The global pharmaceutical industry has seen tremendous growth over the last few decades. The complex nature of the industry coupled with frequent breakthroughs has made it a favorite subject of scrutiny. Since any defect in the packaging of drugs can have serious consequences, assuring the quality of the packaging is of prime interest for every manufacturer. Pharmaceutical products are expected to be free from microbial contamination and safe to use right from production throughout their shelf-life. The drug’s stability can be adversely affected through contamination in the form of oxygen, humidity or microbiological ingress. In order to prevent such risks, integrity tests with high sensitivity are required.
Previously, only sterility testing was conducted on pharmaceutical packaging. However, when it was realized that sterility testing alone is not sufficient to hold the integrity of the medical products, the US FDA published Guidance for Industry for Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products. This emphasised the importance of verification of microbial barrier properties of a pharmaceutical product package (i.e., CCI). FDA defines Container Closure Integrity Testing (CCIT) “as the sum of packaging components that together contain and protect the dosage form”.
Container Closure Integrity Testing is a method of leak detection using a non-destructive packaging inspection system to prevent possible contamination. Such a test is essential since any defect in the container can cause external particles to enter the product, thereby reducing its shelf life. Implementing right Container Closure System has been of prime importance for a manufacturer as it affects both the product and the patient. Hence, the relevance of CCI Testing in the pharmaceutical industry has steadily increased over the years. Contaminants that can enter a product include micro-organisms, reactive gases, and other substances. CCIT ensures product quality is maintained from the point of manufacture throughout its distribution and use. Container closure systems include primary packaging components and secondary packaging components. Components such as a glass vial or syringe, which come into direct contact with the product, are primary packaging components. On the other hand, components that are crucial to ensure correct package assembly, such as aluminum caps, over stoppers etc. are the secondary packaging components
CCI Testing Methods
Container closure integrity testing can be performed in many different ways. Each method has its own merits and demerits. A number of factors have to be considered while selecting appropriate testing methods. These factors include, but are not limited to; the reliability of the test method, material of the primary package and inline versus an offline testing requirement. CCI testing methods can also be selected depending on specific desired outcomes. Examples of desired outcome include: identifying the presence of leak paths, understanding leak path’s location, evaluating leak rate for the whole package, and measuring potential for microbial ingress. The United States pharmacopeia released guidance in 2016 stating that deterministic methods are preferred over probabilistic test method.
1. Probabilistic methods
: Here, the testing methods are more traditional, and the accuracy of the result is uncertain. The probabilistic methods include the following:
- Microbial Challenge by Immersion
- Tracer Liquid Tests (e.g. Dye Ingress)
- Bubble Tests
- Tracer Gas (Sniffer Mode)
2. Deterministic methods
: Such methods provide quantitative results with a higher level of accuracy. The chances of errors are also minimal. The deterministic methods include the following:
- Electrical Conductivity and Capacitance Test (HVLD)
- Laser-based Gas Headspace Analysis
- Mass Extraction
- Pressure Decay
- Tracer Gas (vacuum mode)
- Vacuum Decay
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