In a world of hungry microorganisms, it is critical that medical devicesdesigned to healdo not inadvertently do the opposite by infecting the patient. To prevent infection, a device's packaging, or "sterile barrier system," must maintain sterility over the product's entire shelf life. In fact, packaging can potentially be the weak link in the chain of steps designed to keep a product sterile from the time of production to its final use.
Ed Emerson is the business development manager for Mocon Medical Packaging Group. He is responsible for developing awareness of Mocon's package integrity instruments within the medical device packaging industry. Emerson can be reached at 763-493-6370 or firstname.lastname@example.org.
Opening the Door to Integrity TestingFor all these reasons, there has been discussion of using package integrity testing instruments to support or replace traditional sterility tests. In 2008, the FDA finalized guidance regarding "container and closure system integrity testing . . . as a component of the stability protocol for sterile products." The guidance states that physical testing can be used to verify that the seals are leak free and continuous.
In its guidance, the FDA lists four advantages of container and closure system integrity tests. These include:
• The ability to "detect a breach... prior to product contamination"
• The ability to "conserve samples that may be used for other stability tests"
• The fact that they "require less time than sterility test methods"
• The fact that "the potential for false positive results may be reduced"
However, integrity testing offers other benefits as well. Like traditional microbial challenge testing, it can be used during package development for periodic checks on production or when critical events occur. Unlike the microbial challenge though, integrity testing doesn't incur the delay required for culturing, making it far more convenient and usable. Nor does it require highly trained specialists or incur the same risk of operator error.
Ease of testing means packages can be tested more often over their anticipated lifecycle. This can be critical for packaging that is shipped, handled, and otherwise challenged in ways that may affect its ability to keep contents sterile. Package integrity testing using instrument methods can be more sensitive, repeatable, and reproducible and, therefore, more reliable.
The FDA's guidance notes specific limitations of traditional sterility testing, including:
• The fact that they "will only detect viable microorganisms present at the time of the test"
• The fact that these organisms "can only be detected if they are capable of growth in the specified culture medium"
• The risk of "potential interference due to adventitious microbial contamination . . . at the time of testing"
• The fact that "sterility tests are always destructive of the samples"
In this document, the FDA, for the first time, officially allows physical testing to support sterility testing. The agency lists as acceptable physical testing methods "any properly validated . . . container and closure 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.)"
There is no universal means of package integrity testing, and methods are not all equal. As packages must be adapted to their contents, testing must be adapted to package design, materials, and sealing mechanisms. Testing systems may have to evaluate packages incorporating flexible, semi-rigid, and rigid designs; porous and non-porous materials; laminated polymer, paper, and foil materials; and a variety of sealing technologies. The packages being tested may be unfilled, or filled with solid, liquid, or powdered materials. Further, a validated testing system should comply with recognized consensus standards, such as those published by ANSI/AAMI/ISO and ASTM International. If it stores data, it should comply with applicable electronic data regulations as well. Finally, it should also be simple to operate, requiring a minimum of specialized training.
Test MethodsDepending on package design, a variety of package integrity testing methods may be employed.
• Burst and creep testing entails pressurizing the inside of the package and measuring the pressure required to either cause seals to separate or packaging materials to rupture. Some packages use porous materials, allowing the contents to be gas sterilized through the porous package walls after the package has been sealed; burst testing of these packages can require higher inflow capability in order to achieve sufficient pressure to challenge the package.
• Pressure decay testing identifies failure of a package's seal or materials by measuring the package's ability to maintain a constant internal pressuretypically 50% of burst pressureover a period of time.
• Precise leak testing identifies the size of a leak by measuring the flow rate required to maintain constant pressure within the package.
Multi-testing allows the operator to perform sets of testsflexible combinations of leak testing, creep, and burst testingon the same package sequentially. By combining tests, researchers can gain a clear understanding of a package system's resistance to peel and of seal strength under varying conditions.