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)
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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)
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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)
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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, jcascone@metricsinc.com.
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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