Leak Rate Testing for Freeze Dryers: A Scientific Approach

By Jayasree M. Srinivasan, Ph. D.

Ensuring the vacuum integrity of freeze dryers used in the manufacture of sterile pharmaceutical products is critical for Good Manufacturing Practice (GMP) operations. However, there is currently no widely accepted scientific basis for establishing acceptance criteria for such testing. Presently, these criteria are primarily derived from equipment capability, often suggested by the manufacturer or based on data gathered during the qualification of a new freeze dryer.

The Parenteral Society frequently cites a leak rate specification of 2 x 10⁻² mbar·L/sec for new, clean, dry, and empty freeze dryers, emphasizing that this leak rate should remain stable throughout the freeze dryer’s lifespan. To address this gap, a study was conducted to establish more scientifically grounded leak rate acceptance criteria by investigating the maximum volume of air that can infiltrate the freeze dryer without compromising Class 100 / Grade A microbial specifications.

This study developed a method to measure the exact void volume within the dryer, which includes the air space in chambers, condensers, and connecting ducts. Using a worst-case bioburden value for the infiltrating air, the maximum allowable leak rate was calculated and subsequently converted to the maximum permissible pressure rise during a leak test.