An Assessment of Integrity Testing of Drug Containers and Closures
Quantitative and confirmatory results can be obtained with helium leak testing.
Chairman & CEO
American Hospital Consortium LLC (Pittsburgh)
Conventional sterility test methods, destructive and nondestructive, have fundamental limitations. They do not yield quantitative results and thereby provide questionable assessment of the continued sterility of the component. There are certain shortcomings in traditional sterility testing. It detects viable microorganisms present at the time of the test that can be detected if they are capable of growth in the specified culture medium. It is also subject to potential interference owing to incidental microbial contamination introduced at the time of testing, leading to false-positive readings. Also, sterility tests destroy the samples tested. Companies cannot reexamine the same samples in the event of either positive or negative findings.
Certain physical tests are more useful compared with the conventional (microbial challenge) sterility testing. Furthermore, among the physical tests for package integrity, helium tracer gas leak testing offers significantly more detection sensitivity than other physical test methods1 such as vacuum bubble, dye penetration, and pressure/vacuum decay.
Based on limitations of the traditional sterility test methods, FDA provided a guidance document2 recently that allows manufacturers of drugs and biologics [editor’s note: medical devices, too] to use methods other than conventional microbial-challenge sterility testing to confirm container and closure system integrity as part of the stability protocol.
The most pressing question here is, rather than conducting tests for microbial presence in the interior of the package, is there a more informative and reliable method that can confirm the inability of microbial ingress to the package quantitatively?
As early as 2005, ASTM approved a standard test method3 for “Measuring Package and Seal Integrity Using Helium as the Tracer Gas.” This is an example of a test method with a high degree of accuracy as well as an ability to provide a quantitative and confirmative (pass/fail) result.
Demonstrating the integrity of a container/closure system is generally attempted by microbial-challenge testing instead of the use of physical test methods such as bubble, dye ingress, pressure/vacuum decay, or electrical conductivity testing. But, as demonstrated by Kirsch and colleagues4, none of these methodologies meet the requirement of demonstrating quantitatively, reliably, reproducibly, and with sufficient sensitivity the initial and long-term microbial-barrier properties of a given package.
Kirsch clearly demonstrated the feasibility of measuring helium leak rates quantitatively. In the later stage, using glass vials as test candidates for helium gas, he was able to quantitatively establish practical leak rate limits for vials by establishing a correlation between microbial ingress and helium gas leak rate and determined the critical leak rate. Kirsch also validated his experiment, demonstrating with a greater confidence that the helium-leak-rate methods were highly sensitive and provide a better quantitative assessment of container/closure integrity than conventional microbial-ingress testing.
The probability of microbial-ingress rates using a total of 288 vials at large leak rates approached 100%, whereas at very low leak rates the microbial ingress rates were 0%. A dramatic increase in microbial failure occurred in the leak rate region 10–4.5, which roughly corresponds to leak diameters ranging from 0.4 to 2 µm. Test results also confirmed that the values were observed to be between 10–5 and 10–3 std cc/sec, or higher, which corresponds to an approximate leak diameter of 0.2–2.0 µm. The above values require that they be the result of a single leak. If the leak rate value is the result of a combination of multiple leaks, the defect size would be too small to allow microbial ingress.
Analysis of other tests, such as bubble tests, pressure/vacuum decay, trace gas permeation/leak tests, dye-penetration tests, seal force or electrical conductivity and capacitance tests, etc., lack quantification and sensitivity compared with leak tests that use helium as the tracer gas.
Therefore, helium leak testing is not only more useful than a conventional sterility test, but it is far more confirmatory than other physical tests. It can detect a breach of the container and/or closure system prior to product contamination, can conserve samples that may be used for other stability tests, requires less time than sterility test methods (they often require at least seven days incubation), and produces quantitative results. Hence the principal essence of the helium leak test is that it produces quantitative, reproducible, statistically accurate, and confirmatory results for package integrity.
One known custom equipment and test laboratory currently available for conducting the helium leak test is Leak Detection Associates (Blackwood, NJ).
1. ASTM D3078-02(2008), “Standard Test Method for Determination of Leaks in Flexible Packaging by Bubble Emission”; ASTM F1929-98(2004), “Standard Test Method for Detecting Seal Leaks in Porous Medical Packaging by Dye Penetration; ASTM F2338-07, “Standard Test Method for Nondestructive Detection of Leaks in Packages by Vacuum Decay Method”; ASTM F88-07a, “Standard Test Method for Seal Strength of Flexible Barrier Materials”; ASTM F2097-05, “Standard Guide for Design and Evaluation of Primary Packaging for Medical Products”; WK19936, “New Test Method for Indirect Measurement of Elastomeric Closure Compression Using an Automated Residual Seal Force Tester.”
2. “Container and Closure Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products,” FDA Guidelines, February 2008.
3. ASTM F2391-05, “Standard Test Method for Measuring Package and Seal Integrity Using Helium as the Tracer Gas.”
4. Lee Kirsch, L Nuyen and CS Moeckly, “PDA Journal of Pharmaceutical Science & Technology-I, II, III,” Vol.51, No.5, 1997.