Historically, container closure integrity testing was largely treated as a formality; a check-box to be ticked before submission. After all, to a company which had just gone through the intense process of developing a drug to bring to market, the package is just something to put it in. Even within the field of container testing, the regularity and scientific rigor with which integrity testing was pursued paled in comparison to other container tests, such as chemical characterization, moisture permeation, and light transmission.

The classic “study goal” for CCI testing was to demonstrate sterility for filing purposes. The 1999 packaging guidance released by FDA mentions container integrity as a requirement, but only directly ties it to the concept of microbiological integrity and sterility, hence the resulting popularity of microbial ingress as a test method: if we submerge a unit in a microbe-filled bath, and nothing grows in it, it must not leak, right?

Problems stemming from this type of thinking, including recalls, along with advanced packaging requirements of new drug product formulations and their associated container systems, has initiated a 10+ year trend of increased focus on package integrity issues and assurance. Perhaps the most complete exemplification of this is the revised USP <1207> – Package Integrity Evaluation – Sterile Products. Under the new <1207>, the concept of package integrity is not limited to entry of microoganisms that pose a risk to product sterility, but includes ingress or egress of any material that could have an impact to product quality and safety, stating:

“Suitable container–closure systems adequately store and protect the contained pharmaceutical product. Thus, sterile product–package integrity is the ability of a sterile product container–closure system to keep product contents in, while keeping detrimental environmental contaminants out. Specifically, leaks of concern for sterile product–packages include the following three categories described in Table 1. In other words, the leaks of concern for a given product–package are a function of the degree of package protection demanded by the product to ensure that all relevant product physicochemical and microbiological quality attributes are met through product expiry and use.”

Leaks of Concern Product Quality Risks Posed by Leaks
Capable of allowing entry of microorganisms Failure of product sterility quality attribute
Capable of allowing escape of the product dosage form or allowing entry
of external liquid or solid matter
Failure of relevant product physiochemical quality attributes
Capable of allowing change in headsspace content. For example, loss of headspace inert gases (e.g., nitrogen), loss of headspace vacuum,and/or entry of gases (e.g., oxygen, water vapor, air). Failure of relevant product physiochemical quality attributes and/or hindrance of product access by the end-user

This concept of “leaks of concern” is directly related to the maximum allowable leakage limit (MALL). There tends to be much confusion around the MALL, though at its core, it is a fairly straightforward concept: What is the leak size / rate at which there is a risk to product quality or safety over its intended shelf-life and use?

Furthermore, as part of a comprehensive risk assessment and mitigation strategy, the chapter describes package integrity verification during three product life cycle phases: 1) package development, and package processing and assembly validation; 2) product manufacturing; and 3) commercial product shelf-life stability assessments. This is a critical distinction to be made from historical practices, in which a finished product-package system was “verified” for integrity using a microbial or dye ingress test. Under current best practices, integrity assurance should be built into the package system and an integrity profile generated throughout the lifecycle.

Often times, a comprehensive CCI strategy includes implementing numerous CCI methods to address unique study goals. A strong preference is placed on deterministic methods based on predictable physicochemical phenomena quantitative in nature, compared to probabilistic methods, which rely on a series of probabilistic events (such as microbial ingress and growth), and tend to be qualitative in nature. Other assays, control strategies, and procedures that do not directly test CCI, but may directly characterize or influence it, can and should be included in a comprehensive CCI package. Package component vendor qualification, incoming lot inspection, and in-process residual seal force (RSF) testing are examples of this, defining and ensuring good “inputs” to create container systems.

Understanding the complex inter-workings of requirements, product-package limitations, CCI test options, and broader control and risk mitigation strategies requires an experienced team. CS Analytical consists of founding members of the world’s first cGMP, FDA-registered contract CCI laboratory housing all deterministic technologies as listed in USP <1207>. The resulting laboratory set standards and best practices for industry still used today, many of which are directly incorporated into USP <1207>. CS Analytical is the most trusted source for designing and implementing a comprehensive container closure integrity strategy to industry best practices that reduce organizational risk and exceed regulatory expectations.