er 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 pack-
aging 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 integ-
rity 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.
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