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

METHODS AND MATERIALS


Figure 3: Helium integrity test (HIT) apparatus.
The HIT apparatus includes the following main components (see Figure 3):
  • Pressurized helium supply (not shown)
  • Test chamber
  • Spacer unit
  • Vacuum pumps for bag evacuation and test chamber evacuation
  • Process-control station
  • Detector: Varian mass spectrometer.

Leak test method

The HIT apparatus is composed of a test chamber with a closable lid that when closed, forms a tight seal such that no helium can enter into the test chamber from outside. The test unit is a flexible two-dimensional bag with connecting ports that enable fluid communication with the helium source and vacuum pump. The test chamber is large enough to house the unit to be tested. The test chamber is connected to a vacuum pumping group equipped with the tracer-gas detector for chamber evacuation and gas detection. A second vacuum group is used to evacuate the unit under test before filling it with gas. A tracer-gas filling device (i.e., helium supply) completes the testing apparatus. The unit to be tested is put into the vacuum chamber and connected to service hoses, then the vacuum chamber and the unit are evacuated. During chamber evacuation, the test unit is pressurized with the tracer gas. After a stabilization time, the detector is linked to the vacuum line to detect the tracer gas flow through a leak and drawn in by the pumping group. This method can be made fully automatic, so it depends little on an operator. Its sensitivity can reach < 10-10 cc/s flow rates. To prevent long down times, the HIT system employs an in-line pressure-sensing test method as a preliminary leak test that detects gross leaks before the final automatic leak-test operation using a tracer gas is begun. This approach prevents large quantities of tracer gas from leaking into the atmosphere. A specialized pumping technique reduces the stress on the test unit by reducing the internal pressure of the test part along with the external (i.e., chamber) pressure.

To improve test time per test unit, the test chamber was modified to include spacers that allow the simultaneous testing of four units. The spacers are held upright by connecting rods, and each spacer has enough cavities in it such that when a test bag inflates against it, it does not block the path of helium molecules flowing through the defect. The spacers constrain the test bag in the test chamber, further increasing the helium pressure in the bag and resulting in increased sensitivity of leak detection. The spacers also ensure that test bags experience minimal stress during chamber evacuation by limiting bag expansion.

Test bags

The test bags were prepared by welding two sheets made from ATMI's proprietary TK8 film. To create defective bags, one of the two sheets was modified to incorporate a defective patch. A defective patch is a piece of TK8 film (4 in. x 4 in.), with a 10 μm 1 μm hole drilled by a laser. The laser-drilled holes were validated for defect size by measuring flow rate through the defect area. Hereafter, "defective bags" implies a test bag with a 10 μm defect, and "good bags" implies bags with no defect.

The size of the test bag depends on the size of the two sheets used in making one. The nominal volumes of test bags in this study were 1, 5, 10, 20, and 50 L. The helium leak rates through defective bags and good bags measured using HIT technology are discussed below. The test bags post-HIT tests were further characterized for product performance such as liquid particle count (USP <788>) to ensure that the HIT process did not affect product performance.

Microbiological challenge test method

In this study, test bags for microbial challenge were prepared by thermally welding TK8 film sheets having defects of specific sizes (2, 5, 10, 15, 20, and 50 μm). The test bags were aseptically filled with 50 mL microbial growth medium (trypticase soy broth). The outside of the test bag was sprayed with a 0.9% saline solution containing approximately 106 CFU/mL of Escherichia coli, Staphylococcus aureus and Bacillus spizizenii and approximately 105 CFU/mL of Candida albicans and Aspergillus brasiliensis. The test bags were then transferred to an incubator maintained at 30–35 C and monitored for 15 d. The growth medium inside the test bag was periodically checked for microbial growth, which indicates microbial ingress.

Liquid particle count (LPC) test

A test bag was filled with ultrapure water (deionized water filtered using a 0.05 μm filter) and gently shaken to ensure that all the bag surfaces came into contact with the solution. A sample of the solution from the test bag was then passed through particle measuring equipment (PMS). The instrument reports the number of particles per mL of solution with particle sizes greater than 25 and 10 μm.


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