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TR 27 1998

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reviews both the microbial challenge approach and the alternate physical testing approach for verifying a package's microbial barrier properties. 6. Methods of Establishing Microbial Package Integrity All sterile pharmaceutical packages must prevent the ingress of microorganisms. This section focuses on liquid immersion and airborne microbial challenge test methods and alternate physical test methods useful for establishing a package's microbial barrier properties. In subsection 6.1 the rationale for selecting a microbial challenge test versus a physical test method is discussed. Subsections 6.2 and 6.3 describe how one may directly verify a package's microbial integrity through either liquid immersion or airborne microbial challenge tests. In subsection 6.4 an outline is presented describing how physical leak tests may be validated as an alternative indicator of package microbial integrity. A direct correlation of physical integrity test results to microbial barrier properties can be done by exposing a given population of packages to both physical and microbial challenge tests (subsection 6.4.1 ). An indirect approach is to compare the physical method's sensitivity to leakage rates previously demonstrated as preventing microbial ingress (subsection 6.4.2). 6.1 Microbial Challenge vs. Physical Test Methods For most sterile pharmaceutical packages, the leakage rate specification is that which will prevent the ingress of microorganisms. Such packages must therefore be validated as providing an effective barrier against either airborne and/or liquid-borne microbial ingress. The microbial barrier properties of a package may be demonstrated using either microbial challenge tests or physical tests that have been correlated to microbial ingress. There are several reasons for choosing to use a microbial challenge test. First, there may be no reasonable alternative to microbial challenge tests. For instance, certain closures or packages that rely solely upon a tortuous path to prevent airborne microbial ingress may not be reliably tested by a physical method. A second reason may be that the package design does not lend itself to sufficiently sensitive physical test methods. For example, a package may not tolerate the relatively high differential pressures required for testing by vacuum decay or tracer gas techniques. A third reason may be that the manufacturer does not have the resources or expertise required for developing and validating an alternate physical test method. It is also possible that the product is only intended for limited distribution so that an extensive physical test method validation program cannot be justified. Conversely, a physical test may be the preferred approach for microbial barrier package validation. If a sufficiently sensitive physical test method is available that is compatible with the product-package system, it is often more economical in the long run to invest in developing and validating such a physical test. quantitative results or that can pinpoint the location of leaks. relatively insensitive, yield inconsistent results, are labor intensive, necessitate extensive storage space for sample incubation, and require long test times. Another disadvantage is that microbial Physical tests can be selected that yield qualitative or Microbial challenge tests are Vol. 52, No. 4 I July-August 1998, Supplement 8

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