Container Closure Integrity Testing (CCIT) is a critical quality check for pharmaceuticals. Maybe you are looking for the best method for your drug product fill, or you are trying to determine the difference between the methods. Maybe you have never heard of CCIT testing. In any case, this article will benefit you. We give a brief overview of CCIT testing, how it is done, and which method is regarded as the best in terms of test accuracy and drug product compatibility.
What is CCIT Testing?
Container Closure Integrity Testing (CCIT) is an assay that evaluates the container closure and its ability of maintaining a seal to keep potential contaminants out. Potential contaminants include microorganisms, reactive gases, and other substances. This test is required for parenterals, since the seal quality is critical to maintaining the sterility and quality of the drug product throughout its shelf-life. An inadequate seal can not only accelerate a drug product’s expiration, it can pose a significant risk to the patient’s health if the product loses sterility.
How do we measure container closure integrity?
There are several tests for measuring container closure, but the three most common tests are:
- CCIT by Dye Ingress
- CCIT by High Voltage Leak Detection (HVLD)
- CCIT by Vacuum Decay
We will go into each of these methods in depth.
CCIT by Dye Ingress
The Dye Ingress test is both a destructive and probabilistic method for measuring container closure integrity. For dye ingress, samples and positive controls are submerged into a dye bath. They are subjected to pressure cycles, and they are then visually evaluated or alternatively evaluated by spectrophotometry.
The Dye Ingress test is certainly the least expensive method for measuring container closure integrity, but it comes at a cost in quality. Dye Ingress tests are heavily influenced by operator error. They run the risks of false negatives and false positives due to variance in inspector capabilities. Dye Ingress tests have neither defined standard conditions for inspection, sensitivity, nor reliability. Furthermore, this method is destructive. Samples are contaminated via analysis, and thus consumed by the test. Method development and validation, alone, consume a significant number of units, and this should be understood by the client before they proceed with this method. Finally, the efficacy of Dye Ingress tests decreases if the material is opaque or has a color that interferes with the color of the dye, so it is often not a viable option for some drug products.
CCIT by Dye Ingress is still offered at some laboratories, but it is not considered best practice for testing container closure integrity. CCIT testing is critical to evaluating the safety of a drug product lot. Since Dye Ingress tests are probabilistic, we do not suggest this method for any of our clients.
Advantages:
- Less expensive test
Disadvantages:
- Tests results are based on operator observations, and can therefore cause false positives or negatives very easily
- No defined standard conditions for inspection, sensitivity, or reliability
- Destructive
- Does not work well for opaque or colored drug products
CCIT by High Voltage Leak Detection
High Voltage Leak Detection (HVLD) tests measure container closure integrity by passing a high-voltage probe or brush along the exterior of the container of a product that is electrically conductive. Since the container (which is typically made up of glass, plastic, and rubber) is non- or semi-conductive, a defect in the closure will allow electrons to pass through the highly conductive solution. This will cause an increase in the recorded electrical conductivity. The method is very sensitive.
Despite this test’s high accuracy and deterministic approach, HVLD can only be tested on non-combustible, liquid drug products. The product must also have a higher conductivity than the packaging components. Furthermore, it’s recommended that the effects of exposing the material to electricity be fully understood if the analyzed unit is to be used for other tests.
Advantages:
- Very sensitive and high accuracy test
- Non-destructive
Disadvantages:
- Only effective for drug products with high conductivity
- Cannot be used for combustible or organic drug products
- Electricity may have an effect on product. If the effect is not fully understood, then this will limit use of analyzed samples for additional testing.
- Expensive
CCIT by Vacuum Decay
Vacuum Decay testing offers non-destructive, deterministic CCIT. The test method is simple. The sample is placed in a test chamber (this is a closed environment). The chamber is fixed with a vacuum, and, during analysis, a vacuum is pulled to remove the dead space around the container. Once the dead space is removed, the vacuum is turned off. Pressure changes in the environment is monitored over a set period time. If the container closure is defective, gas will leak out of the container, causing the pressure to rise (i.e. vacuum decay is observed). If the container closure is effective, no gas will leak, and the pressure will remain the same overtime.
This test is regarded as the most sensitive test for CCIT. Some tests can measure defects as small as 1 µm , which effectively means a 10 µm or even a 3-5 µm detection is done very comfortably and reliably. The test does not destroy the units that are sampled, so analyzed samples can be used for additional testing. The test works well with lyophilized and liquid products, and the efficacy of the test is unaffected by conductivity, combustibility, clarity, and the color of the drug product and its component closure system. The test requires only a few seconds or minutes to complete.
Advantages:
- Very sensitive and high accuracy test
- Non-destructive
- No effect on the drug product
- Effective for every product type, including lyophilized products
- Fast – results are produced in seconds to minutes
Disadvantages:
- Expensive
What is the best method?
Historically, dye immersion and microbial immersion were the two leading methods for CCIT. Recently, the USP issued guidance to require deterministic methods to achieve more reproducible and predictable results.
USP <1207> encourages a move towards the more deterministic methods, this recommends that dye immersion tests are avoided and HVLD or vacuum decay tests are used instead.
If we compare all tests discussed, vacuum decay is the best method for CCIT. The method is completely non-destructive, compatible with all drug product types and container closure systems and does not affect the product. The test is also the most sensitive out of the three.
