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Manufacture Technology and Equipment, Small Molecules

Eyes on Continuous Equipment

This article is part of our special focus on "traditional" pharma: The Small Molecule Manufacturer (read more here). You can find more articles from The Small Manufacturer here.

I’ll begin by saying that the term “continuous” is, in many cases, incorrectly used — particularly when referring to “truly continuous” or “discrete continuous” solutions. Continuous processing goes beyond putting well-defined unit operations together in a line; it is about transforming indeterminate quantities of raw materials into a final dosage form by controlling the process with an understanding that any deviation of a critical process parameter (CPP) is directly linked to the product’s critical quality attributes (CQAs). A smart process maintains those CQAs within their tolerance limits without risking material loss or end-product quality. Some prominent unit operations already operate in a continuous manner, such as twin-screw extruders or linear powder blenders. Anyone who claims to be able to accurately define the indefinite quantity of a continuous material stream for their own benefits will come to realize that greater engineering minds will relish the reductio ad absurdum argument opportunity… and win! 

Continuous manufacturing in pharma is gaining momentum because of the growing realization that it is a very efficient way of making drugs, moving away from stepwise and time-consuming batch methods to a fully integrated and closely controlled process that gives excellent product consistency by intrinsic design. Regulatory agencies, such as the US FDA, are also advocating the implementation of continuous manufacturing. The FDA states: “If drug makers paid more attention to high quality manufacturing, it would prevent the regulatory problems that lead to plant closures and costly fixes. Continuous processing also allows manufacturers to respond much quicker to changes in demand, potentially contributing to the prevention of drug shortages.” (1)

As one example, consider Pfizer’s portable, continuous, miniature and modular (PCMM) pod-based mini factories. The PCMM system accelerates the speed at which tablets are produced and by miniaturizing the equipment, the continuous process can be enclosed in a portable, modular facility, which can be shipped by truck to any location in the world and quickly assembled. Once up and running, the system will deliver the capability to transform powders into uncoated tablets in minutes, which can take days or weeks with current technology.

"For small-volume products, time-to-market and production yield are key because of the value of the APIs. For bigger volume drugs, supply chain agility and cost savings are the main drivers for continuous."

The argument that continuous manufacturing is best suited for “large-volume, low-cost” medicines is somewhat dated. In fact, we’re seeing the exact opposite. If you look at market approvals and new launches, it’s quite clear that drug manufacturers are testing and challenging the business case for continuous manufacturing with legacy products, and then using the same platforms to develop higher value pipeline products and file for new drug applications.

As long as you have pharmaceutical excipients (or an API) in a formulation that can be dosed with a loss-in-weight feeder, you can use a continuous manufacturing system. Often, the decision whether to use continuous manufacturing or not is based more on the “processability” of the powders rather than throughput considerations. The implementation drivers, however, will differ depending on the product. For small-volume products, time-to-market and production yield are key because of the value of the APIs. For bigger volume drugs, supply chain agility and cost savings are the main drivers for continuous.  

Equipment innovation

Process intensification in pharma has led to the development of smaller and more compact equipment, but these advances amount to very little without a perfectly designed interface. To cite an example, a critical decision — whether to implement a horizontal or vertical system layout — depends on whether your line must follow the building and material flow requirements of the installation site, or whether you can build from scratch. A brand-new greenfield construction site can readily accommodate a horizontal continuous manufacturing set-up, which, being on one floor, is easier to operate than a vertical one and offers improved efficiency and faster changeover and shorter cleaning times. Often, the interfaces between unit operations (or modules) — whether mechanical, material (physical properties), process (the process itself can become an interface) or the control steps between unit operations — are the biggest issues. Companies need to handle the challenge with their own engineering skills, but should also fully engage with a technology provider that has the relevant knowledge and experience.  

The right control system is also crucial; companies must describe the function and control strategy of their system to regulatory agencies, so having the right interface is essential. Today’s control systems are highly advanced in terms of data exchange with external platforms (such as open database connectivity clients) or providing tools to visualize process parameters in an operator friendly and interactive way. Data management and PAT tools, such as SIPAT from Siemens, enable much greater levels of process understanding and optimization. 

"What’s most important, however, is the end product: a safe and perfect tablet at the end of whatever process is used."

Likewise, we’re seeing more and more reliable (and smart) APC systems hitting the market, such as PharmaMV from Perceptive Engineering, which provide higher levels of monitoring, automation and production — for both today and the future — in anticipation of the forthcoming Industry 4.0 initiative. With better control systems come more efficient data use (detail and transparency) and improved productivity. What’s most important, however, is the end product: a safe and perfect tablet at the end of whatever process is used. Highly integrated, single-floor production lines equipped with advanced process controls will be the new standard in the future of Industry 4.0 — and continuous manufacturing will be the enabler.

The initial financial investment in any continuous manufacturing solution is going to be a challenge; and, as with the implementation of any innovative technology, the early stages are also time-, effort- and cost-intensive, including the associated organizational changes. When — and only when — we establish economies of scale will the financial burden decline as equipment becomes a commodity, as opposed to a tailor-made and engineered-for-purpose solution.

If you are looking to purchase continuous manufacturing equipment, I recommend taking the advice of Fanny Stauffer, Drug Product Lead at UCB Pharma, who, at the 2019 Reality of Continuous Pharmaceutical Manufacturing conference in Durham, UK, said: “Talk — and listen — to your equipment supplier. No one knows more about the technology than the companies who designed and built it. Their insight, guidance and expertise are invaluable.”

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  1. Manufacturing Chemist, “Continuous manufacturing: the facts and the future,” (2019). Available at Last accessed October 28, 2019. 
About the Author
Richard Steiner

Business Development Manager, Continuous OSD Processing at GEA Group

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