C-SOPS. The Center for Structured Organic Particulate Systems (C-SOPS), a multi-university consortium consisting of Rutgers University, Purdue University, the New Jersey Institute of Technology, and the University of Puerto Rico at Mayaguez, is developing a test bed for continuous manufacturing. C-SOPS was founded in 2006 with a $15-million grant from the National Science Foundation and is also funded by industrial partners, which include pharmaceutical manufacturers and equipment producers.

C-SOPS is focused on three areas: manufacturing science, composite synthesis and characterization, and particle formation and functionalization. The center is developing a test bed to show the feasibility of continuous technology for sequentially blending, dry-granulating, lubricating, and tableting of dry powders and granules. By using continuous manufacturing methods, this test bed seeks to develop predictive models for single-process components as well as the integration of these models into hybrid platforms to be used for process control, explains Fernando Muzzio, director of C-SOPS and member of Pharmaceutical Technology's editorial advisory board. The goal of the test bed is to mitigate the three most common problems affecting the quality of finished products made by batch processing: segregation, agglomeration, and compact quality while simultaneously improving process controllability and robustness. Other advantages are facilitation of process scale-up and reducing the size and cost of equipment.

Solid-dosage equipment design

Figure 1: A continuous high-shear granulation and drying system ("ConsiGma," GEA Pharma Systems). (FIGURE 1 IS COURTESY OF GEA PHARMA SYSTEMS.)

In the granulation module, dry ingredients are dosed individually or premixed in the continuous high-shear granulator. After a small dry-mixing section, the granulation liquid is added, so each particle receives the same amount of liquid. The particles follow a granulation track, which mimics the granulation in a batch process. Narrow tolerances between granulation screws and the barrel minimize back-mixing. "The whole wet-granulation process takes place in a few seconds with only a few grams of product in process at the same time, resulting in faster start-up and no losses," says GEA's Van der Goten. The particle size can be adjusted by changing the working level in the granulator, which results in a continuous flow of wet granules with a constant quality and density that is transferred to the dryer. There are no oversized agglomerates and thus no wet-milling.

The dryer module, based on fluid-bed drying principles, splits the continuous flow of granules in packages of 1.5 kg, drying them each in a separate segment of the dryer. When the content of the segment is dry, it is emptied and transferred to the evaluation mode and refilled with a new package of wet granules. The drying curve of each package is monitored. In the evaluation mode, the dried granules can be measured for critical quality attributes such as particle-size distribution, humidity, and content uniformity. At any time, there are only 6 to 9 kg in process, which minimizes the amount at risk in case of an incident (e.g., a power failure). The unit can handle capacities from 500 g to tons, so there is no need for scale-up. Van der Goten says that the unit's small size and modular construction allows for fast deployment and makes it easy to install with existing equipment. "It can perfectly operate in a mixed environment with the possibility to do a parametric release to the next step, a tableting process for instance."

GEA Pharma Systems has sold five CONSIGMA units: two to European pharmaceutical firms, one to an American pharmaceutical company, and two units to two Mexican generics companies.

GEA Pharma Systems also has developed a continuous blender, which can be used for premixing or mixing the external phase into the granules on a continuous basis. Courtoy, another division of GEA Pharma Systems, developed an advanced on-line PAT for its tablet presses, which allows GEA to provide a full continuous production line of solid-dosage forms, says Van der Goten. Such a line is currently under construction at GEA's laboratories in Belgium.

For insight on continuous sterile manufacturing, see "The Potential of Continuous Sterile Manufacturing".

References

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

2. Code of Federal Regulations, Title 21, Food and Drugs Part 210.3(b) (Washington, DC, 2008), p. 138.