by Anne Booth, president, Booth & Associates (Barrington, IL)
While barrier isolator technology for liquid pharmaceuticals and medical devices is still evolving, it is very important that any isolator being put into use is validated. Isolators must meet certain predetermined performance criteria; perhaps the most important of which is a sterility assurance level of 10-3 to 10-6 depending on the exact use.
Anne Booth offered the following isolator validation advice for systems using vaporous hydrogen peroxide (VHP) at the Medical Design & Manufacturing West 99 conference, held in January in Anaheim, CA.
INSTALLATION QUALIFICATION
The documentation should include a detailed description of the physical system and a diagram of the unit layout with interfaces and transfer systems clearly marked. The following items should also be included: equipment description, manufacturers' specifications, construction materials, instruments (with calibration status), utility specifications, HEPA filter certifications, and computer software.
OPERATIONAL QUALIFICATION
The isolators must be checked independently of each other and of the generator. Collect data by performing the following: a mock run to check cycle alarms and alerts, an integrity test for leaks, and a pressure test to ensure positive pressure can be maintained. Establish preventive maintenance and cleaning procedures, document proper air exchanges, and collect data on the piping system that connects the isolator, generator, and outside exhaust.
Each phase of the sterilization cycle must be evaluated, taking into consideration HEPA integrity, computer alarms and alerts, drier capacity and status, sterilization cycle verification, temperature distribution and mapping in the isolator, and uniform sterilant distribution using chemical indicators.
PROCESS QUALIFICATION
Process qualification determines appropriate cycle parameters given the isolator configuration, room temperature, and loading. The system need not be installed in a controlled environment but must be in a room maintained at a constant temperature and relative humidity.
Prior to starting, develop the maximum fixed load configuration to be used during routine operation. Then conduct temperature mapping to determine heat distribution. This analysis, using thermocouples placed throughout the isolator and load, is needed to determine the cold spot within the isolator in order to calculate the maximum safe concentration of hydrogen peroxide that can be used without causing condensation. A good figure is 20%, as anything lower can add considerable time to the sterilization cycle. For best results, the drier capacity should be greater than 12 hours.
Chemical indicators should be placed adjacent to the thermocouples (as well as in difficult locations such as gloves and half-suits) to make a general evaluation of gas distribution. The color should gradually change from white to gray violet within 25 minutes. For most uniform gas distribution, mount fans within the isolator.
Watch for condensation. If it occurs, it can indicate that the gas concentration is too high for the temperature within the isolation, or that the concentration is not uniform. Estimation of the concentration is determined from tables provided with the generator.
STERILIZATION CYCLE DEVELOPMENT
The isolator should be validated to a sterility assurance level of 10-6. The sterilization of all internal surfaces of the isolator and of all external surfaces of the items in the isolator is validated using a resistant biological indicator (BI)—the best to use in this case is Bacillus stearothermophilus with a spore population of 106. Spores are inoculated on carrier material that does not absorb the sterilant and are packaged in Tyvek pouches.
There are two ways to determine the appropriate half cycle. One is to gauge performance of sequential fractional cycles by increasing the gas exposure time for each, similar to the method used in EtO validation. After each fractional cycle, retrieve and sterility test the BIs. The other method is to test pairs of exposed BIs within media tubes in the isolator's worst-case location at intervals during a single gas exposure cycle. In both cases, the time that produces total kill becomes the half-cycle gas exposure time.
STERILIZATION VALIDATION
Once the half-cycle gas exposure time is determined, run three consecutive cycles with BIs and thermocouples. Sterility testing of BIs should yield all negatives if the cycle parameters are correct. The appropriate BI growth controls should all be negative, and the media growth promotion should test positive.
Then run a full cycle to determine the time needed to aerate the isolator completely. The hydrogen peroxide gas should be reduced to an acceptable level, usually 1.0 ppm. Aeration time depends on isolator volume, mass of adsorptive material, and the rate of outgassing from materials. Use a semi-quantitative gas detection tube to gauge aeration efficiency.
At several points, regeneration cycles may be required to remove the humidity from the drying agent. The typical time is 18 hours, but the lower the drier capacity, the longer the process will take.
OTHER VALIDATION ISSUES
Other tests are needed to determine that the gas is not penetrating product containers, supplies, and other objects.
Maintenance of isolator sterility over a period of time should be established and monitored. That means a schedule of routine sampling. Worst-case situations, such as loss of power and transfer of additional supplies, should be included during this period. Periodic inspection of gaskets, ports, and gloves to detect imperfections is essential.
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