In the current version of USP <1207> is a detailed discussion of CCI evaluation during a product life cycle, which states: “Package integrity verification occurs during [at least] three product life cycle phases: 1) the development and validation of the product– package system, 2) product manufacturing, and 3) commercial product shelf-life stability assessments”. The idea behind such a statement is that CCI should be built into the design of the product-package system and the processes that yield it.
A specific, upstream and preventive CCI program gaining popularity as part of a full lifecycle approach to CCI verification is that of a “Capping Study”; a program in which optimal sealing parameters are determined through correlation with low leakage rates. In such programs, there are typically a range of sample sets assembled at capping parameters from very low (aluminum crimp seal barely applied) to very high (possibly yielding stress cracks in the vial neck area). These samples are subsequently assessed for % compression of the stopper and residual seal force (RSF), an indirect measure of the amount of force the stopper is applying to the land-seal of the vial. The third, and most critical part of the triad, is leak testing incorporating USP <1207> methodologies. As each set of samples undergo leak testing, differences in leak performance between the sets can be identified. An ideal set of capping parameters that correlates to consistently low leak rates can be determined. Additionally, an ideal residual seal force range can be identified. Furthermore, by incorporating component dimensional variation into the study design, component dimensional specifications can be established or verified, ensuring integrity performance across the possible matrix of package component dimensional stack-up / overlap / interference fit.
The correlations between capping parameters, RSF, dimensions, and leakage can be immensely valuable. For example, this work can be performed at lab-scale for development purposes, helping to inform final settings for a manufacturing setting. Manufacturing capping settings can be tailored to yield package RSF data in line with laboratory results. Package systems produced on that full-scale line can be further tested for leakage as final confirmation and as part of a complete assembly validation for the product-package system and its assembly processes. These studies can help evaluate risk of future component or process changes, where demonstration of “equal or better” performance may be required.
To further provide insight into the value of this approach, if product is being manufactured at 3 sites, the identified capping settings can be employed at each site, aiding in the transfer and validation process. More importantly, samples can be pulled from the line at each site and routinely checked by RSF as an in-process control. If the samples pulled off the line exhibit RSF values within a range that correlates to reduced risk of leakage and consistent with historical data, capping processes are likely under control. Although this does not guarantee package integrity, it provides an added layer of assurance, and can be referred to as an ongoing seal quality test.
Using a state-of-the-art Genesis Integra capper, which can accommodate a range of package sizes and forces, CS Analytical has both the equipment and in-depth experience to design and implement complete capping studies incorporating numerous variables. Numerous capping optimization and assembly validation studies like these have been performed using LDA SIMS 1284+ helium leak detectors and Lighthouse Instruments headspace analyzers for the pharmaceutical and medical device industries. As the concept of CCI, and inherent CCI specifically, continues to be a topic regulatory agencies are more interested in, it is likely this trend of evaluating CCI in package development and validation will become an expectation. However, this change is one that should be welcomed by industry. Evaluating components prior to their use potentially prevents costly component changes down the road, and can lead to safer, less recall-prone packaging, something CS Analytical remains at the forefront of.