In Short: Revolutionising Small Molecule API Manufacturing: Embracing Miniaturisation and Automation

In this enlightening episode, Adrian La Porta, Technical Director at Bryden Wood, dives deep into the evolving landscape of pharmaceutical manufacturing, focusing on the critical role of Small Molecule Active Pharmaceutical Ingredients (APIs) in modern medicine. As the backbone of the world's most essential medications, the development and production of APIs stand at a crossroads, challenged by the increasing demand for more complex, potent, and targeted molecules. Adrian unveils the limitations of traditional batch chemistry in API manufacturing and explores the revolutionary shift towards miniaturisation, process intensification, and automation. 

Join Adrian as he dissects the groundbreaking technologies reshaping R&D, highlights the inefficiencies of current manufacturing networks, and proposes a new paradigm that promises lean, agile, and environmentally sustainable drug production. He examines the potential of continuous processing and other intensification strategies to enhance chemistry, reduce waste, and improve quality, all while addressing the financial and environmental costs associated with conventional large-scale manufacturing.

This episode is a must-listen for anyone interested in the future of pharmaceuticals, from industry professionals and researchers to healthcare providers and patients. 

Discover how discarding outdated methodologies in favour of innovative, modular manufacturing systems can transform the production of life-saving drugs, making them faster, safer, and more accessible to patients worldwide. 

To learn more about Bryden Wood's Design to Value philosophy, visit www.brydenwood.com. You can also follow Bryden Wood on LinkedIn and X.

Transcript

Intro: 0:09

Hello welcome to Built Environment Matters a monthly podcast brought to you by Bryden Wood an international company of technologists designers architects engineers and analysts working for a better built environment Bryden Wood Believe in Design to Value to cut carbon, drive efficiency, save time, make beautiful places, and build a better future.

Adrian LaPorta: 0:33

Hi all and thanks for joining us on this episode of Built Environment Matters, the Bryden Wood podcast. I'm your host, Adrian LaPorta, Technical Director here at Bryden Wood. Small Molecule Active Pharmaceutical Ingredients, or APIs, continue to be the mainstay of the most important medicines in the world. They make up most of the World Health Organisation's essential medicines, and between 2010 and 2020 accounted for three quarters of new products. Small Molecule's research and development has been revolutionised by new technologies and cutting edge science. This R&D generates more new molecules, more complex, more potent, more targeted than ever before. But can the manufacturing networks for these molecules meet the challenge of making higher volumes, more complex products for more patients, ever faster, at lower cost, whilst eliminating their environmental harms? The factories that make these molecules haven't changed fundamentally in decades. They've successfully produced APIs using batch chemistry because of their flexibility. Increasingly, they aren't meeting our needs. Scaling up from the lab to the thousands of litres scale is time consuming and risky. The processes use and waste large volumes of hazardous chemicals. Large inventories of these chemicals, whilst well managed, are hazardous. Each molecule needs many synthesis stages, and newer molecules need even more. This means that the lead time from starting the first stage to having usable products can be months. with working capital locked up in inventory in the meantime. Scientific and engineering advances can provide a new paradigm for small molecule drug manufacturing, if we discard preconceived ideas. Process intensification, combined with process automation, enables small scale, modular manufacturing systems, which can deliver the lean and agile manufacturing that the industry has been pursuing for decades. Continuous processing is a key intensification strategy, enabling better chemistry, reducing waste and improving quality. Whilst powerful and to be embraced, continuous processing is not the only intensification method. Many well established technologies from other chemical processing sectors are available, alongside new equipment and especially control and analytical technologies. Many have been used in pharmaceuticals already, but not widely. The management of process hazards drives cost. Control of the internal environment for safety and quality increases the volume of the facilities far beyond that of the process. Complicated piping intertwined with robust multi level buildings is expensive to design and build. The fluid volume of the process becomes a small fraction of the volume of the edifice it sits in and process equipment cost becomes a small proportion of the overall capital cost. The multipurpose concept is predicated on manual operations. Although plants use sophisticated control systems, they rely on people loading solids to start and end every batch. So, fewer larger batches means less labour, and so operations will tend to make batch sizes as large as possible. Some products might only need a handful of batches a year, so equipment becomes underutilised. The operator can now use it for another product, but there are two problems here. The plant is now not optimised for either product, a jack of all trades and master of none. Secondly, the plant must be reconfigured, cleaned, and proven to be clean. Increasingly stringent and quite reasonable safeguards against carrying over one product to another mean that changeover requires dismantling and inspection. Changeovers can eat up 40 percent of plant capacity. The supposed flexibility of multipurpose plant is rarely realised in practice. Switching between products being a job for fitters and a shutdown rather than the flick of a switch. Multipurpose plant also fails to be optimised for any unit operation. A batch vessel can be used for reaction, distillation, extraction and crystallisation. But it's not optimised for any of them. There is a double whammy that now makes the vessels even bigger. The lack of optimisation for each operation increases the time each takes, and using the same vessel for sequential operation increases the total time the vessel's used. For a given output, this makes the vessel even bigger. As it gets bigger, it becomes even less efficient as a relative heat transfer area and mixing intensity drops off. This makes each operation longer again in a vicious cycle of dismal efficiency. A lot of this goes unnoticed as the industry has accepted it as the norm. There are more vicious cycles in the effect of equipment size on the factory. Large vessels hold large quantities of solvents, increasing the intrinsic hazard, and the safeguards are needed to protect against these. Large vessels require large utilities, chemical supply systems, and large waste treatment systems. They need large, bespoke industrial buildings. Miniaturisation of batch processing, integrated into a hybrid process and hybrid facilities, allows us to combine the advantages of continuous and intensified batch processing, removing the scale, cost and hazards of conventional facilities. By matching the facility to the needed run rate of the process, and minimising campaigning, we can shrink our batch vessels. Automation is the crucial enabler. Automation breaks the link between the number of batches. There's great interest in smart factories and Pharma 4. 0, but if we just automate outmoded processes designed around manual labour, we'll miss the greatest benefits. Miniaturisation allows us to reduce scale up between clinical trials and commercial manufacturing, reducing time to market and risk. Highly potent and targeted products could use the same equipment for development, clinical manufacturing and commercial production. As batch processes get smaller and faster, they confer the benefits of flow chemistry, including a steadier, more consistent set of processes and data. Miniatusization also opens the door to distributed production. API supply is super globalised, with many APIs only made in one or two plants worldwide. Distributed, responsive production is more resilient and can help address medicine supply issues. Miniaturisation is more powerful when coupled with systemisation. Standardising reactors, filters and dryers simplifies technology transfer and allows us to reuse the same physical skid mounted units from process to process. They can be factory built and maintained and moved from place to place. Restricting vessel sizes transforms design and construction. Small equipment is safer and easier to move. When pipes become small, their design and fabrication are much easier and cheaper. Whole process trains can be built off site. As the high value process systems shrink, they can be decoupled from the buildings, greatly reducing their complexity and cost. Utility loads shrink, and utilities can be supplied by off the shelf modular systems. When we go small, we can go flat. We can move to a single level operation and single level buildings, easing operations, maintenance and construction, and better enabling the use of automated guided vehicles. There are challenges of course. All of our systems, facilities, organisations and regulations have been built on the assumptions of batch processing. But the need for affordable, sustainable medicines is so great and the advantages of integrating the best of chemical manufacturing and automation technologies are so compelling that we simply must take them on.

Intro: 8:31

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