title: Leak testing in parenteral packaging: establishment of direct correlation between helium leak rate measurements and microbial ingress for two different leak types.
abstract: A direct test method using helium leak detection was developed to determine microbial ingress in parenteral vial/rubber closure systems. The purpose of this study was to establish a direct correlation between the helium leak rate and the presence of ingress when vials were submersed under pressure in a broth of bacteria. Results were obtained for two different types of leaks: microholes that have been laser-drilled into thin metal plates, and thin copper wire that was placed between the rubber closure and the glass vial's sealing surface. The results from the microholes showed that the helium leak rate was a function of the square of the hole diameter and fit well with theoretical calculations. The relationship with the wire gave a far more complex dependence and was not modeled theoretically. Comparison with the microbial challenge showed that for microholes a lower size limit was found to be 2 microm with a corresponding leak rate of 1.4 x 10(-3) mbarl/s. For the fine wire experiment the lower limit was 15-microm wire and a corresponding leak rate of 1.3 x 10(-5) mbarl/s. From these tests a safe, lower limit, leak rate was established.
authors.affiliation: Division of Pharmaceutical Development, F. Hoffmann-La Roche, Basel Switzerland. Bradley.Morrical@Roche.com
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Morrical
authors.forename: Marcel
authors.initials: M
authors.lastname: Goverde
authors.forename: Jean
authors.initials: J
authors.lastname: Grausse
authors.forename: Tanja
authors.initials: T
authors.lastname: Gerwig
authors.forename: Lothar
authors.initials: L
authors.lastname: Vorgrimler
authors.forename: Rachel
authors.initials: R
authors.lastname: Morgen
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Büttiker
mesh_terms: D004340:Drug Contamination / Q000517:prevention & control*; D004349:Drug Packaging / Q000592:standards*; D004755:Enterobacteriaceae / Q000254:growth & development*; D004866:Equipment Contamination; D005898:Glass; D006371:Helium / Q000032:analysis*; D007263:Infusions, Parenteral / Q000592:standards*; D013058:Mass Spectrometry; D008962:Models, Theoretical; D011312:Pressure; D011786:Quality Control; D012408:Rubber; D013678:Technology, Pharmaceutical / Q000295:instrumentation / Q000379:methods
chemical_list: D006371:Helium; D012408:Rubber