The adoption of deterministic, quantitative test methods for comprehensive container closure integrity testing (CCIT) has become the norm over the past decade. Recent and future regulatory guidance directives have continued this trend. However, this trend of increasing scrutiny, and thus, increasing complexity for regulated companies, is not in vain. The benefits of such a method are plentiful, and their usage can span the entire lifecycle of a product-package system, right from development of the package, to stability, to analysis of package integrity after distribution cycles. In fact, the need for CCIT at multiple product lifecycle stages is explicitly discussed in USP <1207>.
In the current version of USP <1207>, there are a total of four subsections. USP <1207.1> discusses critical background information and rationale for the selection of an appropriate test method. Included in this subchapter 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.
This is a notable shift from the somewhat pervasive tendency to consider CCI as a checkbox, something verified as a company is assembling documentation for a filing, perhaps after the final configuration and manufacturing has been finalized. This latter approach has inherently more risk. What if the vial-stopper configuration chosen does not have an ideal fit? What if the assembly parameters used for capping that vial do not yield consistently integral final packaging? Situations like this are not uncommon, and can lead to expensive changes, product recall, or risk to patient safety. Fortunately, modern, deterministic methods, such as helium leak detection, can help characterize and mitigate these risks.
Early on in the development process, the inherent integrity of the chosen product-package system should be evaluated, essentially answering the question: “Are these components, when mated optimally, capable of creating an integral seal?”. This concept is called inherent integrity, or whether the package components, as an inherent function of themselves, can create and maintain an integral seal. For a manufacturer considering the implementation of a stopper from a potential catalog or stock of many varieties, for example, a helium leak test study can be developed in order to assess the relative performance of each component. In the experience of LDA and its partners, there can be a significant difference between stoppers with the respect to their ability to create adequate seals, regardless of capping conditions. Future blogs in the LDA resource center will highlight these applications.
A specific, upstream and preventive CCI program that is gaining in popularity 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 helium leak testing. As each set of samples undergo helium 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.
The correlations between capping parameters, RSF, and helium leak rate 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 by helium leak detection as final confirmation and as part of a complete assembly validation for the product-package system and its assembly processes.
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. 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 control, and can be referred to as an ongoing seal quality test. Similarly, helum leak detection can be employed on a routine basis for additional confidence, as helium would be considered a true seal integrity test.
Numerous capping optimization and assembly validation studies like these have been performed using LDA SIMS 1284+ helium leak detector and LDA’s unique range of accessories 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.
