Correlating Residual Seal Force to Container Closure Integrity

Residual seal force (RSF) is the force a stopper exerts on the vial flange surface after a vial is capped and crimped. Described in USP <1207.3> Package Seal Quality Test Methods, RSF testing is a seal quality test, not a leak test. It indicates the quality of the vial package seal and gives insight into the sealing process that produced it.

For a sterile injectable stored at -80°C, good and consistent seal quality is critical to maintain container closure integrity (CCI) at these extreme temperatures. A CCI test tells you whether a container leaked. RSF data tells you how your capping and crimping process created the seal. This case study shows how both data sets were combined into one packaging and process development approach for a vial product requiring deep cold storage.

The CCI of a vial depends on the quality of its seal, and that seal is set during capping and crimping. Deep cold storage adds stress to the seal: at low temperatures, elastomeric stoppers will lose their elasticity, and different vial-stopper combinations can respond very differently to the same sealing process.

Deterministic CCI test methods have given the industry a much clearer view of how primary packaging performs. Ensuring good CCI of a sterile injectable, however, goes beyond CCI testing alone. Correlating RSF testing within the USP <1207> framework to CCI data allows you to optimize and validate the vial sealing process with parameters that give assurance of good CCI.

Carefully designed CCI studies were performed on statistically valid sample sets of stoppered vials. Four capping and crimping settings were used, covering a range from loosely to tightly capped and crimped vials. This produced samples across a wide range of RSF values. Two vial-stopper combinations were tested to find out whether specific primary packaging components could retain CCI at -80°C.

A headspace CCI test method was developed for these storage conditions. The samples were placed in a -80°C freezer containing dry ice, which created a CO₂-rich atmosphere. Any leaking container would therefore ingress CO₂ during storage. Directly after storage, headspace CO₂ analysis was performed non-destructively on each vial: an increase in CO₂ indicated a leak, while no significant increase meant the packaging had remained intact.

The method was checked against positive controls: microwires placed between stopper and vial neck to create undefined sub-micron leaks, laser-drilled vials with well-defined micron hole leaks in the vial body, and gross leak samples. Negative controls completed the data set.

Same sealing settings, same storage conditions, same test method. The two sets of primary packaging components behaved in completely different ways.

Vial-stopper combination X showed high CCI failure rates unless the vials were tightly capped and crimped. To maintain CCI during deep cold storage, this combination requires consistently high RSF values.

Vial-stopper combination Y maintained CCI over the full range of capping and crimping settings and corresponding RSF values, even when loosely capped and crimped.

The choice of primary packaging components can clearly be as decisive as the sealing process itself. For a related study on how vial and stopper selection affects CCI at cryogenic temperatures, see our case study on achieving CCI during cryogenic storage with an optimized vial-stopper combination.

The practical payoff is process design space. A combination that only holds CCI at high RSF leaves little margin in your sealing process. For combination Y, the vial sealing process can be validated with a much larger process design space that still delivers good CCI.

Robust data on seal quality and CCI can support several activities across the product life cycle:

• The choice of appropriate primary packaging components
• Validation of the capping and crimping process
• Implementation of an effective CCI control strategy

Statistically valid correlations between seal quality and CCI enable you to make science-based decisions about your packaging and sealing process, even for deep cold storage. Once a product is in routine manufacturing, a control strategy can extend to inspection of every container, as described in our case study on 100% container closure inspection of freeze-dried product in quarantine.

Download the case study for the full RSF-CCI correlation data, or talk to one of our application scientists about generating seal quality and CCI data for your own vial-stopper combinations.