EP0546931B1 - Freeze drying apparatus - Google Patents

Description

Lyophilization devices are installations intended to dry products, generally organic, by sublimation at very low temperature and very low pressure.

Freeze-dryers are devices comprising two enclosures: a first, in which the products to be treated are arranged and next to it, a second in which is arranged an organ called a trap, intended to receive the water coming from the products. The installation also includes a set of vacuum and cold generating apparatuses and circulation pumps for heat transfer fluids which carry the shelves and the trap at determined temperatures causing sublimation.

A freeze-drying installation of this type is described in document FR-A-2,461,213
In known installations, the temperatures in the chambers are regulated separately by two independent heat and / or cold production circuits. The enclosure, where the products are stored, or desiccation enclosure is crossed by a first circuit supplied with a refrigerating liquid such as that marketed under the name "Freon" and regulated in temperature by a production center for cold and hot of so as to ensure the cooling of the shelves and the freezing of the product, then to heat them to bring the product to the temperatures of primary lyophilization (approximately - 20 ° C) and secondary (approximately 30 ° C).

The enclosure where the trap is located is crossed by a second circuit supplied with a silicone liquid and temperature controlled by a plurality of power stations arranged in parallel, each comprising in known manner a condenser and a Freon exchanger. The choice of different refrigerants is mainly due to the fact that the performance requirements of the circuits are different: the first circuit must both drop to a very low temperature (around -45 to -50 ° C for freezing) but for a short time duration, and high (+ 30 ° C) while the second must ensure only a very low temperature (around -50 to -70 ° C) and this for several hours.

The advantage of such a device is that it is possible to choose refrigeration devices that precisely respond to specific working conditions and offer an optimal performance ratio. The major drawback is that the first circuit is direct expansion and it is difficult to properly control the heat exchange in the first enclosure, that is to say, lyophilization.

However, it turns out, for certain products and in particular pharmaceuticals or the like, that it is not only the drying which is important but the fact that this drying takes place under constant conditions.

Consequently, the problem is no longer the search for an optimal production cost, which is obtained with separate refrigeration circuits, but the search for a device allowing the control of the physical conditions (temperature, pressure) of the desiccation.

There is known a desiccation device comprising a single refrigerant, more precisely a fluid called R11; this device described in patent US-A-3 656 240, includes a cold generator which supplies the two speakers in parallel. Each portion of the circuit has a circulation pump which allows the flow rate in each enclosure to be controlled, but this installation does not allow precise control of heat exchanges. Furthermore, the liquid used cannot be brought to a high temperature above 60 ° C. while maintaining low pressures, of the order of atmospheric pressure. It is therefore impossible to sterilize the speakers with R11 fluid.

However, the desiccation chambers used for very delicate products such as pharmaceuticals must imperatively be free from any equivalent bacteria or pathogenic particle, which is obtained by hot sterilization.

The device of US-A-3,656,240 cannot therefore be used.

The object of the invention is to solve the above drawbacks in order to produce a very precise device for regulating heat production by using a device of the type described in US Pat. No. 3,656,240, that is to say using a the same fluid throughout the installation.

• deux enceintes contiguës communiquant l'une avec l'autre, l'une de dessiccation munie d'étagères destinées à porter le produit à lyophiliser, l'autre contenant un piège destinée à recevoir l'eau contenue dans le produit,
• un ensemble de conduites de circulation de fluide caloporteur reliées entre elles et contenant un seul et même fluide caloporteur,

caractérisée en ce que

• le liquide caloporteur est un liquide silicone capable d'être mis à la température de 122°C au moins tout en restant à la pression d'environ 1000 pascals,
• l'installation comporte un circuit principal fermé comportant en série au moins un groupe frigorifique et une pompe de circulation de telle sorte que le fluide caloporteur circule en continu dans ce circuit,
• le circuit principal est destiné à alimenter au moins un groupe de lyophilisation,
• chaque groupe comporte en parallèle sur le circuit principal une dérivation primaire traversant le piège, et en parallèle une dérivation secondaire traversant les étagères,
• la dérivation secondaire est reliée en parallèle à une conduite munie d'un ensemble de régulation thermique et d'une pompe de circulation autonomes,
• la dérivation secondaire et la conduite forment un circuit secondaire, indépendant du circuit principal,

L'installation selon des modes particuliers de l'invention, et plus particulièrement appliquée au traitement des produits pharmaceutiques, est encore remarquable par les caractéristiques suivantes :

• le circuit principal comporte un réservoir de stockage destiné à assurer la régulation thermique de l'installation;
• elle comporte une dérivation entre les boucles primaires et secondaires de telle sorte que les étagères et le piège puissent être alimentés par l'ensemble secondaire de régulation thermique, en étant séparés du circuit principal.

The subject of the invention is a lyophilization installation of the type comprising:

• two contiguous enclosures communicating with each other, one of desiccation provided with shelves intended to carry the product to be lyophilized, the other containing a trap intended to receive the water contained in the product,
• a set of heat transfer fluid circulation pipes connected together and containing a single heat transfer fluid,

characterized in that

• the heat transfer liquid is a silicone liquid capable of being brought to the temperature of at least 122 ° C. while remaining at the pressure of approximately 1000 pascals,
• the installation comprises a closed main circuit comprising in series at least one refrigeration unit and a circulation pump so that the heat transfer fluid circulates continuously in this circuit,
• the main circuit is intended to supply at least one lyophilization group,
• each group comprises in parallel on the main circuit a primary bypass crossing the trap, and in parallel a secondary bypass crossing the shelves,
• the secondary bypass is connected in parallel to a pipe fitted with an autonomous thermal regulation assembly and circulation pump,
• the secondary bypass and the pipe form a secondary circuit, independent of the main circuit,

The installation according to particular modes of the invention, and more particularly applied to the treatment of pharmaceutical products, is also remarkable for the following characteristics:

• the main circuit includes a storage tank intended to ensure the thermal regulation of the installation;
• it includes a bypass between the primary and secondary loops so that the shelves and the trap can be supplied by the secondary thermal regulation assembly, being separated from the main circuit.

As a variant, the installation comprises two or two-n lyophilization groups, the drying chambers being contiguous in pairs and connected by a communication line controlled by a valve. This variant makes it possible to operate alternately on one or the other freeze-drying group and thus allows almost continuous production.

• la figure 1 est un schéma simplifié d'une première forme de réalisation de l'invention,
• la figure 2 est une variante de réalisation de l'invention.
• les figures 3a, 3b, 3c,3d illustrent les quatre phases principales du fonctionnement de l'installation selon l'invention.
• la figure 4 illustre une installation comportant deux groupes de lyophilisation en parallèle sur le circuit principal;
• la figure 5 illustre l'installation selon la figure 4, les groupes de lyophilisation étant accouplés pour un fonctionnement alterné.

In order to better understand the invention, a non-limiting example of the device according to the invention has been illustrated in the accompanying drawing:

• FIG. 1 is a simplified diagram of a first embodiment of the invention,
• Figure 2 is an alternative embodiment of the invention.
• Figures 3a, 3b, 3c, 3d illustrate the four main phases of the operation of the installation according to the invention.
• FIG. 4 illustrates an installation comprising two lyophilization groups in parallel on the main circuit;
• FIG. 5 illustrates the installation according to FIG. 4, the lyophilization groups being coupled for alternating operation.

In the drawing, it can be seen that the lyophilization installation mainly comprises two enclosures, the desiccation enclosure 1 comprising the shelves 5 on which the products to be dried are placed, and the enclosure 2 where the trap 6 is located, on which the the water contained in the products must migrate; enclosures 1 and 2 communicate via a pipe 3 controlled by a valve 4.

According to the invention, the installation comprises a main temperature regulation circuit 7 forming a closed circuit 7. This circuit includes a cold production unit 16 and a circulation pump 14 so that the temperature regulation in cold is continuous and independent. of any secondary circuit (lyophilization groups).

This main circuit 7 is intended to supply one or more lyophilization groups mounted in parallel.

So that the consumption of cold fluid from one lyophilization group does not have any consequence on the consumption of the other groups. the refrigeration energy reserve must be large. To this end, a tank is provided on the circuit.

On the other hand, the use of a single fluid for lyophilization and sterilization leads to choosing silicone fluids with very broad performances, for example in the family of dimethylsiloxane polymers, but which have a high viscosity which poses a problem at low temperatures.

According to the invention, this problem is solved by using, for the main circuit, large section pipes, diameter of the order of at least 100 millimeters, the pipe itself then constituting the heat reservoir.

In the variant of FIG. 1, the main circuit feeds a lyophilization group.

Each group comprises in parallel on the main circuit 7 a primary bypass 9 which passes through the trap, and a secondary bypass 8 which passes through the shelves.

The secondary bypass 8 is connected to the main circuit by the inlet 20 and outlet 21 pipes, each provided with isolation valves 10 and 12.

On this branch is installed in parallel a pipe 80 controlled by valves 81 and 82 comprising a circulation pump 13, a thermal regulation assembly (hot and cold) 15. When the valves 10 and 12 are closed and the valves 81 and 82 open, the lines 8 and 80 form a secondary circuit, independent of the main circuit 7.

The central control unit 15 includes a refrigeration unit 83 and a heater 84.

The main circuit 7 comprises in parallel a series of refrigeration production plants 16. This arrangement makes it possible both to remedy untimely damage to a power station during treatment and to have greater power flexibility, and consequently this arrangement makes it possible to supply several freeze-drying groups as shown in FIG. 4.

In the variant of FIG. 2, the installation comprises two pipes 85,86 controlled by valves 87,88 which connect the bypass supplying the trap to the secondary circuit. This extension is intended to use the thermal group 15 for reheating the trap and its discharge of water and for cooling the trap after sterilization.

In the variants of FIGS. 4 and 5, the installation comprises two freeze-drying groups mounted in parallel on the main pipe 7 and supplied by the refrigeration unit 16 and the pump 14.

In addition, in the installation according to FIG. 5, the drying chambers 1 and 1 ′ are mounted contiguous and there is provided between them a communication pipe 89 controlled by a set of valves 100. The secondary circuits are also interconnected so as to ensure identical thermal regulation in all the pipes.

The device operates in the following manner (in FIG. 3 the parts in strong lines are the active circuit elements):

Phase 1: freezing of the product (Figure 3a)

• the trap is isolated by closing the communication 4 between the speakers 1 and 2 and by isolating the bypass 9;
• the circulation pump 13 and the thermal power station 15 are isolated (valves 81.82 closed) and
• the shelves 5 are supplied with cold fluid with the main circuit 7 (through the openings of the valves 10 and 12).

Phase 2: lyophilization (Figure 3b)

• when the freezing is complete, the valves 10 and 12 are closed, the valves 81, 82 are opened: thus the secondary circuit 8,80 of the main circuit; we open the communication 4,
• the central heating 84 and the circulation pump 13 are started up, while the trap is supplied by the circulation of the fluid in the bypass 9;
• lyophilization comprises two primary and secondary stages; lyophilization is characterized in that raises the temperature of the product, which is done with the central 84.

When the secondary lyophilization is complete, the dry products are cooled with the cold plant 83.

Phase 3: emptying and sterilization

• on isole les étagères et le piège, du circuit principal 7 : vannes 10, 12, 90, 91 fermées et vannes 87, 88 ouvertes;
• on met en marche la centrale de chauffage 84, la chaleur dans le piège activant la fonte;
• on porte la chaleur dans le circuit a la température de 122°C et on l'y maintient pendant le temps suffisant pour assurer la stérilisation du piège et des étagères.

At the end of lyophilization, the dry products are removed from the drying enclosure (in a manner known per se) and then the trap is emptied of its ice. To this end (Figure 3c):

• the shelves and the trap are isolated from the main circuit 7: valves 10, 12, 90, 91 closed and valves 87, 88 open;
• the heating plant 84 is started, the heat in the trap activating the melting;
• the heat is brought into the circuit at a temperature of 122 ° C. and is maintained there for the time sufficient to ensure the sterilization of the trap and the shelves.

Phase n ° 4: cooling (figure 3d)

In order to avoid too long a cooling time and any thermal shock with the fluid at very low temperature of the main circuit 7, the fluid of the secondary loop is used for cooling: the trap of the main circuit is isolated and it is fed by extension 87.88 of the secondary circuit. The fluid in the secondary circuit 8, 80 is then cooled by the cooling unit 83.

• la régulation de la température des étagères est plus précise puisque l'on peut déterminer avec exactitude les températures entrante et sortante dans le piège et dans les étagères et contrôler les débits;
• la vitesse de sublimation de l'eau peut être contrôlée, cette vitesse dépendant de la température des étagères;
• après leur stérilisation préparatoire, le refroidissement des étagères et du piège est plus rapide et efficace;
• le refroidissement du produit, en fin de lyophilisation secondaire, peut être très rapide voire instantané en mélangeant les liquides des boucles primaires et secondaires.

As can be seen, the temperatures of the trap and of the shelves are regulated with a single and same fluid which circulates in a single circuit, provided with two temperature control units. This arrangement brings the following advantages:

• the regulation of the temperature of the shelves is more precise since it is possible to accurately determine the temperatures entering and leaving the trap and the shelves and controlling the flow rates;
• the speed of sublimation of the water can be controlled, this speed depending on the temperature of the shelves;
• after their preparative sterilization, the cooling of the shelves and of the trap is faster and more efficient;
• the cooling of the product, at the end of secondary lyophilization, can be very rapid or even instantaneous by mixing the liquids of the primary and secondary loops.

In addition, by eliminating the long Freon loop which usually feeds the shelves, the resulting problems are also eliminated, in particular the difficult oil returns, installation constraints and the Freon cost.

Claims (4)

1. A freeze-drying installation of the type comprising:

   - two adjacent chambers (1, 2) which communicate with each other, one (1) being a desiccation chamber provided with shelves (5) intended to bear the product to be freeze-dried, the other (2) containing a trap (6) intended to receive the water contained in the product,

   - a set of pipes for circulating heat transfer fluid, which are interconnected and contain a single heat transfer fluid,

   characterised in that

   - the heat transfer liquid is a silicone liquid capable of being brought to a temperature of 122°C at least while remaining at the pressure of approximately 1000 pascals,

   - the installation comprises a closed main circuit (7) comprising in series at least one refrigerating group (16) and a circulation pump (14) such that the heat transfer fluid circulates continuously in this circuit,

   - the main circuit (7) is intended to feed at least one freeze-drying group,

   - each group comprises in parallel on the main circuit (7) a primary branch (9) passing through the trap (6), and in parallel a secondary branch (8) passing through the shelves (5),

   - the secondary branch (8) is connected in parallel to a pipe (80) provided with an autonomic heat regulation unit (15) and an autonomic circulating pump (13),

   - the secondary branch (8) and the pipe (80) form a secondary circuit, independent of the main circuit (7).
2. A freeze-drying installation for pharmaceutical products according to Claim 1, characterised in that the main circuit (7) comprises a storage reservoir for ensuring the heat regulation of the installation.
3. An installation according to Claim 1, characterised in that it comprises a branch (85, 86) between the main circuit (7) and the secondary branch (8) such that the shelves (5) and the trap (6) can be fed by the secondary heat regulation unit (15), being separated from the main circuit (7).
4. An installation according to Claim 1, characterised in that it comprises two freeze-drying groups, the chambers (1, 1') bearing the shelves being adjacent and connected by a communicating pipe (89) controlled by a valve (100).

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