Container Closure Integrity Testing

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CCIT stands for Container Closure Integrity Testing or seal Integrity Inspection, which is defined by USP1207 as: any packaging leak test (physicochemical or microbiological) that detects a break or breach in the packaging, some tests may also be able to identify the size and/or location of the leak. CCI, which stands for Container Closure Integrity or container seal Integrity, is the ability to ensure that a drug product continues to meet safety and quality requirements.

CCIT is a means to check the stability of aseptically packaged drugs during production, transportation, shelf life and packaging integrity during use, with the aim of preventing the loss of drugs, microbial invasion, leakage of headspace (oxygen, nitrogen, etc.) or the entry of other substances in the package.

The development of CCI should be considered at the same time in the process development phase of the drug. CQA and CPP related to CCI may include the packaging method of the drug, the choice of sealing material, the CCI testing method, the MALL (maximum allowable leakage limit), etc. The development of CCI should focus on the key factors that affect CCI, such as: critical steps, process conditions (including upper and lower limits of the control range), production lines, and historical experience of the packaging system. The outputs developed by CCI also serve as the basis for the URS of the system or equipment, which may include: instructions for the procurement of packaging components, requirements for cleaning, sterilization and molding of packaging materials, requirements for sealing or assembling equipment, requirements for drug stability, storage and distribution environment, and ways of drug use; Through the development of CCI, the MALL of drugs can be identified; The development of CCI also provides more basic information for the selection of CCIT methods.

CCIT must be validated before it can be used in commercial production. Through verification, a deterministic method with sensitivity covering MALL is selected. The choice of MALL for rigid packaging is 6×10-6mbar·L·s-1, equivalent to a pore size of 0.1 to 0.3μm, and the selection of this conservative MALL ensures that the risk of microbial invasion and liquid leakage is low, thus avoiding the need for additional studies (such as microbial or liquid invasion challenge experiments). If the maximum allowable leakage limit of the drug product is not clear or the sensitivity of the sealing test method does not reach the conservative pore size of 0.1-0.3μm, two methods (one of which recommends the microbial challenge method) should be compared and studied. The deterministic method (such as laser headspace analysis, pressure pack attenuation, etc.) and the probabilistic method (such as microbial invasion method) are respectively selected for the two methods. The selection of the method should be based on the evaluation results, and the one with higher sensitivity should be selected as the daily CCIT detection method by comparing the sensitivity of the two methods. CCIT validation challenges the extremes of CCI conditions.

In accordance with the requirements of EU-GMP Appendix 1- Sterile medicinal products, in commercial production, fusion-sealed glass ampoules, BFS units and small volume containers (≤100 ml) should be checked for 100% integrity using a proven method. For other types of packaging products, it is recommended to check 100% of the conditions, otherwise a scientific sampling strategy should be developed based on the knowledge and experience of the container and sealing system used, and the statistical data at the validation stage and the quality trend of the daily CCIT can also be used as a basis or reference for the development of the sampling strategy. CCIT in the commercialization stage should also pay attention to the adverse effects on CCI that may occur during the distribution, transportation and use of the drug (such as changes in environmental pressure and temperature, etc.).

The FDA's industry guidance, "CCIT Replaces Sterility Testing as Part of a Sterile Product Stability Protocol," notes that CCIT can replace sterility testing in stability studies, but not sterility testing at the beginning and final stability program evaluation. In other words, CCIT can be used instead of sterility test at other time points except the early and late stages of stability examination. Compared with CCIT, sterility testing has some disadvantages, such as: the test is destructive, only live microorganisms can be detected, the suitability of the medium, the test results are false positive, and the headspace cannot be examined. Because of these limitations, the FDA recommends the more reliable CCIT as an alternative to sterile product stability protocols. Samples that pass the CCIT test may be further used for other test items in that test cycle, but may not be placed and used in the next cycle.

When the packaging form, sealing method, production process, supplier and equipment of the product are changed, it is necessary to evaluate the impact of the change on CCI, and take appropriate control measures or initiate CCIT re-validation based on the evaluation results.

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