Sterling Pharma Solutions is a global contract development and manufacturing organization (CDMO) with more than 50 years’ experience in providing small molecule API services to the pharmaceutical industry.

With more than 850 people employed across four sites in the UK and U.S., the company specializes in handling complex and challenging chemistries, including highly potent API manufacturing, controlled substances, biocatalysis, fluorinations and antibody-drug conjugate (ADC) research and development.

Sterling’s headquarters in Dudley, Northumberland, UK is home to its global R&D activities, pilot plant, and material sciences center, supporting innovative API development requirements and the scale up of projects to commercial production. In 2021, Sterling announced the establishment of a center of excellence at the site for research into commercial applications of continuous flow chemistry (see side bar below), and appointed Professor Ian R. Baxendale, Chair of Synthetic Chemistry within the Department of Chemistry at Durham University, to advise and champion the team. Contract Pharma had the chance to talk with Professor Baxendale, to discuss how Sterling plans to implement this technology, and the advantages that he foresees for its use in future API development and manufacturing.

Contract Pharma: What are the origins of flow chemistry?

Ian Baxendale: Flow chemistry as an approach and term has been used since the 1970-80s, but did not become common until about the year 2000. The Haber–Bosch process for ammonia synthesis, as well as hydroformylations that are utilized at considerable scale in the polymer industry date back much further, but there has tended to be blurring between “flow chemistry” and “continuous processing,” which are not the same.

Ultimately, “flowing processes,” and thus the foundations of flow chemistry, have been around in many guises for a long time, and are used in many industries, especially when processing large-scale bulk materials involving relatively simple transformation, conducting formulation, and/or enacting certain operations such as precipitation, separation and quenching.

Working in flow can give better control over the process and yields improved economies through better temperature control, or volume throughputs. However, until more recently, it has been less well-established in the performing of more involved and complex chemical transformations.

So, the big question is, “what does flow chemistry have to offer a commercial pharmaceutical manufacturing facility?” where processes often involve multiple steps and require intermediate work-up and purification stages. This is the challenge we face, as it combines highly skilled science, with the economics of business in a highly regulated and long-established development pipeline where batch processing is traditionally preferred.

CP: What are the advantages of flow chemistry?

Baxendale: In its simplest form, flow chemistry offers a different way (compared to batch) of creating ideal chemical environment for a reaction, which it enables through the control of hydrodynamic conditions of the liquids in the reactor. This translates to numerous additional parameters that can be selectively targeted and fine-tuned, and once their impact on a reaction is understood, can be leveraged to effect more efficient chemical change. In other words, we can get closer to the ideal reaction conditions than we could in an equivalent batch reactor.

As well having a more ‘tunable’ manufacturing throughput, the technology affords several additional safety benefits. Intrinsically, a flow reactor is a sealed system that uses small active volumes, making the handling of toxic or hazardous materials inherently safer, whether these be starting materials or reactive intermediates. This could be of more interest to the industry alongside the increased prevalence of higher potency active ingredients in drug development, where additionally the required volumes of active materials potentially suit small footprint, dedicated reactors.

CP: What are the current limitations that the technology has for commercial manufacturing?

Baxendale: I think we have only recently reached the stage where the aspirations and appreciation of what can be potentially enacted in flow at scale, while also having the skilled and experienced practitioners to design and implement effective, safe and commercially viable flow routes have become crystallized.

The technology itself is not a big issue for commercial manufacture, and the main restriction is around its implementation. Obvious limitations center on the lack of pre-existing knowledge and precedent in the area of large-scale manufacturing. As a newer, and less well-understood method, there are concerns about what happens if scale up does not go as expected, and the time frames that may be involved in resolving issues. Additionally, the cost of implementing this technology at scale is an unknown variable, although this can be somewhat mitigated by looking at iterative scaled reactor designs where more work is done in the laboratory to kilogram scale development, before moving to the pilot scale and then to large manufacture.

Switching technologies, and the will to adapt, has also been a challenge. With capacity and resource available in batch reactors, a change of strategy towards flow synthesis is not viewed as a priority. Similarly, batch reactors are validated for processes, with potential delays in establishing and validating flow setups that are not available ‘off the shelf.’

Concern is also often raised around the availability or access to reactor build capability, as well as additional components and auxiliary devices. However, the growing interest in continuous flow means that there are now a number of dedicated manufacturers and distributors that can offer knowledgeable and supportive delivery.

Alongside the manufacturing challenges, there is also the understanding of implementing the technology and the effect it has from a regulatory and quality standpoint. Ensuring harmonization of practices alongside existing protocols and necessary regulations is important to ensure that ultimately, patient safety is in no way compromised.

CP: What steps need to be taken to make the technology more applicable and accessible for pharmaceutical manufacturing?

Baxendale: As always, one of the major challenges is aligning with the regulatory authorities, and ensuring that processes carried out using flow synthesis fit within the guidelines and regulations for producing APIs. FDA advisory documents published in 2019, and expanded upon in 2021, go a long way to creating the fundamental roadmap to a flow processes’ successful regulatory implementation. However, this still leaves a lot of scope for interpretation and future development, which historically is not a comfortable environment for pharmaceutical manufacturing.

In this vein, it will also be necessary to develop and refine process analytical work, as although we are accustomed to having tolerances in a batch process, these are unknown for a dynamic flow process. We need to establish guidance on limitations and have definitions as to how far, and for how long, a flow process could go off specification within a production run, so proper understanding and guidance on controls and analysis, both in in-process monitoring and final material is a must.

If the technology can be proven, and steps can be taken to allow processes to be validated, then companies, and the wider industry will move to adopt it.

CP: What are the areas that can be exploited by the flow chemistry?

Baxendale: Sterling is seeing a massive uptrend in customers looking for dedicated, flow manufacturing solutions. Many of these are being driven by the need to access molecules that require one or more challenging chemical steps that has been identified as potentially hazardous, such as those that involve reagents such as diazomethane and azides. Sterling has a long history of careful and considered hazard evaluation and mitigation, so in many ways flow chemistry falls directly into the suite of available tools that can be applied to overcome challenging chemistries, allowing them to be operated safely at scale.

There are potentially reactions we could look at such as electrochemical oxidation and reduction, where flow chemistry could be advantageous to improve not only chemical selectivity and quality, but also to avoid exposure to toxic intermediates. Additionally, photochemistry lends itself perfectly to flow chemistry, where we are actively pursuing designs to move away from traditional routes that use metal catalysts, to open up new methodologies that are cleaner, more energy efficient and cheaper to run at scale.

CP: Where do you see the technology and its potential use by Sterling in 3-5 years’ time?

Baxendale: Sterling’s view is that continuous flow technology is a key differentiator between contract manufacturers when being selected by customers, and especially between Western and Eastern suppliers. Flow chemistry, like other “new” methodologies, is currently better supported in the West as this is where the pool of knowledge and expertise currently resides. Through investing at this stage, Sterling aims to establish its proficiency in manufacture using flow chemistry as it becomes more relevant to the pharmaceutical industry.

As with most technologies, interest and relevance begins within the academic sector, where the need for delivery in a commercial setting is not as important. For Sterling, being ahead of the curve in terms of trend is important, so that its abilities become known, and knowledge becomes rooted into the company, ensuring that the business does not have to try and catch up later. It is easier to attract customers with the necessary capabilities in place, rather than on a speculative basis.

It is crucial to remember that not every process will be relevant for flow chemistry at commercial scale. What I hope for the future is that appropriate projects will be instantly recognizable by the scientific and commercial teams at Sterling, and the advantages that the technology offers passed to the customers. At the moment, this is possible for lab-scale work, but the step to manufacturing relevance is the expertise and experience upon which we need to build, so that production teams can buy into the advantages that it offers.

Timeframes in the pharmaceutical industry are tight, and the pressure to reduce them further is an ongoing challenge. For flow chemistry to become more widely adopted, it has to offer benefits commercially in terms of the process, but the chemistry also has to work alongside equipment, and the engineering teams need to know the capabilities of the reactors, and validate the set-ups—which may be bespoke for each process—in a timely manner. This is an area that the industry is actively looking to address, with a view to modular units that would afford greater flexibility in reactor set-up and design, and allowing easier exchange of the modules between processes. The adage of failing fast and failing cheap is important to keep in mind, and while always aiming for success, knowing when to step back and look at alternatives is crucial for successful development.

My aim with this group that has been established is to focus initially on certain chemistries that we know are problematic, use technological approaches that are known—but not necessarily used commonly in the pharmaceutical industry—and build from there. Then we will learn what can work, what has potential, and what approaches are not applicable. This experience will be invaluable going forward, and ensuring projects that look translatable to flow, can be evaluated quickly and efficiently.