EP0980503B1 - Method and apparatus for controlling a freeze drying process - Google Patents
Method and apparatus for controlling a freeze drying process Download PDFInfo
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- EP0980503B1 EP0980503B1 EP98922751A EP98922751A EP0980503B1 EP 0980503 B1 EP0980503 B1 EP 0980503B1 EP 98922751 A EP98922751 A EP 98922751A EP 98922751 A EP98922751 A EP 98922751A EP 0980503 B1 EP0980503 B1 EP 0980503B1
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- temperature
- pressure
- chamber
- drying
- ice
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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
- Such a method is, for example, from DE-C-1 038 988 known.
- 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 that is small is against the water vapor pressure at the selected temperature of the ice: For example, corresponds to an ice temperature of -20 ° C a water vapor pressure (in Equilibrium) of 1.03 mbar. So that the water vapor from the ice surface can flow into the drying chamber, the water vapor pressure in the Drying chamber can be significantly smaller than 1.03 mbar. e.g. e.g. 0.4 mbar. It is therefore advisable to use a pressure that is small compared to this pressure value, e.g. 0.05 mbar to choose. Freeze drying usually takes place in one Chamber instead, in which there are temperature-controlled shelves and one Evacuation device, e.g. one combined with a vacuum pump Ice condenser, is connected.
- Evacuation device e.g. one combined with a vacuum pump Ice condens
- the main characteristics of the course of the drying process are two drying phases. As long as crystallized (frozen) Water in the product is called this dry section Main or sublimation drying. If you close the in this phase Drying the shut-off device between the chamber and the Evacuation device for a short time (a few seconds) turns into the chamber of equilibrium water vapor pressure, that of the ruling Ice temperature corresponds. From the pressure increase can directly on the Ice temperature should be closed. This method of measuring the Ice temperature is known under the term barometric temperature measurement and described in DE-PS 10 38 988.
- the temperature of the product may be certain, usually well below Do not exceed 0 ° C to impair the Avoid quality and / or properties of the product.
- the ice cores present in the product become always smaller. In the area of dry marginal zones there are already higher ones Temperatures allowed.
- From DE-PS 10 38 988 is a method of the aforementioned Kind known.
- To determine the transition from main drying to Post-drying measurements are carried out on the medium which also serve to measure the ice temperature. To do this the shut-off times that only a few when measuring the ice temperature Seconds, significantly extended, to two minutes and more. If after shutdown times of this magnitude there is almost a constant difference between the operating pressure and the Saturation vapor pressure sets, it can be assumed that the solid ice has been completely removed from the goods, the main drying is finished. The shelf temperature and the pressure can be on those values are set at which the post-drying takes place should.
- a disadvantage of the described method is the considerable lengthening the cut-off time. If the main drying has not yet ended, then there is Danger of an extension of the blocking time to a no longer permitted Increasing the temperature of the ice-containing goods and thus destroying them in modern freeze drying systems for the pharmaceutical industry the value of a batch already exceeds the DM million mark. Threats to the Product must therefore be avoided at all costs.
- the present invention has for its object a method for Propose control of a freeze-drying process of the type mentioned at the outset, where the disadvantage of longer shut-off times between chambers and evacuation device no longer has to be accepted.
- this object is achieved in that the transition changes from the main drying to the subsequent drying characterizing the Pressure and / or the shelf temperature depending on a decrease the ice temperature.
- This procedure uses the Appearance from that while performing the main drying measured ice temperature values during the transition from main drying to become smaller after drying, which is obviously only apparent Changing the ice temperature is slight but can be done with help modern computers can be determined exactly.
- Control of the freeze drying process only measurements of the Ice temperature are carried out, which only short shut-off times there is a risk of thawing the product no more.
- the measurement of the ice temperature itself is expediently carried out after the start mentioned barometric temperature measurement, i.e. that from the increase in the Chamber pressure after separation of the chamber from its Evacuation device occurs, the ice temperature is derived.
- the increasing chamber pressure is continuously 10 to measured a few hundred times per second. These measured values are one Computer fed.
- the values of the measured in the first seconds Pressure increase result in an increasing, approximately S-shaped curve, i.e. one Curve with a turning point. With the help of the calculator this curve continuously differentiated, i.e.
- the ongoing, short-term and relatively precise determination of the ice temperature allows very early fluctuations beyond the measuring accuracy to determine the ice temperature.
- fluctuations in the chamber pressure or the surface temperature excluded then indicate fluctuations in the Ice temperature for an inhomogeneous ice structure.
- Heat conduction and Water vapor transport are different in zones with very small or grown together large crystals. This also applies to during the Main drying of collapsed products, as water then takes place in some zones Ice is present. Fluctuations in the ice temperature can therefore occur Failure to freeze the product or excessive shelf temperature Clues.
- the invention further relates to a device for performing the method with the features according to claim 8.
- the freeze-drying device shown in Figure 1 comprises the chamber 1 with their footprints 2 and the capacitor 3 connected to them its condensation surfaces 4. On the shelves 2 there are containers (Vial 5) with freeze-dried product. The parking spaces are 2 temperable. They are part of a temperature control circuit 6 Feed pump 7 and refrigeration machine 8. During the heating phase, the Chiller switched off and the cooling / heating medium heated electrically (Heater 9) ..
- One of the closures of the vials 5 inside the chamber 1 and apparatus serving after drying is general designated 10.
- valve 11 Between chamber 1 and condenser 3 is the valve 11, which with Help of the drive 12 is actuated.
- the capacitor 3 is the Vacuum pump set 14.
- Control means are used to control the sequence of the freeze-drying process intended.
- a central controller 16 continuously provides information about the pressure in chamber 1 and the temperature of the shelves 2 fed. Pressure and temperature sensors 17, 18 are used for this purpose Temperature sensor 18 in the temperature control circuit 6 is shown. More appropriate it is when the exit of each of the shelves 2 with a temperature sensor is equipped.
- the controller 16 stands with the Vacuum pump set 14, the refrigerant evaporator 8 and the drive 12 of the Valve 11 in connection.
- the pressure control in chamber 1 is carried out by Switching the vacuum pump set 14 on and off or by controlled inlet from inert gas.
- the shelf temperature is determined using the refrigerator 8 or the heater 9 set.
- the controller 16 is assigned to the computer 21, to which the data from Pressure sensor 17 supplied signals are supplied.
- the computer 21 - as described above - the change in pressure over time (dp / dt) continuously monitored after the valve 11 has been shut off. Immediately after if the maximum of this value is exceeded, the controller 16 receives this Signal to end the cut-off time.
- the diagram according to FIG. 2 shows the chronological sequence of an example for recognize a freeze-drying process.
- Floor space temperature values are in the y direction and pressure values given.
- Dashed curve 23 shows the course of the chamber pressure.
- the dotted line 24 shows the course of the shelf temperature.
- the solid line 25 leaves the Detect continuously measured ice temperature values.
- 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 chamber 1.
- the chamber is then evacuated and the shelves are heated to the desired temperature.
- the main drying takes about 48 hours.
- the control pressure (curve 23) is kept at a certain pressure.
- the shelf temperature (curve 24) is also set to certain values.
- 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. In this method, the residual moisture is obtained from measurements of the desorption rate DR.
- DR Desorbed water mass x100 Hours x mass of dry matter Water in% of dry matter per hour
- the desorption rate during the Post-drying phase measured at certain time intervals (e.g. 10 min)
- the computer calculates the time at which two or more of these measured values a desorption rate would be reached (desorption rate zero point), which the Desired residual moisture only by a tolerable small amount would change, and then the respective residual moisture from the computer temporal integration of the desorption rates from zero to Measurement time is determined.
- the Post-drying characteristic values of pressure and Floor temperature then made when the ice temperature has changed by more than 2 to 3 ° C compared to a highest mean. Also increasing the shelf temperature during the main drying can be made depending on changes in ice temperature become. In the illustrated embodiment, this happens when the ice temperature by more than 1 ° C compared to the highest mean has changed.
- Figure 3 is a diagram in which the solid curve 28 shows the increase in Represents pressure after the valve is shut off between chamber 1 and capacitor 3 takes place.
- This curve is running by the computer 21 differentiated (dashed curve 29). This makes it possible to keep running determine the temporal change in the chamber pressure. As before described, the measurement can be stopped if the temporal Change in pressure exceeds a maximum.
Description
Die Erfindung betrifft ein Verfahren zur Steuerung eines Gefriertrocknungsprozesses,
- bei dem eingefrorenes, in einer evakuierten Kammer auf temperierbaren Stellflächen befindliches Produkt zunächst einer Haupttrocknung und anschließend einer Nachtrocknung unterworfen wird,
- bei dem während der Haupttrocknung laufend die Temperatur des im zu trocknenden Produkt eingeschlossenen Eises gemessen wird und
- bei dem beim Übergang von der Haupttrocknung zur Nachtrocknung der Kammerdruck und/oder die Stellflächentemperatur verändert werden.
- 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,
- during which the temperature of the ice enclosed in the product to be dried is continuously measured during the main drying and
- in which the chamber pressure and / or the shelf temperature are changed during the transition from main drying to post-drying.
Ein derartiges Verfahren ist, zum Beispiel, aus der DE-C-1 038 988 bekannt.Such a method is, for example, from DE-C-1 038 988 known.
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. 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 that is small is against the water vapor pressure at the selected temperature of the ice: For example, corresponds to an ice temperature of -20 ° C a water vapor pressure (in Equilibrium) of 1.03 mbar. So that the water vapor from the ice surface can flow into the drying chamber, the water vapor pressure in the Drying chamber can be significantly smaller than 1.03 mbar. e.g. e.g. 0.4 mbar. It is therefore advisable to use a pressure that is small compared to this pressure value, e.g. 0.05 mbar to choose. Freeze drying usually takes place in one Chamber instead, in which there are temperature-controlled shelves and one Evacuation device, e.g. one combined with a vacuum pump Ice condenser, is connected.
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.The main characteristics of the course of the drying process are two drying phases. As long as crystallized (frozen) Water in the product is called this dry section Main or sublimation drying. If you close the in this phase Drying the shut-off device between the chamber and the Evacuation device for a short time (a few seconds) turns into the chamber of equilibrium water vapor pressure, that of the ruling Ice temperature corresponds. From the pressure increase can directly on the Ice temperature should be closed. This method of measuring the Ice temperature is known under the term barometric temperature measurement and 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 may be certain, usually well below Do not exceed 0 ° C to impair the Avoid quality and / or properties of the product. With As the drying progresses, the ice cores present in the product become always smaller. In the area of dry marginal zones there are already higher ones Temperatures allowed.
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 at Dry product is absorbed or more or less firmly bound. The Removal of this water takes place during the after or Desorption drying instead. 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 the amount of water still available another change in the course of the drying process determining physical conditions initiated.
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 Stellflächcntemperatur und der Druck können auf diejenigen Werte eingestellt werden, bei denen die Nachtrocknung stattfinden soll. From DE-PS 10 38 988 is a method of the aforementioned Kind known. To determine the transition from main drying to Post-drying measurements are carried out on the medium which also serve to measure the ice temperature. To do this the shut-off times that only a few when measuring the ice temperature Seconds, significantly extended, to two minutes and more. If after shutdown times of this magnitude there is almost a constant difference between the operating pressure and the Saturation vapor pressure sets, it can be assumed that the solid ice has been completely removed from the goods, the main drying is finished. The shelf temperature and the pressure can be on those values are set at which the post-drying takes place should.
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 führt.In modernen Gefriertrocknungsanlagen für die Pharma-Industrie erreicht der Wert einer Charge bereits die Millionen-DM-Grenze. Gefährdungen des Produktes müssen deshalb unbedingt vermieden werden.A disadvantage of the described method is the considerable lengthening the cut-off time. If the main drying has not yet ended, then there is Danger of an extension of the blocking time to a no longer permitted Increasing the temperature of the ice-containing goods and thus destroying them in modern freeze drying systems for the pharmaceutical industry the value of a batch already exceeds the DM million mark. Threats 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 has for its object a method for Propose control of a freeze-drying process of the type mentioned at the outset, where the disadvantage of longer shut-off times between chambers and 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 Stellflächentemperatur in Abhängigkeit von einem Absinken der Eistempcratur 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 transition changes from the main drying to the subsequent drying characterizing the Pressure and / or the shelf temperature depending on a decrease the ice temperature. This procedure uses the Appearance from that while performing the main drying measured ice temperature values during the transition from main drying to become smaller after drying, which is obviously only apparent Changing the ice temperature is slight but can be done with help modern computers can be determined exactly. As for the invention Control of the freeze drying process only measurements of the Ice temperature are carried out, which only short shut-off times there is a risk of thawing the product no more.
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 present in the product always smaller. Often after the formation of dry marginal areas Possibility to change the temperature of the Increase floor space without endangering the quality of the product. Also Changes in the drying conditions of this type can be made according to the invention depending on changes in 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 mitteln und zur Feststellung einer bestimmten Änderung der Eistemperatur laufend den höchsten der ermittelten Eistemperatur-Mittclwerte 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. Change the ice temperature values measured during main drying just a little. It is therefore appropriate in the context of the invention, the Ice temperature measurements with the previous measurements average and to determine a specific change in ice temperature continuously the highest of the determined ice temperature mean values with the to compare current ice temperature values. Changes in Ice temperature around 1.2 or 3 ° C can be achieved using this method can be clearly determined.
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 measurement of the ice temperature itself is expediently carried out after the start mentioned barometric temperature measurement, i.e. that from the increase in the Chamber pressure after separation of the chamber from its Evacuation device occurs, the ice temperature is derived. Around according to the general aim of the present invention Keeping shutdown times as short as possible is suggested as follows to proceed: After the chamber has been closed off from it Evacuation device, the increasing chamber pressure is continuously 10 to measured a few hundred times per second. These measured values are one Computer fed. The values of the measured in the first seconds Pressure increase result in an increasing, approximately S-shaped curve, i.e. one Curve with a turning point. With the help of the calculator this curve continuously differentiated, i.e. the change in pressure over time (dp / dt) supervised. It has been found that for a sufficiently accurate Determination of the ice temperature necessary measurement of the pressure rise can be canceled when the pressure rise curve reaches its inflection point reached, i.e. when the first derivative of this curve reaches its maximum reached. The blocking time can therefore already end at this point and the connection between the chamber and the evacuation device again getting produced; this is an exceeding of the ice temperature locked out.
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 Stellflächentemperatur 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 very early fluctuations beyond the measuring accuracy to determine the ice temperature. Are fluctuations in the chamber pressure or the surface temperature excluded, then indicate fluctuations in the Ice temperature for an inhomogeneous ice structure. Heat conduction and Water vapor transport are different in zones with very small or grown together large crystals. This also applies to during the Main drying of collapsed products, as water then takes place in some zones Ice is present. Fluctuations in the ice temperature can therefore occur Failure to freeze the product or excessive shelf temperature Clues.
Die Erfindung betrifft weiterhin eine Vorrichtung zur Durchführung des Verfahrens mit den Merkmalen gemäß Anspruch 8.The invention further relates to a device for performing the method with the features according to claim 8.
Weitere Vorteile der Erfindung sollen anhand der Figuren 1 bis 3 erläutert werden. Es zeigen
Figur 1- schematisch eine Einrichtung zur Durchführung eines Gefriertrocknungsprozesses,
Figur 2- ein Diagramm, das den Ablauf eines Gefriertrocknungsprozesses erkennen läßt und
Figur 3- ein weiteres Diagramm zur Erläuterung der Feststellung der Eistemperatur
- Figure 1
- schematically a device for carrying out a freeze-drying process,
- Figure 2
- a diagram that shows the course of a freeze-drying process and
- Figure 3
- another diagram to explain the 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
Zwischen Kammer 1 und Kondensator 3 befindet sich das Ventil 11, das mit
Hilfe des Antriebs 12 betätigt wird. Dem Kondensator 3 nachgeordnet ist der
Vakuumpumpsatz 14.Between
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, 18. Nur ein
Temperatur-Sensor 18 im Temperierkreislauf 6 ist dargestellt. Zweckmäßiger
ist es, wenn der Austritt jeder der Stellflächen 2 mit einem Temperatursensor
ausgerüstet ist.Control means are used to control the sequence of the freeze-drying process
intended. A
Beim dargestellten Ausführungsbeispiel steht die Steuerung 16 mit dem
Vakuumpumpsatz 14, dem Kältemittelverdampfer 8 und dem Antrieb 12 des
Ventils 11 in Verbindung. Die Drucksteuerung in der Kammer 1 erfolgt durch
Zu- und Abschalten des Vakuumpumpsatzes 14 oder durch gesteuerten Einlass
von Inertgas. Die Stellflächentemperatur wird mit Hilfe der Kältemaschine 8
bzw. der Heizung 9 eingestellt. Mit Hilfe der Steuerung 16 wird auch das
Absperrventil 11 betätigt, um in an sich bekannter Weise die Eistemperatur zu
messen.In the illustrated embodiment, the
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 11 laufend überwacht. Unmittelbar nach
dem Überschreiten des Maximums dieses Wertes erhält die Steuerung 16 das
Signal, die Absperrzeit zu beenden.The
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 Stellflächentemperatur. 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
recognize a freeze-drying process. Floor space temperature values are in the y direction
and pressure values given. Dashed
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 Stellflächentemperatur. 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. Bei diesem Verfahren wird
die Restfeuchte aus Messungen der Desorptionsrate DR gewonnen.
Bei diesem Verfahren wird die Desorptionsrate während der Nachtrockenphase in bestimmten Zeitabständen (z., B. 10 min) gemessen, ein Rechner errechnet aus zwei oder mehreren dieser Meßwerte die Zeit, zu der eine Desorptionsrate erreicht wäre (Desorptionsraten-Nullpunkt), die die gewünschte Restfeuchte nur noch um einen tolerierbaren kleinen Betrag verändern würde, und danach die jeweilige Restfeuchte vom Rechner durch zeitliche Integration der Desorptionsraten vom Nullpunkt bis zum Meßzeitpunkt ermittelt wird.In this process, the desorption rate during the Post-drying phase measured at certain time intervals (e.g. 10 min) The computer calculates the time at which two or more of these measured values a desorption rate would be reached (desorption rate zero point), which the Desired residual moisture only by a tolerable small amount would change, and then the respective residual moisture from the computer temporal integration of the desorption rates from zero to Measurement time is determined.
Erfindungsgemäß werden die Änderungen des Kammerdruckes und der Stellflächentemperatur in Abhängigkeit von einem Absinken der Eistemperatur vorgenommen Beim dargestellten Ausführungsbeispiel werden die die Nachtrocknung kennzeichnenden Werte des Druckes und der Stellflächentemperatur dann vorgenommen, wenn sich die Eistemperatur gegenüber einem höchsten Mittelwert um mehr als 2 bis 3°C geändert hat. Auch die Erhöhung der Stellflächentemperatur 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 alsl°C geändert hat.According to the changes in chamber pressure and Floor space temperature depending on a drop in the ice temperature In the illustrated embodiment, the Post-drying characteristic values of pressure and Floor temperature then made when the ice temperature has changed by more than 2 to 3 ° C compared to a highest mean. Also increasing the shelf temperature during the main drying can be made depending on changes in ice temperature become. In the illustrated embodiment, this happens when the ice temperature by more than 1 ° C compared to the highest mean has changed.
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.Figure 3 is a diagram in which the
Claims (8)
- A method of controlling a freeze-drying process,characterised in that,in which the frozen product located in an evacuated chamber on temperature-controllable surfaces is subjected firstly to main drying and then to secondary drying,in which the temperature of the ice trapped in the product to be dried is measured continually during main drying andthe chamber pressure and/or the surface temperature is/are changed during the transition from main drying to secondary drying,the changes in pressure and/or surface temperature characterising the transition from main drying to secondary drying are performed as a function of a lowering of the ice temperature.
- A method according to claim 1, characterised in that chamber pressure and/or surface temperature are also changed during main drying and in that changes of this type are likewise performed as a function of changes in the ice temperature.
- A method according to claim 1 or claim 2, characterised in that the measured ice temperature values are in each case averaged with the previous measured values and in that, to establish a specific change in ice temperature, the highest of the mean ice temperature values determined is continually compared with the current ice temperature values.
- A method according to claim 1, 2 or 3, characterised in that, to determine the ice temperature, measurements of a pressure increase are continually performed, which pressure increase occurs after the chamber has been shut off from its evacuation means.
- A method according to claim 4, characterised in that, after the chamber has been shut off from its evacuation means, the chamber pressure is measured continually and these measured values are supplied to a computer, in that the computer continually establishes the change in pressure over time (dp/dt) and in that the pressure increase measurement is completed and at the same time the connection between chamber and evacuation means is re-established when the change in pressure over time has reached a maximum.
- A method according to one of the preceding claims, characterised in that, after the transition from main drying to secondary drying, the residual moisture still present in the product to be dried is determined.
- A method according to claim 6, characterised in that the residual moisture is obtained from measurements of the desorption rate, by measuring the desorption rate during the secondary drying phase at given intervals (e.g. 10 mins), a computer calculating from two or more of these measured values the time at which a desorption rate would be reached (desorption rate zero) which would change the desired residual moisture only by a tolerable small amount, and then the respective residual moisture being determined by the computer by integration over time of the desorption rates from zero to the time of measurement.
- A device for performing a method of controlling a freeze-drying process, according to claims 1 to 7, having an evacuated chamber with temperature-controllable surfaces, having means for measuring the temperature of the ice trapped in the product to be dried and for changing the chamber pressure and/or the surface temperature
characterised in that the device is equipped in a manner known per se with a computer (21) and in that a control means (16) is provided which changes the pressure in the chamber (1) and/or the temperature of the surfaces (2) as a function of values supplied by the computer (21).
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19719398A DE19719398A1 (en) | 1997-05-07 | 1997-05-07 | Process for controlling a freeze-drying process |
| DE19719398 | 1997-05-07 | ||
| PCT/EP1998/002335 WO1998050744A1 (en) | 1997-05-07 | 1998-04-21 | Method for controlling a freeze drying process |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0980503A1 EP0980503A1 (en) | 2000-02-23 |
| EP0980503B1 true EP0980503B1 (en) | 2001-07-11 |
Family
ID=7828961
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP98922751A Expired - Lifetime EP0980503B1 (en) | 1997-05-07 | 1998-04-21 | Method and apparatus for controlling a freeze drying process |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US6163979A (en) |
| EP (1) | EP0980503B1 (en) |
| JP (1) | JP2001525049A (en) |
| DE (2) | DE19719398A1 (en) |
| DK (1) | DK0980503T3 (en) |
| ES (1) | ES2161532T3 (en) |
| WO (1) | WO1998050744A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102016215844A1 (en) | 2016-08-23 | 2018-03-01 | OPTIMA pharma GmbH | Method and apparatus for freeze drying |
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| DE19936281C2 (en) * | 1999-08-02 | 2002-04-04 | Bayer Ag | Freeze-drying process |
| EP1236962B1 (en) | 2001-03-01 | 2006-06-07 | Incorporated Administrative Agency National Agriculture and Bio-oriented Research Organization | Process and apparatus for producing a freeze-dried product |
| US6543155B2 (en) | 2001-03-01 | 2003-04-08 | National Agricultural Research Organization | Freeze-dried product and process and apparatus for producing it |
| DE10136498A1 (en) | 2001-07-27 | 2003-02-06 | Steris Gmbh | Chamber for a freeze dryer |
| DE10218007A1 (en) * | 2002-04-23 | 2003-11-06 | Bayer Ag | Freeze dryer |
| WO2004047753A2 (en) * | 2002-11-21 | 2004-06-10 | Transform Pharmaceuticals, Inc. | Freeze-drying microscope stage apparatus and process of using the same |
| WO2005018410A1 (en) * | 2003-07-30 | 2005-03-03 | BSH Bosch und Siemens Hausgeräte GmbH | Method for operating a device with at least one partial programme step of drying |
| DE102004007526A1 (en) * | 2004-02-17 | 2005-09-01 | Oetjen, Georg-Wilhelm, Dr. | Method and device for the freeze-drying of products |
| US7520670B2 (en) * | 2005-04-26 | 2009-04-21 | John Jeffrey Schwegman | Wireless temperature sensing system for lyophilization processes |
| US20090175315A1 (en) * | 2005-04-26 | 2009-07-09 | John Jeffrey Schwegman | Wireless temperature sensing system for lyophilization processes |
| US20060275863A1 (en) * | 2005-05-17 | 2006-12-07 | Yamaha Hatsudoki Kabushiki Kaisha | Method for preserving xanthophyll in algal cell |
| DE102005024536A1 (en) | 2005-05-28 | 2006-11-30 | Hans-Georg Hof | Horizontal freeze-drying plant |
| US20070098591A1 (en) * | 2005-10-31 | 2007-05-03 | Georg Frinke | Method and apparatus for low energy vaporization of liquid oxidizing agents or solutions |
| EP1903291A1 (en) * | 2006-09-19 | 2008-03-26 | Ima-Telstar S.L. | Method and system for controlling a freeze drying process |
| IT1397930B1 (en) | 2009-12-23 | 2013-02-04 | Telstar Technologies S L | METHOD FOR MONITORING THE PRIMARY DRYING OF A LIOFILIZATION PROCESS. |
| US8810394B2 (en) * | 2010-04-16 | 2014-08-19 | Medtronic, Inc. | Reservoir monitoring for implantable fluid delivery devices |
| US9687603B2 (en) | 2010-04-16 | 2017-06-27 | Medtronic, Inc. | Volume monitoring for implantable fluid delivery devices |
| US8434240B2 (en) | 2011-01-31 | 2013-05-07 | Millrock Technology, Inc. | Freeze drying method |
| WO2012108470A1 (en) * | 2011-02-08 | 2012-08-16 | 共和真空技術株式会社 | Calculation method and calculation device for sublimation interface temperature, bottom part temperature, and sublimation rate of material to be dried in freeze-drying device |
| US8549768B2 (en) * | 2011-03-11 | 2013-10-08 | Linde Aktiengesellschaft | Methods for freeze drying |
| DE102012007422B4 (en) | 2012-04-16 | 2024-02-08 | Martin Christ Gefriertrocknungsanlagen Gmbh | Process for freeze-drying substances and system for carrying out this process |
| US8904664B2 (en) | 2012-08-15 | 2014-12-09 | Mimedx Group, Inc. | Dehydration device and methods for drying biological materials |
| US10111910B2 (en) | 2013-01-18 | 2018-10-30 | Mimedx Group, Inc. | Methods for treating cardiac conditions |
| US10206977B1 (en) | 2013-01-18 | 2019-02-19 | Mimedx Group, Inc. | Isolated placental stem cell recruiting factors |
| US9121637B2 (en) * | 2013-06-25 | 2015-09-01 | Millrock Technology Inc. | Using surface heat flux measurement to monitor and control a freeze drying process |
| WO2015109329A1 (en) | 2014-01-17 | 2015-07-23 | Mimedx Group, Inc. | Method for inducing angiogenesis |
| US10605527B2 (en) | 2015-09-22 | 2020-03-31 | Millrock Technology, Inc. | Apparatus and method for developing freeze drying protocols using small batches of product |
| EP3392584B1 (en) * | 2017-04-21 | 2019-12-18 | GEA Lyophil GmbH | A freeze dryer and a method for inducing nucleation in products |
| US11359861B2 (en) | 2018-04-10 | 2022-06-14 | Ima Life North America Inc. | Freeze drying process and equipment health monitoring |
| CN116972601B (en) * | 2023-09-22 | 2023-12-08 | 昆海生物技术(三亚)有限公司 | Vacuum freeze-drying device and freeze-drying method for white tomatoes |
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| DE1038988B (en) * | 1956-08-22 | 1958-09-11 | Leybold Hochvakuum Anlagen | Control method of a freeze-drying and device for its execution |
| US2994132A (en) * | 1956-08-22 | 1961-08-01 | Neumann Karlheinz | Freeze drying apparatus |
| DE1135828B (en) * | 1959-01-10 | 1962-08-30 | Leybold Hochvakuum Anlagen | Freeze drying method and apparatus |
| FR1236607A (en) * | 1959-06-11 | 1960-07-22 | Centre Nat Rech Scient | Method and device for controlling and regulating the freezing and thawing of various substances, and in particular for controlling and regulating freezing-drying operations |
| AU135466A (en) * | 1966-02-08 | 1967-08-10 | Abbott Laboratories | Freese drying method and apparatus |
| GB1190319A (en) * | 1968-08-15 | 1970-05-06 | George Jarvis Tooby | Method for Dehydrating Materials |
| DE2104499A1 (en) * | 1971-02-01 | 1972-08-10 | Leybold Heraeus Gmbh & Co Kg | Control and / or monitoring of processes depending on the vapor pressure, especially in freeze drying |
| US3964174A (en) * | 1975-06-06 | 1976-06-22 | The Regents Of The University Of California | Controlled humidity freeze drying process |
| GB1587409A (en) * | 1976-10-04 | 1981-04-01 | Boc Ltd | Freeze drying |
| US4780964A (en) * | 1987-11-30 | 1988-11-01 | Fts Systems, Inc. | Process and device for determining the end of a primary stage of freeze drying |
| US5035065A (en) * | 1988-06-03 | 1991-07-30 | Parkinson Martin C | Method and apparatus using molecular sieves for freeze drying |
| US5154007A (en) * | 1989-08-17 | 1992-10-13 | Board Of Regents University Of Texas System | Method and apparatus for cryopreparing biological tissue |
| US5367786A (en) * | 1990-11-06 | 1994-11-29 | Jennings; Thomas A. | Method and apparatus for monitoring the processing of a material |
| FR2685065B1 (en) * | 1991-12-12 | 1994-03-04 | Guy Beurel | LYOPHILIZATION REGULATION PROCESS. |
| DE4334902C2 (en) * | 1993-10-13 | 1998-07-02 | Martin Christ Gefriertrocknung | Freeze dryer |
| FR2719656B1 (en) * | 1994-05-03 | 1996-07-26 | Agronomique Inst Nat Rech | Method and device for controlling lyophilization under vacuum. |
| BR9510380A (en) * | 1995-02-14 | 1998-06-02 | George Wilhelm Oetjen | Process for determining residual moisture during drying in a freeze-drying process |
-
1997
- 1997-05-07 DE DE19719398A patent/DE19719398A1/en not_active Withdrawn
-
1998
- 1998-04-21 DE DE59801008T patent/DE59801008D1/en not_active Expired - Lifetime
- 1998-04-21 WO PCT/EP1998/002335 patent/WO1998050744A1/en active IP Right Grant
- 1998-04-21 ES ES98922751T patent/ES2161532T3/en not_active Expired - Lifetime
- 1998-04-21 EP EP98922751A patent/EP0980503B1/en not_active Expired - Lifetime
- 1998-04-21 US US09/423,477 patent/US6163979A/en not_active Expired - Lifetime
- 1998-04-21 JP JP54766598A patent/JP2001525049A/en active Pending
- 1998-04-21 DK DK98922751T patent/DK0980503T3/en active
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102016215844A1 (en) | 2016-08-23 | 2018-03-01 | OPTIMA pharma GmbH | Method and apparatus for freeze drying |
| DE102016215844B4 (en) | 2016-08-23 | 2018-03-29 | OPTIMA pharma GmbH | Method and apparatus for freeze drying |
Also Published As
| Publication number | Publication date |
|---|---|
| DK0980503T3 (en) | 2001-10-22 |
| US6163979A (en) | 2000-12-26 |
| ES2161532T3 (en) | 2001-12-01 |
| DE59801008D1 (en) | 2001-08-16 |
| JP2001525049A (en) | 2001-12-04 |
| DE19719398A1 (en) | 1998-11-12 |
| WO1998050744A1 (en) | 1998-11-12 |
| EP0980503A1 (en) | 2000-02-23 |
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