From academia to the mainstream, a lot of attention has been paid to the concept of flow, popularized by the best-selling book: Flow: The Psychology of Optimal Experience, by Mihaly Csikszentmihalyi. To the author, flow is a state of mind in which a person is fully immersed in, and motivated by, what he or she is doing:
“We have all experienced times when, instead of being buffeted by anonymous forces, we do feel in control of our actions, masters of our own fate. On the rare occasions that it happens, we feel a sense of exhilaration, a deep sense of enjoyment that is long cherished . . . the best moments usually occur when a person’s body or mind is stretched to its limits in a voluntary effort to accomplish something difficult and worthwhile.”
The adjectives “difficult and worthwhile” could apply to advancing the use of continuous manufacturing in the drug industry. Proponents of continuous processing have long preached its gospel, telling us that it will make our operations more efficient, robust, flexible, scalable . . . and less expensive, and that it will deliver manufacturers an “optimal experience.”
Until now, however, the continuous contingent has not been master of its own fate. Countering forces—namely, inertia—have conspired to limit the adoption of continuous processes in the industry. Pharma’s “batch mentality” has prevailed.
That may be changing. Continuous processing may be finding its flow.
In 2007, the Novartis-MIT Center for Continuous Manufacturing was established, with the drug company committing $65 million. This was seen as a major coup for the continuous camp, a sign of things to come. Three years later, “the mindset has changed in the industry,” says Dr. Bernhardt Trout, director of the center and a chemical engineering professor at MIT. “Not that we’ve been the only driving force, but we’ve been helping to promote a focus on continuous manufacturing as a whole and a change in the mindset as a whole.”
FDA has encouraged the shift, realizing the synergies between continuous processing and its manufacturing and product quality initiatives. In March, the Agency held its first-ever symposium on continuous manufacturing, with more than 100 of its personnel present. Representatives from Pfizer, GSK, and academia discussed their work in this area.
Another telltale sign that continuous manufacturing may soon break into pharma is a critical mass of technologies on the market. Products ranging from continuous flow microreactors to continuous tablet presses are steadily being introduced.
“It’s clear to us that the industry believes that this is going to happen, and there’s going to be [some] transition from batch to continuous flow,” says Bill Seiderman, marketing manager with Corning, which this spring unveiled Advanced-Flow reactors for pharma. (Click here for a video of Seiderman exhibiting the equipment at Interphex 2010.)
The clearest indicator of change is investment, Seiderman notes—companies are purchasing equipment, but also setting aside resources within R&D and, more importantly, commercial manufacturing to devote to continuous manufacturing. That’s a change from just a year or two ago, he says.
The same hurdles apply—manufacturers find it hard to abandon perfectly good batch processes and equipment, and some processes lend themselves better to batch—but especially in new product development, the transition is taking place.
It’s a matter of economics, says Siederman, and the more manufacturers understand how they can cut costs by optimizing processes and speeding scale-up, the more they gravitate towards continuous processes. More and more, the environmental profile of continuous processes is factoring in as well, he says. “Suddenly, the greenness of the reaction is part of the discussion,” he says.
Microfluidics recently surveyed potential customers about their willingness to invest in continuous crystallization technologies, and some 80% said they were. Mimi Panagiotou, PhD, the company’s CTO, says adoption is at a tipping point, with Novartis, GSK, Pfizer and smaller manufacturers going continuous.
Microfluidics has introduced new continuous crystallization and multi-phase reaction systems. “Medium- to large-sized pharmaceutical companies are actively looking at continuous manufacturing crystallization techniques,” Panagiotou says. “Up to now, they haven’t found technologies that can actually manufacture and crystallize materials in continuous fashion, and get the particle size and properties that they are looking for.”
Panagiotou, too, says the industry’s mindset has changed. “There is a general realization that technologies that are currently being used are expensive and not very efficient.” Not that batch processes will disappear, of course, but the adoption of continuous methods will be a gradual and steady one, Panagiotou believes. Manufacturers are taking subprocesses and converting them to continuous, she says. “The idea is that, in ten years, you take the whole process and convert it to a seamless, continuous process.” (For more from Dr. Panagiotou, listen here.)
For an industry that is chronically resistant to change, the adoption of continuous processes is proof that it is indeed changing. It’s early yet, Trout acknowledges, but it is happening. Which means the continuous processing crowd must be feeling at least a little bit of flow.
