A comparative evaluation should determine whether microbial intrusion or ingress into the product packaging could occur at those physical integrity test value ranges that have been deemed acceptable for the finished product. This determination should be based on a comparison between microbiological data and the values obtained from physical integrity test method. The comparison of physical integrity testing to microbial ingress testing for assessment of product packaging integrity can be obtained either by direct comparison or by studies that demonstrate that the physical test measures defects that are too small for microbial passage.

Due to its design or material composition, a product packaging system may not permit or yield graded physical test responses when a range of defects is created in the packaging. In some situations, even upon creating artificial defects in a product packaging system, the resulting range of physical testing values may remain approximately the same. In other words, the test method may yield a qualitative rather than a quantitative measure of package leakage. Also, microbial ingress may not occur until exaggerated physical defects are created in the packaging. In such cases, a direct correlation of microbial ingress to a series of physical value ranges is not possible. When this occurs, the testing results become merely pass or fail results conducted on packaging with known defects.

Physical and microbiological methods for product package integrity testing should take into consideration the design of the closure system; the manufacturing method, including the sterilization process; and the intended use of the product. Any particular physical or microbial method may not be applied to all product packaging systems.

During initial integrity evaluations of a packaging system, a number of physical tests may be used. These physical tests may include, but are not limited to, pressure and vacuum decay tests, dye immersion tests, liquid chemical tracer tests, gas ionization of evacuated containers, high-voltage leak detection of plastic or glass containers, visual examination for glass cracks, and gas leakage or package headspace analysis. Other tests that may be valuable in evaluating package seal quality include screw-cap removal torque, elastomeric stopper residual seal force, or heat seal strength.

Microbiological tests may include closure immersion testing for rigid container systems, inoculated shipment testing for certain packaging, and an aerobiological challenge for tortuous path barrier packaging.

Dual function container–closure systems are characterized by the addition of one or more intended functions to that of a container and require special consideration for integrity evaluation. For instance, in the case of small, flexible or rigid containers with an appended device component that allows direct patient injection and drug delivery, a delivery function is added to the container function. Thus, frequently, one compartment of the dual container–closure system is designed to contain the drug or solution prior to use or activation of the system—product containment compartment. Another compartment, different in function and design, either directly delivers the product from the container portion to a fluid pathway for direct injection of the patient or communicates with a sterile pathway of another access device. For example, a prefilled syringe contains a solution (container compartment) and a device component (delivery compartment) physically separated from the container compartment and used to directly administer the drug to the patient.

Therefore, dual container–closure systems typically have at least two compartments that require microbial barrier properties, and packaging integrity after sterilization and/or aseptic filling should be demonstrated for both compartments. In many cases, different portions of the dual system require different integrity testing methods. The selection of the integrity testing method is determined primarily on the basis of the intended objectives or performance requirements of the particular compartment. For example, the solution or drug-containing compartment of the dual container–closure system must be enclosed or sealed in a manner that precludes leakage of product or microbial ingress during and following the manufacturing process (see Selection of Evaluation Methods). On the other hand, the delivery portion of the dual container–closure system frequently contains a fluid pathway that is empty during the sterilization or aseptic filling process and is intended to remain dry until the product container portion is activated prior to use. A covering, a sheath, or perhaps a cap designed to vent during sterilization and storage protects the delivery compartment from airborne microbial ingress throughout the life of the article. However, this portion of the device is frequently not designed to prevent liquid ingress. Liquid ingress can be precluded by secondary packaging or by the physical design of the system itself. Microbial integrity testing of the delivery portion of such a dual container–closure system may include a nonimmersion microbial method or physical integrity test. Microbial testing would include, for example, an aerosolized microbial challenge under defined pressure changes.