Integrity Testing of Flexible Containers - Defects as small as 10 μm can be detected without compromising product cleanliness using helium integrity testing. - BioPharm International

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Integrity Testing of Flexible Containers
Defects as small as 10 μm can be detected without compromising product cleanliness using helium integrity testing.


BioPharm International
Volume 24, Issue 11, pp. 42-49

Data reproducibility


Figure 4: Data reproducibility of HIT system.
Often, even when a constant amount of helium flows through a defect, the ability of the pumping system to carry helium molecules to the detector can vary. In addition, the helium background varies as the equipment operates over a period of 8 h, which may result in variation of the measured leak rate for the same defect size. To minimize this variation, the volume of the test chamber external to the test bag was minimized and the pumping efficiency of the vacuum pumps was optimized. A single defective bag from each of the bag sizes (i.e., 1–50 L), was tested five times to verify the reproducibility of the leak rate through a defect (see Figure 4). The data show a standard deviation of less than 4% for leak rate in all bag sizes tested, except for 1-L bags, which had slightly greater variation at 10%. The higher variation in 1-L bags was due to the relatively high ratio of detector gas to test bag volume, resulting in higher sensitivity input parameters such as tracer gas fill volume and helium background. The box plot of the measured leak rates also indicates that the average leak rate for all defective bags, irrespective of the bag size is above a certain leak rate.

Effect of test bag position


Figure 5: Test chamber with spacer, illustrating test bag positioning.
The test chamber includes a spacer, which splits the test chamber space into four compartments that can each accommodate one test bag. Of the four compartments, the two compartments closer to the test-chamber wall are designated as positions 1 and 4, and the remaining two are designated as position 2 and 3 (see Figure 5).

During the leak-testing process, as the bag walls push against the container wall, some defects may be blocked by the container wall, thus reducing or eliminating helium flowing through the defects and, in turn, preventing its detection. To minimize this risk, spacer bars were placed between the walls of the test bag and container wall to provide a path for the tracer gas to escape. Experimental studies were performed to ensure that there was minimal variability in the amount of helium flowing through the defects due to the position of the bag in the chamber. Experiments were conducted with test bags placed in locations 1 through 4. For each location, five distinct sets of defective test bags per bag size were tested for helium leaks. The box plots showing the leak rates from bags at different positions indicates that there was minimal variation and that the measured leak rates were above a certain leak rate (see Figure 6). A t-test comparing the means of leak rates confirmed with greater than 86% confidence that no significant difference would be observed in the mean of the helium leak rates. Thus, irrespective of the bag position in the test chamber, helium leaks through a defective test bag reach the detector without appreciable loss in the process.


Figure 6: Effect of test bag position in the test chamber on the helium leak rate.
Validation of HIT technology for 10 μm defect detection

A series of experiments was performed to validate that the HIT technology could detect 10 μm defects. In the first set of experiments, good test bags of all sizes (i.e., 1–50 L) were run through the tester, the helium leak rates were recorded, and a baseline leak rate was established. The defective test bags were then tested, and the leak rate through the defective bags was compared with the baseline leak rate. The sequence of testing defective bags versus good bags, smallest bag versus large bag was randomized to avoid trending issues. The helium leak rate through defective bags must be substantially higher than the maximum helium leak rate through good bags to detect 10 μm defects.


Figure 7: Box plot of helium leak rates (cc/sec) of good bags and defective bags.
The good test bags averaged a helium leak rate of 1.17 x 10-5 cc/s, while the defective bags averaged 8.94 x 10-5 cc/s. The variation in the leak rates through good bags was largely due to variation in the helium background, while the variation in defective bag leak rates was largely due to variation in the laser-drilled defect hole sizes. The maximum leak rate, also referred to as baseline leak rate, is the sum of the average leak rate of good bags and four times the associated standard deviation. The baseline leak rate varied with bag size but for further evaluation, the baseline leak rate is the maximum leak rate possible for good test bags irrespective of bag size, 3.4 x 10-5 cc/s (see Figure 7). This meant that if the helium leak rate was higher than the baseline leak rate, there was a defect in the test bag, and the bag would be rejected. The helium leak rate value for all the defective bags tested was higher than the baseline leak rate value, allowing easy distinction between the good and the defective bags (see Figure 7).


Figure 8: Distribution curve for helium leak rate through good bags. The curve shows a good probabliity that good baks will have a leak rate lower than the baseline leak rate.
A statistical analysis (t-test for means) of leak-rate distributions of defective bags versus good bags indicated clear separation (p < 0.1) of leak rates (see Figure 8).

Liquid particle count

While methods using tracer gas have come close to detecting 10 μm defects, they have failed to maintain cleanliness of the test unit. Often such techniques involved connecting the test unit to the tracer-gas supply, evacuation pumps, which can be a source of particle generation. In addition, when the test bags are filled with tracer gas, they are pressurized to a great extent, resulting in film stretching and causing particle shedding. It was the intent of this test to show that no significant increase in the liquid particulate level occurred due to the use of this technology. The ratio of liquid particles generated to the nominal bag volume was highest for 1-L bag because of its higher surface-area-to-volume ratio, making 1-L bags more sensitive to a change in particle concentration as a result of the leak testing process. Therefore, only 1-L bags were tested for verifying particulate generation. It is expected that if 1-L bags do not show a significant rise in the particle count, large bags will not show a significant rise either. A sample of solution from each of the 1-L test bags was run through particle measuring systems equipment, and the data is reported in Table II. The data did not show significant increase in the liquid particle count level indicating that HIT technology does not cause particulate generation and is safe for-point-of-use applications.


Table II: Liquid particle count results (LPC/ml) in 1 L bags.
CONCLUSIONS

Existing integrity-test methods for flexible containers can detect defects in the range of 500–90 μm, but are inadequate for ensuring product sterility. A microbial ingress study conducted on flexible sterile containers revealed that defects as small as 15 μm can compromise sterility, while defects equal to or smaller than 10 μm did not. A novel helium integrity test method developed by ATMI is capable of detecting 10 μm defects during in-line package testing without compromising the cleanliness of the product. The test bags with 10 μm defects had helium leak rate value higher than baseline leak rate value allowing clear distinction between good bags and defective bags. The cleanliness testing post integrity testing revealed that product performance is not affected by the test process.

Vishwas Pethe* is a research engineer, Mike Dove is a manufacturing engineer, and Alex Terentiev is US R&D director, all at ATMI Life Sciences,


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