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Leak Checking SUBs by the Manufacturer and at Point-of-Use

Methods of leak checking SUBs to mitigate risk to operators and processes

Single-use bioreactors (SUBs) are successfully capturing the attention of researchers and manufacturers, offering notable advantages over traditional bioreactors for their flexibility and lower cost. However, unlike multiuse stainless steel or glass vessels, single-use plastic vessels are susceptible to and must be checked for leaks caused by manufacturing error or improper handling. These leaks have the potential to endanger operators or compromise the reaction.

Consider a bioreactor producing pathogenic or otherwise hazardous material, such as viral vaccines. An undetected leak puts operators at risk of exposure, and can lead to contamination of the production environment. The material loss itself may cost thousands to millions of dollars, and put months of production time to waste.

Why do SUBs leak?

While SUBs offer significant advantages over traditional stainless steel or glass vessels, they are, simply put, plastic bags. Therefore, it is important for the manufacturer’s quality control process to leak-check the vessel, ensuring it has no defects greater than 2 µm in diameter (the maximum allowable leakage limit in most applications).

Further, because damage can still occur to the vessel during the handling associated with packaging, shipping, and installation, the end-user should perform additional testing at the point of use.

Methods of leak testing

Helium integrity testing

Helium integrity tests are able to detect leaks with high accuracy, and are often used by manufacturers to ensure that single-use vessels are free of defects down to 2 µm. While integrity tests can be performed using other gases, Helium has an atomic radius of only 31 pm, making it simple to detect leaks at the micron range.

To conduct a helium integrity test, the bag under test is placed inside a vacuum-sealed chamber and is then filled with a known amount of helium. If there are any holes in the bag, helium will escape. Mass spectrometry is then used to quantify the size of the hole based on the amount of escaped helium.

Pressure decay testing

While it is the responsibility of the manufacturer to ensure that any production errors are caught and rectified, it is also good practice for the end-user to conduct further testing. This works to ensure the safety of the operators and the integrity of the bioprocess – both of which are important aspects to quality by design.

Pressure decay tests are a standard method to leak test flexible bags for holes down to about 200 µm in diameter. This is sufficient for point-of-use testing, which is designed to detect the larger holes resulting from handling errors (in comparison, the defects resulting from manufacturing errors are generally around 50 µm and require more sensitive tests for detection).

During a pressure decay test, a bag is pressurized with air to a set level and the system is allowed to stabilize. Pressure change in the bag is then monitored over a set time interval, with any pressure drop directly correlating with hole size.

Pressure decay tests are much faster to set up and conduct than are helium integrity tests, particularly since they don’t require vacuum pumps to ensure the vessel is empty both before and after the test. However, a key additional advantage of pressure decay testing is that it can be performed under GMP cleanroom conditions, after the bag is fully installed into its holding container.

Unlike gas trace testing, pressure decay tests do not introduce otherwise unnecessary gases into the cleanroom. More importantly, no further handling is necessary at this point – meaning that the likelihood of further leaks being introduced to the system can safely be assumed to be negligible.

 

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