacturing the drug. As a result, continuous manufacturing allows us to move more quickly through clinical phases and deliver new medicines to patients at an accelerated rate.
How are recent advances in continuous manufacturing technology impacting the pharmaceutical industry?
We are only just beginning to see the impact of continuous manufacturing in the pharmaceutical industry and are entering an exciting era of discovery and innovation. One of the impacts we are hoping to see is reduced time to market. A key development towards this aim has been getting regulators on board – an essential step to ensure the benefits of reduced time for process development and scale up translate into reduced time to market. Regulators are now much more familiar with the technology, and products utilising continuous processes have been brought to market. In June 2018, the International Council for Harmonisation (ICH) also announced the coming issuance of new guidance (ICH Q13) regarding continuous manufacturing, and I think this will really help progress the technology as well as ensure best practices are shared and implemented.
In the coming years I also expect to see a significant positive impact from increased use of flow reactors for electrochemistry and photochemistry within Pharma. These two techniques have the potential to open up a wide range of greener, more efficient and more selective reaction pathways. Due to limitations on scale up, neither of these techniques are widely implemented as pharmaceutical batch processes. Continuous reactors can address their scale up issues and will allow them to be more widely implemented.
Can you describe a key example of how continuous manufacturing technology can reduce the time and cost associated with drug development, scale-up and manufacture?
We recently encountered an excellent example of how this technology can benefit the industry while working with one of our partners to develop and manufacture a novel drug. In batch, the synthesis reaction for this particular drug took place under extremely cold conditions to prevent a dangerous reagent from evaporating into an explosive and toxic gas. While the process could be carried out strictly in line with HSE requirements, the basis for safety is not as robust as we wanted it to be and in the event of a failure in the cooling system we could be relying solely on the walk-in fume cupboard to remove large quantities of a toxic and explosive gas. Furthermore, if we wanted to scale the reaction up in batch, we would have needed an entirely new facility with expensive and complex safety systems.
As part of our Flowinova project in partnership with the University of Nottingham, we were able to develop a solution to this problem in the form of a continuous process that runs at high pressure and at ambient temperatures. This is intrinsically safer as we have a fail-safe containment philosophy, and as a flow reaction we are also using much less of the hazardous reagent at any one time. Unused reagent can be recycled back through the reactor, which helps to reduce costs and environmental impact. We can also scale up the reaction within our existing GMP laboratory. As a result, we can now look forward to delivering this project by the end of the year, potentially with reduced timelines and costs.
How do you see continuous manufacturing technology evolving?
I think that the next big thing will be the progression of self-optimising reactors, i.e. having sensors that can monitor the critical quality attributes of your product and a control loop to keep these on target. We are likely to evolve in this direction for several reasons. Firstly, processes will be more robust and capable of self-adjusting for variation in feedstocks. This will reduce the need for preceding stages to be as highly controlled and reduce risks to product quality when making changes to supply chains. Secondly, this will automate much of the highly labour-intensive task of running multiple experiments in a DoE and then analysing the data before deciding on the optimal running conditions.
Being able to develop processes faster is something we are particularly interested in at Arcinova, because we have a high turnaround of different molecules. In many cases the experimentation to develop a process is our rate-limiting step and where most of our labour is dedicated within the drug substance team – if some aspects of route development could be automated we would be able to respond to our clients’ needs with greater agility. The golden goal for us would be a system where you just put your reagents into a flow reactor and tell it ‘I want to make this molecule at an optimal balance between quality and cost’ and it will proceed to iterate through the design space and find suitable reaction conditions within a much shorter space of time than could be achieved by a human.
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