Under international regulations, all companies operating in the pharmaceuticals industry are required to inspect the packaging of products that are ready to be sold to verify package integrity and, therefore, their ability to guarantee optimal storage throughout the product’s shelf life.
Tests of this type are essential to protect the health of patients who will use the drugs, and to ensure companies can operate safely, avoiding recalls of damaged product lots.
Container Closure Integrity Testing (CCIT) refers to all inspections identifying seal or structural integrity defects in pharmaceutical packaging. International regulations have established certain general criteria for such tests; however, the regulatory framework governing the sector is particularly complex because of the large repository of regulations that need to be taken into account. The most significant reference is the United States Pharmacopeia (USP chapter) <1207>. But there are also other compendia of standards, such as the European Union Annex 1, GMPs of various countries, and the American Society for Testing and Materials (ASTM) standards.
This diverse regulatory landscape does not clearly establish the required sensitivity level for CCI testing. While international regulations do identify test methods that manufacturers can use (inviting them to always perform deterministic tests and not probabilistic ones, where possible) and specify how these tests are to be conducted, they do not establish the minimum hole diameter a CCIT should be capable of detecting.
CCIT accuracy: Vacuum Decay Method (VDM)
A variety of test methods, including the vacuum decay method, can be used to inspect the integrity of pharmaceutical product packaging.
This test detects changes in the vacuum inside a test chamber into which the pharmaceutical product is placed. Once the product is inside, the machine creates a vacuum and takes two internal pressure level readings a few seconds apart. If the pressure difference exceeds a certain threshold value defined during machine calibration, the product is automatically rejected. This is because an excessive variation in the pressure value means that fluid is flowing from inside the packaging to the outside, due to the different pressure levels on both sides of the container wall.
It is important to calibrate the machine correctly, establishing the pressure variation threshold value above which the product must be rejected; this value is correlated with the minimum detectable diameter of the hole. International regulations, such as USP chapter <1207>, offer no clear guidance on this point, but merely state that the manufacturer must determine the quantity of “acceptable” loss, based on a risk analysis, available technologies and related costs. This last aspect is important because, while tiny losses can be identified, doing so requires oversizing the system, with a significant impact on cost. For example, the technology available to us today can detect extremely small holes, around one micron in diameter, but tests of this kind can only be done in the laboratory, and only a few products can be inspected per minute. A VDM machine designed to work on the production line must be able to analyse hundreds of products every minute, which affects its sensitivity level (which remains very high, detecting holes measuring about five microns in diameter).
The recommendations of the ASTM International standard
While the USP regulation imposes no precise value for maximum acceptable hole diameter, ASTM F2338-09 does provide a little more guidance. Based on a number of case studies, a number of ranges of hole diameters have been identified that are to be considered as targets for companies. For example, ASTM states that the maximum acceptable hole diameter in a one-millilitre syringe is five microns, while the acceptable size is increased to a few hundred microns for flexible containers. This different acceptability level is based on the fact that detection accuracy is greater for rigid containers, and lower for flexible test products. Similarly, small packaging and measurements taken in test chambers with little residual space outside the product offer higher levels of accuracy. Even the viscosity level of the drug can affect test results.
The large number of variables to be considered clearly shows how difficult it is to provide precise guidance on the acceptable leakage level, because so many elements affecting the accuracy of the final result need to be considered. This is why regulators are hesitant to set strict limits and prefer to provide only general guidelines, allowing manufacturers to take the final decision based on their own experience.
To determine which type of inspection should be conducted and to calibrate the machine for accurate results without excessively lengthening testing time, pharmaceutical companies depend on the advice of an expert partner like Bonfiglioli Engineering. Our engineers specialize in the design and construction of customized equipment and can recommend tailored hardware and software solutions based on our customers’ needs and the specific characteristics of their production lines.