Pharmaceutical container/closure integrity. III: Validation of the helium leak rate method for rigid pharmaceutical containers.

Validation of a helium leak rate method for pharmaceutical container/closure integrity quality assurance required the demonstration that this physical testing method was as good or better than microbial immersion challenge testing in detecting potential integrity failures. One lot of rubber-stoppered, broth-filled glass vials also containing defective vials with known leaks were subjected to both helium leak rate and microbial challenge testing. The defective vials were prepared by affixing glass micropipettes (0.1 to 10 microns) into the vial side walls. The validation lot included a 10% seeded defect rate of which about 50% contained leaks with a predicted probability of failing a microbial challenge (> 10%). Helium tracer was placed in the test units by charging them for 4 hours under a 40 psi helium pressure. The critical leak rate after charging was determined to be 10(-7) standard cc/second, and test units with measured leak rates greater than this value were considered helium leak rate failures. Microbial immersion challenge was conducted by exposing the test units in a bath inoculated with 10(9-10) viable E. coli and B. diminuta organisms for 24 hours followed by a 13 day (35 degrees C) incubation. Microbial failures were determined visually. The helium and microbial leak test methods were compared statistically using mean failure rates. The mean helium failure rate was 6.9%, whereas the mean microbial failure rate was 2.8%. The difference between helium and microbial failure rates was significantly greater than zero. Thus, helium leak rate testing was demonstrated to be a suitable pharmaceutical container/closure integrity method for microbial quality assurance of rigid containers.