Though well established in other industries, continuous processing is only now, and only slowly, making its way into the collective pharmaceutical-manufacturing mindset, which is still holding on to traditional, yet reliable, processing methods. There is nothing wrong with most batch processes, but they aren't always the most efficient approach. And, now more than ever, efficiency counts, and continuous processing has the potential to redefine efficiency and quality.

Even as the industry remains rooted in batch processing, there is growing interest in continuous processing. "It certainly has changed," says Paul Mort, principal engineer at Procter & Gamble (Cincinnati, OH) "Ten years ago, my impression was that the pharmaceutical industry held little practical interest in continuous processing. More recently, however, there is a lot more curiosity, especially regarding the implications of continuous processing for process scale-up and control."

The case for continuous processing

"The equipment required for 100-kg/h pharmaceutical processing for a directly compressible tablet is just a couple meters long, including feeding devices, the continuous blender, and an analytical device. The entire system is small enough to be placed over a tablet press for direct discharge," says Tom Chirkot, PhD, PE, laboratory manager at Patterson-Kelley (East Stroudsburg, PA, a division of Harsco Corporation).

Smaller-sized equipment leads to less concern about process scale-up. A batch process can undergo three to five steps of scale-up from the beginning of development through to commercial scale.

"For continuous processing, I could conceivably go through one step of scale-up. I would have equipment to meet my supply needs to Phase 2 and even Phase 3. Then when I need to go the next scale-up, I would do that one scale-up and then use that second equipment and time as my lever to make as much as I need, based on supply-chain demand," explains Mayur Lodaya, PhD, associate research fellow at Pfizer (Ann Arbor, MI).

The key is that time, not capacity, determines the "batch." Continuous processing is inherently advantageous for a product that is in very high demand because the supply chain dictates how many hours the system will operate, increasing or decreasing according to demand.

Continuous processing is not always better than batch systems. There are certainly cases in which a batch process may be the better choice such as when high throughput is not required. "If you have something that you need to run virtually every day that month, or for campaigns that run for a week at a time, continuous processing is ideal," says Chirkot.

"If you require a very uniform residence-time distribution, you may be better off with a batch process. For example, in a coating operation, you want all the particles or tablets to have the same thickness of the coating," says Mort. "The choice of batch or continuous operations may depend on the production scale, control requirements, and availability of raw materials for early-stage development. For example, instead of scaling up from small to large batch unit operations, it may be more efficient to use small-scale batch operations for initial development work and then scale up to a moderate-scale continuous system for production."

Challenges

Despite these benefits, convincing manufacturers to implement continuous processing principles will not be easy.

"Smaller firms may not be as aware [of continuous manufacturing] as some of the larger pharmaceutical companies," says Moheb Nasr, PhD, director of the Office of New Drug Quality Assessment, CDER. "We have made a serious attempt at the agency through our spectrum of initiatives to facilitate and encourage people to utilize such an approach. I don't know if there is an additional need of the agency to provide further clarity of the developed guidances to encourage people to embark on this approach."