Basics on the Integrity of Container Closure Systems
Excerpt from the GMP Compliance Adviser, Chapter 12.G.2, Basics on the integrity of container closure systems
4 min. reading time | by Raimund Brett
Published in LOGFILE 25/2025
The integrity of a primary packaging system (container closure system) is essential to prevent product loss by leakage or evaporation and at the same time protect the product from contamination. The task of a primary packaging system (container closure system) is essentially to prevent the product from being lost (e.g. leakage, evaporation, etc.) and to prevent the product from being contaminated from the outside.
Primary packaging (systems) can consist of one or more components. Examples include ampoules (only one component, glass) and vials (multiple components including a glass container, a stopper (rubber) and a cap (aluminium)).
The following definitions can be made with regard to leaks:
- Lack of tightness/Poor seal integrity: A gap or break in the packaging system through which liquid or gas can escape
- Leakage: The unintentional ingress or escape of substances (solid, liquid, gaseous) through a gap in the packaging or a gap between packaging components
A tight or integral packaging system is one that has no breaks (gaps or damage) that could potentially jeopardise the quality of the product.
For packaging systems used for sterile products, leaks could be divided into three categories according to Figure 1 (based on the USP monograph).
Container Closure Integrity Failures for Sterile Products | ||
Category | Leak type (gap / break) | Product quality risk |
1 | Ingress of microorganisms | Failure of sterility |
2 | Escape of product |
|
3 | Penetration of water vapour, air (oxygen) | Failure of physicochemical quality attributes and/or impaired product access by the end user |
Figure 1 Categories of leaks (according to USP <1207>)
This means that the container closure integrity of a packaging system is not defined per se by passing a microbiological challenge test or a product sterility test. A leak-tight packaging system is one that complies with the Maximum Allowable Leakage Limit (MALL). This limit always depends on the requirements of the product, e.g. specified in mbar*l/s.
It is therefore clear that the seal quality of the container closure system depends on the product and its specific requirements.
USP <1207> identifies categories of the quality requirements on product packaging, as shown in Figure 2:
Quality requirements for the packaging system | |
Category | Requirements |
1 |
|
2 | Sterility, product formulation and gas headspace must be preserved. |
3 | Sterility must be preserved; product access is required (e.g. multi-dose vial). |
Figure 2 Categories of quality requirements of the primary packaging system in accordance with USP <1207>
Category 3 as a sub-category is applicable for multiple dose containers and it can be included either in category 1 or 2. When combining categories 2 and 3, this means that the requirements for the MALL will shift in the product cycle. Category 2 applies after filling and for storage, but the reduced requirements of category 1 apply during use.
There are several studies available on the leakage rates that can be assumed for sterile products. However, due to their complexity, they will not be discussed further here. For detailed information, we recommend studying USP <1207> to <1207.3>. In general, it can be assumed that a helium leakage rate of < 6 x 10-6 mbar*l/s (Kirsch, et al.; PDA J Pharm Sci & Technol 51, 5, 1997) for non-porous, rigid packaging such as vials, prefilled syringes, cartridges, BFS plastic ampoules, ampoules, etc. represents a low risk of microorganism penetration or liquid product loss. This corresponds approximately to a leakage through a defect of 0.1 to 0.3 µm.
It should be reiterated here that the Maximum Allowable Leakage Limit (MALL) is specific to each product/packaging system and must be determined based on scientific data and risk. Knowing the MALL is important as there are different ways of testing for leaks and not all methods are equally suitable for every leak type or MALL. Therefore, if necessary, multiple leak testing options should be available.
Do you have any questions or suggestions? Please contact us at: redaktion@gmp-verlag.de
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