Helium leak test for sterility assurance of a sealed bag. I: Relationship of helium leak and pinhole diameter.
Described herein is an attempt to establish a simpler, more reliable method to maintain the aseptic condition of bulk materials of drug substances. The method would be used in the manufacturing process of our "double-bag" kit system for infusion, which has two compartments, one for the infusion liquid and another for the drug product. To manufacture the kit system, we used a flexible inner container to enclose the bulk under aseptic conditions and a method for ensuring sterility of the container. We used an aluminum laminate bag as the inner container, which was then enclosed in a polyethylene bag. To detect tears or pinholes in the bag, a helium leak test was evaluated. First, a simple experimental model of helium leakage from bags was established. In the model, a pinhole was made in a film disk of the aluminum laminate or polyethylene material used for the inner and outer bags. A helium leak detector was used to measure the escape of helium through the pinhole, and the leak could be detected from a pinhole from 10 microns in diameter. As the bulk product was doubly sealed in an aluminum bag and a polyethylene bag in the manufacturing process to maintain an aseptic condition, we also checked for helium leak from pinholes of film disks after connecting two film disks. The results showed that helium leak was detectable when the pinhole diameters of both film disks were more than 20 microns. Clearly, helium leak is strongly affected by pinhole diameter in both experimental models. We have calculated, for the pinhole geometries studied, helium leak rates by using the Poiseuille Equation. Calculated values were in agreement with experimental values.