Continuous in the Spotlight

What’s the story behind Continuus Pharmaceuticals?

In 2007, Novartis and MIT embarked on a collaboration, targeting the continuous manufacture of small molecule drugs because they recognized how outdated batch processes were. They wanted to break away from conventional manufacturing and establish the best possible production system for these drugs. The end result was the Novartis-MIT Center for Continuous Manufacturing, which was a huge success. By 2011, they had constructed a pilot line at MIT that integrated both upstream and downstream components into a single continuous process. The team was able to take a 200-day batch process and cut it down to just two days, with the additional benefits of reduced footprint (approximately 90 percent reduction), reduced costs (30 to 50 percent), reduced environmental impact, and improved quality.

Continuus Pharmaceuticals is a spin out from the Novartis-MIT collaboration – and many of our team members and advisors were critical architects of the original project, including Professor Bernhardt Trout (MIT) and Tom Van Laar (former head of Global Tech Operations, Novartis). We have also now brought in other outside thought leaders as well. The goal? To bring the benefits of integrated continuous manufacturing to the broader pharma industry and transform small molecule manufacturing. 

What is integrated continuous manufacturing?

There are many different definitions of “continuous manufacturing” across the industry, with companies taking different approaches. Many are implementing batch technologies or batch technical unit operations in a semi continuous or continuous fashion, but the overall paradigm is still batch. Other companies have integrated flow systems for part of the manufacturing process; for example, Vertex Pharmaceuticals has a drug product continuous process, but they have not integrated the upstream API components. 

We are leveraging an integrated continuous manufacturing system that spans the entire production process. Instead of fragmenting the system into separate API processing and drug product processing operations, we have combined everything into one seamless line. There are many benefits with this strategy. For instance, in the current/traditional manufacturing system, many drug product manufacturers have to include corrective steps because of undesirable physicochemical properties introduced by their upstream counterparts. This lack of coordination can make processes very long, expensive, and worst of all, prone to quality problems. It is not unusual for it to take 200-300 days to produce a drug (and in some cases well over a year!), and many of the steps are manual and prone to human error. A more automated and seamless process can remove these mistakes and improve product quality. Integrated manufacturing breaks down siloes and considers the entire manufacturing system, rather than just part of it. 

How is it possible to go from a process taking 200 days, to just two days?

There are many factors that contribute to the reduction. First is the decrease in the number of steps required by eliminating corrective ones, as we consider the process as a whole rather than just the API or formulation. Many steps are also much faster; for example, the residence time for our continuous filter and dryer is in the order of a minute, whereas it can be many hours for a corresponding batch process. Of course, all of this does not get you from 200 days to two days! The biggest contributor is removing the starts and stops that batch manufacturing requires after each unit operation for quality tests to be performed. With ICM, quality is ascertained in-line, using real-time monitors and process analytical technologies that enable the quality of the process material, and ultimately the final drug product, to be predicted. In the current paradigm, when you produce the API, it must be tested and released, creating a long lag time between API production and subsequent formulation steps. With integrated continuous manufacturing, the API remains in situ, and just moves onto the next step. When avoid those stops and starts, you start to observe a significant reduction in manufacturing time. 

What advances in the field have caught your eye?

A number of products have been approved with continuous manufacturing components – many are the result of collaborations similar to the Novartis-MIT. Vertex, for example, is working with GEA, while Johnson & Johnson has been working with Rutgers University, the University of Puerto Rico, and other partners through the Center for Structured Organic Particulate Systems (C-SOPS). Johnson & Johnson actually received approval to produce one of its products, originally approved for batch manufacturing, with a new continuous process. 

We have engaged multiple companies with our integrated continuous manufacturing platform, with projects ranging from targeted solutions, where we investigate how a single unit operation or two can help surmount a specific technical challenge, to broader-scope projects, featuring end-to-end solutions. We have also been working to advance the technology by improving and modifying unit operations. For example, we have developed a more robust and commercial-ready control system with a partner company. 

Much of the interest and concern in the field is related to how regulatory agencies will react, particularly the FDA. We believe they have been pretty vocal about their support for the adoption of better manufacturing systems – not necessarily for the economic benefits, but mainly because of the potential for improved quality and patient safety. To that end, the FDA has engaged with the industry and academia to better understand continuous manufacturing. In fact, we are finishing a three-year project with the Agency, where we are examining and demonstrating how quality can be improved through integrated continuous manufacturing. 

For pharma companies, quality is essential, but costs are also important. There are enormous pressures right now to bring down drug prices – we see it in the news all the time. As a result, many companies – who previously said they were not interested in continuous manufacturing – are coming to us because they know they need to be more efficient and cost effective in their manufacturing activities. 

There is a growing realization that manufacturing systems cannot stay the same forever.