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Fast, flexible leak testing for single-use bioprocessing

Accurate & simplified pressure decay leak test: for small volumes and differing configurations to improve on traditional methods

A revolution in bioprocessing is underway in the form of single-use technologies, particularly bioreactors.  They significantly reduce risks of cross contamination between batches, and eliminate the lengthy and costly cleaning steps necessary for traditional multi-use stainless steel systems, but introduce new challenges associated with leak testing.Operator inspecting a bioreactor as a leak test for single-use bioprocessing.

Single-use technology offers the promise of lower costs, improved flexibility and shorter cycle times for all process skids. However, the technology is perhaps the most mature and impactful for bioreactors. Single-use bioreactors are simply plastic bags that often arrive at the manufacturer pre-sterilized by gamma irradiation, already including all necessary single-use sensors.

Despite their numerous advantages over traditional systems, single-use bioreactors bags and other single-use components do introduce the potential for system leaks. The bioreactor manufacturers conduct highly sensitive helium integrity tests as part of their in-house quality control measures. However, the bioreactor bag is then removed from the test setup, packaged, and shipped to the pharmaceutical manufacturer, where it is unboxed and installed into its holding container as part of a larger setup.

These handling steps all introduce the potential for damage to the bag. System integrity is critical for any bioprocess – and so pressure decay tests are often conducted at the point of use, after the bag has been installed and once no further handling is required.

The conventional equipment used for pressure decay tests is often not sensitive enough to ensure the system is entirely free of leaks. However, it is not feasible to conduct another helium integrity test, as the process is time consuming and would require the introduction an unnecessary gas into the cleanroom environment.

Alicat Whisper-Series for high-accuracy leak testing of single-use bioreactors

Fast and accurate leak checking can require a rather complex setup. When the device under test (DUT) is subjected to a constant pressure within a closed system, any resulting flow is a direct measure of the leak rate. This type of test requires both stable pressure control at the DUT and accurate flow measurement to test for leakage. Leaks are most easily revealed and measured when the meter generates minimal pressure drop (the frictional resistance that the device introduces into the gas line).

Flexboy single use bioreactor bag in operationHistorically, Alicat has provided a two-unit leak checking system using a PC3-Series remote sensing pressure controller to maintain the required test pressure at the DUT, and an M-Series mass flow meter to measure the leak rate. This method is more sensitive than pressure decay, but can be simplified further.

Alicat now recommends a simplified leak test using a single Whisper-Series mass flow controller. The Whisper-Series has a full-scale pressure drop as low as 3.6 mbar (0.052 PSID) and a turned-down pressure drop as low as 0.018 mbar (.00026 PSID), allowing for precise and responsive control with minimal frictional resistance. It can be set to maintain a constant pressure at the DUT, while providing accurate mass and volumetric flow readings in real time. Configured this way, a Whisper-Series device functions as a simultaneous pressure controller and mass flow meter.

This method requires only one device, making it faster and easier to test the bioreactor bag and various other single-use components for leaks.  It is faster and more sensitive than a pressure decay test, and simpler and lower-cost than a multi-device leak checking system.

Alicat leak testing setup showing a low pressure drop Whisper-Series controller and a device under test.