The main methods to test CCIT on pharmaceutical products are:
Probabilistic methods (operator-dependant, give only a pass/fail result):
| Dye ingress test or Blue Ink test | destructive method |
| Water bath test (Bubble test) | destructive method |
| Microbial ingress test | destructive method |
Deterministic methods (give a numeric value as result, not operator dependant)
| Vacuum Decay | nondestructive method |
| Headspace Gas Analysis (HGA) | nondestructive method |
| Lid deflection test (on blister packs) | nondestructive method |
| High Voltage Leak Detection (HVLD) | nondestructive method |
| Mass Extraction | nondestructive method |
| Pressure Decay | nondestructive method |
| Helium leak testing | destructive method |
The regulatory authorities and the guidelines direct consensually the pharma industry to choose deterministic methods instead of probabilistic ones.
Deterministic methods have better quality and repeatability of the results that is the reason why they are preferred.
Probabilistic methods (basically Dye Ingress and Water Bath Test) are used for long time and require low-cost instruments, but the results are influenced by the subjective evaluation (human error), manual skills and adopted procedure, increasing the possibility of contradictory results. These destructive methods do not allow to repeat the test and it is possible to estimate the uncertainty of the method only indirectly.
Since they don’t have a numeric value, but just a pass/fail result, they are difficult to be compared with results of other laboratories, other instruments or different times: this causes a very low reproducibility.
The deterministic methods are non-destructive (except for the helium gas leak test) and consequently they gave the possibility to repeat the test on the same sample and define, in a reliable way, the measurement uncertainty.
In addition, these methods require low, or none handling (again, except the helium gas leak test) and minimize the variability due to the operator. These methods are based on instruments that perform automatic quantitative measurements and the result is a numeric output that can be saved, recorded and statistically analysed following the guidelines.
Between the deterministic methods, the most employed are:
- Vacuum Decay (can be used also online on the 100% of the product)
- Headspace Gas Analysis (can be used also online on the 100% of the product)
- High Voltage Leak Detection (that can be used also online on the 100% of the product)
The more accurate method (with lowest detection limits) is the gas leak test, usually done with helium, but it is a destructive method (no possibility to repeat the test), that require a complicated sample preparation and consequently it is not suitable for quality control on the production. This method is used as comparison on application studies or for development of new materials or types of containers.
In the next articles we will deepen the different methods, pros and cons, limits, problems and fallacies.
