11 Key Control Parameters Of Freeze-Drying Process

The freeze-dried products of biological products need to have a certain physical form; uniform color, qualified residual moisture content, good solubility, high survival rate or potency, and long storage period. Therefore, it is not only necessary to control the seedling making process and the sealed storage after freeze-drying. What is more important is to fully control the parameters of each stage of the freeze-drying process in order to obtain high-quality products. Freeze-drying curve and time sequence are the basic basis for freeze-drying process control.

The lyophilization curve and timing are the basis for operating the lyophilizer. For example, when the cam method and the roller method are used for the automatic control of the freeze dryer, the basis for the cam and roller is the freeze-drying curve and time sequence. Freeze-drying curve and timing, according to certain requirements of the microcomputer, input the freeze-drying curve and timing into the storage of the microcomputer with the operation keyboard.

The freeze-drying curve is the relationship curve between the temperature of the freeze-drying box and the time. Generally, the temperature is taken as the ordinate and the time as the abscissa. It reflects the variation of the plate temperature at different times during the freeze-drying process. The freeze-drying sequence is the opening and closing operation of various equipment at different times during the freeze-drying process. The lyophilization curve is based on the ply because the product temperature is dominated by the ply temperature. Controlling the temperature of the ply also controls the temperature of the product.

Variety of products: Different products have different eutectic points. Products with low eutectic points require low pre-freezing temperature; the temperature of the board layer should be lower when heating. Some products are more affected by freezing, and some products are less affected; generally, bacterial products are more affected by freezing, and viral products are less affected by freezing. It is necessary to find out the optimal freezing rate of a product according to experiments, so as to obtain high-quality products and short freeze-drying time. In addition, different products have different requirements for residual moisture. In order to preserve the product for a long time, some products require a lower residual moisture content. Some are more demanding. For products with low residual moisture content, the freeze-drying time needs to be longer. For products with high residual moisture content requirements, the freeze-drying time can be shortened.

The amount of loading also affects the formulation of the freeze-drying curve. One is the amount of total loading, and the other is the amount of product in each container. The freeze-drying time of a large amount is also long.

The type of container is also a factor to consider, with flat bottomed and cleaner bottles transferring heat better. Vials with uneven bottoms or thick glass will transfer heat poorly, which will obviously take longer to lyophilize.

The performance of the freeze dryer is directly related to the formulation of the freeze drying curve. There are various types of freeze dryers, so their performance is also different. Some machines have good performance, for example, the temperature difference between the layers and parts of each layer is small; the temperature of the condenser is low, and the ice load capacity is large; the water vapor flow resistance between the freeze-drying box and the condenser is small; the vacuum pump Fast pumping speed, good and stable vacuum. Some machines are worse. So despite being the same product. When freeze-drying with different types of freeze-drying machines, the curves are also different. Copying the freeze-drying curves of other types of machines may not produce good products.

Pre-freezing time: There is a large amount of product, and the bottom of the container used is not flat. Instead of placing the product directly on the layer of the freeze-drying box to freeze-dry, the freezer of the freeze-drying box has poor freezer capacity. A machine with a large temperature difference between parts of a layer requires a longer pre-freezing time. In order to make each bottle of product in the box completely frozen, it is generally required to keep the sample for 1-2 hours after the temperature of the sample reaches the predetermined minimum temperature.

Minimum Temperature For Prefreezing:

This temperature depends on the eutectic point temperature of the product, and the minimum pre-freezing temperature should be lower than the eutectic point temperature of the product.

Pre-freezing speed: most machines cannot control the pre-freezing speed, so the pre-freezing rate can only be determined by the pre-freezing temperature and packing time. If the pre-freezing rate is required to be fast, the freeze-drying box will first drop to a lower temperature. Then let the product enter the box; if the rate of pre-freezing is slow, then let the freeze-drying box cool down after the product enters the box.

Condenser Cooling Time:

The condenser requires that at the end of the pre-freezing period, the pre-freezing has not yet ended, and the temperature should start to drop before vacuuming. How much time before is determined by the cooling performance of the condenser machine. It is required that the temperature of the condenser should reach about -40°C when vacuuming is completed after pre-freezing. A good machine generally starts to cool down half an hour before. The cooling of the condenser usually continues from the start until the end of the freeze-drying. The temperature should always be below -40°C.

The end time of pre-freezing: the end of pre-freezing is the operation of the freeze-drying box refrigerator. Usually, the operation of the freezer is stopped when the vacuum is pumped or the vacuum is drawn to the specified requirements.

Vacuum time:

The end of pre-freezing is the time to start vacuuming. It is required that the vacuum degree can reach 1×10-4 mbar in about half an hour. While evacuating, it is also when the vacuum valve between the condensers of the freeze-drying box is opened, and the vacuum pump and the vacuum valve are also opened until the end of the freeze-drying.

Vacuum alarm working time: Since the degree of vacuum is extremely important for sublimation, all new freeze dryers are equipped with vacuum alarm devices. The working time of the vacuum alarm device is from the beginning of heating to the use of the leak correction, or from the beginning of use to the end of freeze-drying. Once the vacuum degree drops during the sublimation process and a vacuum alarm occurs, an alarm signal will be issued on the one hand, and the heating of the freeze-drying box will be automatically cut off on the other hand. At the same time, the freezer of the freeze-drying box is started to cool down the product, so as to protect the product from melting.

Start Heating Time:

It is generally believed that the time to start heating (in fact, the sublimation has already started when the vacuum is pumped). The heating starts after the vacuum reaches 1×10-1 mbar (close to 1×10-1 mmHg). Some freeze dryers use the vacuum relay to automatically turn on the heating, that is, the vacuum reaches 1×10-1 mbar When the heating starts automatically; some freeze dryers start heating half an hour after vacuuming, when the vacuum has reached 1×10-1 mbar or even higher.

Maximum Permissible Temperature For Product Heating:

The maximum permissible temperature for plate heating is determined by the product. During sublimation, the heating temperature of the plate can exceed the maximum allowable temperature of the product because the product is still in the low temperature stage at this time. Increasing the temperature of the plate can promote sublimation; but after freeze-drying the plate The temperature of the layer needs to be lowered to be consistent with the maximum allowable temperature of the product. Due to the temperature difference of heat transfer, the temperature of the board layer can be slightly higher than the maximum allowable temperature of the product.

Working Hours For Correcting Leaks:

The purpose of correcting the leak is to improve the heat transfer in the freeze drying cabinet, and it is usually used during the second stage of work, continuing to restore the high vacuum state. The length of use time is determined by the product type, loading capacity and the value of the set vacuum degree.

Total Freeze-Drying Time:

The total time for lyophilization is the prefreeze time, plus the time for sublimation and second stage work. The total time is determined, and the freeze-drying end time is also determined. This time depends on the type of product, type of bottle, packing method, loading capacity, machine performance, etc. Generally, the freezing time is longer, about 18-24 hours, and some special products need several days.