Container closure integrity (CCI) testing is receiving more attention these days. In fact, the recently revised USP< 1> Injections and Implanted Drug Products (Parenterals)-Product Quality Tests, specifies that “the packaging system should be closed or sealed in such a manner as to prevent contamination or loss of contents. Validation of container integrity must demonstrate no penetration of microbial contamination or gain or loss of any chemical or physical parameter deemed necessary to protect the product.” This revision offers new insight into CCI testing (1), in spite of well established methods available, such as U.S. FDA guidance and PDA technical reports (2–6).
These existing methods show CCI tests are used to measure moisture ingress into lyophilized products, moisture egress out of ophthalmic or blow fill seal products, oxygen ingress into products packaged under vacuum or nitrogen, and microbial ingress into sterile product.
Measuring Leak Rate is Critical
Gaseous leakage is a measure of the rate of gas flow through a leak path under specific conditions of temperature and the concentration or pressure differential across the barrier as measured in pascal cubic meters per second (Pa • m3/s); the pressure differential (ΔP) is typically one atmosphere during the test (1). Here are three typical examples:
- When the shelf package has no headspace pressure differential (e.g., dry nitrogen atmosphere; ΔP = 0), diffusion of oxygen or H2O gas into the package is typically the failure mode.
- When the shelf package has a headspace vacuum (i.e., total or partial vacuum; ΔP
- When liquid leakage is studied, either as liquid escaping or microbial ingress, the absence of leakage is the critical quality attribute (1).
Essentially, all pharmaceutical packages leak to some extent, thus a zero leak rate is not feasible or needed (1). For example, one drug product may be extremely sensitive to oxygen or moisture such that a leak rate close to zero is needed to maintain quality over the shelf life. Conversely, another product may also be sensitive, but to a lesser extent such that some leakage can be tolerated over the shelf life. Thus, a near-zero leak rate would be an unnecessary burden on the second drug product and would be neither science- nor risk-based. So, the maximum allowable leak limit becomes the critical quality attribute. When maintaining sterility and the integrity of the formulation (but not headspace) are requirements for rigid packaging, a leak rate of <6 × 10−6 mbar·L/s (He test) is typical. Keep in mind, failure modes may be exaggerated due to temperature changes, e.g., a room-temperature product subject to cooling or freezing during winter shipping.
When maintaining sterility, integrity of the formulation, and headspace is necessary for rigid packaging, a lower leak rate may be needed. This would be product-specific, i.e., how much oxygen (and for how long) can the formulation tolerate? (1).
For multiple-dose packages, both the shelf life and the in-use maximum allowable leakage limit need to be established since multiple-dose packages must meet their shelf-life specifications after years of storage and then must continue to do so for the last dose after being breached multiple times. For example, a ten-dose, multidose package with a 24-month expiration date must meet its shelf-life specifications in the 23rd month after nine doses have already been extracted; a proper CCI study would address this worst case scenario. In-use dye tests for resealability are typically conducted in this instance (7). For all packages, inherent package integrity must conform to the required product–package maximum allowable leakage limit.
There are various types of container-closure integrity tests. Deterministic tests give a definitive result and are typically physicochemical methods. Probabilistic tests carry an element of uncertainty; microbial methods are probabilistic as are some physicochemical methods. Either type can be quantitative or qualitative, destructive or nondestructive, and/or online or offline. Whatever type of test it is, as always, test method validation is needed. Examples of each type (1) include:
- Deterministic Leak Tests
- Electrical conductivity and capacitance (high-voltage leak detection)
- Laser-based gas headspace analysis
- Mass extraction
- Pressure decay
- Tracer gas detection, vacuum mode
- Vacuum decay
- Probabilistic Leak Tests
- Bubble emission
- Microbial challenge, immersion exposure
- Tracer gas detection, sniffer mode
- Tracer liquid
There are also various package seal tests. These include closure application and removal torque, package burst, package seal strength, residual seal force, and airborne ultrasound (1).
The preceding tests are selected based on the likely failure mode of the package. The typical failure modes for the major primary packages are:
- Ampoules are typically 100% leak tested on line for mechanical or thermal cracks and poor initial heat sealing
- Glass vials may suffer from nonround necks and/or nonround stoppers
- Flexible containers (e.g., large-volume parenteral bags) may have poor welding, thin spots in the sheet, and/or mechanical damage during handling or autoclaving
- Blow fill seal containers may have poor heat seals or physical damage during handling
- Prefilled syringes have various failure modes but the suppliers will have qualified them under various stresses; pharmaceutical companies must ensure such a package will withstand any product-specific stresses during transportation, such as pressure changes, vibration, and temperature changes (e.g., freeze-thaw, summer heat, etc.) (4)
Container Closure Integrity over Shelf Life
The sterility test has been used as a CCI test for many years but suffers from severe flaws. For example, the test is prone to false positives and is essentially incapable of detecting anything but gross leakage (as the numbers in the next paragraph explain). The test is still with us because it remains the primary tool for testing sterility even though a passing result adds almost no assurance the lot is sterile. Conversely, a failing result must be taken as definitive—short of obvious contamination during the test. The probability of detecting a contaminated batch using the sterility test is expressed by the equation p = n(1 – (1 – c)), where p = probability of detection, c = true fraction contaminated, and n = number of units tested (8,9).
In a typical lot, it is apparent from media fills that the true fraction contaminated is less than one in 10,000 (c
Since the sterility test is so inadequate, using it as a CCI test during stability studies is unwise and raises a number of challenges. For instance, what does a failure at 24 months mean? Is your product’s package unsound? Must a company recall every lot of every product in that container-closure system and develop new primary packaging? Is it wise to base such important considerations on a test that is outmoded, laborious, time consuming, prone to false positives, and expensive? Clearly, a proper CCI test should be used (5).
The choice of a suitable CCI test is product and package-specific. Typically one or more of the deterministic or probabilistic tests discussed above are chosen as candidates and validated for use for the packaging configuration. The CCI test for an ambient-headspace, aqueous, 5 mL fill in a 5 mL glass vial with rubber stopper and aluminum seal drug product might be quite different from that for a dual-chamber, prefilled syringe with a lyophilized cake in one chamber and an aqueous solution in the other. Similarly ampoules and blow fill seal packages will require significantly different CCI tests.
In short, for parenteral products in particular, and liquid products in general (but also any other dosage form prone to container-closure failure modes during the shelf life), a proper CCI test provides assurance about the drug product postlaunch, thereby reducing corporate risk of compliance events. Since USP has recently boosted its CCI content, it can be assumed that regulators will soon begin giving the matter even more attention than it is already receiving during application reviews in Washington, D.C., and by investigators while doing onsite inspections (5,6). Companies are wise to anticipate this and begin addressing it internally.
Note: This article originally appeared in the PDA Letter, a publication produced by the Parenteral Drug Association. Oct 3, 2016
- USP <1207> Sterile Product Packaging— Integrity Evaluation
- Carroll, M. et al. PDA Technical Report No. 27: Pharmaceutical Package Integrity, 1998
- PDA, Aspects of Container-Closure Integrity, Technical Information Bulletin No. 4
- Forster, R. PDA Technical Report No. 73: Prefilled Syringe User Requirements for Biotechnology Applications. Bethesda, PDA, 2015.
- 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. FDA, February 2008
- Inspector’s Technical Guide, Leak-Testing Sealed Ampoules of Parenteral Solutions, U.S. FDA, April 28, 1972
- USP <381> Elastomeric Closures for Injections (Functionality Tests, Self-Sealing Capacity)
- Sadowski, M., et al. PDA Technical Report No. 30: Parametric Release of Pharmaceuticals and Medical Devices Terminally Sterilized by Moist Heat. Bethesda, PDA, 2012.
- Larocque, P., “Inconsistent Expectations Clash with Industry Best Practices for Sterile Products,” PDA Letter 51 (June 2015): 20–24, 41.
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