Production-type Pharmaceutical Freeze Dryer

Production-type Pharmaceutical Freeze Dryer

Process scale-up method of Production-type pharmaceutical freeze dryer: a method for scale-up of the production-type pharmaceutical freeze-drying machine from freeze-drying test manufacturing of pharmaceutical bottle preparations. Based on the freeze-drying conditions of the test, it is necessary to theoretically analyze the heat transfer of the medicine bottle on the shelf and the movement of water vapor flowing from the sublimation surface through the drying layer to the box, and correct the drying program of the testing machine and enlarge it to On the production device, the specific steps are as follows:

1. Freeze-drying conditions and result analysis of liquid testing machine

(1) Confirm the shelf size and box size of the testing machine, and whether it is a bottomed tray or a bottomed tray.

(2) Pre-freezing process: shelf cooling speed, freezing speed of liquid medicine, freezing temperature, and pre-freezing time.

(3) Sublimation drying: the initial pumping time, the heating temperature of the board layer, the heating speed, and the temperature change of the product during the sublimation period. During the sublimation period, the vacuum in the box (whether it is controlled or not), the control method (whether it is throttling adjustment control or aeration control), the vacuum instrument (whether it is a Pirani or an absolute pressure vacuum gauge), sublimation drying time, and the wall temperature of the box during the test.

(4) Second stage drying: shelf heating temperature, box vacuum, condenser temperature, second stage drying time.

(5) Analysis of freeze-drying curve: compare the temperature of the product during sublimation drying with the eutectic temperature of the product, from the recorded freeze-drying curve, the temperature difference between the shelf of the medicine bottle at the end, the shelf of the medicine bottle in the center and the product are the same as that of the product. The product of drying time ΔT*θ is calculated.

(6) Theoretical analysis of the heat transfer and water vapor movement of the medicine bottle at the end of the testing machine and the medicine bottle at the center.

(7) The water vapor flow resistance coefficient of the drying layer is estimated based on theoretical analysis and test results.

2. Scale-up to production equipment

(1) Confirm the shelf size and box size of the production equipment.

(2) Compare the basic performance of the production device with the testing machine. If the cooling speed of the shelf of the production device is faster than that of the testing machine, the liquid medicine of the production device will freeze faster, the size of the ice crystals will be different, and the water vapor flow resistance of the drying layer will increase, which will affect the sublimation speed.

(3) Calculate the angular coefficient of radiation heat transfer of the production device and compare it with the testing machine.

(4) Preparatory freezing project: The freezing speed and freezing time are set to be the same as those of the testing machine, and the effect of air convection on the freezing project is considered.

(5) Sublimation drying stage: Set the vacuum of the box and the temperature program of the shelf, theoretically analyze the drying speed, and theoretically calculate the heat transfer of the medicine bottle at the end and the center and the water vapor flow resistance of the drying layer, so as to obtain Sublimation surface temperature and sublimation drying time.

(6) Drying in the second stage: Set the heating temperature of the shelf to be the same as that of the testing machine, and the vacuum of the box should be as consistent as possible with the testing machine and control the temperature of the condenser.

3. Selection of vacuum pressure control value of production device

When enlarging the production device, the selection of the vacuum pressure control value of the box must consider the following factors.

(1) The disintegration temperature of the product

As the eutectic temperature of the product decreases, the water vapor pressure PS value of the sublimation surface must be reduced. Due to the pressure difference of the drying layer, the vacuum pressure of the box must be controlled to a smaller value. During the sublimation drying period, the temperature of the sublimation surface should be lower than the disintegration temperature by 2~5℃.

(2) Water vapor flow resistance of the drying layer of the product

The steam flow resistance in the dry porous layer is related to the concentration of the solution, the filling volume of the vial, and the arrangement of ice crystals during freezing. The vacuum pressure of the box is selected as the sublimation surface water vapor pressure is 10~30% of PS.

(3) Set the same period as the vacuum pressure control value of the testing machine

If the vacuum gauge of the testing machine is a Pirani vacuum gauge, the count of the Pirani vacuum gauge needs to be converted into a real value, so that the capacitance vacuum gauge of the production machine uses the vacuum value as the vacuum pressure control value of the box.

4. The setting of the shelf temperature program of the production machine

There are two methods for setting the shelf temperature program of the production machine.

(1) Set the same as the heating temperature of the shelf of the testing machine, and prolong the sublimation drying time.

For production lyophilizers, less heat is transferred to the central vial than for testing machines, resulting in slower drying. If the sublimation drying time is not prolonged, the drying time of the first stage of the medicine bottle in the center of the freeze-drying machine will enter the second stage of drying in an unfrozen state, and the temperature of the shelf will be raised, and local disintegration of the bottom of the product will occur. , causing the product to be scrapped.

(2) Equivalent to the drying time of the testing machine

The shelf heating temperature of the production lyophilizer was set slightly higher than that of the test machine to achieve the same drying as that of the test lyophilizer, but a theoretical analysis was required.

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