The steady movement from batch to continuous processing in a risk-averse industry.
Experts seem to agree that a paradigm shift to continuous from batch processing in the manufacturing of pharmaceutical products is inevitable. Somewhat surprising, though, is that such a change is moving ahead at a rapid pace, especially in an industry often regarded as risk-averse.
Of course, having an approving nod and stated encouragement from the U.S. Food and Drug Administration (FDA) doesn’t hurt.
“The FDA is a huge proponent for many reasons,” said Andrew Christofides, Lead Engineer of Global Strategy and Technology at Integrated Project Services (IPS), during a recent interview. “It’s aligned with their Quality by Design (QbD) initiative so they’re really the biggest advocate right now for continuous manufacturing for prescription pharmaceutical.
“In continuous manufacturing the process is so much more well defined. You’re running within upper and lower specification limits in each critical parameter, defined throughout the process through the use of Process Analytical Technology (PAT) and the proper implementation of QbD methodology.”
It could open the door for Real Time Release Testing, the ability to evaluate and ensure the quality of in-process and/or final product based on process data. Thus, with proper documentation, there would be no need to quarantine product at the end of production runs.
“Right now, manufacturing experts from the 1950s would easily recognize the pharmaceutical manufacturing processes of today,” Janet Woodcock, Director of the FDA’s Center for Drug Evaluation and Research, said four years ago. “It is predicted that manufacturing will change in the next 25 years as current manufacturing practices are abandoned in favor of cleaner, flexible, more efficient continuous manufacturing.”
Some pharmaceutical and technology experts think that a significant shift may actually occur a lot sooner, possibly in the next 10 years, at least when it comes to the introduction of new pharmaceutical prescription products. Patheon’s Eric Jayjock, PhD, Director of Continuous Manufacturing, is among them.
“Three years ago there were a minority of people really excited about continuous manufacturing,” said Jayjock. “The momentum shift over the last three years has been very significant,” adding that there likely will be an exponential growth curve. “In another three years it will still be a hot topic, not quite the standard yet, but becoming clearer as to the direction headed. Then, in another three years after that, it will get closer.”
He said he would not be surprised if in 10 years most new products in brand-name pharma—possibly 90 percent of them—will be produced via continuous manufacturing, while older or existing products will likely remain in batch for an unspecified turnover period.
“No one is abandoning batch processing,” said Christofides. “There’s this inertia in the prescription pharmaceutical industry—a lot is regulatory. It’s a very risk-averse industry.”
According to Christofides, over the years there has often been a prevailing driver on projects to not change the proven process because of the way a drug file was written, which may tie a company to a specific piece of equipment or method. Still, he sees the move to continuous manufacturing as a very significant change for the industry, one that has garnered strong interest and is taking place in a measured way as pharmaceutical executives try to figure out how to make it happen.
From a technical perspective, it is easy to take batch and move it to a continuous process, Jayjock said. But it’s still a regulated environment, requiring development of the process, taking a QbD type of approach to show an understanding of what is driving the process, and there still is cost involved, including waste material, in order to do those development exercises.
“So there’s still a cost, especially in the branded world,” said Jayjock. “For an existing product, one must consider: is the efficiency we gain in manufacturing going to pay us back and does it financially make sense for the amount of energy and time we put in for converting this from a batch to a continuous process?”
Hundreds of Parts
Another hurdle in converting an existing drug is volume, especially when it comes to cleaning of parts. While a continuous line fits into a footprint, there are hundreds of parts that need to be washed, dried, micro-swabbed, and cleaned well prior to continuing with manufacturing.
“If you’re running a very high-volume product and you can validate very long run times, you are minimizing the amount of cleaning time and there’s a lot more efficiency of scale,” said Jayjock. “As an engineer, it’s something I’d like to see us make major advances on in the next five to 10 years.”
According to Jayjock, for existing products, the economic prospects are brighter when running an extremely high-volume OTC drug or in high-volume, generic-type prescription manufacturing where labor and operating costs go down—thus generating much higher margins.
One of the main benefits for inaugurating a new product into continuous manufacturing is that a lot of material is saved in development.
“Even if you’re running low quantities on a new drug, the savings you have up front are so high you can get away with a lot more and it probably still makes sense to do continuous,” Jayjock said.
Another key advantage over the batch process is the flexible, or tunable, nature of continuous processing.
The tunable process is PAT-integral to a synchronized continuous production line. There’s a self-adjusting, self-tuning aspect to it that provides continuous monitoring and adjustment of moisture content, uniformity and feed rate of the content, and residence time—all critical processing parameters that can be monitored, adjusted, and tuned in a continuous process.
“If you have a continuous line that has a throughput range of, say, 5 to 30 kg/hr, then you can adjust within that range,” said Christofides. “With that aspect of tunability, you perhaps can react to demand changes by varying throughput. Batch processing is much more fixed. There are approved batch sizes that can’t be changed, so even if your quantity demanded, if it’s not well aligned with your batch size, you can be overproducing or building excess inventory.”
Another way to look at it might be from both a business and efficiency perspective.
“Any product we develop in continuous manufacturing we can run in continuous manufacturing and any product we run in batch we can also run in continuous manufacturing,” Jayjock explained. “But any product we run in continuous manufacturing, we can’t necessarily run in batch.”
“Ten years ago the argument was that the regulatory situation was a roadblock, but I think that argument has been pretty well quashed,” said Christofides. “The FDA has been pretty excited about continuous manufacturing. They’ve been very engaged, very supportive, and they are open to flexibility. It has been a great collaboration.”
While relatively few roadblocks to continuous manufacturing in the pharmaceutical industry exist compared with 10 years ago, there still is one large challenge.
“The biggest thing we have to overcome is the skill-set and culture,” said Christofides said. “So much of the pharmaceutical manufacturing world is built around a plug-and-chug type test and repeat philosophy, and we don’t necessarily have the high skill level throughout the entire industry.
“There certainly are companies that have lots of people with high skills, but as an industry we don’t take that same high-tech approach that other industries take. I think the biggest challenge that we have is retooling the industry to think about a technical process in a different way.”
While not available for an interview prior to publishing, Lawrence De Belder also has been deeply involved with continuous manufacturing, assessing business opportunities for the technology for both consumer and pharmaceutical sectors of Johnson and Johnson.
While relocating to Puerto Rico for two years, De Belder over time became the program manager of all continuous manufacturing projects and academic initiatives at Janssen, ensuring coordination, knowledge sharing, and standardization.
He is a strong advocate of pre-competitive collaboration, and within Johnson and Johnson, he serves as a catalyst for partnerships with vendors, academics and other pharma companies. He is co-chair of the Continuous Manufacturing Work Group in the IQ Consortium, a technically focused organization of pharmaceutical and biotechnology companies with a mission to develop transformational solutions that benefit patients, regulators, and the R&D community.
De Belder will join Christofides and Jayjock in the “Tunable Continuous Processing: Reacting to Market Demand” panel at INTERPHEX Live on April 26, 2016 from 10:15–11 am at the Crystal Palace (CP-2).
This article can also be found in the INTERPHEX 2016 Show Daily: Tuesdsay, April 26.
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