The practical limits of aseptic processing isolator sterilization
02/01/2001
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by Russell Madsen
Eliminating detectable levels of microorganisms within an isolator is frequently considered to be a critical requirement. However, there are practical limitations to the true sterilization of isolators and equipment not in contact with product.
The PDA Isolation Technology Task Force, authors of Technical Report No. 34, Design and Validation of Isolator Systems for the Manufacturing and Testing of Health Care Products, believes that demonstration of a three-log reduction of resistant biological indicators during isolator sterilization/decontamination is sufficient for non-product contact surfaces within the isolator for the following reasons:
1. The gas/vapor decontamination process is done only at a point in time. It cannot guarantee a PNSU level equivalent to its defined kill of calibrated biological indicators throughout an established operational period, even if that period is relatively short.
2. Many isolators contain moving parts and protected areas that are very difficult to treat during decontamination. Moving of parts to ensure contact with the gas or vapor is a reasonable precaution, but it may be difficult or impossible to really prove that a mechanism occluded for some percentage of the gas/vapor treatment period is sufficiently treated with the agent.
3. The risk of contamination reaching the product from restricted access locations is small. Even more importantly, because the isolator is a dry environment free of organic material, the ability of vegetative cells to survive in the isolator is limited, and, even if survival were possible, proliferation is impossible.
4. Gas/vapor contact time and concentration is always a trade-off between anti-microbial effectiveness and material compatibility. Very long exposure times may actually introduce more significant hazards to the process because they can increase the friability of soft parts and decrease their useful lifetimes.
Nevertheless, the ability of an isolator to be treated with a gas/vapor decontamination agent in a quantifiable and highly reproducible manner represents one of isolation technology's most important advantages over conventional cleanrooms.
It is impossible to treat cleanrooms with high concentrations of sporicidal agents under truly well controlled conditions and to employ methods ensuring a reasonably uniform distribution of such agents. Also, given the significantly smaller enclosed volume of isolators as compared to even small conventional CleanRooms, far higher concentrations of decontaminating agents can be achieved and maintained in isolators than in cleanrooms.
Methods that have been used for gas/vapor decontamination of isolators include hydrogen peroxide, ozone, peracetic acid and chlorine dioxide. The decontamination method should be able to provide a three-log reduction of biological indicators known to be resistant to the gas/vapor method employed. The three-log reduction can be demonstrated as follows:
1. The complete kill (Total Kill Analysis Method) of a population of at least 10-4 spores/indicator. Data from at least 50 biological indicators over three consecutive test runs is required. (Note: Statistically, the complete kill of a 10-3 biological indicator is equivalent to a >5-log kill. See ISO/DIS 14161 Annex A Figure 4.)
2. Fraction Negative Studies in which a three-log kill or greater spore reduction value is calculated using the Holcomb, Spearman, Karber Procedure, Stumbo Murphy Cochran, Limited Stumbo Murphy Cochran Method, or Limited Spearman Karber Procedure. A suitable number of biological indicators must be used for the method chosen as described in relevant AAMI Standards or ISO/DIS 14161.
3. Any overkill method or variation thereof is acceptable. For the purposes of isolator decontamination a Total Kill Analysis study of a suitable bioindicator with a population of 105 or greater is considered an overkill cycle. Such a cycle indicates a spore log reduction value >7 logs.
4. Bioburden methods may also be used as the basis for the development of a decontamination process. In this case, the user will need to perform studies ascertaining the actual resistance of their bioburden to the decontamination method they plan to employ. Spore bearing organisms are likely to be the most resistant flora against the gaseous decontamination agents currently used in isolator decontamination. The complete inactivation (Total Kill Analysis) of a six-log population of representative bioburden is adequate to demonstrate decontamination of the isolator.
Russell Madsen is VP Scientific and Technical Affairs for the PDA. He can be contacted at [email protected]