Drug product comes in a variety of forms, from liquid to frozen and lyophile. It is filled and stored in a number of container closure systems, including the common glass or plastic vial with rubber stopper and aluminum seal or plastic or glass syringe with needle assembly. In all cases and for all drug product forms, the container closure system must provide an integral barrier that protects stability and sterility of the dosage form for the duration of the product shelf-life. In 2008, the US FDA introduced a new guidance on container and closure system integrity (CCI) testing as a component of the stability protocol for sterile products.
The industry has responded to the regulatory expectations by introducing more precise and sensitive methods for testing the integrity of container closure systems. These methods can be divided into two main categories: one that covers all deterministic methods and the other that includes the probabilistic methods. The deterministic category includes a variety of methods:
- Electrical conductivity and capacitance test (HVLD)
- Laser-based gas headspace analysis
- Mass extraction
- Pressure decay
- Tracer gas (vacuum mode)
- Vacuum decay
The probabilistic category includes method such as:
- Microbial challenge by immersion
- Tracer liquid tests (e.g., dye ingress)
- Bubble tests
- Tracer gas (sniffer mode)
Of these methods listed above, the one most commonly performed is dye ingress testing. This method is quite reliable and fairly inexpensive to set up, as it does not require any special instrumentation, except for a spectrophotometer. It is also suitable for many different container closure systems and product formulations.
The method established at Charles River for Container Closure Integrity Testing (CCIT) is the dye ingress under vacuum. This method is the most common liquid tracer assay and referenced in USP <1207.2>. In this assay, the container and closure system holding the active dosage is immersed in a methylene blue solution and vacuum is applied to the container. The contents of each container are then subjected to spectrophotometry to measure for traces of blue dye in the container. The important factors to be aware of when conducting this test include the differential vacuum (or pressure), the compatibility of the dye with the product, the liquid viscosity and surface tension, and the assay sensitivity.
The acceptable limit for a “no ingress” result for the dye ingress test is based on the principle that “water cannot penetrate pores that allow less than approximately 10-5 scc (standard cubic centimeters) of airflow at a differential pressure across the seal of approximately 1 atmosphere” [PDA Technical Report 27 (1998)]. After applying a safety factor of 10, this equates to 1 µL of dye ingress during a 30-minute exposure at 0.6 bar of pressure. Thus “no ingress” is reported for cases when less than 1 µL of dye enters the sample container.
In addition to container closure testing being offered in Europe, Charles River has recently added this assay to our portfolio in the United States. For more information, contact us at [email protected].