Container Closure Integrity Testing

What is Container Closure Integrity Testing (CCIT)?

Container closure integrity (CCI) refers to the ability of a container and its closure system to maintain product integrity and prevent contamination or leakage. CCI has become a widely known topic in the industry as several recall cases have been linked to container closure integrity issues.

A well-known recall case occurred in 2012 when a large pharmaceutical company had to recall more than 60,000 vials of a cancer drug due to concerns regarding potential cracks in the vials.  In another instance, a medical device manufacturer recalled over 50,000 prefilled syringes in 2016 due to concerns regarding the potential for leakage. The recall was classified as a Class I recall.

These are just a couple examples of CCI failures and the downstream impacts which a lack of process can create.

Regulatory

As a critical safety and quality requirement recognized by the US FDA, there are many guidance documents and standards which dictate how drug manufacturers should approach container closure integrity. We highlight the most prominent regulations below:  

• FDA document “Guidance for Industry – Container and Closure System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products,” which recommends the use of CCIT as an alternative to sterility testing for products that are filled and sealed under aseptic conditions or those that are terminally sterilized.

• USP <1207> is a general chapter in the United States Pharmacopeia (USP) which provides a framework and recommendations regarding the evaluation of container closure integrity (CCI) for sterile and non-sterile pharmaceutical products. USP <1207> provides guidance on the selection and validation of CCI testing methods, sample sizes, use of positive / negative controls and the acceptance criteria for each method. Compliance with USP 1207 is required for the manufacture of pharmaceutical products in the United States.

• Annex I (also known as Annex 1) is a requirement for manufacturers of sterile medicinal products issued by the European Medicines Agency (EMA). Annex I covers a wide variety of topics.  CCIT is a critical component of Annex I because it states that a suitable and validated CCIT method should be used to ensure the integrity of the container closure system, and that the method should be validated for each product.  To many, Annex I is perceived as the counter part to the FDA; however, the EMA enforces these requirements as law, not guidance.  This is a significant difference for pharmaceutical companies operating in EU countries or planning to launch their product in the EU.

Framework of a CCIT Program

At the core, the most critical aspect of deterministic methodologies described in USP <1207> and Annex I is the requirement for analytical method development and validation.

The CCIT analytical method development and validation process involves several steps, including: 

• Method development: During this phase, test parameters begin to be defined that accurately and reliably detect any leaks or defects in the container closure system. The method should be sensitive enough to detect small defects, but not so sensitive that it detects false positives. 

• Method optimization: Once a method is developed, it needs to be optimized to ensure that it is robust and reproducible. This involves testing the method using a range of variables, such as temperature, humidity, and pressure, to ensure that it is reliable under different conditions. 

• Method qualification: After optimization, the method needs to be qualified to ensure that it meets specific criteria for accuracy, precision, and sensitivity. This involves testing the method using a range of samples and comparing the results to a reference method. 

• Method validation: Once the method is qualified, it needs to be validated to ensure that it is suitable for its intended purpose. This involves testing the method using a range of samples, testing conditions, and operators to demonstrate that it is reliable, accurate, and sensitive. 

With a greater focus more then ever on primary package systems regulations and requirements, DDL has established an extensive GMP laboratory encompassing the four (4) most widely accepted deterministic technology platforms.

• Helium Mass Spectrometer (HeLD) – As one of the most versatile instruments, HeLD provides helium leak rates for a myriad of package systems. While under vacuum, pass-fail criteria for the risk of microbial ingress can be evaluated to establish inherent integrity, as well as the impact of assembly process parameters.
  Learn more about HeLD

• High Voltage Leak Detection (HVLD) – This non-destructive test is highly responsive, with a submicron limit of detection. It has become popularized with pre-filled syringes as well as liquid-filled vials and syringes for reliable long-term testing.
  Learn more about HVLD

• Vacuum Decay (VD) – As one of the most robust deterministic testing technologies, this non-destructive test methodology can detect defects in the submicron region. With DDL’s capabilities to fabricate fixtures and flexible chambers, CCI test methodologies can be established with autoinjectors and vials filled with liquid or solid products. Additionally, test methodology for unique and even flexible package systems, such as IV bags and other complex devices, have been successfully established allowing DDL to provide solutions for most package systems.
  Learn more about VD 

• Head Space Analyzer (HSA) – Used heavily in lyophilized and cold storage product package systems, evaluation of the headspace concentration is used to determine the presence of leaks in the primary package system. With laser diodes tuned to a specified frequency, oxygen concentration and C02 concentration can be rapidly obtained. This non-destructive test methodology allows for evaluation of CCI for long term testing, cold storage shipping, and even cryogenic impacts of the integrity of the package.
  Learn more about HSA

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