Continuous Processing. Continuous Evolution

What progress and success stories have been seen in continuous processing over the past several years?
 

Continuous processing got started commercially with oral solid dose about 10 years ago, and then a lot of the focus shifted toward using the approach for both small molecule drug substance and bioprocessing. Today, there are commercially approved continuous processes for both small and large molecules.

Oral solid dosage is still often the main modality when people refer to continuous manufacturing. There have been close to 20 oral solid dose new chemical entity (NCE) pharma products or similar OTC products approved for commercial manufacturing using continuous in the last decade. Approvals using the technology are poised for an uptick because, despite the initial wave of continuous manufacturing-based product approvals, companies bringing these products to market didn’t integrate continuous manufacturing into development programs until after the initial wave of approvals. Since then, these products have been coming through pipelines being developed as continuous processes as opposed to being initially developed as a batch process and then converted to a continuous process in late-stage development.

Now that the approach has been demonstrated and de-risked, companies are revisiting their pipelines and putting programs on a pathway to use continuous manufacturing technology from the very start. As evidenced by activity among equipment vendors, there has been a significant amount of infrastructure put in place over the past few years, which will result in a number of those pipeline programs reaching the market soon.

And what have been the biggest lessons that the industry has learned?
 

The rate of adoption, even for technologies that provide significant benefit over the course of a product lifecycle, will be slow when the technology does not enable a new dosage form. This is certainly the case for small molecule continuous manufacturing. While the benefits of continuous are clear, the traditional approach for manufacturing these products is still readily available. This allows for delayed adoption, particularly among companies who are more conservative and looking for a highly de-risked entry point.

A few years ago, there was a sentiment within the industry that the rate of adoption would increase significantly once CMOs started offering continuous manufacturing capabilities, but this has not been the case; the rate of adoption or conversion to the technology has remained at a similar level. This is because CMOs are required to demonstrate their capability with the technology beyond physical infrastructure by having commercially manufactured products – as a means of demonstrating that continuous manufacturing technology has been fully derisked. Although many large-scale innovators are already using continuous technology on their internal pipelines, many small and emerging companies are waiting for further adoption and carefully evaluating their pipelines to find their entry point.

This has not been the case for other technology adoptions, such as pre-filled syringes relative to vials. In that example, even though the product remains the same, the delivery has changed to provide benefits to the patient and improved margins to the manufacturer. Making the pivot to continuous manufacturing is more akin to the Industry 4.0 transition to electronic batch records and digital notebooks or, for an example outside of pharma, the transition to electric vehicles. The growth curve remains, but there is a delay relative to technology readiness because older technology remains viable and available.

What type of equipment is required for a continuous process and how does it differ from batch?
 

Much of the equipment used for continuous processing of small molecule drugs is not all that different than batch, with some components such as table presses changing very little when used in a continuous process. Typically, the equipment is smaller scale than its equivalent for batch process, specifically for the material handling and blending components.

The real difference with continuous manufacturing is that all equipment is connected and working in unison. This requires automation and software, so that the process can be properly coordinated and controlled as each step runs simultaneously. In this way, continuous versus batch processing is an Industry 4.0 modernization that brings real-time quality monitoring and control to the shop floor.

Moreso than the equipment itself, the use of modern automation, software and real-time sensors within the process makes a significant difference. This has led to greater generalization of the term “continuous processing” in recent years and use of “advanced manufacturing” in its place. While there is a clear difference between continuous and highly automated batch processes from an engineering perspective, from a practical and, more importantly, regulatory perspective, they fall under the same umbrella.

What are the biggest challenges?
 

The biggest challenge is, in some ways, related to one of the technology’s primary benefits: its flexibility. Because of the flexibility in batch size and ability to go directly from clinical to commercial production without scale up, it is important for companies to determine what benefits they are seeking to obtain from the technology and how to achieve them with a specific approach. There is not a one-size-fits-all solution to leveraging the technology. Business cases can be made for its benefits in clinical, lack of scale up, speed to market, launch, initial market launch, ramp up or life cycle management. Therefore, it is important to understand how a continuous manufacturing strategy will address and enhance specific processing needs so that organizations can make the appropriate decisions for each of their programs.

What new innovations are drug manufacturers requesting when it comes to new equipment and technologies?
 

While not necessarily new, drug manufacturers often want to see that we have process analytical technology (PAT) capabilities, both in terms of people and equipment. In some cases, they may be looking for this as part of a real-time release approach, but there is a general expectation that this capability should support the control strategy for a continuous manufacturing product.

The skillset for PAT is unique and does not exist within all organizations. As a result, the pool of qualified personnel is limited and requires a focus on recruitment and retention. Just as important is a strong automation team. Pulling together the real-time data from multiple systems working together in a validated environment is a key element to achieving real-time quality control when leveraging continuous manufacturing and real-time release.

What advice and tips can you offer when it comes to implementing and running a continuous process?
 

Understanding the near- and long-term scope of your program relating to continuous manufacturing is key. Will the benefits be greater initially within development or early commercial, through transitional market growth or primarily through long-term cost of goods sold savings? Is leveraging the technology about enhanced quality assurance, nimbleness in the market, cost, or being an innovator?

Prioritizing the benefits you seek to gain from the technology will help shape the pathway your program should take, basing decision-making around how to maximize key benefits and the impact that has for the lifecycle.

What would you like to see change in the coming years?
 

With further adoption, continuous processing or approaches may be more broadly referred to as “advanced manufacturing.” In that light, it would be great to see further reliance on what the technology enables in comparison to past approaches. Using highly automated systems with real-time quality control capabilities, we can speed development without additional risk to the commercial control strategy. The industry should revisit how we approach validation, filing, process improvement and more given the use of real-time process monitoring and control.