Comparison of Existing Methods for Assessment of CCI at Low Temperatures (Non-shaded = Advantage; Shaded = Inconvenient)
| Category | Modified He Leakage Method (ThermCCI) | Modified He Leakage Method | Headspace Analysis (e.g., Frequency Modulated Spectroscopy) |
|---|---|---|---|
| Sensitivity | High sensitivity | High sensitivity | High sensitivity detection possible. It can potentially detect submicron size effects when measuring time allows |
| Longer turnaround time (days) or a gas “bombing” procedure might be needed for sensitive detection (15) | |||
| Repeatability | Repeatability | Repeatability | For containers with liquid, potential “clogging” with product may prevent oxygen exchange and cause false-negative detections |
| Reference samples | Ability to use NIST-traceable standards for leakage | Ability to use NIST-traceable standards for leakage | Need to prepare reference samples |
| Leak size information | Provides fast information on leak size | Provides fast information on leak size | Dependent upon headspace, volume, pressure, or pre-vacuum |
| Speed | Fast: He is sprayed around the outside of the package (“outside-in” method) (31) | Total measurement time per sample unknown, i.e., time to reach equilibrium in a difussion controlled set up (“inside-out” method) | Fast |
| Direct/Indirect | Direct measurement | Direct measurement | Indirect measurement (measures changes in internal headspace: O2, CO2, water vapor, pressure). No direct assessment of a leak |
| Technology | He leakage is a well established method | He leakage is a well established method | Based upon frequency-modulated spectroscopy (FMS) |
| Temperature | Can adjust temperature (and test ramps) | Can adjust temperature (feasibility of ramps not known) | The test is limited to package that is transparent and contains a targeted gas with its concentration changing by leak. The method would not be able to detect leak in a container packaged and stored under atmospheric pressure because a leak in this container under atmospheric pressure would not result in a measurable change in the concentration of gas headspace |
| Destructive/Non destructive | Destructive (no inline testing, high toxic products) | Non-destructive (although it implies a puncture through the stopper and sealing, hence the flip-off cap needs to be removed and a needle pierced through the seal) | Non-destructive |
| Sample preparation | Extensive sample preparation | No need to remove product. However, for liquid-filled vials, the possibility exists of He absorption into liquid | Minimal sample preparation required, although it usually requires modified atmosphere packaging |
| Investment | Higher cost of leakage testing equipment | Higher cost of leakage testing equipment | Lower cost of leakage testing equipment |
| Correlation to microbial ingress | Correlation to mCCI already established, acceptance criteria available | Not available | Lack of correlation to mCCI (because gas permeation is not a direct measure of mCCI) |
| Other | Combination products/assembled devices that cannot be disassembled without jeopardizing CCI | Not applicable | Not applicable |
| Hard surfaces of rubber components, e.g., laminated tip caps, fully laminated component (hypothesis: large number of very small defects which results in high flow rates even if microbiological tightness is proven) | If He difuses out of the vials, this will slow down diffusion | With availability of headspace, with small clareances in headspace, it could detect the liquid | |
| Background He in the vacuum system | Background He in the vacuum system | Not applicable |