While widely adopted in other industries, such as commodity chemicals, continuous manufacturing is only just starting to be explored as a production process by the pharmaceutical industry. This is primarily because manufacturing pharmaceuticals is more complex and requires more reactions and purification steps. Despite the added complexity, there are a multitude of potential benefits to manufacturing in this way when compared to batch production. For example, the potential savings in terms of time and resource as well as the potential improvements to process efficiencies.

In this article we’ll take a look at the considerations needed to be taken when exploring the viability of continuous processing and what effect continuous flow technologies could mean for the industry moving forward.

What is continuous processing?
Continuous processing is an alternative method of manufacturing to the traditional batch process that is widely adopted in the pharmaceutical industry. A continuous reactor is essentially a complex network of pipes with a small internal volume to surface area ratio. This means manufacturers can theoretically gain greater control over reaction parameters and achieve conditions that were previously unattainable.

This is particularly useful when handling hazardous materials. The microreactors used in continuous manufacturing allow reactions to take place on a much smaller scale, much more frequently, making it easier to quench reactions and avoid adverse bi-products.

The current landscape
While it is not a new idea, continuous manufacturing is still a relatively new concept for the pharmaceutical industry. Most pharmaceutical manufacturers still rely on batch production despite the potential cost and quality benefits of continuous processing. There has also been much discussion surrounding the added flexibility that continuous processing could offer manufacturers, as well as the greater control over reaction parameters, such as concentration, pressure and temperature.

However, adopting continuous processing requires a shift in mindset for the industry. It remains relatively untested in pharmaceutical manufacturing and as such, the regulatory guidance surrounding the processes involved is less comprehensive than those surrounding batch production. This, combined with the cost of buying and installing suitable equipment, means that there is a widespread reluctance to be the first to adopt these technologies.

Used correctly, continuous processing has the potential to create safer and more sustainable processes for active pharmaceutical ingredient (API) manufacturers. That said, it is important that companies take the time to assess the suitability of manufacturing in this way and to fully understand both the benefits and the pitfalls before attempting to introduce continuous processing into operations.

Exploring the potential of continuous production
Time and cost. Continuous manufacturing can run 24/7 until the project is complete, meaning it is possible to minimize the labor and cost implications of starting up and shutting down production in-between batches. This often means that the time taken to manufacture the full project volume is reduced. However, it is also important to consider other factors that could have an impact on project timings.

While time to market may very well be reduced for your customer, once you have completed a project you have to thoroughly clean your continuous reactors to avoid cross-contamination. As a network of pipes varying in length and diameter, cleaning a flow reactor is quite a complex process, which can impact internal turnaround times and result in a delay initiating new projects.

In terms of cost savings, continuous manufacturing can also maximize throughput, as well as reduce the likelihood of costly batch dumping should something go wrong. As reactions take place on a much smaller scale, only a small amount of product would be lost in the event of a pipe failure, which could save a huge amount of money and raw materials.

Risk mitigation. This increased control, added to the smaller quantities being handled at any one time, is particularly useful when handling hazardous materials as the potential for adverse reactions due to a fluctuation in conditions is reduced. In continuous processing it is possible to quench reactive agents as soon as they’ve been used and immobilize any catalysts immediately as opposed to waiting until the end of a batch cycle. Continuous processing is also easily automated, allowing for reduced potential for human error.
Using a process that runs until the end of a project also means that there is less likelihood of quality variations in the final product or discrepancies in process reliability.

Potential hurdles
While there are many possible benefits associated with implementing this kind of technology, it is not without its challenges. Companies must thoroughly assess both sides when determining the suitability of continuous processing.

Product suitability. Flow reactor pipes are more suited to certain types of APIs. As a network of pipes designed to ensure adequate mixing, solids can quite often cause blockages, meaning operators will have to dismantle their kit should a solution precipitate out. There is continuous equipment with wider pipes designed to cater for solids manufacture. Such equipment shakes during use to keep the materials inside moving at all times. This works well should you decide to employ continuous manufacturing to produce solid APIs, but the machinery must be bolted in place and is more expensive than ordinary kit.

ROI. It is true that there are some cost benefits to using continuous processing, particularly when you take into consideration the impact of having to dump a batch of high-value API if something goes wrong. That said, the cost of production equipment for continuous manufacture is high, with even small-scale equipment costing companies in excess of £30K. As a result, the business case for implementation often depends on economic viability.

In addition, it is easy to question the versatility of this expensive machinery. Lab kit is often made from stainless steel, which makes handling acidic formulations difficult due to potential corrosion. This limits the reactions that can be performed, particularly during proof-of-concept (POC) work, unless you invest in non-reactive metal kit which is even more costly. In comparison batch reactors are readily available.

Equipment availability. While scaling a process up may seem relatively straight forward, the reality of obtaining suitable equipment can be more difficult and may require changing supplier.

Ideally, it is best to use commercial equipment that is made from the same material as your POC equipment to avoid changing any of the parameters, which can make sourcing commercial equipment more complicated. One solution is silicon carbide, however, not all suppliers make small-scale versions in this material, meaning much more raw material is required during the early stages.

Making continuous processing a viable alternative for pharmaceutical manufacturers
Continuous manufacturing is in its infancy in the pharmaceutical industry and during these early stages, collaboration across supply chain partners is an ideal way to test the process and explore its potential.

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. So, strategic partnerships could be infinitely beneficial in terms of mitigating risk, containing costs and sharing resources.

Used properly, continuous flow chemistry can broaden the safe operating range of chemical processes and allow companies to develop APIs to their full potential, however it is vital to explore the implications and carefully consider the suitability of the process for specific products. 

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Mark Muldowney is head of technology and innovation at Sterling Pharma Solutions, He is responsible for broadening the CDMO’s technology capabilities and introducing new ways of working into research and development (R&D) and production. He also drives collaboration between both industry and academic intellectual property (IP) specialists.