EP0980503A1 - Method for controlling a freeze drying process - Google Patents

Method for controlling a freeze drying process

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Publication number
EP0980503A1
EP0980503A1 EP98922751A EP98922751A EP0980503A1 EP 0980503 A1 EP0980503 A1 EP 0980503A1 EP 98922751 A EP98922751 A EP 98922751A EP 98922751 A EP98922751 A EP 98922751A EP 0980503 A1 EP0980503 A1 EP 0980503A1
Authority
EP
European Patent Office
Prior art keywords
temperature
drying
pressure
chamber
ice
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP98922751A
Other languages
German (de)
French (fr)
Other versions
EP0980503B1 (en
Inventor
Georg-Wilhelm Oetjen
Peter Haseley
Hubert KLÜTSCH
Marion Leineweber
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GEA Lyophil GmbH
Original Assignee
Steris GmbH
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Filing date
Publication date
Application filed by Steris GmbH filed Critical Steris GmbH
Publication of EP0980503A1 publication Critical patent/EP0980503A1/en
Application granted granted Critical
Publication of EP0980503B1 publication Critical patent/EP0980503B1/en
Anticipated expiration legal-status Critical
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Classifications

    • 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 for controlling a freeze-drying process
  • the frozen product located in an evacuated chamber on temperature-adjustable shelves, it is first subjected to a main drying and then to a subsequent drying,
  • Freeze drying is a process for removing water from a water-containing frozen product, e.g. from pharmaceuticals and food.
  • the process is generally carried out at an air pressure which is small compared to the water vapor pressure at the selected temperature of the ice: eg. an ice temperature of -20 ° C corresponds to a water vapor pressure (in equilibrium) of 1.03 mbar. So that the water vapor can flow from the ice surface into the drying chamber, the water vapor pressure in the drying chamber must be significantly less than 1.03 mbar. so for example. 0.4 mbar. It is therefore expedient to use a pressure which is small compared to this pressure value, for example. 0.05 mbar to choose.
  • Freeze-drying usually takes place in a chamber in which there are temperature-adjustable shelves and to which an evacuation device, for example. an ice condenser combined with a vacuum pump is connected.
  • the drying process is essentially characterized by two drying phases. As long as there is crystallized (frozen) water in the product, this drying section is called the main or sublimation drying. If the shut-off device between the chamber and the evacuation device is closed for a short time (a few seconds) in this phase of drying, the equilibrium water vapor pressure which corresponds to the prevailing ice temperature is established in the chamber. The ice temperature can be directly deduced from the pressure increase. This method for measuring the ice temperature is known under the term barometric temperature measurement and is described in DE-PS 10 38 988.
  • the temperature of the product must not exceed certain values, usually well below 0 ° C, to avoid impairing the quality and / or the properties of the product.
  • certain values usually well below 0 ° C
  • the present invention is based on the object of proposing a method for controlling a freeze-drying process of the type mentioned at the outset, in which the disadvantage of longer shut-off times between the chamber and the evacuation device no longer has to be accepted.
  • this object is achieved in that the changes in the pressure and / or the surface temperature which characterize the transition from the main drying to the secondary drying are carried out as a function of changes in the ice temperature.
  • This method takes advantage of the phenomenon that the ice temperature values measured during the main drying process become smaller during the transition from main drying to post-drying. This obviously only apparent change in the ice temperature is slight, but can be determined exactly with the help of modern computers. Since only measurements of the ice temperature are required to control the freeze-drying process according to the invention, which only require short shut-off times, there is no longer any danger of thawing the product.
  • the ice temperature values measured during the main drying process change only slightly. It is therefore expedient within the scope of the invention to center the ice temperature measured values with the previous measured values and to continuously determine the highest of the determined ice temperature mean values with the respectively current values of the ice temperature to determine a specific change in the ice temperature. Changes in the ice temperature by, for example, 1, 2 or 3 ° C can be clearly determined using this method.
  • the measurement of the ice temperature itself is expediently carried out according to the barometric temperature measurement mentioned at the outset, ie that the ice temperature is derived from the increase in the chamber pressure which occurs after the chamber has been separated from its evacuation device.
  • the ongoing, short-term and relatively precise determination of the ice temperature allows fluctuations in the ice temperature beyond the measurement accuracy to be determined very early. If fluctuations in the chamber pressure or the surface temperature are excluded, then fluctuations in the ice temperature indicate an inhomogeneous ice structure. Heat conduction and water vapor transport are different in zones with very small or grown large crystals. This also applies to products that have collapsed during the main drying process, since water is then present in some zones instead of ice. Fluctuations in the ice temperature can therefore indicate errors when the product freezes or the shelf temperature is too high.
  • FIG. 1 schematically shows a device for carrying out a freeze-drying process
  • Figure 2 is a diagram that shows the sequence of a freeze drying process
  • FIG. 3 shows another diagram to explain the invention Determination of the ice temperature
  • the freeze-drying device shown in Figure 1 comprises the chamber 1 with its shelves 2 and the condenser 3 connected to it with its condensation surfaces 4. On the shelves 2 there are containers (vials 5) with product to be freeze-dried.
  • the shelves 2 can be temperature-controlled. They are part of a temperature control circuit 6 with feed pump 7 and refrigeration machine 8. During the heating phase, the refrigeration machine is switched off and the cooling / heating medium is electrically heated (heating 9) ..
  • a the closure of the vial 5 within the chamber 1 and after the implementation the apparatus used for drying is generally designated 10.
  • valve 11 Between chamber 1 and condenser 3 there is valve 11, which is actuated with the aid of drive 12.
  • the vacuum pump set 14 is arranged downstream of the condenser 3.
  • Control means are provided to control the sequence of the freeze-drying process.
  • a central controller 16 continuously receives information about the pressure in the chamber 1 and about the temperature of the shelves 2.
  • pressure and temperature sensors 17, 1 8 are used. Only one temperature sensor 1 8 in the temperature control circuit 6 is shown. It is more expedient if the outlet of each of the shelves 2 is equipped with a temperature sensor.
  • the controller 16 is connected to the vacuum pump set 14, the refrigerant evaporator 8 and the drive 12 of the valve 11.
  • the pressure control in chamber 1 is carried out by switching vacuum pump set 14 on or off or by controlled inlet of inert gas.
  • the shelf temperature is set with the help of the refrigerator 8 or the heater 9.
  • the shut-off valve 11 is also actuated in order to measure the ice temperature in a manner known per se.
  • the controller 16 is assigned the computer 21, to which the signals supplied by the pressure sensor 17 are also fed.
  • the computer 21 as described further above - the change in pressure (dp / dt) over time after the valve 11 is shut off is continuously monitored. Immediately after the maximum of this value has been exceeded, the controller 16 receives the signal to end the shut-off time.
  • the diagram according to FIG. 2 shows the chronological sequence of an example for a freeze-drying process. Footprint temperature values and pressure values are given in the y direction. Dashed curve 23 shows the course of the chamber pressure. The dotted line 24 shows the course of the surface temperature. The solid line 25 shows the continuously measured ice temperature values. Finally, the dash-dotted line 26 indicates an average product temperature.
  • a freeze-drying process of the type shown begins with the introduction of the frozen product into the chamber 1.
  • the chamber is then evacuated and the shelves heated to the desired temperature.
  • the control pressure (curve 23) is kept at a certain pressure.
  • the shelf temperature (curve 24) is also set to certain values. In the exemplary embodiment shown, the surface temperature increases already after 24 hours. After the ice temperature drops, the pressure control is switched off. The shelf temperature will continue to increase.
  • controller 16 and computer 21 can be used to determine the residual moisture. This is expediently carried out using a method as described in international patent application WO 96/25654.
  • the changes in the chamber pressure and the shelf surface temperature are made as a function of changes in the ice temperature.
  • the values of the pressure and the shelf surface temperature which characterize the after-drying are carried out when the ice temperature has changed by more than 2 to 3 ° C. compared to a highest mean value.
  • the surface temperature during main drying can also be increased depending on changes in the ice temperature. In the exemplary embodiment shown, this happens when the ice temperature has changed by more than 1 ° C. compared to the highest mean value.
  • FIG. 3 is a diagram in which the solid curve 28 represents the increase in pressure which occurs between the chamber 1 and the condenser 3 after the valve has been shut off. This curve is continuously differentiated by the computer 21 (dashed curve 29). This makes it possible to continuously determine the change in chamber pressure over time. As already described, the measurement can be stopped if the change in pressure over time exceeds a maximum.

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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)

Abstract

The invention relates to a method for controlling a freeze drying process, wherein a frozen product is arranged on temperable surfaces in an air-evacuated chamber (1) and undergoes a main drying and after-drying phase. During the main drying phase the temperature of the ice surrounding said product is continuously measured. The pressure in the chamber and/or the temperature of the surfaces are modified during transition from the main drying phase to the after-drying phase. In order to avoid longer idle periods between the chamber (1) and the evacuation device (3, 4, 14) and to determine transition from the main drying phase to the after-drying phase, the invention provides that the pressure and/or the temperature of the surfaces characterizing said transition should be modified according to changes in the temperature of the ice.

Description

Verfahren zur Steuerung eines Gefriertrocknungsprozesses Process for controlling a freeze-drying process
Die Erfindung betrifft ein Verfahren zur Steuerung eines Gefriertrocknungsprozesses,The invention relates to a method for controlling a freeze-drying process,
bei dem eingefrorenes, in einer evakuierten Kammer auf temperierbaren Stellflächen befindliches Produkt zunächst einer Haupttrocknung und anschließend einer Nachtrocknung unterworfen wird,in the case of the frozen product located in an evacuated chamber on temperature-adjustable shelves, it is first subjected to a main drying and then to a subsequent drying,
bei dem während der Haupttrocknung laufend die Temperatur des im zu trocknenden Produkt eingeschlossenen Eises gemessen wird undduring which the temperature of the ice enclosed in the product to be dried is continuously measured during the main drying and
bei dem beim Übergang von der Haupttrocknung zur Nachtrocknung der Kammerdruck und/oder die Stellflachentemperatur verändert werden.in which the chamber pressure and / or the shelf surface temperature are changed during the transition from main drying to post-drying.
Die Gefriertrocknung ist ein Verfahren zur Entfernung des Wassers aus einem wasserhaltigen eingefrorenen Produkt, z.B . aus Pharmaka und Lebensmitteln. Das Verfahren wird im allgemeinen bei einem Luftdruck ausgeführt, der klein ist gegen den Wasserdampfdruck bei der gewählten Temperatur des Eises : Z.B . entspricht eine Eistemperatur von -20° C einem Wasserdampfdruck (im Gleichgewicht) von 1 ,03 mbar. Damit der Wasserdampf von der Eisoberfläche in die Trockenkammer strömen kann, muß der Wasserdampfdruck in der Trockenkammer deutlich kleiner sein als 1 ,03 mbar. also z.B . 0,4 mbar. Zweckmäßig ist es deshalb, einen gegenüber diesem Druckwert kleinen Druck, z.B . 0,05 mbar, zu wählen. Die Gefriertrocknung findet üblicherweise in einer Kammer statt, in der sich temperierbare Stellflächen befinden und an die eine Evakuierungseinrichtung, z.B . ein mit einer Vakuumpumpe kombinierter Eiskondensator, angeschlossen ist. Kennzeichnend für den Ablauf des Trocknungsprozesses sind im wesentlichen zwei Trocknungsphasen. Solange sich noch kristallisiertes (gefrorenes) Wasser in dem Produkt befindet, nennt man diesen Trockenabschnitt die Haupt- oder Sublimationstrocknung. Schließt man in dieser Phase der Trocknung die Absperrvorrichtung zwischen der Kammer und der Evakuierungseinrichtung für eine kurze Zeit (wenige Sekunden), stellt sich in der Kammer der Gleichsgewichtswasserdampfdruck ein, der der herrschenden Eistemperatur entspricht. Aus dem Druckanstieg kann direkt auf die Eistemperatur geschlossen werden. Dieses Verfahren zur Messung der Eistemperatur ist unter dem Begriff barometrische Temperaturmessung bekannt und in der DE-PS 10 38 988 beschrieben.Freeze drying is a process for removing water from a water-containing frozen product, e.g. from pharmaceuticals and food. The process is generally carried out at an air pressure which is small compared to the water vapor pressure at the selected temperature of the ice: eg. an ice temperature of -20 ° C corresponds to a water vapor pressure (in equilibrium) of 1.03 mbar. So that the water vapor can flow from the ice surface into the drying chamber, the water vapor pressure in the drying chamber must be significantly less than 1.03 mbar. so for example. 0.4 mbar. It is therefore expedient to use a pressure which is small compared to this pressure value, for example. 0.05 mbar to choose. Freeze-drying usually takes place in a chamber in which there are temperature-adjustable shelves and to which an evacuation device, for example. an ice condenser combined with a vacuum pump is connected. The drying process is essentially characterized by two drying phases. As long as there is crystallized (frozen) water in the product, this drying section is called the main or sublimation drying. If the shut-off device between the chamber and the evacuation device is closed for a short time (a few seconds) in this phase of drying, the equilibrium water vapor pressure which corresponds to the prevailing ice temperature is established in the chamber. The ice temperature can be directly deduced from the pressure increase. This method for measuring the ice temperature is known under the term barometric temperature measurement and is described in DE-PS 10 38 988.
Solange noch festes Eis im Produkt vorhanden ist, d.h., während der Haupttrocknung, darf die Temperatur des Produktes bestimmte, meist weit unter 0° C gelegene Werte nicht überschreiten, um eine Beeinträchtigung der Qualität und/oder der Eigenschaften des Produktes zu vermeiden. Mit fortschreitender Trocknung werden die im Produkt vorhandenen Eiskerne immer kleiner. Im Bereich trockener Randzonen sind bereits höhere Temperaturen zulässig.As long as there is still solid ice in the product, i.e. during the main drying, the temperature of the product must not exceed certain values, usually well below 0 ° C, to avoid impairing the quality and / or the properties of the product. As the drying progresses, the ice cores in the product become smaller and smaller. Higher temperatures are already permissible in the area of dry edge zones.
Liegt kein Wasser in Form von Eis mehr vor, ist das restliche Wasser am Trockenprodukt absorbiert oder auch mehr oder weniger fest gebunden. Die Entfernung dieses Wassers findet während der Nach- oder Desorptionstrocknung statt. Die in dieser Phase desorbierbare Wassermenge hängt von der Temperatur des Produkts, der Art der Wasserbindung und der jeweils noch vorhandenen Wassermenge ab. Die Nachtrocknung wird durch eine weitere Änderung der den Ablauf des Trocknungsprozesses bestimmenden physikalischen Bedingungen eingeleitet.If there is no more water in the form of ice, the remaining water is absorbed by the dry product or more or less firmly bound. This water is removed during post-drying or desorption drying. The amount of water that can be desorbed in this phase depends on the temperature of the product, the type of water binding and the amount of water still present. Post-drying is initiated by a further change in the physical conditions that determine the course of the drying process.
Aus der genannten DE-PS 10 38 988 ist ein Verfahren der eingangs erwähnten Art bekannt. Zur Bestimmung des Übergangs von der Haupttrocknung zur Nachtrocknung werden Messungen durchgeführt, die auf die Mittel zurückgreifen, die auch der Messung der Eistemperatur dienen. Dazu werden die Absperrzeiten, die bei der Messung der Eistemperatur nur wenige Sekunden betragen, wesentlich verlängert, und zwar auf zwei Minuten und mehr. Wenn sich nach Absperrzeiten dieser Größenordnung eine nahezu konstante Differenz zwischen dem Betriebsdruck und dem Sättigungsdampfdruck einstellt, dann kann davon ausgegangen werden, daß das feste Eis aus dem Gut vollständig entfernt worden ist, die Haupttrocknung also beendet ist. Die Stellflachentemperatur und der Druck können auf diejenigen Werte eingestellt werden, bei denen die Nachtrocknung stattfinden soll . Nachteilig an dem beschriebenen Verfahren ist die erhebliche Verlängerung der Absperrzeit. Ist die Haupttrocknung noch nicht beendet, dann besteht die Gefahr, daß eine Verlängerung der Absperrzeit zu einer nicht mehr zulässigen Temperaturerhöhung des eishaltigen Gutes und damit zu seiner Zerstörung führtJn modernen Gefriertrocknungsanlagen für die Pharma-Industrie erreicht der Wert einer Charge bereits die Millionen-DM-Grenze. Gefährdungen des Produktes müssen deshalb unbedingt vermieden werden.From the aforementioned DE-PS 10 38 988 a method of the type mentioned is known. To determine the transition from main drying to post-drying, measurements are carried out using the means that also serve to measure the ice temperature. For this purpose, the shut-off times, which are only a few seconds when measuring the ice temperature, are significantly extended, to two minutes and more. If, after shut-off times of this magnitude, there is an almost constant difference between the operating pressure and the saturation vapor pressure, it can be assumed that the solid ice has been completely removed from the material, so that the main drying process has ended. The shelf temperature and the pressure can be set to the values at which the post-drying should take place. A disadvantage of the described method is the considerable extension of the shut-off time. If the main drying process has not yet ended, there is a risk that an extension of the shut-off time will lead to a temperature increase of the ice-containing goods which is no longer permissible and thus to its destruction. In modern freeze-drying systems for the pharmaceutical industry, the value of a batch already reaches the DM Border. Hazards to the product must therefore be avoided at all costs.
Der vorliegenden Erfindung liegt die Aufgabe zugrunde, ein Verfahren zur Steuerung eines Gefriertrocknungsprozesses der eingangs erwähnten Art vorzuschlagen, bei dem der Nachteil längerer Absperrzeiten zwischen Kammer und Evakuierungseinrichtung nicht mehr in Kauf genommen werden muß.The present invention is based on the object of proposing a method for controlling a freeze-drying process of the type mentioned at the outset, in which the disadvantage of longer shut-off times between the chamber and the evacuation device no longer has to be accepted.
Erfindungsgemäß wird diese Aufgabe dadurch gelöst, daß die den Übergang von der Haupttrocknung zur Nachtrocknung kennzeichnenden Änderungen des Druckes und/oder der Stellflachentemperatur in Abhängigkeit von Änderungen der Eistemperatur vorgenommen werden. Dieses Verfahren nutzt die Erscheinung aus, daß die während der Durchführung der Haupttrocknung gemessenen Eistemperatur-Werte während des Übergangs von Haupttrocknung zu Nachtrocknung kleiner werden. Diese offensichtlich nur scheinbare Änderung der Eistemperatur ist zwar geringfügig, kann jedoch mit Hilfe moderner Rechner exakt festgestellt werden. Da zur erfindungsgemäßen Steuerung des Gefriertrocknungsprozesses nur noch Messungen der Eistemperatur durchgeführt werden, welche lediglich kurze Absperrzeiten benötigen, besteht die Gefahr des Antauens des Produktes nicht mehr.According to the invention, this object is achieved in that the changes in the pressure and / or the surface temperature which characterize the transition from the main drying to the secondary drying are carried out as a function of changes in the ice temperature. This method takes advantage of the phenomenon that the ice temperature values measured during the main drying process become smaller during the transition from main drying to post-drying. This obviously only apparent change in the ice temperature is slight, but can be determined exactly with the help of modern computers. Since only measurements of the ice temperature are required to control the freeze-drying process according to the invention, which only require short shut-off times, there is no longer any danger of thawing the product.
Während der Haupttrocknung werden die im Produkt vorhandenen Eiskerne immer kleiner. Häufig besteht nach der Ausbildung trockener Randzonen die Möglichkeit, bereits während der Haupttrocknung die Temperatur der Stellflächen zu erhöhen, ohne die Qualität des Produktes zu gefährden. Auch Änderungen der Trocknungsbedingungen dieser Art können erfindungsgemäß in Abhängigkeit von Änderungen der Eistemperatur vorgenommen werden.During the main drying process, the ice cores in the product become smaller and smaller. After the formation of dry edge zones, there is often the possibility of increasing the temperature of the shelves during the main drying without endangering the quality of the product. Changes in the drying conditions of this type can also be made according to the invention depending on changes in the ice temperature.
Die während der Haupttrocknung gemessenen Werte der Eistemperatur ändern sich nur wenig. Es ist deshalb im Rahmen der Erfindung zweckmäßig, die Eistemperatur-Messwerte jeweils mit den vorhergegangenen Messwerten zu mittein und zur Feststellung einer bestimmten Änderung der Eistemperatur laufend den höchsten der ermittelten Eistemperatur-Mittelwerte mit den jeweils aktuellen Werten der Eistemperatur zu vergleichen. Änderungen der Eistemperatur um beispielsweise 1 ,2 oder 3 °C können nach diesem Verfahren eindeutig bestimmt werden. Die Messung der Eistemperatur selbst erfolgt zweckmäßig nach der eingangs erwähnten barometrischen Temperaturmessung, d.h., daß aus dem Anstieg des Kammerdruckes, der nach einer Trennung der Kammer von ihrer Evakuierungseinrichtung eintritt, die Eistemperatur abgeleitet wird. Um entsprechend dem allgemeinen Ziel der vorliegenden Erfindung diese Absperrzeiten möglichst kurz zu halten, wird vorgeschlagen, folgendermaßen vorzugehen: Nach der Absperrung der Kammer von ihrer Evakuierungseinrichtung wird der ansteigende Kammerdruck laufend 10 bis einige 100 mal pro Sekunde gemessen. Diese Messwerte werden einem Rechner zugeführt. Die in den ersten Sekunden gemessenen Werte des Druckanstiegs ergeben eine ansteigende, etwa S-förmige Kurve, d.h. , eine Kurve mit einem Wendepunkt. Mit Hilfe des Rechners wird diese Kurve laufend differenziert, also die zeitliche Änderung des Druckes (dp/dt) überwacht. Es hat sich herausgestellt, daß die für eine ausreichend genaue Feststellung der Eistemperatur notwendige Messung des Druckanstiegs abgebrochen werden kann, wenn die Druckanstiegskurve ihren Wendepunkt erreicht hat, d.h., wenn die erste Ableitung dieser Kurve ihr Maximum erreicht. Zu diesem Zeitpunkt kann deshalb bereits die Absperrzeit beendet und die Verbindung zwischen Kammer und Evakuierungseinrichtung wieder hergestellt werden; damit ist eine Überschreitung der Eistemperatur ausgeschlossen.The ice temperature values measured during the main drying process change only slightly. It is therefore expedient within the scope of the invention to center the ice temperature measured values with the previous measured values and to continuously determine the highest of the determined ice temperature mean values with the respectively current values of the ice temperature to determine a specific change in the ice temperature. Changes in the ice temperature by, for example, 1, 2 or 3 ° C can be clearly determined using this method. The measurement of the ice temperature itself is expediently carried out according to the barometric temperature measurement mentioned at the outset, ie that the ice temperature is derived from the increase in the chamber pressure which occurs after the chamber has been separated from its evacuation device. In order to keep these shut-off times as short as possible in accordance with the general aim of the present invention, it is proposed to proceed as follows: After the chamber has been shut off from its evacuation device, the increasing chamber pressure is measured continuously 10 to a few 100 times per second. These measured values are fed to a computer. The values of the pressure increase measured in the first seconds result in an increasing, approximately S-shaped curve, ie, a curve with an inflection point. With the help of the computer, this curve is continuously differentiated, i.e. the change in pressure over time (dp / dt) is monitored. It has been found that the measurement of the pressure rise necessary for a sufficiently precise determination of the ice temperature can be stopped when the pressure rise curve has reached its inflection point, ie when the first derivative of this curve reaches its maximum. At this point, the shut-off time can therefore be ended and the connection between the chamber and the evacuation device can be re-established; this prevents the ice temperature from being exceeded.
Die laufende, kurzzeitige und relativ genaue Feststellung der Eistemperatur erlaubt es, sehr früh über die Messgenauigkeit hinaus gehende Schwankungen der Eistemperatur festzustellen. Sind Schwankungen des Kammerdruckes oder der Stellflachentemperatur ausgeschlossen, dann deuten Schwankungen der Eistemperatur auf eine inhomogene Eisstruktur hin. Wärmeleitung und Wasserdampftransport sind unterschiedlich in Zonen mit sehr kleinen oder zusammengewachsenen großen Kristallen. Dieses gilt auch für während der Haupttrocknung kollabierte Produkte, da dann in einigen Zonen Wasser statt Eis vorhanden ist. Schwankungen der Eistemperatur können deshalb auf Fehler beim Einfrieren des Produkts oder auf zu hohe Stellfächen- Temperaturen hinweisen.The ongoing, short-term and relatively precise determination of the ice temperature allows fluctuations in the ice temperature beyond the measurement accuracy to be determined very early. If fluctuations in the chamber pressure or the surface temperature are excluded, then fluctuations in the ice temperature indicate an inhomogeneous ice structure. Heat conduction and water vapor transport are different in zones with very small or grown large crystals. This also applies to products that have collapsed during the main drying process, since water is then present in some zones instead of ice. Fluctuations in the ice temperature can therefore indicate errors when the product freezes or the shelf temperature is too high.
Weitere Vorteile und Einzelheiten der Erfindung sollen anhand der Figuren 1 bis 3 erläutert werden. Es zeigenFurther advantages and details of the invention will be explained with reference to FIGS. 1 to 3. Show it
Figur 1 schematisch eine Einrichtung zur Durchführung eines Gefriertrocknungsprozesses,FIG. 1 schematically shows a device for carrying out a freeze-drying process,
Figur 2 ein Diagramm, das den Ablauf eines Gefriertrocknungsprozesses erkennen läßt undFigure 2 is a diagram that shows the sequence of a freeze drying process and
Figur 3 ein weiteres Diagramm zur Erläuterung der erfindungsgemäßen Feststellung der EistemperaturFigure 3 shows another diagram to explain the invention Determination of the ice temperature
Die in Figur 1 dargestellte Gefriertrocknungs-Einrichtung umfaßt die Kammer 1 mit ihren Stellflächen 2 und den daran angeschlossenen Kondensator 3 mit seinen Kondensationsflächen 4. Auf den Stellflächen 2 befinden sich Behälter (Fläschchen 5 ) mit gefrierzutrocknendem Produkt. Die Stellflächen 2 sind temperierbar. Sie sind Bestandteil eines Temperierkreislaufs 6 mit Förderpumpe 7 und Kältemaschine 8. Während der Heizphase wird die Kältemaschine abgeschaltet und das Kühl-/Heiz-Medium elektrisch geheizt (Heizung 9) .. Eine dem Verschluß der Fläschchen 5 innerhalb der Kammer 1 und nach der Durchführung der Trocknung dienende Apparatur ist generell mit 10 bezeichnet.The freeze-drying device shown in Figure 1 comprises the chamber 1 with its shelves 2 and the condenser 3 connected to it with its condensation surfaces 4. On the shelves 2 there are containers (vials 5) with product to be freeze-dried. The shelves 2 can be temperature-controlled. They are part of a temperature control circuit 6 with feed pump 7 and refrigeration machine 8. During the heating phase, the refrigeration machine is switched off and the cooling / heating medium is electrically heated (heating 9) .. A the closure of the vial 5 within the chamber 1 and after the implementation the apparatus used for drying is generally designated 10.
Zwischen Kammer 1 und Kondensator 3 befindet sich das Ventil 1 1 , das mit Hilfe des Antriebs 12 betätigt wird. Dem Kondensator 3 nachgeordnet ist der Vakuumpumpsatz 14.Between chamber 1 and condenser 3 there is valve 11, which is actuated with the aid of drive 12. The vacuum pump set 14 is arranged downstream of the condenser 3.
Zur Steuerung des Ablaufs des Gefriertrocknungsprozesses sind Steuermittel vorgesehen. Einer zentralen Steuerung 16 werden laufend Informationen über den Druck in der Kammer 1 und über die Temperatur der Stellflächen 2 zugeführt. Dazu dienen Druck- und Temperatur-Sensoren 17, 1 8. Nur ein Temperatur- Sensor 1 8 im Temperierkreislauf 6 ist dargestellt. Zweckmäßiger ist es, wenn der Austritt jeder der Stellflächen 2 mit einem Temperatursensor ausgerüstet ist.Control means are provided to control the sequence of the freeze-drying process. A central controller 16 continuously receives information about the pressure in the chamber 1 and about the temperature of the shelves 2. For this purpose, pressure and temperature sensors 17, 1 8 are used. Only one temperature sensor 1 8 in the temperature control circuit 6 is shown. It is more expedient if the outlet of each of the shelves 2 is equipped with a temperature sensor.
Beim dargestellten Ausführungsbeispiel steht die Steuerung 16 mit dem Vakuumpumpsatz 14, dem Kältemittelverdampfer 8 und dem Antrieb 12 des Ventils 1 1 in Verbindung. Die Drucksteuerung in der Kammer 1 erfolgt durch Zu- und Abschalten des Vakuumpumpsatzes 14 oder durch gesteuerten Einlass von Inertgas . Die Stellflachentemperatur wird mit Hilfe der Kältemaschine 8 bzw. der Heizung 9 eingestellt. Mit Hilfe der Steuerung 16 wird auch das Absperrventil 1 1 betätigt, um in an sich bekannter Weise die Eistemperatur zu messen.In the illustrated embodiment, the controller 16 is connected to the vacuum pump set 14, the refrigerant evaporator 8 and the drive 12 of the valve 11. The pressure control in chamber 1 is carried out by switching vacuum pump set 14 on or off or by controlled inlet of inert gas. The shelf temperature is set with the help of the refrigerator 8 or the heater 9. With the help of the control 16, the shut-off valve 11 is also actuated in order to measure the ice temperature in a manner known per se.
Der Steuerung 16 zugeordnet ist der Rechner 21 , dem ebenfalls die vom Drucksensor 17 gelieferten Signale zugeführt werden. Im Rechner 21 wird - wie weiter vorne beschrieben - die zeitliche Änderung des Druckes (dp/dt) nach einer Absperrung des Ventils 1 1 laufend überwacht. Unmittelbar nach dem Überschreiten des Maximums dieses Wertes erhält die Steuerung 16 das Signal, die Absperrzeit zu beenden.The controller 16 is assigned the computer 21, to which the signals supplied by the pressure sensor 17 are also fed. In the computer 21 - as described further above - the change in pressure (dp / dt) over time after the valve 11 is shut off is continuously monitored. Immediately after the maximum of this value has been exceeded, the controller 16 receives the signal to end the shut-off time.
Das Diagramm nach Figur 2 läßt den zeitlichen Ablauf eines Beispieles für einen Gefriertrocknungsprozess erkennen. In y-Richtung sind Stellflächen- Temperatur-Werte und Druck-Werte angegeben. Die gestrichelte Kurve 23 gibt den Verlauf des Kammerdruckes wieder. Die punktierte Linie 24 zeigt den Verlauf der Stellflachentemperatur. Die ausgezogene Linie 25 läßt die laufend gemessenen Eistemperatur-Werte erkennen. Schließlich gibt die strichpunktierte Linie 26 eine mittlere Produkt-Temperatur an.The diagram according to FIG. 2 shows the chronological sequence of an example for a freeze-drying process. Footprint temperature values and pressure values are given in the y direction. Dashed curve 23 shows the course of the chamber pressure. The dotted line 24 shows the course of the surface temperature. The solid line 25 shows the continuously measured ice temperature values. Finally, the dash-dotted line 26 indicates an average product temperature.
Ein Gefriertrocknungsprozess der dargestellten Art beginnt mit dem Einbringen des gefrorenen Produktes in die Kammer 1 . Danach werden die Kammer evakuiert und die Stellflächen auf die gewünschte Temperatur aufgeheizt. Es stellt sich ein thermodynamisches Gleichgewicht ein, bei dem die Haupttrocknung stattfindet. Beim dargestellten Ausführungsbeispiel dauert die Haupttrocknung ca. 48 Stunden. In dieser Zeit wird der Steuerdruck (Kurve 23 ) auf einem bestimmten Druck gehalten. Die Stellplatten- Temperatur (Kurve 24) wird ebenfalls auf bestimmte Werte eingestellt. Beim dargestellten Ausführungsbeispiel erfolgt nach 24 Stunden bereits eine Erhöhung der Stellflachentemperatur. Nach dem Absinken der Eistemperatur wird die Drucksteuerung abgeschaltet. Die Stellfächentemperatur wird weiterhin erhöht. In dieser Phase der Nachtrocknung können Steuerung 16 und Rechner 21 dazu verwendet werden, die Restfeuchte zu ermitteln. Dieses geschieht zweckmäßig nach einem Verfahren, wie es in der Internationalen Patentanmeldung WO 96/25654 beschrieben ist.A freeze-drying process of the type shown begins with the introduction of the frozen product into the chamber 1. The chamber is then evacuated and the shelves heated to the desired temperature. There is a thermodynamic equilibrium at which the main drying takes place. In the illustrated embodiment, the main drying takes about 48 hours. During this time, the control pressure (curve 23) is kept at a certain pressure. The shelf temperature (curve 24) is also set to certain values. In the exemplary embodiment shown, the surface temperature increases already after 24 hours. After the ice temperature drops, the pressure control is switched off. The shelf temperature will continue to increase. In this phase of post-drying, controller 16 and computer 21 can be used to determine the residual moisture. This is expediently carried out using a method as described in international patent application WO 96/25654.
Erfindungsgemäß werden die Änderungen des Kammerdruckes und der Stellflachentemperatur in Abhängigkeit von Änderungen der Eistemperatur vorgenommen. Beim dargestellten Ausführungsbeispiel werden die die Nachtrocknung kennzeichnenden Werte des Druckes und der Stellflachentemperatur dann vorgenommen, wenn sich die Eistemperatur gegenüber einem höchsten Mittelwert um mehr als 2 bis 3 °C geändert hat. Auch die Erhöhung der Stellflachentemperatur während der Haupttrocknung kann in Abhängigkeit von Änderungen der Eistemperatur vorgenommen werden. Beim dargestellten Ausführungsbeispiel geschieht dieses, wenn sich die Eistemperatur gegenüber dem höchsten Mittelwert um mehr als l °C geändert hat.According to the invention, the changes in the chamber pressure and the shelf surface temperature are made as a function of changes in the ice temperature. In the exemplary embodiment shown, the values of the pressure and the shelf surface temperature which characterize the after-drying are carried out when the ice temperature has changed by more than 2 to 3 ° C. compared to a highest mean value. The surface temperature during main drying can also be increased depending on changes in the ice temperature. In the exemplary embodiment shown, this happens when the ice temperature has changed by more than 1 ° C. compared to the highest mean value.
Figur 3 ist ein Diagramm, in dem die ausgezogene Kurve 28 den Anstieg des Druckes darstellt, der nach der Absperrung des Ventils zwischen Kammer 1 und Kondensator 3 erfolgt. Diese Kurve wird vom Rechner 21 laufend differenziert (gestrichelte Kurve 29 ). Dadurch ist es möglich, laufend die zeitliche Änderung des Kammerdruckes festzustellen. Wie bereits beschrieben, kann die Messung abgebrochen werden, wenn die zeitliche Änderung des Druckes ein Maximum überschreitet. FIG. 3 is a diagram in which the solid curve 28 represents the increase in pressure which occurs between the chamber 1 and the condenser 3 after the valve has been shut off. This curve is continuously differentiated by the computer 21 (dashed curve 29). This makes it possible to continuously determine the change in chamber pressure over time. As already described, the measurement can be stopped if the change in pressure over time exceeds a maximum.

Claims

P a t e n t a n s p r ü c h e P a t e n t a n s r u c h e
1 ) Die Erfindung betrifft ein Verfahren zur Steuerung eines Gefriertrocknungsprozesses,1) The invention relates to a method for controlling a freeze-drying process,
- bei dem eingefrorenes, in einer evakuierten Kammer auf temperierbaren Stellflächen befindliches Produkt zunächst einer Haupttrocknung und anschließend einer Nachtrocknung unterworfen wird,in the case of the frozen product, which is located in an evacuated chamber on temperature-adjustable shelves, is first subjected to a main drying and then to a subsequent drying,
- bei dem während der Haupttrocknung laufend die Temperatur des im zu trocknenden Produkt eingeschlossenen Eises gemessen wird und- during which the temperature of the ice enclosed in the product to be dried is continuously measured during the main drying and
- bei dem beim Übergang von der Haupttrocknung zur Nachtrocknung der Kammerdruck und/oder die Stellflachentemperatur verändert werden,- in which the chamber pressure and / or the surface temperature are changed during the transition from main drying to post-drying,
dadurch gekennzeichnet,characterized,
- daß die den Übergang von der Haupttrocknung zur Nachtrocknung kennzeichnenden Änderungen des Druckes und/oder der Stellflachentemperatur in Abhängigkeit von Änderungen der Eistemperatur vorgenommen werden.- That the changes in pressure and / or the surface temperature characterizing the transition from the main drying to after-drying are carried out as a function of changes in the ice temperature.
2) Verfahren nach Anspruch 1 , dadurch gekennzeichnet, daß auch während der Haupttrocknung Kammerdruck und/oder Stellfächentemperatur verändert werden und daß Änderungen dieser Art ebenfalls in Abhängigkeit von Änderungen der Eistemperatur vorgenommen werden.2) Method according to claim 1, characterized in that chamber pressure and / or shelf temperature are changed even during the main drying and that changes of this type are also made depending on changes in the ice temperature.
3) Verfahren nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß die Eistemperatur-Meßwerte jeweils mit den vorhergegangenen Meßwerten gemittelt werden und daß zur Feststellung einer bestimmten Änderung der Eistemperatur laufend der höchste der ermittelten Eistemperatur- Mittelwerte mit den aktuellen Werten der Eistemperatur verglichen werden.3) Method according to claim 1 or 2, characterized in that the ice temperature measured values are averaged in each case with the previous measured values and that the highest of the determined ice temperature mean values are continuously compared with the current values of the ice temperature to determine a specific change in the ice temperature.
4) Verfahren nach Anspruch 1 , 2 oder 3 , dadurch gekennzeichnet, daß zur Bestimmung der Eistemperatur laufend Messungen eines Druckanstiegs durchgeführt werden, welcher nach einer Absperrung der Kammer von ihrer Evakuierungseinrichtung stattfindet. 5) Verfahren nach Anspruch 4, dadurch gekennzeichnet, daß nach der Absperrung der Kammer von ihrer Evakuierungseinrichtung der Kammerdruck laufend gemessen und diese Meßwerte einem Rechner zugeführt werden, daß der Rechner laufend die zeitliche Änderung des Druckes (dp/dt) feststellt und daß die Druckanstiegsmessung beendet und gleichzeitig die Verbindung zwischen Kammer und Evakuierungseinrichtung wieder hergestellt wird, wenn die zeitliche Änderung des Druckes ein Maximum erreicht hat.4) Method according to claim 1, 2 or 3, characterized in that measurements of an increase in pressure are carried out to determine the ice temperature, which takes place after the chamber has been shut off from its evacuation device. 5) Method according to claim 4, characterized in that after the chamber has been shut off from its evacuation device, the chamber pressure is continuously measured and these measured values are fed to a computer, that the computer continuously determines the change in pressure over time (dp / dt) and that the pressure rise measurement terminated and at the same time the connection between the chamber and the evacuation device is restored when the change in pressure over time has reached a maximum.
6) Verfahren nach einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, daß nach dem Übergang von der Haupttrocknung zur Nachtrocknung die noch im zu trocknenden Produkt vorhandene Restfeuchte ermittelt wird.6) Method according to one of the preceding claims, characterized in that after the transition from the main drying to post-drying, the residual moisture still present in the product to be dried is determined.
7) Verfahren nach Anspruch 6, dadurch gekennzeichnet, daß zur Ermittlung der Restfeuchte das aus der Internationalen Patentanmeldung7) Method according to claim 6, characterized in that to determine the residual moisture from the international patent application
WO 96/25654 bekannte Verfahren angewendet wird.Known methods WO 96/25654 is used.
8) Vorrichtung zur Durchführung eines Verfahrens zur Steuerung eines Gefriertrocknungsprozesses nach den Ansprüchen 1 bis 7, dadurch gekennzeichnet, daß die Vorrichtung mit einem Rechner (21 ) ausgerüstet ist und daß eine Steuerung ( 16) vorgesehen ist, die in Abhängigkeit von vom Rechner (21 ) gelieferten Werten den Druck in der Kammer ( 1 ) und/oder die Temperatur der Stellflächen (2) verändert. 8) Device for carrying out a method for controlling a freeze-drying process according to claims 1 to 7, characterized in that the device is equipped with a computer (21) and that a controller (16) is provided which, depending on the computer (21st ) delivered values changed the pressure in the chamber (1) and / or the temperature of the shelves (2).
EP98922751A 1997-05-07 1998-04-21 Method and apparatus for controlling a freeze drying process Expired - Lifetime EP0980503B1 (en)

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DE19719398A DE19719398A1 (en) 1997-05-07 1997-05-07 Process for controlling a freeze-drying process
PCT/EP1998/002335 WO1998050744A1 (en) 1997-05-07 1998-04-21 Method for controlling a freeze drying process

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DK0980503T3 (en) 2001-10-22
ES2161532T3 (en) 2001-12-01
JP2001525049A (en) 2001-12-04
DE19719398A1 (en) 1998-11-12

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