Advancing Continuous Solid-Dosage Manufacturing

Continuous manufacturing for solid-dosage drugs has made significant strides over the past few years and commercial activity is increasing, as was evident at Interphex 2015 in presentations and exhibitions. Industry experts agree that continuous processing offers potential economic benefits, including reduced costs due to lower inventory and significantly increased flexibility of scale. The use of continuous processing is on the upswing because manufacturers are recognizing these economic benefits; research efforts and an increased academic focus have solved many of the initial technology concerns; and there is now greater availability of equipment, said Christine Moore, acting director in the Office of Process and Facilities at FDA's Center for Drug Evaluation and Research (CDER), in an interview with Pharmaceutical Technology.

Continuous processing has long received support from FDA, which has been interacting with the European Medicines Agency, academia, and industry for more than six years to advance the technology, noted Moore in a presentation at Interphex. Continuous processing aligns well with FDA's process analytical technology (PAT) and process validation guidance. Modeling and system monitoring, using PAT for example, allow for greater control, resulting in greater assurance of quality, noted Moore. There are no real regulatory hurdles to continuous manufacturing, but experience is limited, said Moore in the presentation. Experience is growing, however, and "FDA is staffed, trained, and ready to discuss," she said, noting that companies should meet early with FDA to ask questions and discuss their plans for continuous processes.

Significant differences between batch and continuous processing are the way material flows and the measurement and control of the system, noted Moore. In continuous processing, unit operations are connected and interactions can be coupled, thus the control strategy is often different from that of batch processes. It is also important to understand the system dynamics, including how the material mixes and how it can be traced through the system, she explained. Continuous processes are typically plug flow, in which the material is mostly 'first in first out'. A disturbance in feed for a batch mixer is readily evened out during mixing, but mitigation of such disturbances in a plug flow system should be understood and modeled. "You should be measuring at an appropriate measurement frequency so you can detect fluctuations in quality and then have controls in place to make sure you have assurance of quality throughout the entire run," explained Moore in an interview.

Process modeling is a tool that can be used to answer questions such as how material mixes. Because continuous processes are integrated, an integrated model is needed to describe the system, explained Doug Hausner, associate director at the Engineering Research Center for Structured Organic Particulate Systems (CSOPS) at Rutgers, the State University of New Jersey, in a presentation at Interphex. Flowsheet modeling tools can be used to help define a batch and validate that definition, by tracing how the material flows through the system and describing the residence-time distribution in the system. A model can also be used to do process sensitivity analysis and to optimize parameters such as output. Using models for risk assessment is key. "Models allow you to look at variations, such as perturbations in the system, and assess risk for a given product," Hausner added in an interview with Pharmaceutical Technology. Modeling saves money and time by evaluating processes in a computer-modeling environment, which can then be verified in the laboratory, he concluded.

A Pfizer, GEA Pharma Systems, and G-CON Manufacturing collaboration on a PCMM (portable, continuous, miniature, and modular) system was being promoted at Interphex. Pfizer brought the pre-assembled and prevalidated pieces of a prototype PCMM system to its facility in Groton, CT and is now getting the system up and running, said Phil Nixon, executive director for drug product technology and innovation lead for pharmaceutical sciences at Pfizer, in an interview with Pharmaceutical Technology. The prototype system is designed to produce uncoated tablets, but could be modified to add other unit operations, such as coating. The concept could even be used for API synthesis or biologics, added Nixon. "An objective of this project was to make the technology broadly available to the industry," he explained. "The vendors (GEA and G-CON) are offering the equipment commercially, and Pfizer hopes that more companies will use it because that will help advance continuous processing technology." 

Two weeks after Interphex, at a CSOPS workshop, "The Future of Advanced Pharmaceutical Manufacturing," held on May 7, 2015, representatives from pharmaceutical manufacturing, academia, and FDA gathered to discuss how to further advance continuous manufacturing in the pharmaceutical industry. A strong academic base is important for innovation, noted Janet Woodcock, director for CDER, in the keynote address. "FDA's vision for what needs to be done next to advance continuous manufacturing is closely aligned with the vision at CSOPS," commented Hausner in discussing the workshop with Pharmaceutical Technology. "This vision includes a focus on process modeling and a greater scientific understanding of the process, for example." One of the next steps for CSOPS, which was spurred on by an invitation from Woodcock at the workshop, will be to put together a document to serve as input for a draft guidance on continuous manufacturing.