Container Closure Integrity (CCI) testing is a central aspect of contamination control for a product. Contamination control strategy begins with the design, qualification, and validation of a facility, equipment, and processes. Product containers and closures are a crucial element of contamination control.
Package integrity is the ability of the package to prevent loss, maintain sterility, and maintain the internal environment (such as headspace).
In 2008, the FDA issued a Guidance on Container Closure Integrity Testing (FDA Guidance Container and Closure System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products February 2008 (here). In that document, the FDA put forth the idea that although sterility testing must be performed on release, alternative testing to verify the integrity of the container closure system (CCI) may be performed as part of the stability protocol. Alternative tests may be advantageous because they may detect a breach in the container/closure before contamination, may take less than seven days, may allow the sample to be used for other tests if the CCI method is non-destructive, and may have reduced risk of false positives.
Since then, there has been an increasing focus in the industry on CCI throughout the product lifecycle. The product lifecycle includes early-stage development of components and design, controls for incoming components, manufacturing equipment and processing, storage and transport, and stability of the product through its shelf life.
Critical product parameters to be controlled can include sterility, headspace, and means of access to the product in the container. Aspects of the product packaging can include complex package designs such as syringes, syringe assemblies, and bulk containers. There can be unique challenges based on the materials of construction, design, and manufacturing processes.
More than one CCI test method may be appropriate for a product, depending on the stage of the product in development and the critical parameters to be controlled at that stage. Test method selection should be based on the ability of the technology to test the product container integrity for the specific product at the Maximum Allowable Leakage Limit (MALL) at that stage of the lifecycle, based on the type of defects expected. A risk assessment in accordance with ICH Q9, Quality Risk Assessment, can be used to guide decision making. For example, for a sterile product during the development stage, a company may decide to assess a container-closure package with a test method capable of detecting 0.1-0.3 micron leaks to assess the risk of sterility failures. At a later stage such as shipping, a risk assessment based on defects found may determine that the most probable defect outcomes for the product are detectable by another test method that has a higher MALL.
Probabilistic test methods, such as dye ingress, microbial challenge, and bubble emission are less preferred as they are not readily quantifiable, more uncertain, and more difficult to validate. The detection limit for these types of methods may be higher and harder to define. Deterministic methods such as vacuum decay, pressure decay, laser-based gas headspace analysis and others are more reproducible, quantitative, and often less invasive.
As with all analytical test methods, the test method selected must be appropriate to the product and its container and be proven through scientifically acceptable studies to be capable of detecting a breach in the container closure system at the MALL identified to be appropriate for the life stage of the product. Positive controls consist of leak artifacts, which may be products with leaks that are due to defects. However, it can be difficult to obtain naturally occurring product leaks that are consistently measurable. Some positive controls, especially those that are used to test the MALL and the Limit of Detection (LOD) have simulated defects with a known geometry (laser bored holes, for example). The ideal test method validation is conducted with both naturally occurring and simulated defects as positive controls.
An upcoming USP chapter (USP <382>) to become official on December 1, 2025, describes requirements for functional suitability of elastomeric components of parenteral products. The chapter is applicable to vials and bottles with elastomeric stoppers, syringes with elastomeric plungers that have needle shields or tip caps, cartridges with elastomeric plungers and lined seals, pen, jet and related injectors with elastomeric components, blow-fill-seal plastic containers with elastomeric lined caps, and infusion containers that have elastomeric ports. This chapter delineates requirements for testing packaging systems for CCI, including establishment of MALL and sampling of product units. When it becomes effective, pharmaceutical companies will be expected to be able to show adherence to the requirements of this chapter.
If your firm needs guidance regarding appropriate development of CCI testing strategies, Lachman can help! Please reach out to us at LCS@Lachmanconsultants.com for a consultation.
References
USP <382> Elastomeric Component Functional Suitability in Parenteral Product Packaging/Delivery System
Annex I (EudraLex Volume 4)
USP <1207> Package Integrity Evaluation-Sterile Products
USP <1207.1> Package Integrity Testing in the Product Life Cycle-Test Method Selection and Validation
USP <1207.2> Package Integrity Leak Test Technologies
USP <1207.3> Package Seal Quality Test Technologies
PDA Technical Report 86 Industry Challenges and Current Technologies for Pharmaceutical Package Integrity Testing (2021)
FDA Guidance Container and Closure System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products February 2008
