FR2782155A1 - System for regulation of gas pressure in freeze-drying tank, uses water vapor in the tank, the pressure of which can be maintained by varying the amount of condensation - Google Patents

Abstract

Procedure consists in regulation of the gas, which is entirely water vapor, pressure in the tank (1) by varying the amount of condensation of water vapor onto a refrigeration system (3), of which the efficiency can be modified rapidly in order to correct variations in the pressure in the tank and maintain it at the design pressure. The efficiency of operation of the refrigeration system is changed by altering the flow rate of the liquid nitrogen that functions as a refrigerant.

Description

The present invention relates to an inexpensive device for adjusting

  gas pressure automatically

in a lyophilization tank.

  We know that these devices are used to lyophilize certain substances, in particular biological materials, generally contained in open bottles that are placed inside the tank on shelves. During a freeze-drying cycle, the desiccation of these substances is controlled by essentially acting on two independent parameters: the temperature of the shelves, and the gas pressure in the tank. To carry out a good quality freeze-drying, these two parameters must take values which vary, as a function of time, according to certain profiles to which the operator of the freeze-dryer

seeks to comply.

  The present invention relates to the regulation of the pressure parameter in the tank. The pressure due to water vapor tends to increase due to drying and, at the same time, to decrease due to the condensation of water vapor on a cold trap connected to the tank itself - the need for regulation if we want to apply a target gas pressure on the

substances to be lyophilized.

  Known devices maintain an extremely low temperature in the trap so as to condense the water vapor as efficiently as possible, the trap being

  generally made up of a classic refrigeration system.

  As is known, these compressor refrigeration systems are difficult to maintain, are noisy and use heat exchange fluids (such as Freon) which are harmful to the environment. The situation has recently improved in this respect, these conventional systems being gradually replaced by cryogenic systems using liquid nitrogen as the heat exchange fluid; the large quantities of liquid nitrogen required to do this, however, make these systems expensive, and the need has arisen for a regulatory device which would be less

greedy in cryogenic fluid.

  As for the pressure regulation, it is ensured, in these devices according to the prior art, by injecting dry gas into the tank. This gas, which must obviously be noncondensable under the conditions corresponding to the freeze-drying cycle, can for example be air or nitrogen. These known devices have serious drawbacks: - the total pressure in the tank is thus adjusted, and not directly the partial pressure due to water vapor, as it would be desirable to properly control desiccation, - lyophilization requiring a rigorous asepsis, the injected gas must be very carefully filtered and sterilized to avoid any risk of contamination of the substances to be lyophilized, and - the micrometric valves controlling the injection of said gas and controlled by the pressure gauge measuring the pressure in the

  tank, are a delicate operation.

  The invention makes it possible to adjust the pressure throughout the lyophilization without undergoing any of the drawbacks mentioned above, by purely and simply eliminating the incondensable gas, and by maintaining said pressure of the gas contained in the tank, which is therefore purely consisting of water vapor, at the set value by varying the condensation rate of water vapor on a refrigerant system whose efficiency, adjustable, can be quickly modified to counteract deviations of said pressure

  with respect to said set value.

  It will be advantageous to assign the control of the efficiency of said refrigerant system to a computer system capable of comparing the set value at each instant of the freeze-drying cycle at pressure

real in the tank.

3 2782155

  According to particular characteristics, the freeze dryer according to the invention comprises a refrigerant system consisting of a condenser in which nitrogen circulates with an adjustable flow rate, so that the efficiency of said refrigerant system can be checked simply

by modifying said flow.

  As in the known devices, the refrigerating system here has the task of condensing the water vapor extracted from the substances to be lyophilized, but in the device according to the invention, the losses of specific heat of the refrigerating fluid are reduced to a minimum; in other words, the temperature of the trap is as high as possible, taking into account the water vapor pressure to be maintained in the tank. This results in an economy

  substantial in the consumption of liquid nitrogen.

  Other benefits, purposes and features of the

  present invention will emerge from the description below

  of an embodiment of the invention presented as

  example, said description based on the two figures

  annexed, in which: FIG. 1 schematically represents a freeze dryer according to the prior art, and FIG. 2 schematically represents a freeze dryer

according to the invention.

  In the two figures, one can see a lyophilization tank 1 containing a certain number of shelves 2 on which vials (not shown) containing the substances to be lyophilized have been placed. Vacuum pumps (not shown) allow air to be removed from the freeze dryer at the start of the cycle. A refrigerant system, mainly consisting of a condenser 3, is connected to the tank itself by means of a valve 4 which is closed periodically to defrost the trap. Liquid nitrogen enters the condenser 3 through a valve 9 which makes it possible to modify the flow rate at will. A conventional pressure gauge 5 measures the gas pressure inside the

tank 1.

  FIG. 1 illustrates a device for regulating the pressure according to the prior art. An incondensable dry gas "X", for example air or nitrogen, can be injected as desired into the tank through a micrometric valve 6 after passing through a sterilizing filter 7. A thermometer 11 measures the temperature in a point on the condenser 3. A control system 8, connected both to the pressure gauge 5 and to the micrometric valve 6, injects gas X into the tank as soon as the pressure there drops below the set pressure at the instant considered in the freeze-drying cycle, while a control system 12, connected both to the thermometer 11 and to the valve 9, adjusts the flow of liquid nitrogen in the condenser 3 so as to maintain a

adequately low temperature.

  FIG. 2 illustrates a device for regulating the pressure according to the invention. A control computer system 10, connected to both the pressure gauge 5 and the valve 9, corrects any deviation of the actual pressure in the tank from the set pressure at the instant considered in the lyophilization cycle, by increasing the flow of liquid nitrogen, so as to accelerate the condensation of water vapor, when it is desired to reduce the pressure, and by reducing said flow otherwise. The temperature of the condenser 3 varies accordingly, but - and this is an essential merit of the invention, the regulation of the steam pressure is not subject to the measurement of the temperature of the condenser, but directly and only to

  the measurement of said pressure itself.

  The water vapor pressure regulation tests according to the invention have shown that it operates advantageously with extremely short reaction times, thanks to the fact that cryogenic liquid nitrogen systems have a power instant refrigeration

practically unlimited.

  Finally, note an additional advantage of the pressure regulation device according to the invention compared to the prior art. It should be known that the lyophilization cycle essentially comprises two distinct stages: in the first (called "primary desiccation"), the ice is sublimated in which the substances to be lyophilized are dissolved; in the second ("secondary desiccation"), water is extracted chemically bound to said substances. Secondary drying is carried out at higher shelf temperatures, and at much lower pressures, than the values

  used during primary drying.

  The difficulty comes from the fact that one can only pass into secondary drying once one is sure that the primary drying is well completed. In conventional freeze dryers, the completion of primary drying is signaled by a rise in temperature within the substances to be freeze dried, but this temperature measurement is not very reliable because it depends on the position of the temperature probes; we therefore have to wait in addition for a certain period of precaution. On the other hand, in the device according to the invention, the completion of the primary drying is detected immediately and reliably, because the sudden decrease in the flow of extracted water vapor results in a decrease in the nitrogen flow

  liquid required to condense it (at constant pressure).

Claims (4)

  1.- Method for regulating the gas pressure in a lyophilization tank (1), characterized in that the pressure of the gas, which is purely made up of water vapor, is maintained at the set value by varying the rate condensation of water vapor on a refrigerant system (3) whose efficiency, adjustable, can be quickly modified to correct deviations from said   pressure in relation to said setpoint.   2.- Method according to claim 1, characterized in that the efficiency of said refrigerant system (3) is controlled by a computer system (10) capable of comparing the set value at each instant of the cycle of   freeze-drying at actual pressure in the tank (1).   3. Freeze dryer characterized in that it comprises the organs necessary for implementing the process of   claim 1 or claim 2.   4. Freeze dryer according to claim 3, characterized in that said refrigerant system (3) consists of a condenser in which nitrogen circulates with an adjustable flow rate, and in that the efficiency of said refrigerant system varies according to said flow.