Preservation of container closure integrity (CCI) of a parenteral drug product is critical over the shelf-life of a product. Use of CCI testing is a viable alternative to sterility testing, and, according to FDA guidance, may be more useful than sterility testing in demonstrating the potential for product contamination over the shelf-life or dating period.1 There are many advantages to using CCI testing in lieu of sterility testing, including conservation of samples, fast results, and sensitivity that can pinpoint a leak in a vial or syringe system. It must be noted, however, that container and closure system integrity tests cannot demonstrate a product’s initial sterility.
The pharmaceutical industry has used glass as a primary material for containment systems due to a variety of characteristics that enable generally safe and efficient drug delivery. However, there are many risks associated with glass, including issues such as breakage, delamination, leachables, and physical and chemical compatibility with the drug product itself that can affect the safety and efficacy of a pharmaceutical product. A container closure system should be sufficiently tight in order to protect the drug product and the environment. Cracks, holes, stopper and plunger deformities, ill-fitting caps, or needle punctures may result in the ingress of unwanted gases, and/or harmful microbiological or particulate contamination, which ultimately may affect the end user. Leaks can be detected using a variety of CCI test methods, including dye ingress, vacuum decay, headspace analysis, helium leak, and electrical conductivity and capacitance test (high voltage leak detection). These test methods vary in sensitivity and outcome, and factors should be evaluated, including: the product and its packaging, the application of the method and the results produced, cost and the pharmaceutical manufacturer’s understanding, and knowledge of the test method in association with their product.
Dye ingress testing has historically been the CCI test of choice. However, the testing requires the destruction of the drug product, must be performed using clear sample containers, and results may be affected by issues such as protein clogging. The test is strictly visual, so the drug product can be in its final configuration (vial or syringe), and requires only that the dye be seen to prove ingress. While this method is basic and efficient, requiring no special instruments or technology, it does lack standard guidelines and there is no clear path to follow on analysis. While most compendia recommend dye ingress testing for CCI, the method is nearly outdated and more sensitive methods have been developed. Dye ingress may provide a gross analysis, so it is best used to discover cracks and misaligned components. In some cases where no other means of CCI has been proven, capillaries of known internal diameters can be inserted into sample configurations to quantitate a leak of a known size. The capillaries are inserted and epoxied into place and are usually between 10 and 20 microns, depending on the methylene blue solution’s surfactant composition.
Vacuum decay is a non-destructive test that can be used on solid drug products. A qualitative test, vacuum decay can be performed on vials of any color and those with labels in place; however, syringes must be empty. In this method, the container is placed in a test chamber and a vacuum applied. The test chamber is isolated from the vacuum source and a pressure transducer is used to monitor the test chamber for the level of vacuum and the change in that level over time. Vacuum decay is a rise in test chamber pressure. While this method requires specific instrumentation and leaks can be detected by audible and/or visual signals, there are a few drawbacks. Protein clogging can prevent leak detection and liquid leaks may contaminate the test chamber. Additionally, this method is labor-intensive, since each type of container must have its own chamber, and actual container defects may or may not be detected. Vacuum decay offers only a pass/fail result so the location of the leak cannot be determined. For specific issues, more sensitive test methods are recommended.
Headspace analysis uses frequency modulation spectroscopy as an optical measurement method (Figure 1). The test offers high sensitivity and is non-destructive. In this method, the light from the near-infrared semiconductor is tuned to match the internal frequency of the water molecule at 1400 nm. The amount of light absorbed is proportional to the water vapor concentration. The number of frequencies absorbed is proportional to the total headspace pressure. Light passes through the vials inside the sample holder and measures the amount of light or frequencies absorbed, which is proportional to the pressure inside the vial. Although this test provides a quantitative result that illustrates whether a container is leaking, it cannot pinpoint the location of the leak.
This rapid test can be conducted on a wide variety of containers ranging in size from 1mL to 2L; however, the containers must be transparent. There must be sufficient headspace in the container through which light can pass and acquire a reading. The test cannot be used on syringes, but it may prove more accurate than either dye ingress or vacuum decay testing.
Helium leak is a highly sensitive test method that provides the most accurate and reproducible results. This instrument uses a mass spectrometer to detect the rate of helium leaking from a sealed container. It only detects helium ions, so the presence of other gases within the vial or atmosphere does not matter. The use of helium provides a safer alternative to other gases such as hydrogen, which is unstable and highly explosive. The vials or syringes can either arrive pre-filled with helium or be filled manually. Vials can contain either liquids or lyophilized product but syringes must be empty. Various sizes of chambers attach to the instrument, which allow for the size of the container analyzed to be as large as 500 mL. The instrument applies a high vacuum to the chamber where the helium escapes the container as a leak rate that is measured quantitatively. Additional instrumentation reads the concentration of helium inside the sample, which is used to calculate the actual leak rate of the container. Although this test destroys the product sample, it is more sensitive than any of the other methods, and can pinpoint a gross leak using an external sniffer probe. The analysis can also use laser drilled positive controls of a known hole size to demonstrate failing leak rates. In addition, this type of CCI testing can be done at low temperatures, -80˚C and near cryogenic conditions. This aids pharmaceutical manufacturers whose product must be shipped or stored at low temperatures.
High voltage leak detection (HVLD) is a non-destructive test method that applies high voltage current to liquid filled glass or plastic containers. The current is applied to the non-conductive container and looks for a voltage differential, which would represent an integrity breech. The testing requires no sample preparation, produces rapid results, and accuracy is not dependent on operator skill. This method of CCI testing is especially practical for stability studies, biologics, as well as any containment system that holds a liquid with little to no headspace, where helium leak is not advised, as in prefilled syringes. This method does require some special fixtures to be made to match to container closure configuration, much like vacuum decay.
To help ensure a safe and effective drug product, pharmaceutical manufacturers must show that a drug product is stable within its packaging for the duration of its lifecycle. Environmental factors such as temperature, humidity, and light may affect drug product packaging. Since all products labeled sterile are expected to be free from microbial contamination, sterility testing may not be enough to ensure the integrity of the drug product.
Alternative test methods, including those listed above, may be more reliable when attempting to confirm the container closure integrity of a drug product’s primary containment system. Such testing may help pharmaceutical manufacturers detect a breach in a container or delivery system prior to product contamination or evaluate the cause of defects in less time than is required by sterility testing. While there is no one container closure integrity test method that works for every product, a combination of testing may prove effective in addition to or in lieu of sterility testing for parenteral drug products.
1. “Guidance for Industry: Container and Closure System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products,” U.S. Food and Drug Administration, February 2008, http://www.fda.gov/RegulatoryInformation/Guidances/ucm146074.htm, accessed September 11, 2013.
Louis Brasten is the Supervisor of Routine and Functional Analysis/Filling Services at West Pharmaceutical Services Inc. An 18-year veteran of the pharmaceutical industry, Louis’s background includes work in Quality Control and Analytical Services. He can be reached at Louis.Brasten@westpharma.com. Alicia Brydzinski and Barbara Jacobs are Scientists in West’s analytical laboratory.
This article appeared in the March 2014 issue of Controlled Environments.