(MINI WEBINAR) The rise of flow chemistry in API development and manufacturing: Navigating challenges with continuous processing

13th Apr 2023

In this 10 minute webinar, Will Reynolds, Flow Chemistry Development Chemist and Mark Muldowney, Head of Technology and Innovation, discuss the rise of flow chemistry in API development and manufacturing, and navigating challenges with continuous processing.

Welcome to the rise of flow chemistry in API development and manufacturing navigating challenges with continuous processing. My name is Emily Hardcastle, Senior Marketing Manager here at Sterling, and today I’m joined by Will Reynolds and Mark Muldowney.

Hi I’m Will Reynolds and I’m a Continuous Process Development Chemist at Sterling Pharma Solutions. And I’m Mark Muldowney, Head of Innovation at Sterling Pharma Solutions.

Will has a PHD in synthetic organic chemistry from the University of Bath and has worked in chemical process R&D for the last eight years. He has over 10 years of experience dedicated to flow chemistry and joined Sterling in July 2021. Mark possesses a PhD in chemistry from Newcastle University and joined our organisation in 1996 as a Development Chemist. He then went on to become group leader followed by Head of Technical Services and in 2015 he became Sterling’s Head of Technology and Innovation. I will now hand it over to Will who will begin.

In this webinar we will be discussing the rise of continuous processing and where it’s going in popularity, the advantages that continuous processing has over batch, make comparisons between continuous processes and traditional batch type processes, and go over some of the key considerations when thinking about implementing continuous manufacturing processes.

Batch manufacturing has long been the method of choice within the pharmaceutical industry, but under certain circumstances continuous processes can bring significant advantages to API manufacturing. Continuous manufacturing has been widely adopted within the fine chemical industries and Med-Chem labs have been utilising continuous processing technology for over 20 years. However, this hasn’t translated well to API production on a manufacturing scale.

Continuous manufacturing has the potential to improve the safe handling of many hazardous materials and reactions, and the global flow chemistry market is expected to grow by about 11.2 percent through to 2030. We will discuss how pharmaceutical and biotechnology organisations can begin to realise the advantages of continuous manufacturing in their processes.

Some of these advantages include improvements to efficiency, safety, cost effectiveness, and quality of chemical manufacturing processes.

Thanks, Will. So, Mark, please could you explain how continuous manufacturing can positively impact efficiencies?

Due to the small size of the reactors there is significant efficiencies in heat and mass transfers and flow reactors such that more hazardous chemistries can be actually performed in these units without risk of significant failures.

So what about safety? How can continuous processing affect the operators working on these types of projects?

Due to limited inventory of material in the reactor at any one time, more hazardous chemistries can be performed. Especially using groups like nitro compounds, azides, cyanides, and diazonium compounds.

Thanks Mark. In terms of quality, how can continuous processing help support a high level of control of a customer’s projects?

Once the reactive system has hit steady state, assuming there’s no deviations that occur, the product quality coming out the reactor will be the same all the way through the run which means that there’s going to be less need for interactions between the operators, and there’s going to be less need for monitoring and you’re just continuously processing without stop and start unlike batch reactors.

And as discussed the safety improvements using limited inventories, the fact the reactor will continuously  run without having to be stop started, the fact that there should be less need for manual intervention in the reactors, means that this will all lead to cost savings and efficiencies.

That’s really interesting, especially the statistic around flow chemistry having the potential to reduce pharmaceutical manufacturing costs by up to 40 percent. And that actually leads us on nicely into discussing the benefits of batch versus continuous manufacturing. So Will, could you talk us through this slide please?

Advantages of batch processes are that you can more easily handle solids, the regulatory guidelines are much more well defined because they’ve been operated for many years, and modelling of batch processes tends to be more well understood compared to continuous processes. Some advantages of continuous processes are that they are easier to scale between lab and manufacturing, they are better suited to handling hazardous materials as we’ve already discussed, there is less opportunity for human error and better product quality as a result, and it could be easier to monitor your reaction conditions during a process. There are benefits and drawbacks to both batch and continuous processes and it’s important to look at all of these points in detail when you’re determining which is the most suitable type of process for your chemistry.

Over the next few slides we’re going to look at some of the issues that have to be considered when going from batch to flow. For example, regulatory, infrastructure, safety, and actually what can be achieved in flow over batch.

When you’re looking at a regulatory considerations there’s many years of practice in batch chemistry but there’s very few in flow chemistry, and what has been done has been looking more towards the drug product and the drug substance area. Such that there is not a lot of guidelines out there for people to follow and there’s not a lot of experience within the industry. So you need to actually go with a partner who have a significant background in regulatory compliance and quality inspections.

And how does Sterling fit into this, Mark?

At Sterling, we have over 50 years of experience in regulatory approvals and manufacturing to GMP.

Infrastructure costs need to be considered as well because there are a significant number of small-scale manufacturers of equipment, but unfortunately they don’t build production scale equipment including ATEX rated equipment, and this means that you need to be able to transcribe from laboratory to plant.

So, your chemistry and engineering team need to understand how they’re going to transcribe the chemistry from laboratory equipment into production equipment. Often this equipment is not available and will have to be built by the company doing the production so everybody needs to understand the safety and engineering applications, and need to understand the cost that’s going to be involved in actually developing this new equipment. Especially if it has to be ATEX rated if you’re going to take things onto the pilot plant and then to the main plant from hundreds of kilos to thousands of kilos. This will have a cost implication that needs to be factored in when you’re developing these processes.

Of course, that’s something we factored in when we established our Centre of Excellence in continuous flow chemistry back in 2021, with the installation of multiple flow chemistry platforms into a research lab to allow investigation into a wide range of chemical processes, as well as equipment to undertake hazard evaluation studies.

Great, so what’s the next thing to consider?

Safety as well is another key part that we have at Sterling. Hazard evaluation departments are going to be key in developing these new technologies. Again, there are very few equipment suppliers and/or experts at hazard evaluation in flow chemistry, so this is an area of expertise that’s going to develop as the years progress. At Sterling we do have a significant experience in hazard evaluation. Our team can do a variety of different tests to make sure that what we are developing in the laboratory actually works on the plant as well in a safe manner, and is not going to cause any issues.

So how will batch versus flow chemistry play out over the coming years?

Flow chemistry will not replace batch chemistry. It has certain advantages that batch chemistry is difficult to perform. Such as using hazardous materials or high temperatures and pressures, such that flow chemistry will complement batch chemistry in looking at how to deliver drugs of the future in the most efficient and cost effective manner. For that, you need to have a partner who can actually deliver everything from the laboratory development, to hazard evaluation, to the engineering expertise putting this on the plant, and understanding where flow chemistry can fit in and complement the batch chemistry, and deliver a product that is a high quality and high yielding.

At Sterling, with the flow applications we are currently looking at are looking at more hazardous materials like use of azides and use of diazomethane and other hazardous reactive materials like that.

Finally, Mark, could you please talk a little about our flow chemistry capabilities here at Sterling?

Our dedicated and highly experienced flow chemists working in our technology team are using state-of-the-art laboratory equipment to convert problematic batch chemistry into feasible flow processes. We are currently evaluating several hazardous and inefficient chemistries to kilo scale, with the help of our academic advisors and external equipment manufacturers. Also our in-house team of highly experienced processing engineers are helping to develop this and turn this into plant processes.

Great, thank you. With that we conclude and we thank you for listening today. If you have any questions please head to the contact page on our website or email enquiries@sterlingpsl.com. For more information on our continuous capabilities, head to sterlingpharmasolutions/technologies/flow.

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