Alternatives for Container and Closure Systems Sterility Testing

While sterility testing can be cumbersome and time consuming, there are FDA-approved options regarding container and closure system integrity testing. In fact, the Food and Drug Administration (FDA) recently released a guidance document on container and closure system integrity testing in lieu of sterility testing as a component of the Stability Protocol for Sterile Products. The document offers an alternative approach, if the approach satisfies the requirements of the applicable statutes and regulations.

Aimed at manufacturers, the guidance offers alternative testing methods other than sterility testing to confirm container and closure system integrity as a part of the stability protocol for sterile biological products, human and animal drugs, and medical devices.

The purpose of stability testing is to provide evidence on how the quality of a substance or product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light. Products labeled as sterile are expected to be free from viable microbial contamination throughout the product's entire shelf life or dating period. This enables manufacturers to establish or modify recommended storage conditions, retest periods and shelf life or dating period, as the case may be.

Currently, manufacturers of drugs and biologics purporting to be sterile are required to test each batch or lot, to ensure that the product in question conforms to sterility requirements. They must also maintain a written testing program designed to assess stability characteristics and meet stability testing requirements.

Manufacturers of medical devices are required to validate processes, including sterilization, for a device purporting to be sterile, although stability testing should be part of the design validation of such devices. Also, in vitro diagnostic products for human use are required to be labeled with stability information.

The minimum sterility testing generally performed as a component of the stability protocol for sterile products is at the initial time point (release) and final testing interval (i.e., expiration). Additional testing is often performed at appropriate intervals within this time period (e.g., annually).

Alternatives to sterility testing as part of the stability protocol, such as replacing the sterility test with container and closure system integrity testing, might include any properly validated physical or chemical container and closure system integrity test (e.g., bubble tests, pressure/vacuum decay, trace gas permeation/leak tests, dye penetration tests, seal force or electrical conductivity and capacitance tests, etc.), or microbiological container and closure system integrity tests (e.g., microbial challenge or immersion tests).

Such tests may be more useful than sterility testing in demonstrating the potential for product contamination over the product’s shelf life or dating period. The advantages of using such container and closure system integrity tests in lieu of sterility tests in the stability protocol for sterile products include: detecting a breach of the container and/or closure system prior to product contamination; conserving samples that may be used for other stability tests; requiring less time than sterility test methods which require at least seven days incubation; and reducing false positive results with some alternative test methods when compared to sterility tests.

To implement container and closure system integrity testing as an alternative to sterility testing, the FDA recommends manufacturers consider the following: a container and closure system integrity test may replace sterility testing in a stability program at time points other than the product sterility test prior to release; container and closure system integrity tests do not replace sterility testing methods for product sterility testing prior to release; any validated container and closure system integrity test method should be acceptable provided the method uses analytical detection techniques appropriate to the method and is compatible with the specific product being tested.

The guidance document, as well as alternative testing options, can be difficult to understand. For more about the content of the guidance, contact CBER’s Office of Compliance and Biologics Quality at 301-827-3031; CDER’s Office of Pharmaceutical Science at 301-796-1228; CDRH’s Office of Device Evaluation at 240-276-3747; or CVM’s Office of New Animal Drug Evaluation at 301-827-6963.

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Alternatively, call Dr. Norm Howe, Sr. Partner, directly at 734.740.9924