EP3504496B1 - Method and apparatus for freeze-drying - Google Patents

Method and apparatus for freeze-drying Download PDF

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Publication number
EP3504496B1
EP3504496B1 EP17752124.2A EP17752124A EP3504496B1 EP 3504496 B1 EP3504496 B1 EP 3504496B1 EP 17752124 A EP17752124 A EP 17752124A EP 3504496 B1 EP3504496 B1 EP 3504496B1
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Prior art keywords
pressure
product
nucleation
condenser
product chamber
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German (de)
French (fr)
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EP3504496A1 (en
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Timo HEINZ
Jens Philipp
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Optima Pharma GmbH
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Optima Pharma GmbH
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Priority to SI201730848T priority Critical patent/SI3504496T1/en
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    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F26—DRYING
    • F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
    • F26B5/00—Drying solid materials or objects by processes not involving the application of heat
    • F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
    • F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing

Definitions

  • the invention relates to a method and a device for freeze drying.
  • Freeze drying also known as lyophilization or sublimation drying, is a method for the gentle drying of high-quality products, in particular pharmaceutical products or biotech products, for example vaccines, or food, in particular for the production of milk powder.
  • a product is defined as any preparation which is suitable for freeze-drying.
  • These are in particular liquid or semi-solid aqueous preparations such as solutions, emulsions or suspensions.
  • the products to be dried are filled into containers such as small bottles, so-called vials, injection bottles or others and dried in these.
  • Known freeze-drying systems comprise a product chamber in which a condenser is arranged or which is connected to a condenser.
  • a condenser In the product chamber, several heating and cooling plates are provided, one above the other, on which the containers, in particular the vials, with the product to be dried filled therein are placed.
  • the product Before the actual drying process, the product is cooled and frozen, the product usually being cooled to a certain freezing temperature and the freezing temperature being maintained until the solvent component of the product is frozen. Freezing usually takes place at atmospheric pressure. Freezing is also known as crystallization. The beginning of freezing is known as nucleation or nucleation.
  • the drying process following freezing can be divided into primary drying and secondary drying.
  • primary drying a vacuum is applied and the solvent contained in the product is sublimed at temperatures below freezing point.
  • secondary drying more solvent bound in the product is evaporated.
  • a quality of nucleation has a strong influence on the quality of the product obtained by the freeze-drying.
  • it is proposed to improve the nucleation that first of all cooling to a temperature close to or below the phase transition temperature takes place, the pressure in the product chamber being above atmospheric pressure.
  • the products are cooled at a temperature of the shelves of -7 ° C over a period of approx. 15 minutes.
  • the pressure in the product chamber is then rapidly reduced to atmospheric pressure. This is achieved, for example, by opening a valve to a condenser.
  • the shelves are then cooled to a temperature between approx. -40 ° C and -45 ° C for further freezing. Freezing is followed by the actual drying process.
  • nucleation or nucleation begins in a pressure range that varies depending on the type and concentration.
  • the time span between nucleations can be several minutes. This can result in sublimation of the initially frozen products, which manifests itself in small, dry areas on the surface.
  • the steps cause vacuum-induced nucleation.
  • a pressure drop is achieved in the product chamber with a high pressure drop rate, a pressure below the product-specific nucleation pressure being established in the product chamber.
  • a pressure range within which the products freeze in conventional vacuum-induced nucleation processes is approximately skipped. As a result, all products nucleate in a short period of time. Since a pressure in the product chamber was already reduced before the pressure drop, only a pressure difference of a few millibars needs to be compensated.
  • the product chamber is preferably cooled by means of known adjusting plates.
  • the in the product chamber arranged shelves to a temperature of approx. -20 ° C to approx. -3 ° C, in particular from approx. -14 ° C to approx. -5 ° C, cooled.
  • the temperature of the setting plates is kept constant via steps a) to d) of the method.
  • the product-specific nucleation pressure and / or the pressure range to be skipped by closing and opening the valve can be suitably selected by the person skilled in the art depending on the application, for example depending on the product and / or a size of the product chamber.
  • the pressure in the condenser is lowered to a pressure in the range from approx. 0.005 to approx. 3 mbar.
  • the pressure in the product chamber is reduced by approx. 0.3 mbar to approx. 2.5 mbar by opening the valve and / or the pressure in the product chamber is reduced to a pressure by opening the valve is lowered below the triple point of the product.
  • the vacuum-induced nucleation takes place in the inventive method at a temperature which is below the freezing point of the product. If the products are filled in small quantities, the pressure drop not only causes nucleation but also complete crystallization of the products.
  • a step for freezing the products is provided after the vacuum-induced nucleation, with the product chamber being further cooled for this purpose. In one embodiment, the low pressure level in the product chamber is maintained.
  • a method of freeze drying of products comprising a method for nucleation is created, a subsequent freezing and sublimation of the solvent taking place while maintaining the pressure between the product chamber and the condenser after opening the valve.
  • the pressure in the product chamber is increased for complete freezing, for example the product chamber is brought back to atmospheric pressure.
  • the temperature of the shelves also remains unchanged for freezing and sublimation in one embodiment.
  • a device for freeze-drying products comprising a product chamber, a condenser connected to the product chamber via a valve and a control device
  • the control device for Carrying out the method for nucleation according to one of claims 1 to 5 is set up and designed.
  • the control device is designed in such a way that it can be carried out completely automatically with predeterminable process parameters.
  • the control device comprises, for example, adjusting elements for actuating the valve provided between the product chamber and the condenser. In other embodiments, it is carried out semi-automatically.
  • the control device sends acoustic or optical signals, for example, by means of which a user is supported in carrying out the method. For example, a user is asked to close or open the valve between the product chamber and the condenser.
  • a central control device 5 is provided which is connected wirelessly or via data lines to the setting plates 20, the condenser 3, the valve 4, the valve 60 and the vacuum pump 6 or elements thereof for the exchange of sensor and / or control signals.
  • the communication paths shown by arrows are to be understood only schematically and do not show any wiring.
  • several control devices are provided.
  • each or individual of the named components can be assigned their own control device, by means of which, for example, the temperature of the setting plates 20 is regulated to a temperature predetermined by the central control device 5.
  • valve 4 is initially opened and the product chamber 2 is in communication with the condenser 3.
  • a temperature in the product chamber 2 and the condenser is lowered to a value which is below the freezing point of the product.
  • this takes place in that the setting plates 20 are cooled to a temperature which is approximately 3 to 20 ° C. below the freezing point of the product.
  • the pressure in the product chamber 2 and the condenser 3 is first lowered until a first defined pressure is reached, which is below atmospheric pressure and above a product-specific nucleation pressure at which nucleation begins.
  • the vacuum pump 6 is operated in a suitable manner, the vacuum pump 6 being operated, for example, by means of the control device 5.
  • the first defined pressure can be specified product-specifically by a person skilled in the art, with the control device 5 having a man-machine interface for this purpose in one embodiment.
  • valve 4 When the first defined pressure is reached, the valve 4 is closed.
  • a pressure in the product chamber 2 and the condenser 3 is monitored by means of the control device 5 and, by means of the control device 5, an actuation of the valve 4 when it is reached first defined pressure.
  • the valve 4 is actuated by a user.
  • Fig. 2 shows the device 1 with the valve 4 closed. After the valve 4 is closed, the pressure in the product chamber 3 is maintained and the pressure in the condenser 4 is further reduced by means of the vacuum pump 6. A further lowering of the pressure in the condenser 3 takes place, for example, until a second defined pressure is reached in the condenser 3 which is below the product-specific nucleation pressure.
  • the valve 4 When the second defined pressure is reached, the valve 4 is opened.
  • a pressure in the condenser 3 is also monitored by means of the control device 5 and, by means of the control device 5, the valve 4 is actuated when the second defined pressure is reached.
  • the valve 4 is actuated by a user.
  • the second defined pressure can also be specified product-specifically by a specialist.
  • the person skilled in the art specifies the pressure which is to be set in the product chamber 2 after opening the valve 4, the control device 5 based on this value taking into account the properties of the device 1, such as the size of the product chamber 2, the second defined pressure is determined.
  • the pressure in the condenser 3 is lowered over a predetermined period of time.
  • Fig. 3 shows the device 1 after the opening of the valve 4 between the product chamber 2 and the condenser 2 after or when the second defined pressure is reached in the condenser 3, as indicated by arrows in FIG Fig. 3 indicated the pressure in the product chamber 2 is lowered to a pressure below the product-specific nucleation pressure.
  • Fig. 4 shows schematically a course of a product temperature 7 and a course of the pressure 8 in a product chamber 2 (cf. Fig. 1 ) when carrying out the method according to the invention.
  • the temperature of the shelves 20 in the product chamber 2 (cf. Figs. 1 to 3 ) is represented by a line 9.
  • the temperature of the setting plates 20 is about -10 ° C.
  • a pressure 8 in the product chamber 2 and the condenser 3 (cf. Fig. 1 ) until a first defined pressure is reached, which is below the Atmospheric pressure and above a product-specific nucleation pressure at which nucleation begins.
  • a second step b) the valve 4 between the product chamber 2 and the condenser 3 is closed.
  • a third step c) the pressure in the product chamber is maintained and the pressure in the condenser 3 is further reduced until a second defined pressure is reached which is below the product-specific nucleation pressure.
  • a fourth step d) the valve 4 between the product chamber 2 and the condenser 3 is opened and a pressure equalization is achieved as a result.
  • the pressure equalization has the effect that the pressure in the product chamber 2 is reduced in a short time to a pressure below the product-specific nucleation pressure.
  • the pressure which has been reduced to approx. 0.7 mbar, causes nucleation, with the nucleation occurring in all products within a product chamber 2 almost simultaneously. Due to the prevailing low temperature, the products freeze completely in the case of small filling quantities, without the need for a further lowering of the temperature of the shelves 20. The period of time at which the products are completely frozen or crystallized is marked with II.
  • a subsequent sublimation of the frozen product takes place in the illustrated embodiment, likewise while maintaining the pressure that is established after the completion of step 4) and while maintaining the temperature of the shelves at approx. -10 ° C.
  • these process parameters are only exemplary and the steps according to the invention for an improved freezing process can be combined with other process steps for complete freezing or drying.

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  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Mechanical Engineering (AREA)
  • General Engineering & Computer Science (AREA)
  • Drying Of Solid Materials (AREA)
  • Confectionery (AREA)

Description

Die Erfindung betrifft ein Verfahren und eine Vorrichtung zur Gefriertrocknung.The invention relates to a method and a device for freeze drying.

Gefriertrocknung, auch als Lyophilisation oder Sublimationstrocknung bezeichnet, ist ein Verfahren zur schonenden Trocknung hochwertiger Produkte, insbesondere Pharmaprodukte oder Biotechprodukte, beispielsweise Impfstoffe, oder Lebensmittel, insbesondere zur Herstellung von Milchpulver.Freeze drying, also known as lyophilization or sublimation drying, is a method for the gentle drying of high-quality products, in particular pharmaceutical products or biotech products, for example vaccines, or food, in particular for the production of milk powder.

Als Produkt wird im Zusammenhang mit der Anmeldung jede Zubereitung bezeichnet, welche sich für die Gefriertrocknung eignet. Dabei handelt es sich insbesondere um flüssige oder halbfeste wässrige Zubereitungen, wie beispielsweise Lösungen, Emulsionen oder Suspensionen.In connection with the application, a product is defined as any preparation which is suitable for freeze-drying. These are in particular liquid or semi-solid aqueous preparations such as solutions, emulsions or suspensions.

Die zu trocknenden Produkte werden in Behältnisse, wie kleine Fläschchen, sogenannte Vials, Injektionsflaschen oder andere gefüllt und in diesen getrocknet.The products to be dried are filled into containers such as small bottles, so-called vials, injection bottles or others and dried in these.

Bekannte Gefriertrocknungsanlagen umfassen eine Produktkammer, in welcher ein Kondensator angeordnet ist oder welche mit einem Kondensator verbunden ist. In der Produktkammer sind mehrere, übereinander angeordnete, beheiz- und kühlbare Stellplatten vorgesehen, auf welchen die Behältnisse, insbesondere die Vials, mit dem darin abgefüllten, zu trocknenden Produkt platziert werden,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, several heating and cooling plates are provided, one above the other, on which the containers, in particular the vials, with the product to be dried filled therein are placed.

Vor dem eigentlichen Trocknungsvorgang erfolgt ein Abkühlen und Einfrieren des Produkts, wobei üblicherweise das Produkt auf eine bestimmte Gefriertemperatur abgekühlt wird und die Gefriertemperatur bis zum Einfrieren des Lösungsmittelanteils des Produkts beibehalten wird. Ein Einfrieren erfolgt üblicherweise bei Atmosphärendruck. Das Einfrieren wird auch als Kristallisation bezeichnet. Der Beginn des Einfrierens wird als Keimbildung oder Nukleation bezeichnet.Before the actual drying process, the product is cooled and frozen, the product usually being cooled to a certain freezing temperature and the freezing temperature being maintained until the solvent component of the product is frozen. Freezing usually takes place at atmospheric pressure. Freezing is also known as crystallization. The beginning of freezing is known as nucleation or nucleation.

Der auf das Einfrieren folgende Trocknungsvorgang kann in eine Primärtrocknung und eine Sekundärtrocknung unterteilt werden. Bei der Primärtrocknung wird ein Vakuum angelegt und das in dem Produkt enthaltene Lösungsmittel bei Temperaturen unter dem Gefrierpunkt sublimiert. Bei der Sekundärtrocknung wird stärker in dem Produkt gebundenes Lösungsmittel verdampft.The drying process following freezing can be divided into primary drying and secondary drying. During primary drying, a vacuum is applied and the solvent contained in the product is sublimed at temperatures below freezing point. During secondary drying, more solvent bound in the product is evaporated.

Wie beispielsweise in US 8,240,065 B2 beschrieben, hat eine Qualität der Keimbildung einen starken Einfluss auf die Qualität des durch die Gefriertrocknung erhaltenen Produkts. Gemäß US 8,240,065 B2 ist zur Verbesserung der Keimbildung vorgeschlagen, dass zunächst eine Abkühlung auf eine Temperatur nahe oder unterhalb der Phasenübergangstemperatur erfolgt, wobei der Druck in der Produktkammer über dem Atmosphärendruck liegt. Beispielsweise erfolgt eine Abkühlung der Produkte bei einer Temperatur der Stellplatten von -7°C über einen Zeitraum von ca. 15 Minuten. Für die Keimbildung erfolgt dann eine rasche Druckabsenkung in der Produktkammer auf Atmosphärendruck. Dies wird beispielsweise durch Öffnen eines Ventils zu einem Kondensator erreicht. Anschließend werden für ein weiteres Einfrieren die Stellplatten auf eine Temperatur zwischen ca. -40°C und -45°C abgekühlt. An das Einfrieren schließt sich dann der eigentliche Trocknungsvorgang an.As for example in US 8,240,065 B2 described, a quality of nucleation has a strong influence on the quality of the product obtained by the freeze-drying. According to US 8,240,065 B2 it is proposed to improve the nucleation that first of all cooling to a temperature close to or below the phase transition temperature takes place, the pressure in the product chamber being above atmospheric pressure. For example, the products are cooled at a temperature of the shelves of -7 ° C over a period of approx. 15 minutes. For nucleation, the pressure in the product chamber is then rapidly reduced to atmospheric pressure. This is achieved, for example, by opening a valve to a condenser. The shelves are then cooled to a temperature between approx. -40 ° C and -45 ° C for further freezing. Freezing is followed by the actual drying process.

Aus DE 199 36 281 A1 ist ein vakuumindiziertes Einfrieren bekannt, wobei zunächst bei einer Temperatur in der Produktkammer, die oberhalb des Gefrierpunkts der Produkts liegt, ein Druck in der Produktkammer bis zum Einsetzen einer sichtbaren Kristallisation des Lösungsmittels abgesenkt wird. Die Temperatur der Stellplatten liegt dabei beispielsweise bei +10 °C. In einem zweiten Schritt wird die Temperatur in der Trocknungskammer auf eine Temperatur abgesenkt, die unter dem Gefrierpunkt des Produkts liegt oder mit diesem identisch ist, bis zum Abschluss der Kristallisation des Lösungsmittels. In einem weiteren Schritt erfolgt eine Primärtrocknung durch Sublimation des Lösungsmittels bei vermindertem Druck.Out DE 199 36 281 A1 vacuum-induced freezing is known, with a pressure in the product chamber first being lowered at a temperature in the product chamber which is above the freezing point of the product until the onset of visible crystallization of the solvent. The temperature of the shelves is, for example, +10 ° C. In a second step, the temperature in the drying chamber is lowered to a temperature which is below or identical to the freezing point of the product until the solvent has crystallized. In a further step, primary drying takes place through sublimation of the solvent under reduced pressure.

Bei einem vakuuminduzierten Einfrieren lässt sich beobachten, dass die Nukleation oder Keimbildung in einem je nach Art und Konzentration variierenden Druckbereich einsetzt. Die Zeitspanne zwischen den Nukleationen kann bei mehreren Minuten liegen. Dies kann zur Folge haben, dass bei den zuerst eingefrorenen Produkten eine Sublimation einsetzt, was sich in kleinen, trockenen Arealen an der Oberfläche äußert.In the case of vacuum-induced freezing, it can be observed that nucleation or nucleation begins in a pressure range that varies depending on the type and concentration. The time span between nucleations can be several minutes. This can result in sublimation of the initially frozen products, which manifests itself in small, dry areas on the surface.

Aus US 2003/116027 A1 ist ein Verfahren zur Überwachung eines Gefriertrocknungsprozesses mittels optischer Strahlung bekannt. Verfahren und/oder Vorrichtungen zum Gefriertrocknen sind weiter aus US 2010/242301 A1 , CN 104 677 084 A , US 2012/102982 A , WO 00/40910 A1 und US 2010/107436 A1 bekannt.Out US 2003/116027 A1 a method for monitoring a freeze-drying process by means of optical radiation is known. Methods and / or devices for freeze drying are further out US 2010/242301 A1 , CN 104 677 084 A , US 2012/102982 A , WO 00/40910 A1 and US 2010/107436 A1 known.

AUFGABE UND LÖSUNGTASK AND SOLUTION

Es ist eine Aufgabe der Erfindung, ein verbessertes Verfahren zur Keimbildung bei der Gefriertrocknung von Produkten und Verfahren zur Gefriertrocknung von Produkte sowie eine Vorrichtung zu dessen Durchführung zu schaffen.It is an object of the invention to provide an improved method for nucleation in the freeze-drying of products and a method for freeze-drying of products as well as an apparatus for carrying out the same.

Erfindungsgemäß wird ein Verfahren zur Keimbildung bei der Gefriertrocknung von Produkten in einer mit einem Kondensator über ein Ventil verbundenen Produktkammer geschaffen, umfassend die in zeitlicher Folge nacheinander durchzuführenden Schritte:

  1. a) Absenken des Drucks in der Produktkammer und dem Kondensator bei einer Temperatur, die unterhalb des Gefrierpunktes des Produkts liegt, bis ein definierter Druck erreicht wird, welcher unterhalb des Atmosphärendrucks und oberhalb eines produktspezifischen Keimbildungsdrucks, bei welchem eine Keimbildung einsetzt, liegt;
  2. b) Schließen des Ventils zwischen der Produktkammer und dem Kondensator;
  3. c) Beibehalten des Drucks in der Produktkammer und weiteres Absenken des Drucks in dem Kondensator; und
  4. d) Öffnen des Ventils zwischen der Produktkammer und dem Kondensator nach oder bei Erreichen des produktspezifischen Keimbildungsdrucks in dem Kondensator, sodass der Druck in der Produktkammer auf einen Druck unterhalb des produktspezifischen Keimbildungsdrucks abgesenkt wird.
According to the invention, a method for nucleation during the freeze-drying of products in a product chamber connected to a condenser via a valve is created, comprising the following steps to be carried out one after the other:
  1. 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 nucleation begins;
  2. b) closing the valve between the product chamber and the condenser;
  3. c) maintaining the pressure in the product chamber and further reducing the pressure in the condenser; and
  4. d) opening the valve between the product chamber and the condenser after or when the product-specific nucleation pressure is reached in the condenser, so that the pressure in the product chamber is reduced to a pressure below the product-specific nucleation pressure.

Die Schritte bewirken eine vakuuminduzierte Keimbildung. Durch das Öffnen des Ventils wird ein Druckabfall in der Produktkammer mit einer hohen Druckabfallrate erzielt, wobei sich in der Produktkammer ein unterhalb des produktspezifischen Keimbildungsdrucks liegender Druck einstellt. Ein Druckbereich, innerhalb dessen die Produkte bei herkömmlichen vakuuminduzierte Keimbildungsverfahren einfrieren, wird annähernd übersprungen. Dies hat zur Folge, dass alle Produkte in einer kleinen Zeitspanne nukleieren. Da ein Druck in der Produktkammer vor dem Druckabfall bereits abgesenkt wurde, ist nur eine Druckdifferenz von wenigen Millibar auszugleichen.The steps cause vacuum-induced nucleation. By opening the valve, a pressure drop is achieved in the product chamber with a high pressure drop rate, a pressure below the product-specific nucleation pressure being established in the product chamber. A pressure range within which the products freeze in conventional vacuum-induced nucleation processes is approximately skipped. As a result, all products nucleate in a short period of time. Since a pressure in the product chamber was already reduced before the pressure drop, only a pressure difference of a few millibars needs to be compensated.

Ein Kühlen der Produktkammer erfolgt vorzugsweise mittels bekannter Stellplatten. Dabei werden in vorteilhaften Ausgestaltungen des Verfahrens die in der Produktkammer angeordneten Stellplatten auf eine Temperatur von ca. -20°C bis ca. -3°C, insbesondere von ca.-14°C bis ca. -5°C, gekühlt. Die Temperatur der Stellplatten wird in vorteilhaften Ausgestaltungen über die Schritte a) bis d) des Verfahrens konstant gehalten.The product chamber is preferably cooled by means of known adjusting plates. In advantageous refinements of the method, the in the product chamber arranged shelves to a temperature of approx. -20 ° C to approx. -3 ° C, in particular from approx. -14 ° C to approx. -5 ° C, cooled. In advantageous embodiments, the temperature of the setting plates is kept constant via steps a) to d) of the method.

Der produktspezifische Keimbildungsdruck und/oder der durch Schließen und Öffnen des Ventils zu überspringende Druckbereich sind durch den Fachmann je nach Anwendungsfall, beispielsweise in Abhängigkeit des Produkts und/oder einer Größe der Produktkammer geeignet wählbar.The product-specific nucleation pressure and / or the pressure range to be skipped by closing and opening the valve can be suitably selected by the person skilled in the art depending on the application, for example depending on the product and / or a size of the product chamber.

In vorteilhaften Ausgestaltungen wird der Druck in dem Kondensator auf einen Druck im Bereich von ca. 0,005 bis ca. 3 mbar abgesenkt. Alternativ oder zusätzlich ist in vorteilhaften Ausgestaltungen vorgesehen, dass der Druck in der Produktkammer durch Öffnen des Ventils um ca. 0,3 mbar bis ca. 2,5 mbar abgesenkt wird und/oder der Druck in der Produktkammer durch Öffnen des Ventils auf einen Druck unterhalb des Tripelpunkts des Produkts abgesenkt wird.In advantageous refinements, the pressure in the condenser is lowered to a pressure in the range from approx. 0.005 to approx. 3 mbar. Alternatively or additionally, it is provided in advantageous embodiments that the pressure in the product chamber is reduced by approx. 0.3 mbar to approx. 2.5 mbar by opening the valve and / or the pressure in the product chamber is reduced to a pressure by opening the valve is lowered below the triple point of the product.

Die vakuuminduzierte Keimbildung erfolgt bei dem erfindungsgemäßen bei einer Temperatur, die unterhalb des Gefrierpunktes des Produkts liegt. Bei kleinen Füllmengen der Produkte bewirkt der Druckabfall nicht nur eine Keimbildung, sondern eine vollständige Kristallisation der Produkte. In anderen Ausgestaltungen ist nach der vakuumindizierten Keimbildung ein Schritt zum Einfrieren der Produkte vorgesehen, wobei zu diesem Zweck die Produktkammer weiter abgekühlt wird. In einer Ausgestaltung wird dabei das niedrige Druckniveau in der Produktkammer beibehalten.The vacuum-induced nucleation takes place in the inventive method at a temperature which is below the freezing point of the product. If the products are filled in small quantities, the pressure drop not only causes nucleation but also complete crystallization of the products. In other embodiments, a step for freezing the products is provided after the vacuum-induced nucleation, with the product chamber being further cooled for this purpose. In one embodiment, the low pressure level in the product chamber is maintained.

Gemäß einer vorteilhaften Ausgestaltung wird ein Verfahren Gefriertrocknung von Produkten umfassend ein Verfahren zur Keimbildung geschaffen, wobei ein nachfolgendes Einfrieren und eine Sublimation des Lösungsmittels unter Beibehaltung des sich nach Öffnen des Ventils zwischen der Produktkammer und dem Kondensator einstellenden Drucks erfolgen. In anderen Ausgestaltungen wird der Druck in der Produktkammer für ein vollständiges Einfrieren erhöht, beispielsweise wird die Produktkammer wieder auf Atmosphärendruck gebracht. Die Temperatur der Stellplatten bleibt für Einfrieren und eine Sublimation in einer Ausgestaltung ebenfalls unverändert.According to an advantageous embodiment, a method of freeze drying of products comprising a method for nucleation is created, a subsequent freezing and sublimation of the solvent taking place while maintaining the pressure between the product chamber and the condenser after opening the valve. In other configurations, the pressure in the product chamber is increased for complete freezing, for example the product chamber is brought back to atmospheric pressure. The temperature of the shelves also remains unchanged for freezing and sublimation in one embodiment.

Erfindungsgemäß wird eine Vorrichtung zur Gefriertrocknung von Produkten umfassend eine Produktkammer, einen mit der Produktkammer über ein Ventil verbundenen Kondensator und eine Steuereinrichtung geschaffen, wobei die Steuereinrichtung zum Durchführen des Verfahrens zur Keimbildung nach einem der Ansprüche 1 bis 5 eingerichtet und ausgebildet ist. Die Steuereinrichtung ist dabei in einer Ausgestaltung derart ausgebildet, dass eine vollständig automatische Durchführung mit vorgebbaren Prozessparametern möglich ist. Die Steuereinrichtung umfasst zu diesem Zweck beispielsweise Stellelemente für eine Betätigung des zwischen der Produktkammer und dem Kondensator vorgesehenen Ventils. In anderen Ausgestaltungen erfolgt eine halbautomatische Durchführung. Die Steuereinrichtung sendet dabei beispielweise akustische oder optische Signale, mittels welcher ein Nutzer bei der Durchführung des Verfahrens unterstützt wird. Beispielsweise wird ein Nutzer aufgefordert, das Ventil zwischen Produktkammer und Kondensator zu schließen oder zu öffnen.According to the invention, a device for freeze-drying products comprising a product chamber, a condenser connected to the product chamber via a valve and a control device is created, the control device for Carrying out the method for nucleation according to one of claims 1 to 5 is set up and designed. In one embodiment, the control device is designed in such a way that it can be carried out completely automatically with predeterminable process parameters. For this purpose, the control device comprises, for example, adjusting elements for actuating the valve provided between the product chamber and the condenser. In other embodiments, it is carried out semi-automatically. The control device sends acoustic or optical signals, for example, by means of which a user is supported in carrying out the method. For example, a user is asked to close or open the valve between the product chamber and the condenser.

KURZBESCHREIBUNG DER ZEICHNUNGENBRIEF DESCRIPTION OF THE DRAWINGS

Weitere Vorteile und Aspekte der Erfindung ergeben sich aus den Ansprüchen und aus der nachfolgenden Beschreibung von bevorzugten Ausführungsbeispielen der Erfindung, die nachfolgend anhand der Figuren erläutert sind. Dabei zeigen:

Fig. 1
eine schematische Darstellung einer erfindungsgemäßen Vorrichtung zur Gefriertrocknung;
Fig. 2
eine schematische Darstellung der Vorrichtung zur Gefriertrocknung gemäß Fig. 1 bei geschlossenem Ventil;
Fig. 3
eine schematische Darstellung der Vorrichtung zur Gefriertrocknung gemäß Fig. 1 bei einem Druckausgleich bei geöffnetem Ventil; und
Fig. 4
schematisch einen Verlauf einer Produkttemperatur und einen Verlauf des Drucks in einer Produktkammer bei Durchführung des erfindungsgemäßen Verfahrens.
Further advantages and aspects of the invention emerge 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
a schematic representation of a device according to the invention for freeze drying;
Fig. 2
a schematic representation of the device for freeze drying according to Fig. 1 with the valve closed;
Fig. 3
a schematic representation of the device for freeze drying according to Fig. 1 in the event of pressure equalization with the valve open; and
Fig. 4
schematically a course of a product temperature and a course of the pressure in a product chamber when carrying out the method according to the invention.

DETAILLIERTE BESCHREIBUNG DER AUSFÜHRUNGSBEISPIELEDETAILED DESCRIPTION OF THE EMBODIMENTS

  • Fig. 1 zeigt schematisch eine Vorrichtung 1 zur Gefriertrocknung von Produkten umfassend eine Produktkammer 2 mit Stellplatten 20, einen mit der Produktkammer 2 über ein Ventil 4 verbundenen Kondensator 3 und eine Steuereinrichtung 5. Die Vorrichtung 1 umfasst weiter eine Vakuumpumpe 6, welche mit dem Kondensator 3 über ein Ventil 60 verbunden ist. Fig. 1 shows schematically an apparatus 1 for freeze-drying products comprising a product chamber 2 with adjusting plates 20, a condenser 3 connected to the product chamber 2 via a valve 4, and a control device 5. The apparatus 1 further includes a vacuum pump 6, which is connected to the condenser 3 via a Valve 60 is connected.
  • Fig. 2 und 3 zeigen die Vorrichtung 1 zur Gefriertrocknung gemäß Fig. 1 bei geschlossenem bzw. offenem Ventil 4, wobei die Steuereinrichtung 5 zur besseren Übersicht in Fig. 2 und 3 nicht dargestellt ist. Figs. 2 and 3 show the device 1 for freeze drying according to FIG Fig. 1 with the valve 4 closed or open, the control device 5 being shown in FIG Figs. 2 and 3 is not shown.

In dem in Fig. 1 dargestellten Ausführungsbeispiel ist eine zentrale Steuereinrichtung 5 vorgesehen, welche mit den Stellplatten 20, dem Kondensator 3, dem Ventil 4, dem Ventil 60 und der Vakuumpumpe 6 oder Elementen davon zum Austausch von Sensor- und/oder Steuersignalen drahtlos oder über Datenleitungen verbunden ist. Die durch Pfeile dargestellten Kommunikationswege sind jedoch lediglich schematisch zu verstehen und zeigen keine Verdrahtung. In anderen Ausgestaltungen sind mehrere Steuereinrichtungen vorgesehen. Weiter kann jeder oder einzelnen der genannten Komponenten eine eigene Steuereinrichtung zugeordnet sein, mittels welcher beispielsweise eine Temperaturregelung der Stellplatten 20 auf eine von der zentralen Steuereinrichtung 5 vorgegebene Temperatur erfolgt.In the in Fig. 1 A central control device 5 is provided which is connected wirelessly or via data lines to the setting plates 20, the condenser 3, the valve 4, the valve 60 and the vacuum pump 6 or elements thereof for the exchange of sensor and / or control signals. However, the communication paths shown by arrows are to be understood only schematically and do not show any wiring. In other embodiments, several control devices are provided. Furthermore, each or individual of the named components can be assigned their own control device, by means of which, for example, the temperature of the setting plates 20 is regulated to a temperature predetermined by the central control device 5.

Für das erfindungsgemäße Verfahren ist vorgesehen, dass zunächst das Ventil 4 geöffnet ist und die Produktkammer 2 mit dem Kondensator 3 kommuniziert ist. Eine Temperatur in der Produktkammer 2 und dem Kondensator ist auf einen Wert abgesenkt, der unterhalb des Gefrierpunktes des Produkts liegt. Dies erfolgt in vorteilhaften Ausgestaltungen indem die Stellplatten 20 auf eine um ca. 3 bis 20°C unterhalb des Gefrierpunktes des Produkts liegende Temperatur abgekühlt werden.For the method according to the invention it is provided that the valve 4 is initially opened and the product chamber 2 is in communication with the condenser 3. A temperature in the product chamber 2 and the condenser is lowered to a value which is below the freezing point of the product. In advantageous embodiments, this takes place in that the setting plates 20 are cooled to a temperature which is approximately 3 to 20 ° C. below the freezing point of the product.

Für ein vakuuminduziertes Einfrieren wird zunächst der Druck in der Produktkammer 2 und dem Kondensator 3 abgesenkt, bis ein erster definierter Druck erreicht wird, welcher unterhalb des Atmosphärendrucks und oberhalb eines produktspezifischen Keimbildungsdrucks, bei welchem eine Keimbildung einsetzt, liegt. Zu diesem Zweck wird die Vakuumpumpe 6 geeignet betrieben, wobei ein Betrieb der Vakuumpumpe 6 beispielsweise mittels der Steuereinrichtung 5 bewirkt wird.For vacuum-induced freezing, the pressure in the product chamber 2 and the condenser 3 is first lowered until a first defined pressure is reached, which is below atmospheric pressure and above a product-specific nucleation pressure at which nucleation begins. For this purpose, the vacuum pump 6 is operated in a suitable manner, the vacuum pump 6 being operated, for example, by means of the control device 5.

Der erste definierte Druck kann produktspezifisch von einem Fachmann vorgegeben werden, wobei zu diesem Zweck die Steuereinrichtung 5 in einer Ausgestaltung eine Mensch-Maschine-Schnittstelle aufweist.The first defined pressure can be specified product-specifically by a person skilled in the art, with the control device 5 having a man-machine interface for this purpose in one embodiment.

Bei Erreichen des ersten definierten Drucks wird das Ventil 4 geschlossen. Vorzugsweise wird ein Druck in der Produktkammer 2 und dem Kondensator 3 mittels der Steuereinrichtung 5 überwacht und mittels der Steuereinrichtung 5 eine Betätigung des Ventils 4 bei Erreichen des ersten definierten Drucks bewirkt. Es ist jedoch auch denkbar, dass das Ventil 4 durch einen Nutzer betätigt wird.When the first defined pressure is reached, the valve 4 is closed. Preferably, a pressure in the product chamber 2 and the condenser 3 is monitored by means of the control device 5 and, by means of the control device 5, an actuation of the valve 4 when it is reached first defined pressure. However, it is also conceivable that the valve 4 is actuated by a user.

Fig. 2 zeigt die Vorrichtung 1 bei geschlossenem Ventil 4. Nach Schließen des Ventils 4 wird der Druck in der Produktkammer 3 beibehalten und der Druck in dem Kondensator 4 mittels der Vakuumpumpe 6 weiter abgesenkt. Ein weiteres Absenken des Drucks in dem Kondensator 3 erfolgt beispielsweise bis in dem Kondensator 3 ein zweiter definierter Druck erreicht wird, welcher unterhalb des produktspezifischen Keimbildungsdrucks liegt. Fig. 2 shows the device 1 with the valve 4 closed. After the valve 4 is closed, the pressure in the product chamber 3 is maintained and the pressure in the condenser 4 is further reduced by means of the vacuum pump 6. A further lowering of the pressure in the condenser 3 takes place, for example, until a second defined pressure is reached in the condenser 3 which is below the product-specific nucleation pressure.

Bei Erreichen des zweiten definierten Drucks wird das Ventil 4 geöffnet. Vorzugsweise wird ein Druck in dem Kondensator 3 dabei ebenfalls mittels der Steuereinrichtung 5 überwacht und mittels der Steuereinrichtung 5 eine Betätigung des Ventils 4 bei Erreichen des zweiten definierten Drucks bewirkt. Es ist jedoch auch bei diesem Schritt denkbar, dass das Ventil 4 durch einen Nutzer betätigt wird.When the second defined pressure is reached, the valve 4 is opened. Preferably, a pressure in the condenser 3 is also monitored by means of the control device 5 and, by means of the control device 5, the valve 4 is actuated when the second defined pressure is reached. However, it is also conceivable in this step that the valve 4 is actuated by a user.

Auch der zweite definierte Druck kann produktspezifisch von einem Fachmann vorgegeben werden. In anderen Ausgestaltungen ist vorgesehen, dass durch den Fachmann der Druck vorgegeben wird, welcher sich nach Öffnen des Ventils 4 in der Produktkammer 2 einstellen soll, wobei die Steuereinrichtung 5 anhand dieses Wertes unter Berücksichtigung der Eigenschaften der Vorrichtung 1, wie beispielsweise der Größe der Produktkammer 2, den zweiten definierten Druck ermittelt. In wieder anderen Ausgestaltungen erfolgt ein Absenken des Drucks in dem Kondensator 3 über eine vorgegeben Zeitspanne.The second defined pressure can also be specified product-specifically by a specialist. In other embodiments, it is provided that the person skilled in the art specifies the pressure which is to be set in the product chamber 2 after opening the valve 4, the control device 5 based on this value taking into account the properties of the device 1, such as the size of the product chamber 2, the second defined pressure is determined. In yet other configurations, the pressure in the condenser 3 is lowered over a predetermined period of time.

Fig. 3 zeigt die Vorrichtung 1 nach dem Öffnen des Ventils 4 zwischen der Produktkammer 2 und dem Kondensator 2 nach oder bei Erreichen des zweiten definierten Drucks in dem Kondensator 3, wobei wie durch Pfeile in Fig. 3 angedeutet der Druck in der Produktkammer 2 auf einen Druck unterhalb des produktspezifischen Keimbildungsdrucks abgesenkt wird. Fig. 3 shows the device 1 after the opening of the valve 4 between the product chamber 2 and the condenser 2 after or when the second defined pressure is reached in the condenser 3, as indicated by arrows in FIG Fig. 3 indicated the pressure in the product chamber 2 is lowered to a pressure below the product-specific nucleation pressure.

Fig. 4 zeigt schematisch einen Verlauf einer Produkttemperatur 7 und einen Verlauf des Drucks 8 in einer Produktkammer 2 (vgl. Fig. 1) bei Durchführung des erfindungsgemäßen Verfahrens. Die Temperatur der Stellplatten 20 in der Produktkammer 2 (vgl. Fig. 1 bis 3) ist durch eine Linie 9 dargestellt. Die Temperatur der Stellplatten 20 liegt dabei bei ca. -10°C. Fig. 4 shows schematically a course of a product temperature 7 and a course of the pressure 8 in a product chamber 2 (cf. Fig. 1 ) when carrying out the method according to the invention. The temperature of the shelves 20 in the product chamber 2 (cf. Figs. 1 to 3 ) is represented by a line 9. The temperature of the setting plates 20 is about -10 ° C.

In einem ersten Schritt a) wird ein Drucks 8 in der Produktkammer 2 und dem Kondensator 3 (vgl. Fig. 1) abgesenkt, bis ein erster definierter Druck erreicht wird, welcher unterhalb des Atmosphärendrucks und oberhalb eines produktspezifischen Keimbildungsdrucks, bei welchem eine Keimbildung einsetzt, liegt.In a first step a), a pressure 8 in the product chamber 2 and the condenser 3 (cf. Fig. 1 ) until a first defined pressure is reached, which is below the Atmospheric pressure and above a product-specific nucleation pressure at which nucleation begins.

In einem zweiten Schritt b) wird das Ventil 4 zwischen der Produktkammer 2 und dem Kondensator 3 geschlossen.In a second step b) the valve 4 between the product chamber 2 and the condenser 3 is closed.

In einem dritten Schritt c) wird der Druck in der Produktkammer beibehalten und der Druck in dem Kondensator 3 weiter abgesenkt bis ein zweiter definierter Druck erreicht wird, welcher unterhalb des produktspezifischen Keimbildungsdrucks liegt.In a third step c) the pressure in the product chamber is maintained and the pressure in the condenser 3 is further reduced until a second defined pressure is reached which is below the product-specific nucleation pressure.

In einem vierten Schritt d) wird das Ventil 4 zwischen der Produktkammer 2 und dem Kondensator 3 geöffnet und dadurch ein Druckausgleich erzielt. Wie schematisch bei I dargestellt bewirkt der Druckausgleich, dass der Druck in der Produktkammer 2 in kurzer Zeit auf einen Druck unterhalb des produktspezifischen Keimbildungsdrucks abgesenkt wird.In a fourth step d) the valve 4 between the product chamber 2 and the condenser 3 is opened and a pressure equalization is achieved as a result. As shown schematically at I, the pressure equalization has the effect that the pressure in the product chamber 2 is reduced in a short time to a pressure below the product-specific nucleation pressure.

Der auf ca. 0,7mbar abgesenkte Druck bewirkt eine Keimbildung, wobei die Keimbildung in allen Produkten innerhalb einer Produktkammer 2 nahezu gleichzeitig erfolgt. Aufgrund der herrschenden niedrigen Temperatur frieren die Produkte bei kleinen Füllmengen vollständig ein, ohne dass eine weitere Absenkung der Temperatur der Stellplatten 20 notwendig ist. Die Zeitspanne, zu welcher die Produkte vollständig eingefroren oder kristallisiert sind, ist mit II gekennzeichnet.The pressure, which has been reduced to approx. 0.7 mbar, causes nucleation, with the nucleation occurring in all products within a product chamber 2 almost simultaneously. Due to the prevailing low temperature, the products freeze completely in the case of small filling quantities, without the need for a further lowering of the temperature of the shelves 20. The period of time at which the products are completely frozen or crystallized is marked with II.

Eine daran anschließende Sublimation des eingefrorenen Produkts erfolgt in dem dargestellten Ausführungsbeispiel ebenfalls unter Beibehaltung des sich nach Abschluss von Schritt 4) einstellenden Drucks und unter Beibehaltung der Temperatur der Stellplatten von ca. -10°C. Diese Prozessparameter sind jedoch lediglich beispielhaft und die erfindungsgemäßen Schritte für einen verbesserten Einfriervorgang sind mit anderen Verfahrensschritten für ein vollständiges Einfrieren oder eine Trocknung kombinierbar.A subsequent sublimation of the frozen product takes place in the illustrated embodiment, likewise while maintaining the pressure that is established after the completion of step 4) and while maintaining the temperature of the shelves at approx. -10 ° C. However, these process parameters are only exemplary and the steps according to the invention for an improved freezing process can be combined with other process steps for complete freezing or drying.

Claims (7)

  1. Method for nucleation in the freeze-drying of products in a product chamber (2), the product chamber (2) being connected to a condenser (3) via a valve (4), comprising the following steps to be carried out one after the other in a time sequence:
    a) lowering the pressure in the product chamber (2) and the condenser (3) at a temperature lying below the freezing point of the product until a defined pressure is reached, lying below atmospheric pressure and above a product-specific nucleation pressure at which nucleation commences;
    b) closing the valve (4) between the product chamber (2) and the condenser (3);
    c) maintaining the pressure in the product chamber (2) and further lowering the pressure in the condenser (3);
    d) opening the valve (4) between the product chamber (2) and the condenser (3) after or upon reaching the product-specific nucleation pressure in the condenser (3) such that the pressure in the product chamber (2) is lowered to a pressure below the product-specific nucleation pressure.
  2. Method for nucleation in the freeze-drying of products according to Claim 1, characterized in that trays (20) arranged in the product chamber (2) are cooled during steps a) to d) to a temperature of about -20°C to about -3°C, in particular of about -14°C to about -5°C.
  3. Method for nucleation in the freeze-drying of products according to Claim 1 or 2, characterized in that the pressure in the condenser (3) is lowered in step c) to a product-specific nucleation pressure in the range of about 0.005 mbar to about 3 mbar.
  4. Method for nucleation in the freeze-drying of products according to Claim 1, 2 or 3, characterized in that the pressure in the product chamber (2) is lowered in step d) by about 0.3 mbar to about 2.5 mbar by opening the valve (4).
  5. Method for nucleation in the freeze-drying of products according to one of Claims 1 to 4, characterized in that the pressure in the product chamber (2) is lowered in step d) to a pressure below the triple point of the product by opening the valve (4).
  6. Method for the freeze-drying of products comprising a method for nucleation according to one of Claims 1 to 5, characterized by the further step of
    e) freezing the product and sublimation of the solvent while maintaining the pressure established after opening the valve (4) between the product chamber (2) and the condenser.
  7. Apparatus for the freeze-drying of products comprising a product chamber (2) and a condenser (3), the product chamber (2) being connected to the condenser (3) via a valve (4), and a control device (5), characterized in that the control device (5) is designed and set up for implementing the method for nucleation according to one of Claims 1 to 5.
EP17752124.2A 2016-08-23 2017-08-15 Method and apparatus for freeze-drying Active EP3504496B1 (en)

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DE19654134C2 (en) 1996-04-25 2003-08-07 Messer Griesheim Gmbh Freeze drying method and apparatus
DE19719398A1 (en) 1997-05-07 1998-11-12 Amsco Finn Aqua Gmbh Process for controlling a freeze-drying process
CA2360112A1 (en) * 1999-01-05 2000-07-13 Victor Bronshtein Vacuum control system for foam drying apparatus
DE19936281C2 (en) 1999-08-02 2002-04-04 Bayer Ag Freeze-drying process
SE0001453D0 (en) 2000-04-19 2000-04-19 Astrazeneca Ab Method of monitoring a freeze drying process
DE20008915U1 (en) 2000-05-19 2001-06-28 Martin Christ Gefriertrocknungsanlagen GmbH, 37520 Osterode Freeze dryer
DE102004007526A1 (en) 2004-02-17 2005-09-01 Oetjen, Georg-Wilhelm, Dr. Method and device for the freeze-drying of products
US8794013B2 (en) * 2006-02-10 2014-08-05 Praxair Technology, Inc. Method and system for nucleation control in a controlled rate freezer (CRF)
EP1903291A1 (en) * 2006-09-19 2008-03-26 Ima-Telstar S.L. Method and system for controlling a freeze drying process
US8240065B2 (en) 2007-02-05 2012-08-14 Praxair Technology, Inc. Freeze-dryer and method of controlling the same
US8839528B2 (en) 2011-04-29 2014-09-23 Millrock Technology, Inc. Controlled nucleation during freezing step of freeze drying cycle using pressure differential ice fog distribution
CN104677084A (en) * 2015-02-13 2015-06-03 黄少峰 Instant decompression device and freeze-drying device with same

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