Integrating “high-voltage leak detection” into automated visual inspection

The protection of patient health starts with ensuring the safety of pharmaceutical products even before they reach healthcare providers. Every recall caused by defective or leaking containers is one too many. As the pharmaceutical industry continues to evolve towards safer processes, a key trend is driving positive change: the growing demand for leak detection complementary to visual inspection. 

Visual inspection has been the industry standard for decades and remains indispensable. It helps to detect unwanted particles and cosmetic defects before the drugs reach the patients. However, the risk of tiny holes, invisible to the human eye and high-resolution cameras, might remain. They enable microorganisms or other contaminants to enter the primary packaging.

Container closure integrity testing (CCIT) technologies check each individual container for the smallest leaks. They complement visual inspection and ensure the integrity of the containers. Considering the latest advancements in drug development in both sensitive and expensive therapeutic areas such as immunotherapy, gene therapy, oncology, and biologics, 100% integrity testing is of particular interest.

The role of Annex 1

Comparing the 2018 version of EU GMP Annex 1 with the latest version (effective since August 2023), container closure inspection now plays a much more prominent role, both in scope and detail of the guideline.

For the first time, Annex 1 is harmonised with the WHO and 56 PIC/S member countries, significantly increasing its global relevance and impact. For example, Chapter 8.22 emphasises the importance of CCIT to ensure the safety and quality of pharmaceutical products. The guideline requires 100% integrity testing for fusion-sealed containers (up to 100 ml). One of the methods adaptable for commercial use is high-voltage leak detection (HVLD). 

These regulatory changes reflect a global market trend towards stricter safety standards, as well as the growing adoption of HVLD as a standard requirement in automated inspection systems. Chapter 8.22 further mentions that visual inspection alone is insufficient to check container integrity, making the combination with other testing methods like HVLD even more important. Chapter 8.23 clarifies that products using systems other than fusion should also be tested for integrity using validated methods.

HVLD is specifically recommended as a validated method in both Annex 1 and in chapter 1207 of the United States Pharmacopeia (USP), where a whole chapter is dedicated to methods for assessing package integrity.

HVLD is specifically recommended as a validated method in both Annex 1 and in chapter 1207 of the United States Pharmacopeia (USP)

Understanding leak formation

Leaks can occur at various stages of the container lifecycle, making leak testing a crucial part of final quality inspection. Tiny leaks can already develop during the glass formation process due to imperfections or stress in the glass. If containers are overfilled or the filling equipment is not properly calibrated, overpressure and potential breaches might occur during the actual filling process. Furthermore, transport-related issues such as rough handling, high-speed contact with other containers, or temperature changes can cause cracks or fractures in the glass. Apart from process-related leaks, vulnerable container parts such as the tip of an ampoule are susceptible to damage during handling and storage.

Leaks can be permeable and non-permeable, depending on the nature of the breach and the container's design. Permeable leaks involve breaches that permit the passage of liquids. They result in a loss of product content, leading to potential contamination. Non-permeable leaks, on the other hand, refer to breaches that allow the passage of gases or vapours through the container wall without a significant flow of liquid. They can also weaken the container's material. Over time, the container becomes more prone to breakage or failure, which can lead to leaks while processing. 

How HVLD ensures leak-free containers

HVLD is a precise, non-destructive method used to assess the integrity of pharmaceutical containers. For the process to work effectively, the liquid inside the container must be conductive. If the container is intact, only a minimal amount of high voltage current can flow through it. If, however, the container has a small crack or hole, the conductive liquid allows a large current to pass through, triggering the system to detect the leak. The container is then automatically rejected.

HVLD is a precise, non-destructive method used to assess the integrity of pharmaceutical containers

The effectiveness of HVLD is influenced by several key factors that must be carefully controlled when setting up the inspection process.

For example,