Helium Leak Test for Sterility Assurance of a Sealed Bag. II: Establishing a Test Method for the Manufacturing Process

Abstract

To establish a simpler and more reliable method for retaining the aseptic condition of freeze-dried bulk product of a drug substance, a helium leak test method was developed. The bulk product is for the new kit system for infusion of our antibiotic product.

In manufacturing the kit system, the bulk product needs to be transported outside of the aseptic area. We had to use a proper container to enclose the bulk product under aseptic conditions and establish an appropriate method for sterility assurance of the container. We decided to use a flexible aluminum laminate bag as a container and to seal it in a poly-ethylene bag. To detect tears or pinholes in the bag, a helium leak test was considered.

As a tear model, a pinhole of known diameter was made in the aluminum laminate bag which was then filled with helium and sealed in a polyethylene bag. Helium leaking from the pinholes was measured with a helium leak detector, and leakage from a pinhole of more than 50 μm in the aluminum laminate bag could be detected. The amount of leakage was strongly affected by the pinhole diameter, and we developed a scientific approach for measuring leakage using the Poiseiulle Equation. The detection sensitivity of our method was enough to retain an aseptic condition inside the aluminum laminate bag, confirmed by the results of the process simulation test using our helium leak test. We concluded that our helium leak test was useful for sterility assurance of the bulk product sealed in the aluminum laminate bag in the manufacturing process of our kit system for infusion of our antibiotic product.