Breaking With Tradition

Continuous manufacturing is the norm in many industries, but for pharma – despite the well-documented cost and quality benefits associated with continuous – batch manufacturing remains king. The availability of standard batch reactors and the simplicity of their use means that old habits die hard.

With many continuous processes relatively untested and with regulatory guidance somewhat lacking, the industry’s hesitance to embrace continuous is understandable. For continuous manufacturing to be more widely adopted, companies must be aware of its operational advantages as well as the challenges posed by its use. Armed with this knowledge, companies can fully assess whether continuous processes are appropriate for their business needs.

Mitigating risks

There are many reasons for pharma companies to embrace continuous manufacturing. A continuous manufacturing process can run consistently until a project is complete, minimizing the labor and cost associated with starting up and shutting down production between batches – and slashing manufacturing times. Throughput can also be maximized using continuous processes. Importantly, a continuous process avoids batch dumping. In batch processing, if something goes wrong then the entire batch will often need to be discarded – a waste of precious time and raw material; in other words, highly undesirable. In a continuous chemical process, reactions take place on a much smaller scale so even if there was a pipe failure, only a small amount of product would be lost. Not only can manufacturers reduce quantities of material used – saving money and unnecessary interactions with hazardous products – the automated nature of the technique means that fluctuations in reaction conditions can be minimized, and the possibility of human error reduced. Additionally, it’s possible to immediately quench reactive agents as soon as they’ve been used rather than waiting until the end of a cycle.

A continuous process is very different to batch manufacture – and so it requires a different set of skills. The equipment is also expensive – even small-scale equipment can cost companies in excess of £30,000. Yes, continuous manufacturing offers many benefits, but the business case for implementation will often come down to economic viability.

If you can make the investment, rewards can follow; however, continuous manufacturing should not be implemented just for the sake of it; the process needs to be carefully evaluated for the product. The success and scale-up of any project relies on suitable product selection. Plug flow reactor pipes are only appropriate for certain types of API reaction for example they work well for homogenous solutions. Literature also suggests alkyl lithium reactions are renowned for generating solids that build up and block reactors during this type of processing. Solids can often cause blockages because a narrow network of pipes is used to ensure adequate mixing. Should a solution precipitate out (as happens frequently with processes involving concentrated solutions) then the operators must dismantle the kit, which is time consuming. Continuous equipment with wider pipes designed for solids manufacture does exist and uses oscillating baffle reactors to ensure the material inside continues to move. Though this type of equipment provides a pertinent alternative for solid API production, it is more complicated to use than ordinary kit (and more expensive!).

It goes without saying that you should buy your equipment from a reputable supplier – a company that understands the continuous process and its challenges. Ever since the early days of continuous implementation, finding the right equipment has been its own challenge. It is best to use commercial equipment made from the same material as your proof-of-concept (POC) equipment to avoid affecting any of the reaction parameters, but this can make sourcing commercial equipment more complicated. One solution to this problem is silicon carbide, which has anti-corrosive properties (particularly useful for acidic reactions), but not all suppliers make small-scale versions in this material.

With this in mind when it comes to making decisions about the equipment most appropriate for your project, buying in is not the only option. Third party suppliers can design and build equipment to fit the specific chemistry needs of customers. Engaging with CDMOs can be a good way to begin to explore the viability of continuous processing.

Making the final decision

Continuous manufacturing is still in its infancy in the pharma industry, but many organizations are showing high interest because of the potential for increased manufacturing efficiencies and reduced costs. But be warned: continuous can only be successful when the correct equipment is supported by robust scalable chemistry and systematic process design, along with suitable process analytical technology. 

Expertise is vital – and so I also recommend collaborations. Some companies, for example, have partnered with academic institutes to learn more about continuous manufacturing. Other companies embark on strategic collaborations with the aim of sharing resources and costs, and mitigating risks.

If used correctly, continuous manufacturing allows companies to more efficiently develop APIs and broaden the safe operating range of chemical processes. Just remember to do your homework and consider the suitability of continuous processing for specific your product before taking the plunge.