How to verify the temperature uniformity of a vacuum freeze dryer

How to verify the temperature uniformity of a vacuum freeze dryer

The shelf temperature uniformity verification is a very important part of the vacuum freeze dryer (hereinafter referred to as: freeze dryer) equipment verification. The author is engaged in GMP verification work in the pharmaceutical factory. The following methods and results of the temperature uniformity verification of the freeze dryer are introduced as follows to learn from each other.
1 Verify the instrument used
(1) Kaye Validator X2005 Verifier.
(2) Thermocouple probe input module (SIM).
(3) IRTD-400 intelligent temperature standard.
(4) LTR-40/140 dry well temperature reference.
(5) T-type thermocouple probe.
(6) Temperature calibration point: -40 °C, 0 °C, +40 °C.
2 Methods and results
2.1 Thermocouple calibration
Prepare 36 numbered T-type thermocouple probes, perform calibration correction at low temperature -40 °C, high temperature 40 °C, and confirm the thermocouple deviation at 0 °C. The calibration read deviation should be less than 0.5 °C.
2.2 Thermocouple arrangement
The qualified thermocouples are introduced into the freeze-drying box through the verification holes, and the 36 thermocouple probes are uniformly fixed on the 10 shelves of the freeze-drying box, wherein the first, second, ninth and tenth layers are evenly distributed. Three thermocouple probes are arranged, and four thermocouple probes are evenly arranged in the third, fourth, fifth, sixth, seventh, and eighth layers.
2.3 Laminate temperature confirmation
At the same time, the lyophilizer and the temperature verification device are started to confirm the slab temperature. Run the lyophilizer as follows.
(1) Set the heat transfer oil inlet temperature to -40 °C. After running the freeze dryer, the heat transfer oil inlet and outlet temperature balance, continue to run for more than 30 min, and investigate the plate temperature fluctuation and uniformity when the equipment is kept at -40 °C.
(2) Set the temperature of the heat transfer oil inlet to 0 °C, run the freeze dryer, and balance the temperature of the heat transfer oil inlet and outlet for more than 30 min. When the equipment is kept at 0 °C, the temperature and uniformity of the lamellar temperature are investigated.
(3) Set the temperature of the heat transfer oil inlet to 40 °C. After running the freeze dryer, the temperature of the heat transfer oil inlet and outlet is balanced, and continue to run for more than 30 minutes. When the equipment is kept at 40 °C, the temperature fluctuation and uniformity of the plate layer are investigated.
2.4 Thermocouple Calibration Confirmation
After the completion of the lamination temperature verification, the deviation of the used thermocouple is confirmed to confirm that the thermocouple deviation drift in the verification meets the limit requirement. The read bias of the used thermocouple should still be less than 0.5 °C.
2.5 Qualification criteria
2.5.1 Thermocouple Calibration Eligibility Criteria
All thermocouples have a non-calibration deviation of less than 1.0 °C, and the read deviation is less than 0.5 °C within 3 minutes after calibration. The calibration failure thermocouple does not appear in the calibration report. The calibration is acceptable and the thermocouple can be used in the verification.
2.5.2 slab temperature verification eligibility criteria
(1) During the holding process at -40 °C, 0 °C, and 40 °C, the temperature fluctuation at each point of the ply is less than ±1.5 °C (based on the average plate temperature), and the ply temperature control performance is acceptable.
(2) Under the conditions of -40 °C, 0 °C, 40 °C, the maximum and minimum temperature difference of all test points on each layer at the same time is less than 2.0 °C, and the uniformity of the layer temperature is qualified.
(3) After verification, the thermocouple calibration is confirmed, and the layer temperature verification data is valid. Otherwise, the verification fails and the calibration and verification must be performed again.
2.5.3 Thermocouple Calibration Confirmation Eligibility Criteria
The thermocouple calibration was confirmed at -40 °C, 40 °C, and 0 °C. It was confirmed that the reading deviation of all the test thermocouples at each temperature was less than 0.5 °C of the calibration standard. The thermocouple with no confirmation failure was confirmed in the calibration confirmation report, and the calibration was confirmed. The layer temperature verification is valid.
2.6 Verification data analysis
After the temperature in the freeze-dried cabinet is equilibrated at -40 °C, 40 °C, and 0 °C, the operation is continued for 30 minutes. The statistical data of the heat distribution verification of the temperature verification instrument during each temperature operation are shown in Table 1.
-40 °C for 30 min.
Min of Min: -40.78 °C T33;
Max of Max: -39.13 °C T04;
Max Range: 1.65 °C
Continuous operation at 0 °C for 30 min:
Min of Min: -0.91 °C T31; Max of Max: 0.49 °C T17;
Max Range: 1.40 °C
Continuous operation at 40 °C for 30 min:
Min of Min: 38.14 °C T31; Max of Max: 39.58 °C T06;
Max Range: 1.44 °C
3 Conclusion
The laminar temperature was confirmed, and the temperature control and temperature uniformity of the ply was confirmed at -40 °C, 0 °C, and 40 °C, respectively. The temperature of the ply was varied within the allowable fluctuation range, and the freeze dryer was operated at no load. The uniformity of the temperature distribution of the laminar layer meets the design requirements.
(1) During the temperature maintenance process at -40 °C, 0 °C, 40 °C, the laminar temperature control fluctuation ≤ ± 1.5 °C, meeting the temperature control performance requirements.
(2) Under the conditions of -40 °C, 0 °C, 40 °C, the maximum and minimum temperature difference of all lamellar layers at the same time is ≤2.0 °C, and the uniformity of lamellar temperature meets the requirements.