Written By BRANDON ZURAWLOW / Chief Scientific Officer

Adoption of deterministic, quantitative test methods for comprehensive container closure integrity testing (CCIT) has become the norm over past two decades. This trend has largely been driven by recent and pending regulatory guidance. However, as is common with many guidance documents and requirements, they incorporate best practices that have been observed in industry. Thus, the increasing scrutiny of container closure integrity strategies by regulators, and the resulting increased complexity for regulated companies, is not in vain. The benefits of deterministic container closure integrity methods are plentiful, and their usage can span the entire lifecycle of a product-package system, right from development of the package, assembly validation, to stability, to analysis of package integrity after distribution cycles. In fact, the need for container closure integrity testing at multiple product lifecycle stages is explicitly discussed in USP <1207>.

This largely has to do with the fact that container closure integrity testing, or simply package integrity, can be considered an attribute – it may be helpful to draw parallels between the concept of package integrity and drug stability. For example, the stability of a drug product can be impacted by numerous factors – storage temperature, moisture, oxidation, pH shifts, extractables and leachable as well as other critical elements. Throughout the drug development and manufacturing lifecycle, including the formulation and scale-up process, variables impacting drug stability are evaluated and risk to patient safety is minimized. It would be inconceivable to move straight from discovery to manufacturing. In addition, each drug product must be considered in its own light. Container closure integrity should be considered in the same way. There are a number of variables that impact container-closure integrity, and these variables are present at different lifecycle stages of the product.

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 container closure integrity testing and 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 container closure integrity 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 container closure integrity testing as a checkbox. For example, something verified as a company is assembling documentation for a filing, perhaps after the package configuration and manufacturing process has been finalized. This latter approach has inherently more risk. What if the vial-stopper configuration chosen does not have an ideal fit, causing leakage or machinability issues? What if the assembly parameters used for capping the vial do not consistently yield product-packages with container closure integrity? What if the vial, stopper, and crimp seal are unable to maintain integrity during shipment on dry ice? Situations like this are not uncommon, and can lead to expensive design and process changes, product recall, or risk to patient safety. Fortunately, container closure integrity strategies incorporating studies using modern, deterministic methods can help characterize and mitigate these risks by directly evaluating them throughout the product lifecycle.

While the benefits of batch-release testing and stability samples are relevant in the broader context of successful container closure integrity testing strategy, the purpose of this blog is to provide examples of critical container closure integrity studies that are relevant in earlier product life-cycle phases, namely prior to final product submission and regulatory approval.

Early on in the development process, the inherent integrity of the chosen product-package system should be evaluated, essentially answering the question: “Are these package components capable of creating an integral seal when used together in my anticipated use-case?”. This concept is called inherent integrity, which may be re-defined as whether the package components, as an inherent function of their physical and/or chemical properties, can create and maintain an integral seal.  Oftentimes, this question is answered using empty packages – allowing for more flexible study design and increased sensitivity relative to product-filled units. It is well-known that the presence of product in the package system can interfere in certain cases – clogging of small defects being a good example. Testing empty packages in early stages thus makes testing to the maximum allowable leakage limit a more achievable goal.

For a manufacturer considering purchase of a vial stopper from a catalog or existing stock of many options, for example, a leak test study can be developed in order to assess the relative performance of each component. There can be a significant difference between stoppers with the respect to their ability to create adequate seals, regardless of capping conditions, possibly due to dimensions or incompatible elastomer coatings, which will be further explored in upcoming CSA blogs.

That said, a specific, upstream and preventive CCI study 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).

After creation, the percent 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 are measured, often over time. The third, and most critical part of the triad, is sensitive leak testing using helium leak detection or headspace analysis. 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 that also correlates to low propensity for leakage.

If the package system is expected to maintain integrity after certain other process variables, such as sterilization, or distribution on dry ice, for example, this also represents an ideal time to evaluate the impact of those variables on container closure integrity. By incorporating storage on dry ice, for example, headspace analysis may be used as the leak detection method of choice – measuring ingress of CO2 into the package system over time as an indicator of leakage.

The correlations between capping parameters, RSF, and leakage can be immensely valuable. For example, this work can be performed at the lab-scale level for development purposes, helping to inform final settings in manufacturing. While it may not be feasible to take lab-scale capping parameters and replicate them on manufacturing equipment, manufacturing capping settings can be tailored to yield package RSF data in line with laboratory results. Package systems produced on that full-scale line may be further evaluated for container closure integrity 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 three different 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 check. 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. Not all CCI control strategies are leak tests themselves. Visual inspection for cracks is another risk mitigation strategy that is relevant for CCI, but not sufficient alone to demonstrate it.

Numerous capping optimization and assembly validation studies like these have been performed using LDA SIMS 1284+ helium leak detectors and Lighthouse Instruments headspace analysis instruments. As the concept of container closure integrity testing, and inherent container closure integrity specifically, continues to be a topic regulatory agencies are more interested in, it is likely that this trend of evaluating container closure integrity 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 may prevent costly component changes down the road, and can lead to safer, less recall-prone packaging.