In my most recent blog, I discussed the single most prevalent trend in the field of modern container closure integrity testing: the adoption of deterministic, quantitative test methods. 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, CCIT at multiple product lifecycle stages is explicitly discussed in the proposed revisions to USP <1207>.
In the proposed revisions to USP <1207>, currently in USP PF, 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.
In the first step, the inherent integrity of the chosen product-package system should be evaluated, essentially answering the questions “Are these components, when mated optimally, capable of creating an integral seal?”. Furthermore, one may wish to evaluate processing variables, such as sterilization techniques, etc., and their impact, if any, on CCI. In manufacturing, CCIT may be used as part vendor qualification, in statistical sampling and analysis of containers off the line, etc., and CCI testing as part of a stability program demonstrates the ability of the package to remain integral over the shelf-life of the product.
Until recently, assessment of CCI during product-package development and manufacturing was not a widespread practice. Considering a lack of guidance, CCI was frequently treated as a “check-box” in a filing, something that can be confirmed once other determinations have been made. Frequently, this approach leads to something I call “reactive CCIT”, in which an integrity issue that could have been avoided arises late in the product development or release process. An example of a “reactive CCIT” program would be as follows: the client produces two lots of product in screw-cap bottles, only to find that there are a significant number of packages that are leaking in one of the lots. In cases like these, clients frequently ask us to develop and validate a test method to screen out the leaking packages from the lot. These types of programs are particularly taxing on both the contract lab and the client company: there is high risk, a condensed timeline, and significant cost associated with rejecting an entire lot.
Unfortunately, I frequently tell the client that this situation could have been avoided. If considering the same screw-cap container, subsequent investigation may reveal that the troublesome lot did not have adequate torqueing of the closure. If a study incorporating torque values was performed in the package-development stage, the client would have an idea of the appropriate torque range shown to correlate with a low probability of leakage. For example, a study may have sample sets of packages assembled with different application torques, and evaluated by a helium mass spectrometry method, the most sensitive quantitative method currently in our arsenal of deterministic CCIT methods. Studies such as these establish optimal application torque values, as well as expose any issues with the inherent ability of the package to create an integral seal. If performed early on in the product-package development process, data generated through such studies can support changes to the package components used or the way they are assembled, thus reducing risk of leakage later in the pipeline. Studies like these are what I would call “Preventative CCI”, in which the behavior of a chosen package system is characterized prior to implementation.
Preventative CCI programs can present themselves in a number of ways. Characterizing the torque vs. leak rate of a product-package system is only one example. Another example is the use of CCI tests such as helium to choose packaging components. For a manufacturer considering the implementation of one of four stoppers or plungers, for example, a helium leak test study can be developed in order to assess the relative performance of each component. In my experience, there can be a significant difference between stoppers with the respect to their ability to create adequate seals.
Another preventative CCI program frequently conducted at Whitehouse Labs is what we call 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 (possible 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, 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, if product is being manufactured at 3 sites, the identified capping settings can be employed at each site. 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, capping processes are likely under control. Although this does not guarantee package integrity, it provides an added layer of control.
In recent years, the number of requests for “reactive” CCI programs has significantly diminished while there has been a dramatic increase in requests for “preventative” CCI programs, which characterize the package prior to its implementation. As inherent CCI continues to become a topic regulatory agencies are more interested in, it is likely this trend 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.