But what benefits can flow chemistry bring to process development and API manufacturing? And should companies be choosing continuous manufacturing instead of batch production? In this article, Mark Muldowney, Head of Technology and Innovation at Sterling Pharma Solutions, discusses how opting for continuous processing could mean safer, more efficient operations for API manufacturers, as well as outlining the various challenges associated with continuous production.
Continuous versus batch production
Why has the pharmaceutical industry been so slow to adopt continuous manufacturing? Continuous processing has been widely used in the production of commodity chemicals for decades; however, the pharmaceutical industry has been slow to adopt this production method despite the potential benefits it can bring to the manufacturing process.
Manufacturing pharmaceuticals is generally more complex and requires more reactions and purification steps. As a result, multipurpose batch reactors are traditionally the “go to” choice. However, the nature of continuous processing means that these reactions can take place on a much smaller scale in a much more controlled environment, which is infinitely beneficial, particularly when manufacturing hazardous APIs.
The benefits of continuous manufacturing
Batch processes are designed around the limitations of the available equipment, meaning that, sometimes, the optimum conditions for specific reactions are not achievable when using batch reactors. Using continuous flow equipment instead can help to mitigate this. By doing reactions in more compact microreactors — with a smaller internal volume to surface area ratio — manufacturers can not only gain more control of the reactor parameters, but also achieve conditions that were previously unattainable.
This increased control of variables such as concentration, pressure and temperature, when combined with a reduced reaction time, makes continuous processing an attractive prospect for companies looking to manufacture hazardous substances or APIs with unstable by-products. That said, although the reactor may be small, the holding tanks for reagents and product are still substantial, meaning that it’s still necessary to handle large amounts of hazardous materials. Using continuous processing, it’s possible to quench reactive agents as soon as they have been used, whereas in batch production, the operator must wait until the process is complete. The microreactors used in continuous manufacturing have high mixing efficiencies, effective heat removal and low process inventories, allowing operators to safely quench by-products and immobilise any catalysts. By not holding unquenched product or starting materials, it is possible to limit the probability of adverse reactions. Continuous processing is also easily automated, leaving less room for human error.
In addition, continuous processing allows pharmaceutical manufacturers to reduce the likelihood of costly batch dumping. In the event of a pipe failure, only a small amount of product would be lost — instead of the entire batch — which can save a substantial amount of money and raw materials.
Saving time and resources
In terms of cost savings, continuous manufacturing can also maximise throughput and eliminate the labour and cost implications of starting up and shutting down production. Traditional batch manufacturing requires starting a process and stopping it before moving onto the next step, whereas continuous reactors can be allowed to run 24/7 until the project is complete. This also means that there is less likelihood of quality variations and discrepancies in process reliability.
That being said, although the length of time it takes to complete the process itself may be reduced, it’s important to consider other factors that could have an impact on your internal turnaround time. For example, how long will it take to commission and set up the correct equipment and how long will it take to clean your continuous reactors after you’ve delivered a project? There are no hard and fast rules regarding how to clean continuous equipment to avoid cross-contamination, but it goes without saying that it’s vitally important to ensure that it’s cleaned thoroughly before initiating a new project. A lot of people don’t think about the knock-on effect that this could have, so it’s important to consider the wider picture as well.
Scaling a continuous process up is relatively straightforward, providing the right equipment is available. It is important when designing a process that ease of scale-up is considered, as it may be necessary to change the supplier to get the right production equipment. This can of course be costly, which brings us to the biggest challenge of implementing continuous manufacturing processes. Cost versus return on investment means that the business case for implementing continuous manufacturing often depends on economic viability. The cost of the production equipment is high; even small laboratory equipment can cost in excess of £30,000 and the versatility of the machinery is often called into question. For example, lab kit is mostly made from glass or stainless steel, which can corrode when it’s combined with acidic formulations. This limits the reactions you can do … and replacing lab kit with equipment made from non-reactive metals is very expensive.
One solution is silicon carbide; however, not all suppliers make micro versions of kit in this material yet. So, a lot more raw material may be required for proof of concept work. Added to this, there are huge implications should you purchase the wrong equipment. Ideally, you want to be using commercial equipment made out of the same materials as the proof of concept or lab equipment to avoid altering the process conditions, which makes investing in new equipment for scale-up once a process has been developed more complex. In addition, companies must factor in the direct cost of training employees to use the equipment properly. As such, it’s easy to see how even setting a lab up to investigate flow processes can be an expensive business.
Regulatory considerations
The cost factor becomes an even bigger issue when the current regulatory landscape for manufacturing APIs is considered. Regulatory agencies such as the US Food and Drug Administration (FDA) and the Medicines and Healthcare products Regulatory Agency (MHRA) do not specify how companies should manufacture APIs. Instead, they provide guidelines on how best to ensure current good manufacturing practice (cGMP) standards. How this is achieved, however, is at the manufacturer’s discretion. Although, with flow chemistry becoming more prominent, it is likely that regulatory bodies will eventually choose to standardise their approaches and provide stricter instructions regarding its use. This means a lot of companies are reluctant to make the upfront investment in new technology and to dedicate the time and resource needed to develop ways of working until the landscape is clearer and they have had the chance to learn from the mistakes of others.
Is continuous manufacturing the right fit?
Finally, it is important to consider the mechanics. Continuous processing is not suitable for all APIs. A flow reactor is essentially a network of pipes, varying in length, diameter and material of construction, which is designed to ensure the adequate mixing of materials during a reaction. The complex set-up of pipes means they can be prone to blockages when manufacturing solids. Operators can be faced with dismantling their entire kit if a solution is too concentrated and precipitates out or the equipment they are using is not suitable for solids. There is equipment designed to cater for the continuous manufacturing of solids; however, it’s very expensive. The pipework is wider to accommodate the compounds and the machines shakes as the reaction takes place to keep the solids moving and mix them thoroughly. Although this works well, it does mean that the machinery needs to be bolted in place.
Moving forward: collaboration across the supply chain
When deciding whether to use continuous processing, the considerations are vast and the upfront investment is huge. Consequently, outsourcing is becoming an attractive alternative to developing capabilities internally, particularly for companies that are testing the viability of this type of manufacturing. Forming long-term strategic partnerships with contract manufacturers who are already successfully utilising continuous chemistry can mitigate the risk, contain costs and allow companies to access expertise they may not have in-house. Continuous processing can only be successful when the right equipment is supported by robust and scalable chemistry, systematic process design and efficient process analytical technology (PAT) — meaning a skilled team is absolutely vital.
At present, knowledge of continuous processing is limited across the industry. However, by encouraging collaboration and knowledge sharing among supply chain partners, API manufacturers will be able to realise the full benefits. At Sterling Pharma Solutions, we have recently launched a project with one of our customers to investigate the use of flow chemistry to manufacture one of their APIs. The project is in its early stages; however, it could potentially reduce cycle times, enable us to quench dangerous by-products faster and more efficiently scale-up our processes within minutes of reactions being completed.
Final thoughts
Continuous manufacturing has gained popularity during the last decade, with more and more API manufacturers exploring its viability to introduce safer and more sustainable processes into their operations. Used properly, continuous flow chemistry can give manufacturers greater control of process parameters such as concentration, pressure and temperature, in turn broadening the safe operating range of chemical processes and allowing companies to develop APIs to their full potential. In addition, the nature of continuous manufacturing allows operators to quench the hazardous by-products produced during chemical processes quickly and efficiently. However, before exploring continuous flow processes, it’s important that manufacturers give careful consideration to the suitability of continuous manufacturing for their products and take the time to understand the benefits and potential pitfalls of processing in this way.
