EP0546932B1 - Process for controlling freeze drying - Google Patents
Process for controlling freeze drying Download PDFInfo
- Publication number
- EP0546932B1 EP0546932B1 EP92403332A EP92403332A EP0546932B1 EP 0546932 B1 EP0546932 B1 EP 0546932B1 EP 92403332 A EP92403332 A EP 92403332A EP 92403332 A EP92403332 A EP 92403332A EP 0546932 B1 EP0546932 B1 EP 0546932B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- trap
- shelves
- temperature
- water
- flow
- 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.)
- Expired - Lifetime
Links
Images
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 present invention relates to a new regulation method applied to lyophilization.
- Lyophilization very generally and schematically, is a sublimation drying process at very low temperature and very low pressure.
- Freeze-dryers are devices comprising a chamber in which the products to be treated are arranged, and next to it a set of vacuum and cold generating devices and pumps for circulation of heat transfer fluids.
- the chamber has an organ, called a trap; it is a surface element intended to receive the water coming from the products. It is brought to very low temperature by circulation of a refrigerating fluid.
- each shelf is a tray through which pass conduits inside which circulates a coolant so that all the shelves are at the same temperature.
- freeze-drying consists in establishing and maintaining, in the enclosure subjected to a predetermined pressure, between the trap and the shelves a difference in temperatures: there is an exchange of heat between the hot and cold sources which results in a transfer of water particles to the cold source.
- the frozen water evaporates without going through the state intermediate liquid: it is sublimation, and is deposited on the coldest surface in the form of crystals.
- the treatment consists of placing the products on the shelves, lowering the temperature of the shelves at a controlled speed in order to freeze them, then cooling the trap, then creating a vacuum in the chamber.
- the temperature difference between the shelves and the trap, for a given pressure, is sufficient, the sublimation of the water contained in the products begins.
- the shelves are then reheated to bring them to a temperature slightly lower than the eutectic point of the product, that is to say generally around -18 ° C. (this temperature varies according to the nature of the product and can therefore be quite different depending on the case).
- the temperature of the product is substantially constant. As soon as this is completed, that is to say when all the frozen water contained in the product has been transferred to the trap, the temperatures of the shelves and of the product rise.
- the end of the sublimation is measured by the evolution of the temperature of the shelves and controlled by time: throughout the duration of the sublimation the temperature of the shelves is kept constant by supply of energy: the shelves are heated to approximately -20 ° C. This supply of energy is consumed by the transfer of water and when the product is empty of water this energy raises its temperature.
- the shelves While maintaining the temperature of the trap at approximately -50 ° C, the shelves are heated to the temperature of approximately +30 ° C while the vacuum is pushed up to approximately a few Pascals (approximately 10-2 millibar). Under this rise in temperature combined with the drop in pressure, the bonds of the water particles are broken and the bound water evaporates and is transferred to the trap.
- a major difficulty in drying by lyophilization is the duration of the treatment which is several hours.
- the invention aims to resolve these drawbacks.
- the subject of the invention is a method for regulating a lyophilization installation comprising two contiguous enclosures communicating with each other, one provided with shelves intended to carry a product to be lyophilized, the other containing a trap. intended to receive the water contained in the product, and a set of pipes for circulation of the heat transfer fluids to cool the trap and to maintain the temperature of the shelves, the process being characterized in that continuously measuring the evaporative flow c ' is to say the flow of evaporated water transferred to the trap and we act on the temperature of shelves in order to get as close as possible to a predetermined optimal flow.
- the values of the heat fluxes of the shelves are compared, on the one hand to that of the trap, on the other hand in order to refine the measurements.
- this process makes it possible to know at all times the real flow rate of the water received by the trap and therefore the speed of sublimation.
- the device also includes a vacuum pump not shown in the diagram.
- the products are first placed on the shelves at a temperature of around 20 ° C. Their rapid freezing is carried out with the primary circuit.
- the supply of shelves with primary fluid is cut off and they are supplied with secondary fluid; the trap is supplied with primary fluid and a vacuum is created and communication between the speakers is opened.
- the inlet 15 and outlet 16 temperatures of the trap and the flow 17 of the fluid passing through it are measured continuously, on the other hand, the inlet and outlet temperatures 18 and 19 of the secondary fluid passing through the shelves. as well as its flow 20.
Landscapes
- 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)
Description
La présente invention concerne un nouveau procédé de régulation appliqué à la lyophilisation.The present invention relates to a new regulation method applied to lyophilization.
La lyophilisation, d'une manière très générale et schématique, est un procédé de séchage par sublimation à très basse température et très faible pression.Lyophilization, very generally and schematically, is a sublimation drying process at very low temperature and very low pressure.
Les lyophilisateurs sont des appareils comportant une chambre dans laquelle sont disposés les produits à traiter, et à côté un ensemble d'appareils générateurs de vide, et de froid et des pompes de circulation des fluides caloporteurs. La chambre comporte un organe, appelé piège; c'est un élément de surface destiné à recevoir l'eau provenant des produits. Il est porté à très basse température par circulation d'un fluide frigorifique.Freeze-dryers are devices comprising a chamber in which the products to be treated are arranged, and next to it a set of vacuum and cold generating devices and pumps for circulation of heat transfer fluids. The chamber has an organ, called a trap; it is a surface element intended to receive the water coming from the products. It is brought to very low temperature by circulation of a refrigerating fluid.
Les produits sont posés sur des étagères régulièrement réparties dans tout le volume de la chambre, et chaque étagère est un plateau dans lequel passent des conduites à l'intérieur desquelles circule un fluide de refroidissement de sorte que toutes les étagères soient à la même température.The products are placed on shelves regularly distributed throughout the volume of the room, and each shelf is a tray through which pass conduits inside which circulates a coolant so that all the shelves are at the same temperature.
Le principe de la lyophilisation consiste à établir et maintenir, dans l'enceinte soumise à une pression prédéterminée, entre le piège et les étagères une différence de températures : il se produit un échange de chaleur entre les sources chaudes et froides qui se traduit par un transfert des particules d'eau sur la source froide.The principle of freeze-drying consists in establishing and maintaining, in the enclosure subjected to a predetermined pressure, between the trap and the shelves a difference in temperatures: there is an exchange of heat between the hot and cold sources which results in a transfer of water particles to the cold source.
Lorsque les températures sont très basses, très inférieures au point de solidification (entre environ - 20°C et - 50°C), et à très faible pression (quelques pascals), l'eau gelée s'évapore sans passer par l'état liquide intermédiaire : c'est la sublimation, et se dépose sur la surface la plus froide sous forme de cristaux.When the temperatures are very low, far below the solidification point (between - 20 ° C and - 50 ° C), and at very low pressure (a few pascals), the frozen water evaporates without going through the state intermediate liquid: it is sublimation, and is deposited on the coldest surface in the form of crystals.
Le choix des pressions et températures est déterminé de telle sorte que l'on se trouve toujours sous le point de changement d'état de l'eau: le transfert se réalise par différence des tensions de vapeur.The choice of pressures and temperatures is determined so that one is always under the point change of state of the water: the transfer takes place by difference of the vapor pressures.
Le traitement consiste à placer les produits sur les étagères, à baisser à vitesse contrôlée la température des étagères afin de les congeler puis à refroidir le piège en faisant ensuite le vide dans la chambre. Lorsque l'écart de température entre les étagères et le piège, pour une pression donnée, est suffisant la sublimation de l'eau contenue dans les produits commence.The treatment consists of placing the products on the shelves, lowering the temperature of the shelves at a controlled speed in order to freeze them, then cooling the trap, then creating a vacuum in the chamber. When the temperature difference between the shelves and the trap, for a given pressure, is sufficient, the sublimation of the water contained in the products begins.
En outre et de manière connue il est nécessaire d'entretenir dans la chambre un débit de fuite d'air, réglable.In addition and in a known manner, it is necessary to maintain an adjustable air leakage rate in the chamber.
Les courbes représentées en annexe montrent l'évolution des températures et de la pression dans la chambre en fonction du temps, dans le cas d'un exemple de lyophilisation réalisé sur des produits pharmaceutiques:
- la première étape est celle de la congélation des produits (a) et refroidissement du piège (d) : afin d'assurer une bonne et complète congélation, c'est à dire dans toute la profondeur du produit on refroidit les étagères (b) à la température d'environ -45°C; la vitesse de ce refroidissement est contrôlée afin d'éviter l'apparition de tensions sur les parois des cellules de matières organiques vivantes, entre d'un côté l'eau et de l'autre la glace, tensions qui déchirent et détruisent lesdites cellules.
- the first stage is that of freezing the products (a) and cooling the trap (d): in order to ensure good and complete freezing, that is to say throughout the entire depth of the product, the shelves (b) are cooled to the temperature of about -45 ° C; the speed of this cooling is controlled in order to avoid the appearance of tensions on the walls of the cells of living organic matter, between water on the one side and ice on the other, tensions which tear and destroy said cells.
On réchauffe ensuite les étagères pour les porter à une température légèrement inférieure au point eutectique du produit, soit généralement à environ -18°C (cette température varie en fonction de la nature du produit et peut donc être assez différente selon les cas).The shelves are then reheated to bring them to a temperature slightly lower than the eutectic point of the product, that is to say generally around -18 ° C. (this temperature varies according to the nature of the product and can therefore be quite different depending on the case).
Lorsque les étagères atteignent leur températures la plus basse on refroidit le piège.When the shelves reach their lowest temperature, the trap is cooled.
Pendant le chauffage des étagères on met en marche la pompe à vide (c).
- la seconde étape, c'est à dire la sublimation, commence pratiquement dès le début de la mise sous vide.
- the second step, ie sublimation, begins practically from the start of the vacuum.
Pendant toute la durée de la sublimation, la température du produit est sensiblement constante. Dès que celle-ci est achevée, c'est à dire lorsque toute l'eau gelée contenue dans le produit a été transférée sur le piège, les températures des étagères et du produit montent.Throughout the duration of the sublimation, the temperature of the product is substantially constant. As soon as this is completed, that is to say when all the frozen water contained in the product has been transferred to the trap, the temperatures of the shelves and of the product rise.
En pratique la fin de la sublimation est mesurée par l'évolution de la température des étagères et contrôlée par le temps: pendant toute la durée de la sublimation la température des étagères est maintenue constante par apport d'énergie: on chauffe les étagères à environ -20 °C. Cet apport d'énergie est consommé par le transfert de l'eau et lorsque le produit est vide d'eau cette énergie élève sa température.In practice, the end of the sublimation is measured by the evolution of the temperature of the shelves and controlled by time: throughout the duration of the sublimation the temperature of the shelves is kept constant by supply of energy: the shelves are heated to approximately -20 ° C. This supply of energy is consumed by the transfer of water and when the product is empty of water this energy raises its temperature.
En réalité il reste une petite quantité d'eau, que l'on appelle "l'eau liée". Ce sont des particules d'eau qui restent comme accrochées aux éléments solides par des ponts ou champs électriques.
- cette "eau liée" est éliminée dans la troisième phase dite de désorption.
- this "bound water" is eliminated in the third so-called desorption phase.
Pendant que l'on maintient la température du piège à environ -50 °C, les étagères sont chauffées jusqu'à la température d'environ +30 °C pendant que le vide est poussé jusqu'à environ quelques Pascals (environ 10-2 millibar). Sous cette élévation de température conjuguée à la baisse de pression les liaisons des particules d'eau sont brisées et l'eau liée s'évapore et est transférée sur le piège.While maintaining the temperature of the trap at approximately -50 ° C, the shelves are heated to the temperature of approximately +30 ° C while the vacuum is pushed up to approximately a few Pascals (approximately 10-2 millibar). Under this rise in temperature combined with the drop in pressure, the bonds of the water particles are broken and the bound water evaporates and is transferred to the trap.
Une difficulté importante de la dessiccation par lyophilisation est la durée du traitement qui est de plusieurs heures. On essaie donc de trouver des écarts de températures, c'est à dire des différences de tensions de vapeur entre le piège et le produit optimales pour une pression déterminée régnant dans la chambre et une température du piège fixée de manière à réduire le plus possible le temps de traitement.A major difficulty in drying by lyophilization is the duration of the treatment which is several hours. We therefore try to find differences in temperature, that is to say differences in voltage steam between the trap and the product optimal for a determined pressure prevailing in the chamber and a temperature of the trap fixed so as to reduce the treatment time as much as possible.
Il est très difficile de déterminer ces conditions optimales car elles dépendent en grande partie du produit que l'on traite. Lorsqu'il s'agit de produits pharmaceutiques, leur coût est tel que l'on ne peut pas réaliser des études sur des échantillons. Jusqu'à présent on pallie cet inconvénient en réalisant des relevés de mesures statistiques qui sont reproductibles. Il est en effet indispensable de pouvoir reproduire le même traitement à plusieurs lots successifs d'un même produit, de manière à obtenir exactement le même produit final.It is very difficult to determine these optimal conditions because they depend largely on the product being treated. In the case of pharmaceutical products, their cost is such that studies on samples cannot be carried out. Up to now, this drawback has been remedied by carrying out reproducible statistical measurements. It is indeed essential to be able to reproduce the same treatment in several successive batches of the same product, so as to obtain exactly the same final product.
La durée du traitement peut être réduite en accélérant la sublimation par augmentation des différences de températures entre le piège et les étagères. Cependant on se heurte à deux problèmes majeurs:
- il est plus facile et moins coûteux d'augmenter la température des étagères que d'abaisser celle du piège déjà très basse, mais on est limité par la température de fusion : au dessus de cette température seuil l'eau sublimée se liquéfie et il n'y a plus de transfert vers le piège.
- la sublimation est plus rapide au début du traitement car elle commence toujours par l'eau qui se trouve en surface puis elle descend progressivement dans la profondeur et le temps de parcours de l'eau contenue dans les couches inférieures jusqu'à la surface allonge la durée du transfert. La durée du traitement dépend donc de la hauteur du produit contenu dans les récipients, et également de la surface d'échange supérieure.
- it is easier and less expensive to increase the temperature of the shelves than to lower that of the already very low trap, but we are limited by the melting temperature: above this threshold temperature the sublimated water liquefies and it doesn there is more transfer to the trap.
- sublimation is faster at the start of treatment because it always begins with the water on the surface, then it gradually descends into the depth and the travel time of the water contained in the lower layers to the surface lengthens the duration of transfer. The duration of the treatment therefore depends on the height of the product contained in the containers, and also on the upper exchange surface.
Lorsque la distance que la vapeur doit parcourir à travers le produit devient importante la sublimation se ralentit et on l'accélère en augmentant la température des étagères avec le risque exposé précédemment de se situer au delà de la température de fusion.When the distance that the vapor has to travel through the product becomes significant, the sublimation slows down and it is accelerated by increasing the temperature of the shelves with the risk described above of being above the melting temperature.
En outre lorsque la sublimation est trop rapide il peut se produire une dégradation du produit par érosion de la matière: les particules s'échappent trop rapidement et brisent les cellules constituant le produit. Et les produits défectueux doivent être éliminés.In addition, when the sublimation is too rapid, degradation of the product can occur due to erosion of the material: the particles escape too quickly and break down the cells constituting the product. And defective products must be eliminated.
Cette perte est d'autant plus coûteuse que les produits sont chers.This loss is all the more expensive as the products are expensive.
En pratique la seule solution retenue jusqu'à maintenant est de conserver entre les étagères et le produit une différence de températures constante jusqu'à la fin de l'étape de sublimation (caractérisée par une augmentation de la température du produit). Mais cette solution ne permet pas de maîtriser réellement la vitesse de la sublimation, et elle ne permet pas de changer la nature du produit ou simplement la forme des récipients, c'est a dire la surface d'échange.In practice, the only solution retained so far is to keep a constant temperature difference between the shelves and the product until the end of the sublimation stage (characterized by an increase in the temperature of the product). But this solution does not really control the speed of sublimation, and it does not change the nature of the product or simply the shape of the containers, ie the exchange surface.
Le document US-A-3.487.554 décrit une installation de lyophilisation de ce type.The document US-A-3,487,554 describes a freeze-drying installation of this type.
L'invention a pour objectif de résoudre ces inconvénients.The invention aims to resolve these drawbacks.
L'invention a pour objet un procédé de régularisation d'une installation de lyophilisation comportant deux enceintes contigües communiquant l'une avec l'autre, l'une munie d'étagères destinées à porter un produit à lyophiliser, l'autre contenant un piège destiné a recevoir l'eau contenue dans le produit, et un ensemble de conduites de circulation des fluides caloporteurs pour refroidir le piège et pour maintenir la température des étagères, le procédé étant carctérisé en ce qu'en continu on mesure le flux évaporatoire c'est a dire le débit d'eau évaporée transférée sur le piège et on agit sur la température des étagères afin de se rapprocher le plus possible d'un flux optimal prédéterminé.The subject of the invention is a method for regulating a lyophilization installation comprising two contiguous enclosures communicating with each other, one provided with shelves intended to carry a product to be lyophilized, the other containing a trap. intended to receive the water contained in the product, and a set of pipes for circulation of the heat transfer fluids to cool the trap and to maintain the temperature of the shelves, the process being characterized in that continuously measuring the evaporative flow c ' is to say the flow of evaporated water transferred to the trap and we act on the temperature of shelves in order to get as close as possible to a predetermined optimal flow.
Des modes particuliers de réalisation de l'invention sont encore remarquables par les caractéristiques suivantes:
- on établit en continu le bilan thermique des étagères vers le piège en mesurant:
- . la différence de températures du fluide caloporteur entre l'entrée et la sortie des étagères,
- . le débit du fluide circulant dans les étagères,
- . le débit de fuite d'air et la température de l'air entrant dans l'enceinte où se trouve le produit,
- the heat balance from the shelves to the trap is continuously established by measuring:
- . the temperature difference of the heat transfer fluid between the inlet and the outlet of the shelves,
- . the flow rate of the fluid circulating in the shelves,
- . the air leakage rate and the temperature of the air entering the enclosure where the product is located,
En variante le flux évaporatoire est mesuré à partir du bilan thermique calculé en continu sur le piège en mesurant:
- . la différence de températures du fluide caloporteur entre l'entrée et la sortie du piège,
- . le débit du fluide circulant dans le piège,
- . the temperature difference of the heat transfer fluid between the inlet and the outlet of the trap,
- . the flow rate of the fluid circulating in the trap,
Selon l'invention encore on compare les valeurs des flux thermiques des étagères, d'une part à celui du piège, d'autre part afin d'affiner les mesures.According to the invention also the values of the heat fluxes of the shelves are compared, on the one hand to that of the trap, on the other hand in order to refine the measurements.
Comme on le voit ce procédé permet de connaître à tout moment le débit réel de l'eau reçue par le piège et donc la rapidité de la sublimation.As can be seen, this process makes it possible to know at all times the real flow rate of the water received by the trap and therefore the speed of sublimation.
Ce procédé apporte de nombreux et très importants avantages:
- il permet d'indiquer dans quelle mesure il est possible d'augmenter la température des étagères par rapport au taux de sublimation maximal théorique, donné par le seuil de température de fusion .
- il permet de déterminer le débit optimal, pour un produit prédéterminé, au delà duquel des dégradations par érosion apparaissent;
- il permet de maîtriser les paramètres de fonctionnement et alors d'assurer la reproductibilité des cycles de traitement;
- il est applicable sur tous les lyophilisateurs, quelle que soit leur taille, aux constantes près des appareils (valeur en eau de l'appareil, débit d'air), et en rapportant le taux de sublimation par unité de surface;
- en outre il permet de connaître avec une meilleure précision le début et la fin de l'étape de sublimation.
- it indicates to what extent it is possible to increase the temperature of the shelves compared to the theoretical maximum sublimation rate, given by the melting temperature threshold.
- it makes it possible to determine the optimal flow rate, for a predetermined product, beyond which degradations by erosion appear;
- it makes it possible to control the operating parameters and then to ensure the reproducibility of the treatment cycles;
- it is applicable on all freeze-dryers, whatever their size, with the constants near the devices (water value of the device, air flow), and by reporting the rate of sublimation per unit area;
- in addition, it allows the beginning and end of the sublimation stage to be known with greater precision.
L'invention sera mieux comprise à l'aide de l'exemple de réalisation suivant accompagné d'un schéma d'une installation illustrée au dessin sur lequel :
- la figure 1 représente les courbes de fonctionnement;
- la figure 2 est le schéma selon l'invention.
- Figure 1 shows the operating curves;
- Figure 2 is the diagram according to the invention.
Sur ce schéma l'installation comporte
- une première enceinte 1 dans laquelle les produits sont disposés. Cette enceinte comporte une pluralité d'étagères métalliques 2 traversées par des conduites de circulation de fluides caloporteurs;
la première enceinte 1 communique avec une seconde 3 dans laquelle se trouve le piège 4. Celui-ci est essentiellement constitué d'au moins un élément de surface 5 de grande taille, métallique, traversé aussi par des conduites de circulation de fluides caloporteurs. La communication entre les deux enceintes se fait par une conduite 6 dont l'ouverture est contrôléepar une vanne 7.
- a
first enclosure 1 in which the products are arranged. This enclosure comprises a plurality ofmetal shelves 2 crossed by pipes for circulation of heat transfer fluids; - the
first enclosure 1 communicates with a second 3 in which the trap 4 is located. The latter essentially consists of at least one large surface element 5, metallic, also traversed by pipes for circulation of heat transfer fluids. Communication between the two enclosures is via a line 6, the opening of which is controlled by avalve 7.
Deux circuits de circulation de fluide caloporteur sont prévus:
- un premier circuit 8 de production de froid qui alimente en parallèle et indépendamment le piège 4, et les étagères 2; il comporte une pompe de
circulation 9 et une ou plusieurs (deux dans le schéma) unités 10 de production de froid disposées en parallèle, ce qui permet d'adapter la production de froid à la demande et surtout d'intervenir immédiatement en cas de panne d'une unité; ce circuit permet d'obtenir des température de -50 °C à -70 °C. un deuxième circuit 11 de production de froid et de chaleur qui alimente, également en parallèle et indépendamment, les étagères et le piège. Il comporte une pompe decirculation 12 et un échangeur de chaleur 13 pour la production de froid etun réchauffeur 14; ce circuit permet d'obtenir des températures allant de -30°C à +40°C.
- a first cold production circuit 8 which supplies the trap 4 and the
shelves 2 in parallel and independently; it includes acirculation pump 9 and one or more (two in the diagram)cold production units 10 arranged in parallel, which makes it possible to adapt cold production to demand and above all to intervene immediately in the event of a breakdown of a unit; this circuit makes it possible to obtain temperatures from -50 ° C to -70 ° C. - a
second circuit 11 for producing cold and heat which supplies, also in parallel and independently, the shelves and the trap. It comprises acirculation pump 12 and aheat exchanger 13 for the production of cold and aheater 14; this circuit makes it possible to obtain temperatures ranging from -30 ° C to + 40 ° C.
Le dispositif comporte en outre une pompe à vide non représentée sur le schéma.The device also includes a vacuum pump not shown in the diagram.
L'installation fonctionne de la manière suivante:The installation works as follows:
Les produits sont préalablement posés sur les étagères à température de 20°C environ. Leur congélation rapide est réalisée avec le circuit primaire.The products are first placed on the shelves at a temperature of around 20 ° C. Their rapid freezing is carried out with the primary circuit.
En fin de congélation on coupe l'alimentation des étagères en fluide primaire et on les alimente avec le fluide secondaire; on alimente le piège en fluide primaire et on fait le vide et on ouvre la communication entre les enceintes.At the end of freezing, the supply of shelves with primary fluid is cut off and they are supplied with secondary fluid; the trap is supplied with primary fluid and a vacuum is created and communication between the speakers is opened.
On mesure en continu, d'une part les températures d'entrée 15 et sortie 16 du piège et le débit 17 du fluide qui le traverse, d'autre part les températures 18 d'entrée et 19 de sortie du fluide secondaire traversant les étagères ainsi que son débit 20.The
Ces données introduites en continu dans un calculateur donne le flux évaporatoire et permettent à l'opérateur d'agir sur les températures par comparaison à un flux optimal prédéterminé.These data, introduced continuously into a computer, give the evaporative flow and allow the operator to act on the temperatures by comparison with a predetermined optimal flow.
En fin de sublimation on inverse le fonctionnement du circuit secondaire qui réchauffe rapidement les étagères et les porte à la température d'environ 30°C.At the end of sublimation, the operation of the secondary circuit is reversed, which quickly heats the shelves and brings them to the temperature of around 30 ° C.
Claims (3)
- A method for regulating a freeze-drying installation comprising two adjacent chambers which communicate with each other, one (1) provided with shelves (2) intended to bear a product to be freeze-dried, the other (3) containing a trap (4) intended to receive the water contained in the product, and a set of pipes, (8, 11) for circulating the heat transfer fluids for cooling the trap (4) and for maintaining the temperature of the shelves (2), the process being characterised in that the evaporative flow, that is to say the flow of evaporated water transferred to the trap (4), is measured continuously, and the temperature of the shelves (2) is adjusted so as to keep as close as possible to a predetermined optimum flow.
- A regulation process according to Claim 1, characterised by the fact that the heat balance of the shelves towards the trap is established continuously by measuring:. the difference in temperatures of the heat transfer fluid between the entrance to and the exit from the shelves,. the flow of the fluid circulating in the shelves,. the leakage rate of air and the temperature of the air entering the enclosure in which the products are located,by converting this information into quantities of energy per unit of time, and by taking into account the heat input of the pumps for circulating the heat transfer fluid, then this energy balance is converted into weight of water, which gives the quantity of water transferred per unit of time, namely the instantaneous rate of sublimation or evaporative flow.
- A regulation method according to Claim 1, characterised by the fact that the evaporative flow is measured from the heat balance calculated continuously at the trap by measuring:. the difference in temperature of the heat transfer fluid between the entrance to and the exit from the trap,. the rate of flow of fluid circulating in the trap,by converting this information into quantities of energy per unit of time, and by deducting the heat input of the pumps for circulating the heat transfer fluid of the trap, the value of water of the freeze-dryer and the value of water of the air entering the chamber via the escape orifice.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9115462 | 1991-12-12 | ||
| FR919115462A FR2685065B1 (en) | 1991-12-12 | 1991-12-12 | LYOPHILIZATION REGULATION PROCESS. |
| US08/075,651 US5428905A (en) | 1991-12-12 | 1993-06-11 | Process for the regulation of lyophilization |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0546932A1 EP0546932A1 (en) | 1993-06-16 |
| EP0546932B1 true EP0546932B1 (en) | 1995-09-27 |
Family
ID=26229114
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP92403332A Expired - Lifetime EP0546932B1 (en) | 1991-12-12 | 1992-12-09 | Process for controlling freeze drying |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US5428905A (en) |
| EP (1) | EP0546932B1 (en) |
| JP (1) | JPH06180181A (en) |
| CA (1) | CA2085071A1 (en) |
| FR (1) | FR2685065B1 (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2719656B1 (en) * | 1994-05-03 | 1996-07-26 | Agronomique Inst Nat Rech | Method and device for controlling lyophilization under vacuum. |
| DE19719398A1 (en) * | 1997-05-07 | 1998-11-12 | Amsco Finn Aqua Gmbh | Process for controlling a freeze-drying process |
| US6122836A (en) * | 1998-05-07 | 2000-09-26 | S.P. Industries, Inc., The Virtis Division | Freeze drying apparatus and method employing vapor flow monitoring and/or vacuum pressure control |
| EP1563237A2 (en) * | 2002-11-21 | 2005-08-17 | Transform Pharmaceuticals, Inc. | Freeze-drying microscope stage apparatus and process of using the same |
| US7089681B2 (en) * | 2002-11-26 | 2006-08-15 | Alkermes Controlled Therapeutics, Inc. | Method and apparatus for filtering and drying a product |
| US6935049B2 (en) * | 2003-12-24 | 2005-08-30 | Edward K. Alstat | Method and apparatus for reclaiming effluent from a freeze-drying process, and uses for effluent |
| DE102004007526A1 (en) * | 2004-02-17 | 2005-09-01 | Oetjen, Georg-Wilhelm, Dr. | Method and device for the freeze-drying of products |
| US7347004B1 (en) | 2005-01-13 | 2008-03-25 | Lyophilization Services Of New England, Inc. | Freeze drying apparatus and method |
| CN101614469B (en) * | 2009-07-30 | 2010-10-06 | 上海东富龙科技股份有限公司 | Full-automatic intelligent vacuum freeze dryer |
| US9121637B2 (en) | 2013-06-25 | 2015-09-01 | Millrock Technology Inc. | Using surface heat flux measurement to monitor and control a freeze drying process |
| US9863699B2 (en) * | 2014-06-09 | 2018-01-09 | Terumo Bct, Inc. | Lyophilization |
| US10605527B2 (en) | 2015-09-22 | 2020-03-31 | Millrock Technology, Inc. | Apparatus and method for developing freeze drying protocols using small batches of product |
| ES2774058T3 (en) * | 2017-04-21 | 2020-07-16 | Gea Lyophil Gmbh | A lyophilizer and a method of inducing nucleation in products |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1286002A (en) * | 1961-01-17 | 1962-03-02 | Usifroid | Process for the regulation of freezing-drying operations and installation for its implementation |
| US3487554A (en) * | 1965-09-23 | 1970-01-06 | George Tooby | Method and apparatus for dehydrating materials |
| US3466756A (en) * | 1967-11-06 | 1969-09-16 | George Tooby | Method for dehydrating materials |
| SU953396A1 (en) * | 1979-05-08 | 1982-08-23 | Всесоюзный Научно-Исследовательский Биотехнический Институт | Method of determining material sublimitation heat |
-
1991
- 1991-12-12 FR FR919115462A patent/FR2685065B1/en not_active Expired - Fee Related
-
1992
- 1992-12-09 EP EP92403332A patent/EP0546932B1/en not_active Expired - Lifetime
- 1992-12-10 CA CA002085071A patent/CA2085071A1/en not_active Abandoned
- 1992-12-11 JP JP4353130A patent/JPH06180181A/en active Pending
-
1993
- 1993-06-11 US US08/075,651 patent/US5428905A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| FR2685065A1 (en) | 1993-06-18 |
| JPH06180181A (en) | 1994-06-28 |
| US5428905A (en) | 1995-07-04 |
| FR2685065B1 (en) | 1994-03-04 |
| CA2085071A1 (en) | 1993-06-13 |
| EP0546932A1 (en) | 1993-06-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0546932B1 (en) | Process for controlling freeze drying | |
| EP0163579B1 (en) | Method and apparatus for freezing the soil | |
| FR2461213A1 (en) | VACUUM APPARATUS, IN PARTICULAR FOR THE PRESERVATION OF FOOD PRODUCTS | |
| EP0730719A1 (en) | Refrigerating exchanger, method for controlling same, and refrigeration facility comprising said exchanger | |
| FR2694076A1 (en) | Refrigeration system and its operating method. | |
| FR2715211A1 (en) | Method of operating a refrigeration system and refrigeration system operating according to this method. | |
| CH642158A5 (en) | AIR COOLING DEVICE. | |
| FR2715213A1 (en) | Method and apparatus for operating a refrigeration system, characterized by regulating the maximum operating pressure. | |
| FR2689064A1 (en) | Operating method for operating a compartmentalized means of transport refrigeration system. | |
| FR2715212A1 (en) | Method and apparatus for operating a refrigeration system, characterized by regulation of the engine coolant. | |
| FR2533679A1 (en) | HEATED CABINET | |
| FR2533270A1 (en) | PROCESS AND DEVICE FOR THE RAPID REGENERATION OF AUTONOMOUS CRYOGENIC PUMPS | |
| FR2549585A1 (en) | Evaporator for an installation with a closed thermodynamic loop for the flow of a working fluid, and installation incorporating this evaporator | |
| EP0506498A1 (en) | Steam cooking apparatus for food products | |
| CH658122A5 (en) | REFRIGERATION APPARATUS AND REFRIGERATION TRAP COMPRISING SUCH AN APPARATUS. | |
| EP2739918B1 (en) | System and method for optimising the operation of a heat pump system | |
| FR2844035A1 (en) | Extraction and ejection system for water vapour in pressurised air inside a spacecraft has evaporator with decompression chamber and control unit | |
| EP0076759B1 (en) | Apparatus for continuously determining the heating value of gases | |
| FR2928907A1 (en) | BEVERAGE DISPENSING APPARATUS PROVIDED WITH A HEAT-BUILDING ELEMENT | |
| FR2831950A1 (en) | Fluid temperature regulator has casing with internal fins to increase heat exchange rate between chamber and flow duct | |
| EP0546931B1 (en) | Freeze drying apparatus | |
| FR2503333A1 (en) | METHOD AND APPARATUS FOR HEAT PRODUCTION | |
| EP1101071B1 (en) | Method for removing ice crystals in a heat exchanger generating a diphasic liquid-solid refrigerant | |
| FR2831949A1 (en) | Phase change material fluid temperature regulator has casing containing material with internal plates for increased heat exchange | |
| EP3194874B1 (en) | Heat pipe and method for making a heat pipe |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): BE CH DE FR GB IT LI NL |
|
| 17P | Request for examination filed |
Effective date: 19931210 |
|
| 17Q | First examination report despatched |
Effective date: 19940720 |
|
| GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
| AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): BE CH DE FR GB IT LI NL |
|
| REF | Corresponds to: |
Ref document number: 69205128 Country of ref document: DE Date of ref document: 19951102 |
|
| ITF | It: translation for a ep patent filed |
Owner name: SAIC BREVETTI S.R.L. |
|
| GBT | Gb: translation of ep patent filed (gb section 77(6)(a)/1977) |
Effective date: 19951216 |
|
| PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
| 26N | No opposition filed | ||
| REG | Reference to a national code |
Ref country code: GB Ref legal event code: IF02 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: CH Payment date: 20031218 Year of fee payment: 12 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20041231 Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20041231 |
|
| REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: NL Payment date: 20061215 Year of fee payment: 15 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GB Payment date: 20061220 Year of fee payment: 15 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: IT Payment date: 20061231 Year of fee payment: 15 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: BE Payment date: 20070103 Year of fee payment: 15 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: DE Payment date: 20070228 Year of fee payment: 15 |
|
| BERE | Be: lapsed |
Owner name: *BEUREL GILLES Effective date: 20071231 Owner name: *BEUREL SERGE Effective date: 20071231 Owner name: *BEUREL GUY Effective date: 20071231 |
|
| GBPC | Gb: european patent ceased through non-payment of renewal fee |
Effective date: 20071209 |
|
| NLV4 | Nl: lapsed or anulled due to non-payment of the annual fee |
Effective date: 20080701 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20071231 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20080701 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20080701 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GB Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20071209 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20071209 |
|
| PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 20100122 Year of fee payment: 18 |
|
| REG | Reference to a national code |
Ref country code: FR Ref legal event code: ST Effective date: 20110831 |
|
| PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20110103 |