In the annals of napkin illustration, continuous drug tablet manufacturing may have only one entry: Fernando Muzzio’s 2003 depiction of a tableting line for Janet Woodcock, then head of the US Food and Drug Administration’s Center for Drug Evaluation and Research, at a restaurant in New Brunswick, New Jersey.
The occasion was a meeting of the Center for Advanced Pharmaceutical Manufacturing, a group of drug company engineers engaged in process design. “I took advantage of the fact that we were sharing a nice dinner to ask her why the FDA was not in support of continuous manufacturing,” recalls Muzzio, a chemical engineer.
“She looked at me and asked, ‘What’s continuous manufacturing?’ ” Muzzio grabbed a napkin and drew a quick schematic of belts and feeders, a blender, and a tablet press. “She asked me how big is this thing, and I said, ‘Well, it fits in this room.’ ”
Woodcock was to speak later in the evening about the agency’s upcoming guidelines for process analytical technology (PAT), a method of statistical analysis that would expand the range of manufacturing techniques allowed under FDA quality standards. A quick study, Woodcock mentioned that continuous manufacturing was consistent with the guidelines being developed, Muzzio says.
In no way does Muzzio claim to have influenced the FDA’s position on continuous manufacturing. But two years after that talk, he helped launch the Center for Structured Organic Particulate Systems (C-SOPS) at Rutgers University.
C-SOPS, which Muzzio still heads, has emerged as a hub for implementing continuous processing in drug tableting. Drug companies and, more recently, pharmaceutical services firms, have been hiring its alumni, who are now helping spread the technology across the drug industry.
Continuous manufacturing, ubiquitous in many other industries, is only beginning to make inroads in pharmaceuticals, a highly profitable, tradition-bound sector that for decades felt little incentive to redesign its manufacturing base. This started to change after a wave of patent expiries and attendant profit dip beginning in the early 2000s. The regulatory hurdle dropped in 2004 when the FDA publicly stated that continuous manufacturing would be consistent with PAT.
Continuous processing is a more efficient means of tablet manufacturing primarily because it entails real-time monitoring and control. Batch production, on the other hand, requires each run to be tested after completion, a time-consuming process that often results in the loss of entire batches. Continuous processes also allow all ingredients to be added simultaneously in correct proportion and sent directly to a tablet compression line rather than added premixed in large amounts with poor control of the powder’s composition. But converting to a continuous process poses challenges in mechanical engineering as well as particle design. Much of the drug industry’s work on meeting these challenges started at C-SOPS.
Based at Rutgers, the center has members from nearly every major drug company, key manufacturing and control technology suppliers, and three academic partners: Purdue University, the University of Puerto Rico, and the New Jersey Institute of Technology. In 2006 C-SOPS landed an engineering research center grant from the National Science Foundation, which, along with matching funds from members and associated grants, netted it about $100 million over 10 years.
The grant fueled a transformation of C-SOPS from traditional academic research lab to a “state of the art” process development lab, according to Douglas Hausner, a physical and analytical chemist who is associate director for industrial relations and business development at the center. In its early days, C-SOPS embarked on several projects with GlaxoSmithKline, most designed to test the technology. Then, in 2012, came a proposal for a major engagement from another member, Janssen.
Janssen, a unit of Johnson & Johnson, was interested in establishing its first continuous tableting line. For the initial foray it had chosen a recently launched HIV drug, Prezista. The company floated the idea of C-SOPS developing a prototype manufacturing line at Rutgers that it could replicate at its plant in Gurabo, Puerto Rico.
The center approved the project and received $2 million of the NSF funding to support it. “We began working with Janssen in a collaborative fashion, where we at the university were somewhat playing the role of a contract development organization,” Hausner says.
Mauricio Futran, vice president of advanced technology at Janssen, says the company chose an approved drug with well-known physical characteristics as the test candidate.
“Even though the continuous technology is quite robust, people were skeptical going into it,” he says. “Introducing a new technology on top of the normal risk of bringing a new drug to market was not really desired.” The prototype designed at Rutgers was replicated in Puerto Rico, where Janssen added “bells and whistles” to comply with FDA standards, he says.
Continuous tableting remains a close-knit community, with C-SOPS at the middle. Futran, who was chair of Rutgers’s chemical engineering department in 2011, was familiar with the center’s work. Eric Jayjock, a C-SOPS engineer, designed the Janssen prototype and was hired by the drug firm to oversee its implementation in Puerto Rico.
Jayjock later extended the center’s reach a step further when he was hired by Patheon, a contract development and manufacturing organization (CDMO), to implement continuous tableting. “I am a poster child for the center,” he quips.
Jayjock’s involvement started after he completed his PhD at Rutgers in 2011, and Muzzio, who had been his faculty adviser, asked him if he’d be interested in working on the Janssen prototype.
He later joined Janssen, working in Puerto Rico for three years to build the commercial version of the prototype. “Then Patheon called me and asked if I’d be interested in leading a program to make continuous tableting happen in the CDMO world.” There, as director of continuous manufacturing, he developed a modular system that can be configured for individual clients’ needs.
Patheon is currently making test batches in Greenville, North Carolina, for one customer and doing development work for two others. Meanwhile, Hovione, another CDMO, has started up a continuous tableting line at its site in East Windsor, New Jersey, staffed in part by former C-SOPS engineers, to serve Vertex Pharmaceuticals, a C-SOPS alumnus.
And continuous tableting is advancing at other major drug companies, with C-SOPS members such as Pfizer and Eli Lilly and Company starting lines. Last year, GSK entered a four-year collaboration with the Rutgers group to implement a continuous process at one of its facilities.
Work is likely to pick up in the CDMO field as well, though the cost of installing a line may be a barrier to smaller companies, according to Muzzio. Meanwhile, C-SOPS faculty formed an independent company, Integra Continuous Manufacturing Systems, headed by Muzzio with licensing know-how from Rutgers, to help non-C-SOPS members implement the technology.
“Over a 10-year period, we went from having a cohort of R&D people who had a few supporters in the upper management thinking continuous tableting could be good for the industry, to continuous tableting as something that all these companies are taking a serious look at,” Hausner says. Even though the FDA has yet to publish formal guidance, the agency’s general nod to the concept has transformed drug tablet manufacturing.
“It’s now a commercial reality, not just with the organizations we worked with a decade or more ago,” Hausner says. “Everybody is looking at it and doing it at different levels.”