Drug Formulation | Industry Spotlights & Insight Articles

Accelerating Drug Development with Continuous Manufacturing

The pharmaceutical industry has historically taken a cautious approach to most new advancements, but now it is embracing the possibilities of continuous manufacturing technologies. While traditional batch-based processes are still more common, there are several products on the market that have utilized continuous manufacturing practices.

The pharmaceutical industry has historically taken a cautious approach to most new advancements, but now it is embracing the possibilities of continuous manufacturing technologies. While traditional batch-based processes are still more common, there are several products on the market that have utilized continuous manufacturing practices.

Continuous manufacturing is not a new idea. The first reports of continuous can be traced back to the 18th century and has been established in many other industries such as food and automotive for many years. The pharmaceutical sector began to test continuous manufacturing in the 19990’s and interest soared in the 2000’s. By 2009, the FDA decided that it was time to develop a regulatory framework to enable continuous manufacturing. 

The definition of continuous processing is something that is still a matter of some debate and is being actively discussed, but in general differentiates itself from batch processing by being uninterrupted from start to finish. Batch production involves the sequential processing and testing of material across multiple discrete. In comparison, continuous manufacturing combines the full manufacturing stream into a single, fully integrated flow. This “continuous” production eliminates built-in production gaps and can drastically shorten manufacturing times. 

Why companies are switching 

Flexibility and Responsiveness: 

Continuous manufacturing offers a more flexible and controlled approach to drug development and API synthesis. In challenging reactions continuous manufacturing is more appropriate as it allows precise control of the conditions. This improved control of reactivity also allows for easier optimisation of processes with decreased cycle times and fast turnarounds. 

The modern pharmaceutical industry has changed and now requires a more flexible approach to product volume. Gone are the days of the multi-thousand tonne blockbuster drugs, and instead the majority of future drugs will be at the single digit tonne scale.  

This shift in volume requires a complementary fast-paced and flexible approach to manufacturing which has driven the development of modern flow technologies. Production systems are now modular in their design, with the necessary components being employed for the specific project. What one day would be used to synthesise 10kg per day of one API could the next – after careful disassembly, cleaning and re-engineering – be used for the next API project. 

Safety & Predictability 

One of the most pressing issues facing pharmaceutical companies is mixing issues stemming from upscaling traditional batch manufacturing processes. While a great deal of work has gone into creating innovative methods of improving mixing performance, batch production will by its very nature be less predictable and reliable than continuous manufacturing. An example can be seen in the use of mixing in plug-flow (tubular) reactors, which allows for greater control and consistency across varying scales. 

Additionally, drug recalls due to manufacturing defects have risen sharply in the last decade. Contamination during the manufacturing process is one of the main causes. Continuous manufacturing processes sharply reduce the risk of contamination by eliminating the need to move products between stages. 

Environment & Sustainability  

Continuous manufacturing has been heralded as a pivotal part of reducing the carbon footprint of pharmaceutical manufacturing. Improvements in mixing and heat transfer enables chemical reactions to be carried out more with less or even zero solvent, reducing waste. Estimates put average waste reduction at approximately 33%. 

Continuous manufacturing has been shown to reduce carbon footprint of some products by up to 80%. This, combined with the ability for end-to-end product creation in a single facility reduce the risk of environmental exposure and minimizes transportation costs and pollution output.  

Continuous Manufacturing: Success Stories 

Companies that have embraced continuous manufacturing technologies have seen impressive return on investment. Vertex won approval for Orkambi in July 2015. It was the first drug to be approved by the FDA while using a fully continuous drug product manufacturing process. Since then, larger pharma companies including Johnson & Johnson and Eli Lilly have explored using the technique. J Johnson & Johnson secured another first in 2016 when the FDA cleared the drugmaker to switch from batch to continuous production for its HIV medicine Prezista. 

Kai Lee (Principal Scientist, Pfizer) delivered a presentation at Oxford Global’s Formulation event, where he explained how his companies new PCMM is creating new opportunities for product manufacturing.  

Pfizer’s PCMM technology is a first-of-a-kind manufacturing system that accelerates the speed of tablet production. The pharmaceutical industry has been trending toward lower-volume products, driven by an increased focus on precision medicine approaches to develop and commercialize new therapies. This creates a need for smaller, more flexible continuous processing technologies. 

By miniaturizing the equipment, the continuous process can be enclosed in a portable, autonomous space called a POD, which can be transported to any location in the world and quickly assembled. 

Highlights of PCMM’s potential for smaller, more flexible, continuous processing technologies include: 

  • A PCMM facility has a 60 to 70% smaller footprint than a conventional production facility. 
  • PCMM enables use of the same equipment for development, clinical trials and commercial manufacturing. 

Kai Lee explains that “This technology shortens the manufacturing process from weeks to minutes. There are currently a few candidates being manufactured on the PCMM platform globally for clinical studies or as commercial products. Pfizer is aiming that 80% of its small molecule solids will be developed and manufactured using PCMM technology. The technology allows real time mixing of ingredient and enables increased speed to market with lower costs. It is also integrated with Process Automation controls, and more importantly, the data capture from this platform technology generates increased product knowledge and greater quality assurance. All this leads to shorter cycle times faster technology transfer and reduces process variability.” 

Conclusion

Continuous processing offers many rather clear advantages over traditional batch-wise operation. Despite this, it has not yet become routinely used across the pharmaceutical industry. Embracing continuous manufacturing will show the public and investors that pharma companies are modernising and improving efficiency and lowering their carbon outputs. The benefits of continuous manufacturing production futureproof facilities, equipping them to produce multiple current medicines as well as upcoming innovative therapies, creating safer and more affordable treatments for patients. It is clear that the narrative is beginning to shift with the number of drugs created with continuous production more than tripling in the last five years.