Maintenance of microbiological control and quality: In stability
- Container-Closure Integrity
The ability of the container-closure system to maintain the integrity of its microbial barrier hence, the sterility of a drug product throughout its shelf life, should be demonstrated.
Sterility testing at the initial time point is not considered sufficient to demonstrate the microbial integrity of a container-closure system.
Documentation of the sensitivity of the container-closure integrity test should be provided.
- Preservative Effectiveness
The efficacy of preservative systems to control bacteria and fungi inadvertently introduced during drug product use should be demonstrated at the minimum concentration specified for drug product release or at the minimum concentration specified for the end of the expiration dating period, whichever is less.
The efficacy of preservative systems is judged by their effect on microorganisms, microbial challenge assays should be performed.
The United States Pharmacopeia (USP) provides a microbial challenge assay under the title “Antimicrobial PreservativesEffectiveness.”
For purposes of the stability protocol, the first three production lots should be tested with a microbial challenge assay at the beginning and end of the stability period.
Chemical assays to monitor the concentration of preservatives should be performed at all test intervals.
For subsequent lots placed on stability, chemical assays may be adequate to demonstrate the presence of specified concentrations of preservatives, and such testing should be carried out according to the approved stability study protocol.
- Pyrogen or Endotoxin Testing
For drug products purporting to be pyrogen free, it is recommended that pyrogen or endotoxin tests be carried out at the beginning and end of the stability period as part of the approved stability study protocol.