EP3462116B1 - Method for freeze-drying - Google Patents

Description

APPLICATION AREA AND PRIOR ART

The invention relates to a method for freeze drying.

Freeze drying, also known as lyophilization or sublimation drying, is a process for the gentle drying of high-quality products, in particular pharmaceutical products or biotech products, for example vaccines, or foods, for example for the production of milk powder.

In connection with the application, a product which is provided with a solvent is any preparation which is suitable for freeze-drying. These are in particular liquid or semi-solid aqueous preparations, such as solutions, emulsions or suspensions.

It is known to fill the products to be dried in containers, such as small vials, so-called vials, injection bottles or others and to dry them.

Known freeze drying systems comprise a product chamber in which a condenser is arranged or which is connected to a condenser. In the product chamber, a plurality of heatable and coolable shelves, which are arranged one above the other, are provided, on which the containers, in particular the vials, with the product to be dried filled are placed,

The actual cooling process is followed by cooling and freezing of the product, usually cooling the product to a certain freezing temperature and maintaining the freezing temperature until the solvent content of the product freezes. Freezing is also known as crystallization. The beginning of freezing is called nucleation or nucleation.

The drying process following the freezing can be divided into a primary drying and a secondary drying. During primary drying, a vacuum is applied and the solvent contained in the product is sublimed at temperatures below freezing. During secondary drying, solvent that is more strongly bound in the product is evaporated.

Out DE 199 36 281 A1 vacuum-induced freezing is known, crystallization being preceded by a phase in which a pressure in the product chamber is reduced until visible crystallization of the solvent begins. For a subsequent crystallization according to DE 199 36 281 A1 the pressure in the product chamber is raised to atmospheric pressure or kept reduced. The pressure reduction in the first phase can take place at ambient temperature. Alternatively, the first phase involves reducing the temperature to a temperature that lies between the freezing point of the solution and the ambient temperature.

With some products, freezing can lead to an uncontrolled escape of gases, also known as outgassing. With larger filling levels there is a risk that the product will foam up to the point that the product escapes from the unlocked container.

For example, it is off US 3,233,333 f For freeze-drying of food, it is known to provide degassing before freezing. In connection with the application, a controlled removal of gases is referred to as degassing, while an uncontrolled escape of gases is referred to as outgassing.

According to US 3,233,333 a precooling phase is initially provided, the product being brought to a temperature just above the freezing point of water, for example between + 1 ° C and + 6 ° C. The product is then introduced into a vacuum chamber for degassing and the pressure is gradually reduced, the temperature remaining essentially constant. After degassing, the pressure and temperature are further reduced for freezing.

Out US 2003/116027 A1 a method for monitoring a freeze-drying process by means of optical radiation is known.

TASK AND SOLUTION

It is an object of the present invention to provide a method for freeze-drying in which the formation of bubbles during freezing is prevented.

This object is achieved by the method having the features of claim 1. Advantageous refinements are described in the subclaims.

According to the invention, a method for freeze-drying a product, which is filled in containers, in particular in vials, and provided with a solvent is provided in a product chamber, which comprises a freezing phase and a drying phase, wherein a pressure is reduced in the product chamber before the freezing phase, whereby for a Degassing a pressure drop takes place gradually while approaching at least one stopping point, the pressure drop being stopped at the at least one stopping point for partial degassing, and after a defined stopping point time period and / or after detection of the completion of the partial degassing, the pressure drop continues, with on a pressure increase in the product chamber is detected during or before the method is carried out for the at least one breakpoint, and the breakpoint duration is defined on the basis of a course of the pressure rise and / or the completion of the partial degassing is detected.

The degassing while driving at breakpoints is also referred to as fractional degassing.

The pressure drop for the degassing is also referred to as the degassing phase. With decreasing pressure, more bound gas inclusions are dissolved. The gradual lowering ensures safe process control.

It is provided that a pressure increase in the product chamber is detected at the at least one stopping point. In one embodiment, the rise in pressure is recorded in the run-up to an actual freeze drying, with a stop point duration being defined on the basis of the recorded data. Alternatively, the detection is carried out while freeze-drying is being carried out, the completion of the partial degassing being detected on the basis of a course of the pressure rise. Such an observation allows a controlled process control even for unknown products and high filling levels. The data recorded in this way can then also be used to determine the breakpoint duration for subsequent processes.

In an advantageous embodiment, a gradient of the pressure increase at the at least one breakpoint is evaluated as an indicator for the completion of the partial degassing. If the gradient falls below a defined threshold value, the pressure reduction for degassing can be continued. This enables optimized process control with short stopping phases in reducing the pressure.

The number of stopping points can be suitably selected by the person skilled in the art depending on the boundary condition, such as filling level, number of vials, product composition, etc. At least two breakpoints are preferably provided. As the number of vials increases, more stop points are preferably selected. Depending on the application, the breakpoints are evenly or unevenly distributed in a pressure reduction area.

The pressure drop is preferably stopped at a number of breakpoints for partial degassing, the drop in pressure continuing each time after a breakpoint time period defined for the respective breakpoint and / or after detection of the completion of the partial degassing at the respective breakpoint.

In one embodiment, a large number of breakpoints are provided, so that the pressure is reduced quasi-continuously.

A pressure drop is interrupted at each stop. For this purpose, for example, a valve that connects the product chamber and / or a condenser to a vacuum pump is closed. To detect completion of degassing at a breakpoint, i.e. for a certain pressure, the effect is used that the inert gas escaping from the product, in particular air, is not condensed on the condenser and thus causes an increase in pressure in the product chamber. If the condenser is separated from the product chamber by an intermediate valve, this preferably remains open so that any steam escaping from the product is bound to the condenser and thus does not cause an increase in pressure. In an alternative embodiment, the vacuum pump is suitably controlled to interrupt the pressure drop and / or a gas, in particular an inert gas, is supplied.

A target or end value of the pressure in the degassing phase can be suitably selected by the person skilled in the art depending on the application. In an advantageous embodiment, the degassing is reduced to a pressure between approximately 2 mbar and approximately 50 mbar, in particular to a pressure between approximately 2 mbar and approximately 20 mbar.

The degassing can be carried out at ambient temperature or at a temperature above the ambient temperature. In advantageous refinements, the temperature is reduced continuously or in stages during the degassing by lowering the pressure in the product chamber, with a rate of pressure decrease and a rate of temperature decrease are selected such that the pressure in the product chamber is always higher than the saturation vapor pressure for each product temperature that arises.

For this purpose, in one embodiment, the breakpoints for reducing the pressure are determined as a function of a temperature of the product chamber, in particular as a function of a temperature of setting plates which are used for temperature regulation of the product chamber. The temperature is reduced when the pressure drops, i.e. the temperature decrease begins before the target pressure of the degassing phase is reached. The temperature drop can begin before, with or after the pressure drop. In the case of a gradual pressure and temperature reduction, it is also conceivable that the respective partial reductions are not carried out at the same time, but at different times from one another.

The temperature drop during degassing enables freezing, in particular vacuum-induced freezing, immediately after degassing. Appropriate process control and, in particular, a suitable choice of the pressure reduction rate and the temperature reduction rate ensure that, despite the temperature reduction, boiling of the solvent is prevented and only gases, in particular air, contained in the product escape.

A target or end value of the temperature in the degassing phase can be suitably selected by the person skilled in the art depending on the application. In advantageous refinements, the temperature is reduced for the degassing to a temperature of approximately -10 ° C. to approximately 10 ° C., in particular to a temperature of approximately -2 ° C. to approximately 5 ° C.

In one embodiment, the pressure is increased again for freezing the product while lowering the temperature to a temperature below the freezing point after degassing. In advantageous configurations, the pressure drop for the degassing is followed by a further pressure drop at a temperature below the freezing point for vacuum-induced freezing. An advantageous method for vacuum-indicated freezing is, for example, that which has not yet been published DE 10 2016 215 844.9 described.

The vacuum-indicated freezing is preferably carried out by a) lowering the pressure in the product chamber and the condenser at a temperature which is below the freezing point of the product until a defined pressure is reached which is below atmospheric pressure and above a product-specific nucleation pressure, at which a Nucleation begins, lies; b) closing the valve between the product chamber and the condenser; c) maintaining the pressure in the product chamber and further lowering the pressure in the condenser; and d) opening the valve between the product chamber and the condenser after or upon reaching the product-specific nucleation pressure in the condenser, so that the pressure in the product chamber is reduced to a pressure below the product-specific nucleation pressure. By opening the valve, a pressure drop in the product chamber is achieved with a high pressure drop rate, a pressure below the product-specific nucleation pressure being established in the product chamber.

The degassing phase is preferably provided immediately after loading the product chamber and, depending on the type of loading, usually takes place starting from an atmospheric pressure.

In a device for freeze-drying a product filled in containers, in particular in vials, comprising a product chamber, a vacuum pump connected to the product chamber and a control device, it can be provided that the control device is set up to carry out the described method. It is also possible to suitably convert existing devices by adapting the control device. Depending on the design, the vacuum pump is connected to the product chamber either directly or via a condenser. If degassing takes place while the temperature is being reduced, a device for regulating the temperature in the product chamber is preferably also provided. The temperature of the product chamber is preferably regulated by means of known setting plates.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1

eine schematische Darstellung einer Vorrichtung zur Gefriertrocknung und

Fig. 2

schematisch einen Verlauf des Drucks in einer Produktkammer, einen Verlauf einer Temperatur von Stellplatten der Produktkammer, und einen Verlauf einer Produkttemperatur bei Durchführung einer vorteilhaften Ausgestaltung des erfindungsgemäßen Verfahrens.

Further advantages and aspects of the invention result from the claims and from the following description of preferred exemplary embodiments of the invention, which are explained below with reference to the figures. Show:

Fig. 1

is a schematic representation of a device for freeze drying and

Fig. 2

schematically shows a course of the pressure in a product chamber, a course of a temperature of the setting plates of the product chamber, and a course of a product temperature when carrying out an advantageous embodiment of the method according to the invention.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Fig. 1 shows schematically a device 1 for freeze-drying products comprising a product chamber 2 with setting plates 20, a condenser 3 connected to the product chamber 2 via an intermediate valve 4 and a control device 5. The device 1 further comprises a vacuum pump 6 which is connected to the condenser 3 via a Vacuum valve 60 is connected.

In the in Fig. 1 In the illustrated embodiment, a central control device 5 is provided, which is connected to the setting plates 20, the condenser 3, the intermediate valve 4, the vacuum valve 60 and the vacuum pump 6 or elements thereof for the exchange of sensor and / or control signals wirelessly or via data lines. However, the communication paths represented by arrows are only to be understood schematically and do not show any wiring. In other configurations, several control devices are provided. Furthermore, each or individual of the components mentioned can be assigned its own control device, by means of which, for example, the control plates 20 are temperature-controlled to a temperature specified by the central control device 5.

For freeze-drying, products containing solvents are filled into containers, especially vials, and introduced into the product chamber.

According to the invention, a degassing phase is provided before a freezing phase and a drying phase following the freezing phase, wherein a pressure in the product chamber 2 is gradually reduced to a pressure below the atmospheric pressure and above a product-specific nucleation pressure in the degassing phase, a pressure drop at at least one stopping point for a partial degassing is interrupted. After a defined breakpoint period has elapsed and / or after detection of the completion of the partial degassing for this breakpoint, the pressure reduction is continued.

Fig. 2 shows schematically a course of the pressure in a product chamber 2, a course of a temperature of the setting plates, and a course of a product temperature when carrying out an advantageous embodiment of the method according to the invention.

According to the in Fig. 2 The process shown is a pressure reduction for the degassing step by step at 12 stops. The at each of the stops Pressure reduction stopped for partial degassing. For this purpose, for example, the vacuum valve 60 according to Fig. 2 closed, the intermediate valve 4 remains open.

After a defined breakpoint time period has elapsed and / or after detection of the completion of the partial degassing, the pressure reduction is continued, for example by opening the vacuum valve 60 again.

As in Fig. 2 recognizable, the pressure in the product chamber 2 increases due to the escaping gases after the pressure drop has stopped at the stopping points. This effect is used according to the invention to define a breakpoint duration in advance of a process implementation and / or to detect the completion of a partial degassing at a breakpoint during a process implementation.

In an advantageous embodiment of the invention, a gradient of the pressure rise is used as an indicator of progress in the degassing. A small or almost vanishing gradient indicates that the degassing has been completely or at least essentially completed for certain pressure conditions. This effect is used in particular at the breakpoints with a lower pressure level.

In the illustrated method, the temperature of the setting plates 20 is reduced during the degassing from an ambient temperature of approximately 20 ° C. to a temperature just above or below 0 °, i.e. just above the freezing point of the solution.

By degassing with a simultaneous lowering of the temperature, a vacuum-induced freezing by further lowering of pressure and temperature is possible immediately after the degassing phase. Alternatively, it is possible to raise the pressure to atmospheric pressure for a freezing process.

The temperature of the product chamber is regulated via the setting plates 20 (cf. Fig. 1 ), where a product temperature follows a shelf temperature. In the case of degassing with a lowering of temperature, the process is preferably carried out in such a way that the pressure in the product chamber 2 is always higher than the saturation vapor pressure for each product temperature that occurs, so that despite the lowering of the temperature and pressure, boiling of the solvent is avoided and only the gases enclosed in the products escape.

For this purpose, the breakpoints for an interruption of the pressure reduction are suitably determined depending on the temperature. A determination is possible in particular as a function of a temperature of the setting plates, taking into account that a product temperature usually follows a setting plate temperature, as in Fig. 2 shown.

In alternative embodiments, the pressure is reduced for the degassing at ambient temperature, and in order to avoid boiling, a pressure drop is preferably limited to a pressure above the saturation vapor pressure of approximately 23.4 mbar.

Claims (9)

1. Method for freeze-drying of a product provided with a solvent and filled in containers, in particular in vials, in a product chamber (2), the method comprising a freezing phase and a drying phase, wherein prior to the freezing phase a pressure reduction occurs in the product chamber,
   characterized in that
   for degassing, the pressure reduction occurs prior to the freezing phase to a pressure below the atmospheric pressure and above a product-specific nucleation pressure gradually by approaching at least one hold point, wherein the pressure reduction is stopped at the at least one hold point for a partial degassing and the pressure reduction is continued after expiration of a defined hold point period and/or after detection of completion of the partial degassing, wherein at the at least one hold point a pressure increase in the product chamber (2) is detected during or prior to performing the method and the hold point period is defined and/or the completion of the partial degassing is detected, based on a course of the pressure increase.
2. Method according to claim 1, characterized in that a gradient of the pressure increase at the at least one hold point is evaluated as an indicator for completion of the partial degassing.
3. Method according to claim 1 or 2, characterized in that a plurality of hold points is provided such that the pressure reduction is quasi-continuous.
4. Method according to claim 1, 2 or 3, characterized in that the product chamber (2) is connected to a vacuum pump (6) via a vacuum valve (60), wherein at the at least one hold point the vacuum valve (60) is closed, wherein preferably the product chamber (2) is connected to a condenser (3) via an intermediate valve (4), and the intermediate valve (4) remains open at the hold points.
5. Method according to any of the claims 1 to 4, characterized in that for the degassing procedure, the pressure reduction is to a pressure between approximately 2 mbar and approximately 50 mbar, in particular to a pressure between approximately 2 mbar and approximately 20 mbar.
6. Method according to any of the claims 1 to 5, characterized in that during degassing by pressure reduction in the product chamber (2) the temperature is lowered continuously or gradually, wherein a pressure reduction rate and a temperature reduction rate are selected such that, for each product temperature generated, the pressure in the product chamber (2) is always superior to the saturation vapour pressure.
7. Method according to claim 6, characterized in that for the degassing procedure, the temperature reduction is to a temperature of approximately -10 °C to approximately 10 °C, in particular to a temperature of approximately -2 °C to approximately 5 °C.
8. Method according to any of the claims 1 to 7, characterized in that, subsequent to the pressure reduction for degassing, a further pressure reduction occurs at a temperature below the freezing point for vacuum-induced freezing.
9. Method according to any of the claims 1 to 8, characterized in that the pressure reduction for degassing occurs subsequent to loading the product chamber and initiating from an atmospheric pressure.

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