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A US government report on advanced manufacturing promotes continuous manufacturing of pharmaceuticals, which has had recent commercial success but faces challenges for widespread adoption.
The US government’s National Science and Technology Council (NSTC), which sets national goals for Federal science and technology investments, listed continuous manufacturing of pharmaceuticals as one of five manufacturing technology areas of emerging priority in its April 2016 report on advanced manufacturing (1). As reported in the April issue of the Equipment & Processing Report, continuous biopharmaceutical manufacturing and other advanced biopharmaceutical manufacturing technologies are also listed as emerging priority areas. Government support can make a difference in promoting continuous manufacturing of pharmaceuticals, say the report authors, who suggest that, “Future Federal investments may focus on broadly applicable and enabling technologies, demonstrating their return-on-investment required for mainstream adoption” (1).
Multiple US government agencies already involved with projects include the National Science Foundation (NSF), National Institutes of Health, National Institute of Standards and Technology, Department of Defense, the Biomedical Advanced Research and Development Authority (BARDA), and FDA’s Center for Drug Evaluation and Research (CDER). FDA has often stated its support of continuous manufacturing, which it sees as having the potential to contribute to quality. FDA’s guidance, Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base (2), published in December 2015, outlines how CDER’s Emerging Technology Team (ETT) is working with companies to facilitate understanding of such technologies in order to appropriately regulate it, Michael Kopcha, PhD, RPh, director of FDA’s Office of Pharmaceutical Quality, told Pharmaceutical Technology (3). Some potential regulatory concerns, such as the definition of a batch, have already been resolved, and two continuous manufacturing processes for tablets have been approved for commercial production: a Vertex process is described in the report (1), and approval of a Janssen process was announced in April (4).
One of the most significant achievements in developing continuous processing for pharmaceuticals has been using a science-based approach to developing engineering systems, says Doug Hausner, Associate Director for Industrial Relations and Business Development at the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS), an academic–industry consortium that has been working on continuous manufacturing with NSF support for the past ten years. “This approach to formulation is different from the old way of looking primarily at pharmacokinetics; now we’re looking at materials characterization and how minor changes affect manufacturability as part of a system,” Hausner explains. “Modeling is a key tool in development of these systems; it can show you where variability exists and what the failure modes are so that you can control the process.” C-SOPS has worked closely with developers, regulators, as well as users in both academia and industry to help drive this technology forward. While there is currently a gap between the cutting-edge of research and what is available commercially for modeling software, this could quickly close as adoption picks up and as regulators look to use this as a communication tool for relating process understanding, says Hausner.
“Models allow you to understand how materials and processes relate. This greater understanding is valuable because it allows more rapid development. You can potentially ‘skip’ some of the traditional process development steps. Some of our current work, for example, involves using multivariate analysis to elucidate similarities between processes and determine how many tests you really need to do to get to an answer,” says Hausner. The ability to have faster development, which can translate to the business benefit of market exclusivity, is a potential driver for greater use of continuous manufacturing.
Experts agree that a broader understanding of continuous manufacturing is needed to drive greater commercial use. A 2015 FDA grant included funding for training at C-SOPS. “Part of this training includes hands-on, intensive training, initially for FDA’s ETT team, and then for the broader industry. Trainees will gain experience running the integrated line at the Rutgers University C-SOPS lab. We want to give people exposure to this and thereby grow the level of continuous manufacturing expertise in the industry,” says Hausner.
A template or “road map” for development, based on the experiences learned by early adopters, would help the industry adopt continuous manufacturing, suggests Hausner. Regulatory science is another challenge, although progress is being made in understanding the risks and developing appropriate requirements for continuous manufacturing. Equipment, including having more standard connections and communication between PAT and processing equipment, is another challenge that will need to be overcome.
Another step forward for equipment for continuous processing was the development and installation of a prototype Portable Continuous Miniature Modular (PCMM) system for tablet production in Pfizer’s Groton, CT facility in 2015. The prototype was built as a collaboration between Pfizer, G-Con, and GEA, and the system won the International Society for Pharmaceutical Engineering Facility of the Year Equipment Innovation Category Award in 2016.