The vacuum integrity of freeze dryers is critical for process control and maintaining confidence in sterility assurance – it is therefore key for manufacturing sterile pharmaceutical products.
Although discussions on this topic have been widely published, there is no universally recognized standard, empirical standard, or scientific rationale on which to base acceptable limits on leak rates. Historically, the calculations were based on a single orifice, but this is no longer considered adequate for modern practice.
To provide a view from industry practitioners on a leak rate specification, BioPhorum has published Lyophilizer Leak Rate Testing – An Industry Survey and Best Practice Recommendation, which also gives recommendations on best practices for lyophilizer leak rate testing.
“This is a very good paper on a topic on which many organizations seem to have little guidance,” said Michael Gosmer, Drug Product Technical Specialist at Novavax. “It does well to illustrate the principle of theoretical leak rate vs. practical leak rates. I think this paper will help many in their decisions on how to proceed with a production leak rate that can assure system integrity.”
Published in the Journal of Pharmaceutical Sciences, the paper also contains a review of the scientific literature in the public domain and, most importantly, a perspective from 14 pharmaceutical companies on the leak rate specifications commonly used in industry.
The survey included laboratory, clinical, and commercial scale lyophilizers with chamber and condenser volumes ranging between 3.46–32.5m3. Survey questions covered leak rate specifications and rationale, lyophilizer volume, frequency of testing and failures, data trending, and detailed leak test methodology practices.
It found that most companies do not have a standard leak rate specification. Instead, this varies with the lyophilizer and is site-specific within a company.
Based on the survey results and team discussions, the paper recommends a best practice approach for the lyophilizer leak rate test. This includes the necessary preparation activities after steam-in-place sterilization, defining a period of stabilization to eliminate pressure and temperature fluctuations, and details of the test conditions and the test period.
The method described is suitable for frequent leak rate determination to avoid the loss of multiple batches if there is a leak rate failure and is a huge step forward in defining an industry-agreed best practice specification.
For routine manufacturing practice, the team suggests that the operational leak rate should not exceed 20 μbar L/s. Additional guidance in the paper provides recommendations for large volume and older lyophilization equipment.