Understanding and overcoming the challenges in chemical synthesis at a global CDMO

Andrew Kennedy and Jono West from Sai Life Sciences are interviewed about the work they do and how they utilise Radleys equipment in order to understand and overcome chemical synthesis challenges. To discuss your project or application needs, book time with an expert at Radleys: click here for a live calendar. 

Can you introduce yourself and tell us a little bit about your role at Sai Life Sciences?

My name’s Jono West. I’m head of safety and scale-up labs at Sai Manchester, Alderley Park.

Can you talk about the facilities that you have here at Sai? What sort of equipment do you use?

We are spread across two buildings at Alderley Park. We’ve got chemistry and analytical labs. Our analytical labs are fully equipped with all the latest analytical kit. In the chemistry labs, we have a lot of Radley’s equipment and we go from a few milliliters scale up to 35 L scale in our scale-up lab.

What are the features and benefits you look for in your synthesis equipment for small scale work?

When working on small-scale projects, we’re really focusing on parallel experimentation. What we want is equipment that is flexible, easy to use, produces good quality results and allows us to work as efficiently as possible.

When your process cameras are scaling up from gram to kilogram scale, what are the challenges they face and what do they look for in the equipment that they use?

When we’re working on a larger scale, we want to use equipment that’s representative of what we’ll be using on an even larger scale. Reactor-Ready and Reactor-Ready Pilot platforms allow us to use vessels that mimic those in our pilot and manufacturing plants. They also have great data logging capabilities and the flexibility to switch between vessels on that platform in under 30 minutes.

What would your team miss the most about that equipment if you had to work in a different way?

If we didn’t have Radleys equipment, I think one of the things we’d miss is the technical support and after-sales service. Whenever we have a query or an issue with the equipment, Radleys are always on hand to help, answering our questions and keeping our business on track.

What’s the main thing that your customers are looking for when they come to you with projects, and how does Radleys’ equipment help you deliver on that?

Our customers are looking for the right material at the right time and of the right purity. Radleys kit helps us do that because it is reliable. We have great service if something goes wrong and we need it fixed. What our customers also want is the intellectual property behind that manufacturing process. Radley’s equipment gives us that data logging capability so that we can give them a summary of what’s happened, which they can then take forward.

What does that mean for the business in terms of how it helps you to deliver on projects?

As a business, it means that we are competitive and we can deliver the projects that our customers need, in the fastest time possible.

Can you just introduce yourself, tell us about your role here at Sai Life Sciences?

I’m Andrew Kennedy. I’m Site Head at Sai Life Sciences, Manchester, based at Alderley Park. I joined the company two years ago, I was the first UK employee, and with a couple of other colleagues, we were tasked with setting up the new labs, recruiting staff and buying all the new equipment. We are now in a place where there are 60 staff members across about 20,000 square foot of lab space. We have been working on projects for approximately the last 18 months.

What are the main goals of the company?

Sai is a contract development and manufacturing organization. We work with pharma companies, biotechs, to help deliver their drug substances, develop packages and manufacture commercial quantities for them. Here at Manchester, we are very much focused on the development side. We do non-GMP manufacture here, but our site is set up as a process research and development centre of excellence, where we design processes and start to think about the scale-up of those processes.

That’s the unique selling point here at Manchester, but Sai as an overall company, delivers services across the whole project life cycle, from discovery all the way through to launch.

What makes Sai unique compared to other CRO/CDMOs?

Sai Life Sciences is fairly unique in the sense that we have operations here in the UK and in India. In India, the main focus is discovery, development and manufacture, whereas here, we focus on the development side.

What’s unique is that we can work on processes here in the UK, at the site here at Alderley Park, and we can then tech transfer those processes over to India, to benefit from that low-cost manufacturing option while also giving our clients the excellence in process R&D here in the UK.

Obviously, pharmaceutical companies have a lot of their own internal experience, whereas for biotechs, you may actually be helping to drive their development for them. Sai is able to help those different types of customers through their journey of drug development.

Can you talk about the facilities that you have here at Sai and what sort of equipment your chemists use?

As previously mentioned, we’ve set ourselves up as a process research and development centre of excellence. We’re very much focused on route scouting, process development and then small scale-up. We have the equipment to screen reactions on a small scale and then slowly move the development into slightly larger scales. The maximum scale we can go to here is 35 L, so we span that sort of 1 ml vial to the 35 L range.

As soon as projects need larger volumes than this, we then transfer those processes over to our sites in India, where we can operate on the pilot-scale or into commercial manufacturing. The equipment here that we have from a process perspective, allows us to do that. We’re also well supported from the analytical side with all of the in-process analyses done largely by the chemists, using LC/MS, GC/MS, NMR, and then we have an analytical department that also assists us in releasing those products to the customers.

What are the main challenges that your bench and process chemists face in their day-to-day work specifically on the synthesis side?

What we’re finding with a lot of our customers, is that time is critical for any project. They want the delivery yesterday! We really are limited in terms of the amount of time we can spend on process development, route scouting and the scale-up. So as a chemist, we need to be able to operate in a parallel fashion. For most of our projects, we need to operate parallel reaction screening experimentation, using design of experiments to try and get to the answers a lot quicker than we would’ve done by traditional means.

This means that we can move forward through those projects a lot quicker than we would’ve done previously, and that is important for a customer. They don’t want to spend a long time on process development before they actually achieve material scale-up.

From a small-scale perspective, that is the biggest challenge where we’re looking to get those key answers as quickly as we can using parallel experimentation tools.

As we then move into scale-up, what the customer is looking for is speed, but also quality. We need to do the work here to ensure that when we do scale-up, those processes are scaled-up efficiently. We are aiming to not repeat or rework batches.

As we start to increase the scale of our operation here in Manchester, we need to try and learn about those processes to ensure that that future scale-up is not delayed and that the delivery of the material is also on time.

The Mya 4 adds the complexity of being able to screen multiple reactions at different temperatures. The beauty of the Mya 4 from our chemists’ perspective, is that it can operate in a number of different modes and screen up to 32 reactions across four different temperatures in small vials which is really helpful at the very start of a project. As we start to scale up, having the ability to run four experiments at four different temperatures with overhead stirring is really important because it starts to give us a feel for how those processes will scale up.

That’s also important when doing heterogeneous reactions and crystallization because operating those in a magnetic stir environment is not normally that process-relevant. So, it’s important to be able to start to move into equipment that starts to resemble a plant vessel as soon as possible, and that’s where the Mya 4 really adds value.

When you process, do you go to that scale-up process from grams up to kilograms? What are the challenges they face at that point? What do you look for in the equipment that you use at that stage?

Once we’ve completed those screening experiments, we then look to start scaling up the processes, and it’s important that we start to move into equipment that starts to resemble our scale-up equipment. So again, we focus mainly on the Radleys Reactor-Ready’s to be able to help us do that. They have the capability of programming reactions and can implement reaction ramps and program additions. They give us the ability to map the process parameter data from those processes. It is really important to provide our scale-up colleagues with that information as we start to scale up the chemistry.

The Reactor-Ready’s are very versatile in the sense that you can operate from anything from 250 ml up to 5 L, and that gives our chemists a lot of flexibility in terms of the scale they operate. Sometimes we’re short on material and may not have enough material to run large batches.

The AVA software is also really helpful because it allows us to program the chemistry, to be able to operate those chemistries in the Reactor-Ready and it gathers all of the relevant process data, which actually helps us to understand a little bit about the process safety and start to think about how do we need to design our process as we move into larger vessels. Once we’ve done it on that Reactor-Ready scale, we then look to move into our Reactor-Ready Pilot, assuming a customer wants a larger delivery.

Radleys pilot-scale reactors go from 5 to 35 L and that’s a really nice scale to be able to deliver up to a kilo or two for our customers. Our labs in Manchester are currently non-GMP, so that first pre-clinical delivery is possible within that scale of vessel. As they are very similar in design to the lab version of the Reactor-Ready, it means that process transfer is fairly seamless, and we can again, gather all of the relevant process data using those pilot Reactor-Ready equipment, which we can then pass on to our process engineering teams, ready for tech transfer into a pilot plant or for manufacturing over in India.

I had had previous experience with Radleys with my former organization at GlaxoSmithKline, as had my colleague Jono and we felt that having that close relationship with a single company for quite a large amount of our process equipment was quite important.

That mindset has certainly developed as we’ve grown in the last two years. We’ve increased the number of Mya 4s, Reactor-Ready’s etc. to accommodate the increase in the number of chemists, and having that close relationship with Radleys has been really helpful, as they helped ensure that we got that equipment on time so that we were not delaying the start-up of our labs, etc.

What does the future of CDMOs, like Sai Life Sciences, look like over the next few years?

What we’re seeing from quite a lot of the large pharma companies, is that they want CDMOs to be largely self-sufficient. They don’t want to have to drive the development. They want to leave a project with a CDMO and just come back to them at the end when the project’s finished. They don’t want to have too much oversight.

Therefore, we need to be really excellent in our delivery. That is the quality of the science that we generate, but also the quality of the delivery in terms of the equipment we use and the materials we then produce. I can see that the CDMO business, certainly in the UK, is going to be independently delivering projects, with maybe some input from those pharma companies.

In contrast to that, I think that for smaller biotechs, this will be a very different game, and there’s certainly going to be, I think, a lot more projects where we will ultimately add in a lot more value outside of just process development. We’ve got a team here with a huge amount of experience across the pharma industry, and we will be able to support some of those biotechs in some of the other packages of work. So for things like Genotox risk assessments, understanding that process scale-up is essential.

We’ll ultimately help them plan the future of their drugs. Obviously, pharma companies don’t need that support. They have that internally, but the biotechs do sometimes benefit from those additional support mechanisms that we can provide.

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