Analysis and Annealing Solution for Sudden Product Temperature Drop During Vacuum Pull-Down in Lyophilization

1. Observation

During lyophilization runs at the customer’s site, the following phenomenon was observed:

• After completion of the freezing step and at the onset of vacuum pull-down,
• The product temperature probe inside certain samples showed a sudden and sharp decrease,
• The indicated temperature temporarily dropped to approximately −60 °C to −70 °C,
• The temperature then gradually recovered once the chamber pressure stabilized.

This behavior occurred mainly during the initial vacuum application and was not observed simultaneously in all vials or probes.

2. Initial Assessment

Based on the review of the equipment performance and operating conditions, the following points were confirmed:

• The freeze dryer’s cooling capacity and shelf temperature performance are normal, with a minimum shelf temperature capability of −45 °C;
• The observed temperature drop does not indicate uncontrolled cooling or equipment malfunction;
• The phenomenon is characterized as a transient probe reading, rather than a uniform decrease in the true bulk product temperature.

3. Mechanism Analysis Under Vacuum Conditions

This phenomenon is most commonly associated with amorphous formulations, such as peptide and biological products, during the vacuum pull-down stage of lyophilization.