The Application of CCIT in the Drug Lifecycle

The full name of CCIT is package integrity test or container-closure integrity test. USP1207 defines it as a container-closure integrity test, which is any package leak test (either physicochemical or microbiological) that detects the presence of a package breach or gap. Some tests may also be able to identify the leak magnitude and/or location. The full name of CCI is package integrity or container-closure integrity. CCI is the ability to ensure that drugs continuously meet safety and quality requirements.

CCIT serves as an approach for inspecting the package integrity of sterile packaged drugs during the manufacturing, transportation and transfer, shelf-life stability study, and during use. It is intended to prevent drug loss, microbial ingress, headspace gas (oxygen, nitrogen, etc.) leakage, or the ingress of other substances inside the package.

The development of CCI should also be considered during the process development phase of drugs. CQA and CPP related to CCI may include packaging methods for drugs, selection of sealing materials, CCI testing methods, MALL (maximum allowable leakage limit), etc. The development of CCI should focus on the critical elements affecting CCI, such as critical steps, process conditions (including upper and lower limits of control range), historical experience of production lines, packaging systems, etc. The outputs of CCI development also serve as the basis for system or equipment URS, which may include: packaging component procurement instructions, packaging material cleaning, sterilization, molding requirements, sealing or assembly equipment requirements, drug stability requirements, storage and distribution environment, drug dosage methods, etc. 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 being used for commercial production. Through validation, select a deterministic method with sensitivity that can cover MALL; The optional MALL for rigid packaging is 6 × 10-6 mbar·L·s-1, equivalent to a pore size of 0.1~0.3μm. The selection of this conservative MALL ensures a lower risk of microbial ingress and liquid leakage, thus eliminating the need for additional research (such as microbial or liquid ingress challenge experiments). If the maximum allowable leakage limit of the drug is unclear or the sensitivity of the integrity test method cannot reach the conservative pore size of 0.1-0.3 μm, then 2 methods (1 of which is recommended for microbial challenge) need to be used for comparison and study. The two methods are to choose deterministic methods (such as laser headspace analysis, pressure decay, etc.) and probabilistic methods (such as microbial ingress method), respectively. The selection of methods should be based on the assessment results. By comparing the sensitivity of the two methods, the method with higher sensitivity should be selected as the routine CCIT method. CCIT validation shall challenge extreme CCI conditions.

According to the requirements of EU-GMP Annex 1 Manufacture of Sterile Medicinal Products, in commercial production, glass ampoules, BFS units and small volume containers (≤100 ml) closed by fusion should be subject to 100% integrity testing using validated methods. For large volume containers (>100 ml) closed by fusion, reduced sampling may be acceptable where scientifically justified and based on data demonstrating the consistency of the existing process, and a high level of process control. Statistical data during the validation stage and routine CCIT quality trends can also serve as a basis or reference for formulating sampling strategies. During the commercial stage, CCIT should also focus on the possible adverse effects on CCI during drug distribution, transportation, and use (such as environmental pressure and temperature changes).

The FDA Guidance for Industry "Container and Closure System Integrity Testing in lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products" states that CCIT can replace sterility testing in stability studies, but cannot replace sterility testing at the initial and final stability protocol assessments. Except for the initial and final stages of stability study, CCIT can be used in lieu of sterility testing at other time points. Compared with CCIT, aseptic testing has some disadvantages, such as being destructive, only detecting viable microorganisms, suitability of the culture medium, false positive test results, and inability to detect headspace gases. Due to the above limitations, FDA recommends using CCIT, which has higher reliability, as an alternative method for the stability protocol for sterile products. The samples passed CCIT can be further used for other testing items in this testing cycle, but cannot be stored and used for the next testing cycle.

In case of any changes in the packaging form, sealing method, production process, supplier, and equipment of the product, it is necessary to assess the impact of the changes on CCI and take appropriate control measures or initiate CCIT revalidation based on the assessment results.

Parts of the article are derived from United States Pharmacopeia （USP）1207.