In February 2008, the FDA (CBER, CDER, CDRH and CVM!) published the Guidance for Industry "Container and Closure System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products".

This guideline includes recommendations to manufacturers of biological products, medicinal products for human and veterinary use and also of medical devices allowing them to use methods other than sterility testing during stability testing in order to prove the integrity of containers and closures for sterile products. This guideline now replaces the draft of the same title of January 1998.

Manufacturers of sterile medicinal products and biological products have to prove for every batch that the product in question fulfils the requirements of sterility testing. At the same time, these products are subject to the requirements on stability testing laid down in 21 CFR 211.166.

This guidance refers exclusively to the replacement of sterility testing by suitable container and closure integrity tests within the framework of stability testing. It cannot be applied to release testing!

Products labelled as "sterile" are expected to be free from viable micro-organisms over the complete shelf life. For these products, sterility is a stability feature.

The minimum requirements of stability testing demand that sterility testing be carried out both at the beginning and at the end of stability testing. Apart from that, yearly tests are often conducted additionally. However, it is well known that the meaningfulness of sterility testing is quite limited. For this reason, the FDA recommends in this guidance that protocols for stability testing should rather include alternative methods that are more reliable than sterility testing.

Nevertheless, the document does not advise any concrete test methods or acceptance criteria. It merely mentions some possible principles in general (like dye penetration test, electrical conductivity, pressure/vacuum decay). It goes without saying that these alternative methods also have to be adequately validated.

The complete FDA guidance can be found here:
http://www.fda.gov/cber/gdlns/contain.pdf

Author:
Dr Günter Brendelberger
On behalf of the European Compliance Academy (ECA)