Continuous Progress in Continuous Manufacturing - Pharmaceutical Technology

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PharmTech Europe

Continuous Progress in Continuous Manufacturing
Industry buy-in is increasing as pharma companies proceed with select projects and research.

Pharmaceutical Technology
Volume 35, Issue 9, pp. 44-47

Process understanding and control

Despite the challenges, some feel that the divide between batch and continuous manufacturing can and should be overcome. "What we have now is not a batch paradigm," said Fernando Muzzio, professor of chemical engineering at Rutgers University, president of Mixing Consultants, and a member of Pharmaceutical Technology's editorial advisory board. "We mix in batch, we roller-compact continuously, we then lubricate in batch, and then tablet or capsule-fill continuously. Then we coat in batch and package continuously." Muzzio, who also spoke at the Interphex panel discussion, is center director of the Engineering Research Center For Structure Organic Particulate Systems, a multi-university consortium consisting of Rutgers University, Purdue University, the New Jersey Institute of Technology, and the University of Puerto Rico at Mayagüez. The center, which is funded by National Science Foundation and industrial partners, including 35 pharmaceutical manufacturers and equipment producers, is involved in research and development for continuous processing.

To move to continuous processing, Muzzio noted even the simplest route, continuous direct compression of tablets, requires many measurement points and data streams (e.g., feed rate, blend uniformity, humidity, shear, compression, thickness) that need to be interpreted in context. The key, he said, is building a predictive model that can relate all of the measurement points to the process variables to control product quality. Full closed-loop automated control is a requirement to achieve reliable performance. For example, commercial technology for monitoring powder density in real time is an issue, and there is currently nothing that is "plug and play," he said. Muzzio's team has continuous direct-compression and continuous dry-granulation lines operating at the center and is currently working on developing a continuous wet-granulation line.

The feasibility of developing continuous processes for specific unit operations requires advances in pharmaceutical equipment design and operation. "To make continuous mixing, granulation, and drying possible for small-scale operations, such as in the pharmaceutical industry, systems needed to be developed with very limited or no start-up and shutdown waste that reach steady state in an extremely short time," says Kris Schoeters, product manager of continuous processing at GEA Pharma Systems, a pharmaceutical equipment provider. He points to the company's ConsiGma continuous granulation, drying, and tableting line as an example. Designed in a modular way, the system consists of a patented twin-screw granulator, a segmented continuous fluid-bed dryer, and granule-conditioning unit to prepare dry granules for the tablet press.

"Each module has been optimized to achieve steady state very rapidly (sometimes within seconds) and to ensure plug-flow of the product throughout the system. The whole system is controlled by an advanced process control system; all modules have to communicate with each other seamlessly to form an intelligent-control system with feed-forward and feedback loops. The control system is, in fact, one of the major design challenges for continuous processing," says Schoeters.

Another challenge is ensuring plug-flow while maintaining consistent mixing characteristics. The twin-screw granulator, for example, contains "tightly intermeshing corotating twin screws and kneading elements, which provides a self-cleaning and self-emptying effect and, hence, ensures real plug flow," says Schoeters.

On the horizon

Developing continuous processes for specific unit operations and coupling them is one way to achieve continuous manufacturing. In this approach, drug-substance manufacturing and solid-dosage manufacturing are separate, and specific unit operations in solid-dosage manufacturing are developed as continuous processes and coupled. A more holistic or end-to-end approach is being considered by Novartis, through a 10-year, $65-million collaboration that the company formed with the Massachusetts Institute of Technology (MIT) in 2007, with the goal of developing a fully integrated platform for continuous manufacturing that would integrate drug-substance manufacturing with finished drug-product manufacturing.

Bernhardt Trout, director at the Novartis–MIT Center for Continuous Manufacturing and professor of chemical engineering at MIT, explained that the focus of the collaboration is not trying to redesign the process unit by unit, but rather to look at API and finished-drug product manufacturing as a whole. To that end, the center is researching and developing new technologies, including applying different chemistries to produce a desired API. Thus far, the center has developed a prototype, bench-scale integrated continuous manufacturing platform for API and solid dosage manufacturing. The fully integrated, end-to-end system has been run several times, and steady-state runs for up to a week at a time were planned for August 2011. The process and its control system will be used as a research tool to test start-up and shut-down strategies and to introduce new technologies for integration and further testing through 2011 and beyond.


1. E. Greb, Equipment and Processing Report, Mar. 17, 2010,, accessed Aug. 22, 2010.

2. FDA, Guidance for Industry: PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance (Rockville, MD, September 2004).

3. A. Pellek and P. Van Arnum, Pharm. Technol. 9 (3), 52–58 (2008).

4. Code of Federal Regulations, Title 21, Food and Drugs, Part 121, Sec. 210.3,, accessed Aug. 23, 2011.


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