An Overview of New PAT Freeze-Drying Methods Based on Shelf Temperature Inlet/Outlet Difference or Chamber/Condenser Pressure Difference: Theory and Practical Use
Abstract
1. Introduction
2. Theory
2.1. ΔT Method
- The sensible heat linked to the temperature change of the entire apparatus (shelves, bottles, liquid, or ice in vials);
- The heat released or absorbed by phase transitions (crystallization of ice during freezing or sublimation of ice during primary drying).
2.2. ΔP Method
3. Materials and Methods
4. Primary Drying Sublimation
4.1. Data Treatment
4.2. Kv Distribution Determination
4.3. Product Temperature Estimation
4.4. Lyo Homogeneity
4.5. Process Transfer
5. Ice Crystallization
6. Conclusions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
Nomenclature
Abbreviations | |
GMP | Good manufacturing practices |
PAT | Process Analysis Technology |
QbD | Quality by Design |
TDLAS | Tunable Diode Laser Absorption System |
Symbols | |
Av | Area of vial outer section (m2) |
Cp,oil | Oil specific heat capacity (J/kg.°C) |
dM/dt | Total sublimation or crystallization rate (kg/h) |
Kv | Shelf to vial heat transfer coefficient (W/m2.°C) |
M, m | Mass of ice in a vial, total mass of ice (kg,g) |
Pchamber | Chamber capacitance pressure (µbar) |
Pcondenser | Condenser capacitance pressure (µbar) |
<P> | Chamber, condenser average capacitance pressure (µbar) |
Qoil | Silicone oil flow in the shelves (kg/h) |
Rp | Cake resistance (m/s) |
Tb | Product bottom temperatures (°C) |
Ts | Shelf temperature (°C) |
ΔHs, ΔHc | Enthalpy of water phase transition, sublimation, or crystallization (J/kg) |
ΔTI/O | Shelf liquid inlet/outlet difference (°C) |
G | Overall combined heat capacity of the shelves and vials: glass + water or ice (J/°C) |
Appendix A
Freeze Dryer | Example |
---|---|
Optima CS-5 5 m2, 6 shelves | Figure 1: the freeze dryer was fully loaded by 20R vials filled with 6.2 mL of 8% sucrose placebo. During primary drying, the pressure was set to 133 µbar and the shelf temperature to −5 °C. |
Figure 2: This example compares the correlation <P>ΔP vs. mass flow determined by ΔT method for several experiments. (1) The freeze dryer was fully loaded by 2R, 6R, or 10R vials containing pure water (2R, 6R) or an 8% sucrose solution (10R). During primary drying, the pressure was set to 133 µbar and the shelf temperature to −5 °C. (2) Test with 10 R vials in same conditions as (1), but with reduced number of vials (2/6 shelves). (3) Condenser test: 6 trays of water covering the complete shelves (89 kg of water) were loaded in the freeze dryer, and a complete freeze-drying cycle was performed. During primary drying, the pressure was set to 100 µbar. The shelf temperature was raised from −45 °C to 20 °C in 1.5 h and maintained at 20 °C for 65 h, until the trial was stopped after full sublimation of the ice. | |
Figure 9A: freezing experiment. The freeze dryer was fully loaded with 20 R vials filled with 10 mL of pure water. The vials initially equilibrated at 0 °C were brought to −45 °C in 1 h. The temperature was then kept at −45 °C for more than five hours. | |
USIFROID SMH 90 3 m2 5 shelves | Figure 8: full load of 10 R vials, undisclosed formulation. During primary drying, the pressure was set to 133 µbar and the shelf temperature to +5 °C. Vials were loaded on trays. |
IMA Lyomax 29 29 m2, 13 Shelves | Figure 3: refers to the mass flow measurement according to the ΔP and ΔT methods during the primary drying of the commercial product “A”. Further information is not disclosed. |
Figure 6A: refers to a technical run of the commercial product “B”. During this non-GMP run, Ellab temperature probes were used to monitor the product temperature. The shelf temperature profile during primary drying is indicated in the figure. Further information is not disclosed. | |
IMA Lyofast 35 35 m2, 15 shelves | Figure 5A,B, Figure 6B and Figure 7 are related to the same technical run of an undisclosed placebo formulation: 14 of the 15 shelves of the freeze dryer were filled with 2R vials containing 1 mL of an undisclosed formulation. During the primary drying, the pressure was set to 60 µbar and the shelf temperature profile is disclosed in the figure. During this non-GMP run, Ellab temperature probes were used to monitor the product temperature. |
Figure 9B: freezing part of lyophilization cycle. 142000 2R vials filled with 1 mL of water were loaded in the freeze dryer (qualification run). The vials were first equilibrated at 5 °C, then the shelf temperature was brought to −45 °C in about 1.2 h. The temperature was kept at −45 °C for several hours. |
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Authelin, J.R. An Overview of New PAT Freeze-Drying Methods Based on Shelf Temperature Inlet/Outlet Difference or Chamber/Condenser Pressure Difference: Theory and Practical Use. Pharmaceutics 2025, 17, 1277. https://doi.org/10.3390/pharmaceutics17101277
Authelin JR. An Overview of New PAT Freeze-Drying Methods Based on Shelf Temperature Inlet/Outlet Difference or Chamber/Condenser Pressure Difference: Theory and Practical Use. Pharmaceutics. 2025; 17(10):1277. https://doi.org/10.3390/pharmaceutics17101277
Chicago/Turabian StyleAuthelin, Jean René. 2025. "An Overview of New PAT Freeze-Drying Methods Based on Shelf Temperature Inlet/Outlet Difference or Chamber/Condenser Pressure Difference: Theory and Practical Use" Pharmaceutics 17, no. 10: 1277. https://doi.org/10.3390/pharmaceutics17101277
APA StyleAuthelin, J. R. (2025). An Overview of New PAT Freeze-Drying Methods Based on Shelf Temperature Inlet/Outlet Difference or Chamber/Condenser Pressure Difference: Theory and Practical Use. Pharmaceutics, 17(10), 1277. https://doi.org/10.3390/pharmaceutics17101277