EP3462116A1 - Method and device for freeze-drying - Google Patents

Abstract

The invention relates to a method and an apparatus for freeze-drying of a container, in particular vials filled, provided with a solvent product in a product chamber (2), comprising a freezing phase and a drying phase, wherein before the freezing phase in the product chamber for degassing a pressure reduction to a pressure below the atmospheric pressure and above a product-specific nucleation pressure gradually starting at least one breakpoint, wherein the pressure reduction stopped at the at least one breakpoint for a partial degassing and after a defined breakpoint period and / or after detection of the completion of the partial Degassing the pressure reduction is continued, wherein at the at least one breakpoint, a pressure increase in the product chamber (2) is detected during or before carrying out the method and based on a curve of the pressure increase the breakpoint Zei defined duration and / or the completion of the partial degassing is detected.

Description

The invention relates to a method and a device for freeze-drying.

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

In the context of the application, the term "solvent-containing product" refers to any preparation which is suitable for freeze-drying. These are, in particular, liquid or semisolid aqueous preparations, such as, for example, 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 other and to dry in these.

Known freeze-drying plants comprise a product chamber in which a condenser is arranged or which is connected to a condenser. In the product chamber a plurality of superimposed, heatable and coolable adjustable plates are provided, on which the containers, in particular the vials, are placed with the product to be dried, which is to be dried,

Cooling and freezing of the product takes place prior to the actual drying operation, usually cooling the product to a certain freezing temperature and maintaining the freezing temperature until the solvent content of the product has been frozen. Freezing is also called crystallization. The beginning of freezing is called nucleation or nucleation.

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

Out DE 199 36 281 A1 For example, vacuum-induced freezing is known, wherein crystallization is preceded by a phase in which a pressure in the product chamber is lowered until the onset of visible crystallization of the solvent. For a subsequent crystallization is according to DE 199 36 281 A1 the pressure in the product chamber raised again to the atmospheric pressure or kept reduced. The pressure reduction in the first phase can be done at ambient temperature. Alternatively, in the first phase, the temperature is reduced to a temperature that is between the freezing point of the solution and the ambient temperature.

For some products, freezing may result in uncontrolled escape of gases, also known as outgassing. For larger filling heights, there is a risk that the product will foam up to the point of outgassing, so that the product escapes from the unclosed container.

It is for example off US 3,233,333 for a freeze-drying of food known to provide a degassing before freezing. In the context of the application, controlled removal of gases is referred to as degassing, whereas uncontrolled escape of gases is referred to as outgassing.

According to US 3,233,333 First, a pre-cooling phase is provided, wherein the product is brought to a temperature just above the freezing point of water, for example between + 1 ° C and + 6 ° C. Subsequently, the product is introduced into a vacuum chamber for degassing and the pressure is lowered stepwise, wherein the temperature remains substantially constant. After degassing, the pressure and temperature are further lowered for freezing.

TASK AND SOLUTION

It is an object of the present invention to provide a method and apparatus for freeze-drying in which blistering upon freezing is prevented.

This object is achieved by the method and the device having the features of claims 1 and 10. Advantageous embodiments are described in the subclaims.

According to a first aspect, there is provided a process for the freeze-drying of a solvent-containing product filled in containers, in particular vials, in a product chamber comprising a freezing phase and a drying phase before the freezing phase in the product chamber, a pressure is lowered, for a degassing, a pressure reduction stepwise under approaching at least one breakpoint, wherein the pressure reduction stopped at the at least one breakpoint for a partial degassing and after a defined breakpoint period and / or after a detection of the conclusion of the partial degassing, the pressure reduction is continued, wherein at the at least one breakpoint, a pressure increase in the product chamber during or before a performance of the method is detected and based on a curve of the pressure rise defined the breakpoint period and / or the completion of the partial Degassing is detected.

The degassing under approach of breakpoints is also referred to as fractionated degassing.

The pressure reduction for the degassing is also referred to as degassing phase. With decreasing pressure, more strongly bound gas inclusions are dissolved. The gradual reduction guarantees a safe process control.

It is provided that at the at least one breakpoint, a pressure increase in the product chamber is detected. In one embodiment, the increase in pressure is detected in advance of an actual freeze-drying, wherein a hold-point time duration is defined on the basis of the acquired data. Alternatively, the detection takes place during a performance of a freeze-drying, wherein the conclusion of the partial degassing is detected on the basis of a course of the pressure rise. Such observation allows a controlled process management even for unknown products and high filling heights. The data thus acquired may then also be used to establish the breakpoint duration for subsequent processes.

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

Depending on the boundary conditions, such as filling level, number of vials, product composition, etc., the number of breakpoints can be suitably selected by the person skilled in the art. Preferably, at least two breakpoints are provided. Preferably, as the number increases Vials have chosen more breakpoints. The breakpoints are distributed evenly or unevenly in a pressure reduction range depending on the application.

Preferably, the pressure reduction is stopped at a plurality of breakpoints for a partial degassing, wherein in each case after expiration of a defined breakpoint period for the respective breakpoint and / or after detection of the completion of the partial degassing at the respective breakpoint, the pressure reduction is continued.

In one embodiment, a plurality of stops is provided, so that the pressure reduction is quasi-continuous.

At each breakpoint a pressure drop is interrupted. For this purpose, for example, a valve which connects the product chamber and / or a condenser to a vacuum pump is closed. For the detection of a completion of degassing at a breakpoint, i. for a given pressure, the effect is used that the inert gas escaping the product, in particular air, is not condensed on the condenser and thus causes a pressure increase in the product chamber. If the condenser is separated from the product chamber by an intermediate valve, it preferably remains open so that any vapor escaping from the product is bound to the condenser and thus causes no pressure increase. In an alternative embodiment, the vacuum pump is suitably activated for interrupting the pressure reduction and / or a gas, in particular an inert gas, is supplied.

A target or final value of the pressure in the degasification phase can be suitably selected by the person skilled in the art, depending on the application. In an advantageous embodiment, a pressure reduction is carried out for the degassing to a pressure between about 2 mbar and about 50 mbar, in particular to a pressure between about 2 mbar and about 20 mbar.

Degassing may be carried out at ambient temperature or at a temperature above ambient temperature. In advantageous embodiments, the temperature is lowered continuously or stepwise in the degassing by pressure reduction in the product chamber, wherein a pressure reduction rate and a temperature reduction rate are chosen such that for each adjusting product temperature of the pressure in the product chamber is always higher than the saturation vapor pressure.

For this purpose, in one embodiment, the holding points for the pressure reduction as a function of a temperature of the product chamber, in particular depending on a Temperature of control panels, which are used for a temperature regulation of the product chamber, set. The temperature reduction takes place at a pressure drop, ie, the temperature reduction begins before the target pressure of the degassing phase is reached. The temperature reduction can begin before, with or after the pressure reduction. In a gradual pressure and temperature reduction, it is also conceivable that the respective partial subsidence are not carried out simultaneously but with a time delay to each other.

By lowering the temperature during degassing is immediately following the degassing a freezing, in particular a vacuum-induced freezing is possible. By means of suitable process control, and in particular a suitable choice of the pressure reduction rate and the temperature reduction rate, it is ensured that boiling of the solvent is prevented despite the drop in temperature and only gases, in particular air, contained in the product escape.

A target or final 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 embodiments, a temperature reduction takes place for degassing to a temperature of about -10 C to about 10 ° C, in particular to a temperature of about -2 C to about 5 ° C.

In one embodiment, the pressure is increased again to freeze the product while lowering the temperature to a temperature below the freezing point after degassing. In advantageous embodiments, subsequent to the pressure reduction for the degassing, a further pressure reduction takes place at a temperature below the freezing point for a vacuum-induced freezing. An advantageous method for a vacuum-induced freezing is, for example, in the not yet published DE 10 2016 215 844.9 to which reference is hereby fully made. The vacuum-induced 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 the 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 lowered to a pressure below the product specific nucleation pressure. Opening the valve causes a pressure drop in the product chamber achieved a high pressure drop rate, wherein in the product chamber below the product-specific nucleation pressure is set pressure.

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

According to a second aspect, there is provided 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, wherein the control device is set up to carry out the described method. It is also possible to retrofit existing devices by adapting the control device suitable. Depending on the design, the vacuum pump is connected directly or via a condenser to the product chamber. If degassing is carried out while lowering the temperature, preferably a device for regulating the temperature in the product chamber is also provided. A temperature control of the product chamber is preferably carried out by means of known actuators.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1

eine schematische Darstellung einer erfindungsgemäßen 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 will become apparent from the claims and from the following description of preferred embodiments of the invention, which are explained below with reference to the figures. Showing:

Fig. 1

a schematic representation of a device according to the invention for freeze-drying and

Fig. 2

schematically a profile of the pressure in a product chamber, a curve of a temperature of control 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 1 schematically shows a device 1 for the freeze-drying of products, comprising a product chamber 2 with control 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.

In the in Fig. 1 illustrated embodiment, a central control device 5 is provided, which is connected to the control 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 show no wiring. In other embodiments, a plurality of control devices are provided. Furthermore, each or individual of said components may be assigned its own control device, by means of which, for example, a temperature control of the adjusting plates 20 takes place at a temperature predetermined by the central control device 5.

For lyophilization, products mixed with solvents are filled into containers, in particular in vials, and introduced into the product chamber.

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

Fig. 2 schematically shows a profile of the pressure in a product chamber 2, a curve of a temperature of the adjusting 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 method shown is a pressure reduction for the degassing step by step starting from 12 breakpoints. In this case, the pressure reduction is stopped for a partial degassing at each of the breakpoints. For this purpose, for example, the vacuum valve 60 according to Fig. 2 closed, the intermediate valve 4 remains open.

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

As in Fig. 2 Recognizable increases due to the escaping gases, the pressure in the product chamber 2 after stopping the pressure reduction at the breakpoints. This effect is used according to the invention to define a breakpoint duration in advance of a process execution and / or to detect the completion of a partial degassing at a breakpoint during a process execution.

In an advantageous embodiment of the invention, a gradient of the pressure rise is used as an indicator of progress of degassing. A small or almost vanishing gradient indicates that the degassing is complete or at least substantially for certain pressure conditions. This effect is used especially at the lower pressure levels.

In the illustrated method, during the degassing, a temperature reduction of the control plates 20 from an ambient temperature of about 20 ° C to a temperature just above or below 0 °, i. E. just above the freezing point of the solution.

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

A temperature regulation of the product chamber via the control plates 20 (see. Fig. 1 ), wherein a product temperature follows a platen temperature. In a degassing under temperature reduction process is preferably carried out such that for each adjusting product temperature of the pressure in the product chamber 2 is always higher than the saturation vapor pressure, so that despite lowering the temperature and pressure boiling of the solvent is avoided and only the gases enclosed in the products escape.

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

In alternative embodiments, a pressure reduction for the degassing at ambient temperature, wherein in order to avoid boiling, a pressure reduction takes place is preferably limited to a pressure above the saturation vapor pressure of about 23.4 mbar.

Claims (10)

A process for the freeze-drying of a product, in vials, filled with a solvent-containing product in a product chamber (2), comprising a freezing phase and a drying phase, wherein before the freezing phase in the product chamber, a pressure is lowered, characterized in that for degassing a pressure reduction to a pressure below the atmospheric pressure and above a product-specific nucleation pressure is carried out gradually starting at least one holding point, wherein the pressure reduction stopped at the at least one breakpoint for a partial degassing and after a defined breakpoint period and / or after detection of the conclusion the partial degassing the pressure reduction is continued, wherein at the at least one breakpoint, a pressure increase in the product chamber (2) during or before a performance of the method is detected and based on a curve of the pressure increase the holding point t-defined period of time and / or the completion of the partial degassing is detected. A method according to claim 1, characterized in that a gradient of the pressure increase at the at least one breakpoint is evaluated as an indicator for completion of the partial degassing. A method according to claim 1 or 2, characterized in that a plurality of holding points are provided, so that the pressure reduction is quasi-continuous. 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), the vacuum valve (60) being closed at the at least one stopping point, preferably the Product chamber (2) with a capacitor (3) via an intermediate valve (4) is connected and the intermediate valve (4) remains open at the breakpoints. Method according to one of claims 1 to 4, characterized in that for the degassing, the pressure reduction to a pressure between about 2 mbar and about 50 mbar, in particular to a pressure between about 2 mbar and about 20 mbar, takes place. Method according to one of claims 1 to 5, characterized in that in the degassing by lowering the pressure in the product chamber (2) the temperature is lowered continuously or stepwise, wherein a pressure reduction rate and a temperature reduction rate are chosen such that for each adjusting product temperature, the pressure in the product chamber (2) is always higher than the saturation vapor pressure. A method according to claim 6, characterized in that for the degassing, the temperature reduction to a temperature of about -10 C to about 10 ° C, in particular to a temperature of about -2 C to about 5 ° C. Method according to one of claims 1 to 7, characterized in that subsequent to the pressure reduction for the degassing, a further pressure reduction takes place at a temperature below the freezing point for a vacuum-induced freezing. Method according to one of claims 1 to 8, characterized in that the pressure reduction for the degassing is carried out subsequent to loading of the product chamber and starting from an atmospheric pressure. Device for the freeze-drying of a product filled in containers, in particular in vials, comprising a product chamber (2), a vacuum pump (6) connected to the product chamber (2) and a control device for carrying out the method according to one of claims 1 to 9.

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