Design and Construction of a Potent Pharmaceutical CGMP Suite - Pharmaceutical Technology

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Design and Construction of a Potent Pharmaceutical CGMP Suite
The author describes the approach taken to develop a facility dedicated to handling potent and cytotoxic drug substances.


Pharmaceutical Technology


Construction and installation

Two significant challenges were the limited available physical footprint for the renovation and how to maximize throughput of the area given all involved processes needing containment. A 1:1 ratio of equipment-to-isolators was not practical, so a series of hard-wall isolators each with three to five multioperation docking ports was constructed.

The system needed to be more sophisticated than simply placing equipment in a "box," because such an approach would result in poor ergonomics and contaminate mechanical and electrical non-process surfaces of the equipment. A baffle or plate was needed to separate these areas of equipment. If this plate could be standardized about its periphery, it could be installed or interchanged at multiple locations on any given isolator within the facility.

In addition to the standardization of the docking locations, each piece of processing equipment had to penetrate each standardized plate in a manner that placed the processing surfaces in an ergonomically viable space within the isolator. Once the required equipment was installed, the plates formed the rear wall of the isolator. The isolator was then sealed and negatively pressurized. Each was also fitted with a variety of utilities inside including electric, water, compressed air, and vacuum.

It was essential that long process trains such as milling, screening, granulating, fluid-bed drying, sizing, blending, compressing, and film coating could be constructed in one room simultaneously. Getinge LaCalhene (Rochester, NY) was selected to build the system. Familiar brands of processing equipment were chosen for the integration to mitigate any potential client apprehension.

Shipping the necessary processing equipment (mills, blenders, granulators, and a roller compactor) to Getinge's facility and then building a full-sized mock-up facility proved to be a challenge. However, a full-sized mock-up facility is necessary to determine that each piece of equipment is properly positioned within the isolator when installed.

After fabrication, the system was installed and validated. Several clinical supplies have been successfully manufactured within these isolators and the feedback from the team, now working in the area, has been very positive. In the future, as long as a given piece of equipment can penetrate a vertical 3-ft2 plate with the product contact surfaces on one side, it can be adapted to work within the system. Or if bench-top space is needed, blank plates can be installed. The limitations of the system are primarily related to size, as certain pieces of equipment will not work through a vertical plate. Separate isolators integrated with our tablet press and fluid bed unit were also designed and installed.


Figure 1: An isolated fluid-bed dryer that was specially designed for the new potent products facility. (IMAGE COURTESY OF THE AUTHOR)
Isolated equipment includes: a Fluid Energy Jet-O-Mizer micronizer, Fitzpatrick Fitz L1A, Globe Pharma Mexi-Blend (0.5 to 16 quart), Vector TFC Lab micro roller compactor, Fluid Air Pharm X High Shear Granulator with 1L, 2L, 4L, and 8L bowls, Vector FLM1 fluid-bed dryer/top-spray granulator, Quardro Comil U-5 model, Riva 10-station instrumented Picolla tablet press, capsule filling devices, and tablet film coater (see Figures 1–3).


Figure 2: The custom multiuse, hard-wall isolator was engineered to house up to three pieces of processing equipment. (IMAGE COURTESY OF THE AUTHOR)
Because of the hard-wall isolation technology and resulting containment verification, Metrics eliminated any need for the use of bulky suits with powered air purifying respirators. Processing rooms are essentially clean while in-process. The improved comfort and cleanliness has been a popular milestone for the team members.


Figure 3: An integrated tablet press for the potent-products facility. (IMAGE COURTESY OF THE AUTHOR)
Several policy instruments have been enacted or altered as a result of this new capacity. If the compound is deemed highly potent at a projects' inception?that is, if the operator exposure limit is determined to be less than one micron per cubic meter of breathing zone air?then all processing operations are conducted in a the new facility.

More conservative cleaning verification policies pertaining to the new capacity were implemented. After every batch or campaign, a comprehensive health-based cleaning verification of shared surface areas is conducted. This new procedure requires high-performance liquid chromatography recovery of the active pharmaceutical ingredient below a residual threshold after every batch or campaign of batches, regardless of what a subsequent activity may be. One-hundred-percent cleaning verification supplants a cleaning validation program. As a result, there is an analytical record that proves every active is removed properly after every processing event.

Joe Cascone is director of potent pharmaceutical development at Metrics,

References

1. Occupational Safety & Health Administration, US Department of Labor, OSHA Technical Manual, http://www.osha.gov/dts/osta/otm/otm_toc.html, accessed Aug. 21, 2009.

2. Assessing the Particulate Containment Performance of Pharmaceutical Equipment (ISPE, 2005), http://www.ispe.org/cs/ispe_good_practice_guides_section/ispe_good_practice_guides, accessed Aug. 21, 2009.


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