A vitally important assay used across various stages of drug development and manufacturing, container closure integrity testing (CCIT) involves evaluating packaging systems to determine their ability to protect the stability and sterility of pharmaceutical products.
The evolution of CCIT
Manufacturers have been performing container closure integrity tests for many years and the perceived importance of these tests has steadily increased. In the first official regulatory guidance on this matter released in 2008, the Food and Drug Administration (FDA) established CCIT as a requirement, closely tying it to the concept of microbiological integrity.
In the same year, the European Commission published guidance relating to the manufacture of sterile medicinal products. In Annex 1, the regulator stated “Containers should be closed by appropriately validated methods. Containers closed by fusion, e.g. glass or plastic ampoules, should be subject to 100% integrity testing.”
While both the FDA and the European Commission stressed the importance of CCIT, neither described exactly how tests should be performed. Many test methods have thus been developed. One early example is the microbial ingress test, which involves immersing samples in a ‘broth’ containing the microbial test organism to observe whether the organism then grew inside the container. Pressure or vacuum may sometimes be applied.
Other CCIT methods have been developed to evaluate the ingress of moisture and reactive gases, which can affect the stability of drugs. The egress of the drug itself (a leakage) is also of critical importance. In these tests, manufacturers use vacuum-based systems to identify the presence of miniscule leaks in containers.
Accepted by the regulatory bodies, the blue dye ingress test is an example that the industry has used for decades. In this method, test subjects are placed in a vacuum chamber and immersed in a blue dye solution. When the chamber is returned to atmospheric pressure, any visible trace of the blue solution inside a container indicates a leak is present.
While this method’s popularity has prevailed for years, the current market environment for leak detection is changing once again.
Time for change
In August 2016, the US Pharmacopeial Convention’s revision of Chapter <1207> prompted a new direction for CCIT. The revised chapter advised that, for the CCIT of new pharmaceutical products, drug developers should move away from “probabilistic” methods towards greater use of “deterministic” ones.
As the blue dye ingress test relies on a subjective visual inspection and evaluates a random series of sequential events, it is considered a probabilistic test. Deterministic tests, on the other hand, are objective, quantitative, and measure a fixed chemical and physical end-point.
Encouraged by the regulations, the industry is now mid-transition. In 2021, a quick in-webinar poll conducted by Pfeiffer Vacuum revealed that just over one third of pharma companies (34% of respondents) are currently using a mix of the blue dye ingress and deterministic methods. Plus, 27% responded that while they are still using the blue dye ingress test, they have plans to change.
Pharma 4.0
Another factor driving the industry to change is the need for greater process efficiency, which can often be achieved through modern, deterministic solutions. Across the pharmaceutical industry, teams are tasked to do more with less – and quality control is no exception. Performing in-process controls with the blue dye ingress test can be slow due to the need for an ideally 30-minute immersion time. In addition, test results are based on an operator, which opens up room for false positives and negatives and makes the method impossible to automate.
In the fast-approaching era of Pharma 4.0, where companies are increasingly seeking new ways to automate production and gain more and more data from each process, the blue dye ingress test is starting to show its age. The need for traceability within quality control systems is increasing too, and this is something that the blue dye ingress test also fails to support. While the test remains popular, it is no longer considered best practice.
Deterministic CCIT solutions
As a growing number of companies decide now is the right time to modernise their approach to CCIT, they can find themselves in safe hands with the leak detection experts at Pfeiffer Vacuum. Founded in 1890, Pfeiffer Vacuum is credited with many ground-breaking vacuum innovations. With the extension of its technologies to the world of CCIT, Pfeiffer Vacuum is answering the industry’s need for modern, deterministic solutions and tight sensitivity levels.
For reliable, fast and efficient in-process controls, Pfeiffer Vacuum’s patented and USP <1207> recognised Mass Extraction Technology and patented Optical Emission Spectroscopy (OES) instruments are the perfect replacement for the blue dye ingress test. As the systems are non-destructive, they can even be used in applications where 100% inspections are required. The company also offers a unique tracer gas solution based on helium mass spectroscopy, ideal for early-stage laboratory testing due to its high sensitivity.
With trend analysis, 21 CFR Part 11 compliance, the possibility for automation, and some of the best detection limits on the market, Pfeiffer Vacuum’s technologies are fit for the future of the pharmaceutical industry.
To learn more about CCIT, including a comprehensive case study of different leak testing methods for pharmaceutical products, download the new whitepaper ‘Saying goodbye to blue dye: How to navigate the changing world of CCIT’ below.
