MXPA97007083A - Drying process and apparatus by congelac - Google Patents

Abstract

The present invention relates to a process for carrying out freeze drying of liquid material in a container, in which the containers are automatically moved through various process steps up to, and including subjecting to vacuum drying conditions, the process steps comprise: (a) loading grids with containers to be filled, so that the containers are kept separate in individual positions in the grids, each container comprises a container base and a vessel wall having an outer surface and an interior surface, (b) wash the containers and grids, the containers are in an inverted position so that the washing water will drain from them, (c) sterilize the containers and the grids, (d) fill the containers with material liquid to be frozen in them; (e) rotate the containers containing the liquid material to be frozen at a speed no less than required This is to maintain the liquid in a substantially uniform thickness cover against the inner surface of the container wall by the action of the centrifugal force while the liquid material is subjected to sufficient freezing conditions to freeze the material such as the cover, where the containers are removed from the racks and rotated away from the racks and after a pre-set time to complete the freezing, the rotation of the containers is stopped and returned to the racks, and (f) moving the racks with the containers that contain the material that has been kept frozen in individual positions inside and through a vacuum drying chamber to dry the material that has frozen

Description

PROCESS AND DRYING DEVICE BY FREEZING The present invention relates to a new process of freeze drying (lyophilization). This process is particularly advantageous for freeze drying pharmaceutical products. The invention also includes the lyophilized products produced by the process. Freeze drying or lyophilization is generally used to increase the stability and, therefore, the storage life of the materials. As such, it is particularly useful where it is known that a material is unstable or less stable in aqueous solution, as is often the case with pharmaceutical materials. In its simplest form, freeze drying consists of freezing the aqueous material in a jar and then subjecting the material to a vacuum and drying. The conventional method of freeze drying is to load all of the jars filled containers into chilled shelves in a sealed, freeze drying chamber. The shelf temperature is then reduced to freeze the product. At the end of the freezing period, the aqueous material REF: 25669 freezes like a plug in the bottom of the bottle. The pressure in the chamber is then reduced and simultaneously the shelves are heated causing the frozen water to sublime leaving a freeze-dried plug in the bottom of the bottle (Figure 4A). The complete lyophilization cycle normally takes 20 to 60 hours, depending on the product and the size of the bottle. The disadvantages of this conventional method are as follows: a) the time taken to freeze a product; b) the freeze drying process is in batches rather than continuous; c) except in automated, very sophisticated installations, human operators must necessarily load the jars' trays in the freeze-drying chamber, which leaves the product open to contamination; d) the process is exhaustive in energy when the power consumption of the clean room is taken into account; e) the freeze drying apparatus is very expensive and takes up a large area of space, which is necessarily very expensive because it must be kept clean or sterile to a high standard; f) the bottles are subjected to a number of discontinuous handling operations such as in-line, high-speed filling, transfer to holding tables, and transfer to and from trays. These operations expose the damage or contamination to the jars, create particles in the clean area, and require supervision by the operator. European Patent No. EP-A-0048194 for "freezing by lining" describes a method of material such that the resulting lyophilized product forms a relatively thin coating or "liner" in the bottle. In this method, the aqueous material is placed in a flask which is then slowly turned on its side in a freezing bath. The frozen product per liner is then loaded in a conventional lyophilization chamber and dried over a six-hour cycle (page 7). However, although this method results in, allegedly, a "liner-dried" material, the distribution may be non-uniform. Also, relatively long lyophilization times may be required. The above winding method also suffers from other disadvantages, which include: a) the amount of liquid that can be placed in the bottle is limited, since above a certain limit, some liquid would spill; b) there is a risk of spillage in any case during the winding process; c) winding in a liquid refrigerant may result in contamination by the refrigerant; d) this rolling process can result in a less uniform roll (giving a longer drying time); and e) a rolling process may result in a longer freezing time (compared to the present invention). U.S. Patent No. 3952541 describes an apparatus for freezing an aqueous solution or suspension, which comprises a refrigerated tank having at least one plate, which has the materials to be frozen, mounted on a shaft to rotate approximately 10 to 20 revolutions per minute around the base of the tank. The tank can be adjusted to tilt at a 45 ° angle (as an example) and a fan mounted inside the tank ceiling blows cold air around the cooled tank. Once the product is frozen, it appears that the jars would have to be transferred to a separate drying chamber, for approximately 11 1/2 hours. The complete lyophilization cycle takes 12 hours and the product obtained is of a paraboloidal shape, internally concave. The disadvantages of this process are that the time is still long (12 hours), the process must be operated in the form of batches and is not able to handle a large yield of jars. Additionally, when the open, frozen product is transferred from the refrigerated tank to a drying chamber, apparently a human operator must come into contact and the product must be kept in a frozen lid until it is transferred. British Patent No. 784784 describes a freeze drying process in which containers containing liquid material are subjected to a centrifugal force at a low vacuum. The low vacuum causes the water to be released and the effect of the centrifugation helps to suppress the formation of bubbles and foams as the liquid boils under reduced pressure. Both this step and the drying step comprise subjecting the container to traumatic operations that can cause particles in the clean area of the process, and breakage of the final product. Additional freeze-drying processes are described in British Patents Nos. 1199285 and 1370683, and the North American Patent No. 3769717. It is an object of the present invention to avoid or mitigate at least some of the disadvantages mentioned above. It is a further object of the invention to provide a lyophilization process and apparatus with shorter cycle times than the process and apparatus mentioned above. It is still a further object of the invention to provide the lyophilization apparatus that can be housed in a smaller space than the conventional freeze-drying apparatus and also preferably to eliminate the need for a human operator to come into contact in the parts critical of the process to minimize human contamination of the product. According to a first aspect of the present invention, there is provided a process for carrying out freeze drying including a freezing step for rotating around the longitudinal axis the container containing the liquid material to be freeze-dried. a speed not less than that to keep the liquid in a liner of substantially uniform thickness against the inner walls of the container by the action of the centrifugal force, while the liquid material is subjected to sufficient freezing conditions to freeze the liquid material in the liquid. shape of the aforementioned lining. Preferably, the bottles are rotated around their axes while remaining in the substantially horizontal position. This helps to achieve a uniform distribution of liquid around the interior of the container. The apparatus for carrying out the process of the first aspect of the invention forms the second aspect of the invention. Accordingly, the apparatus for rapid freezing of a liquid material contained in a sterilized container for subsequent drying is provided in a manner such that the liquid material forms a liner of substantially uniform thickness on the inner walls of the container; the apparatus comprising: a rotatable clamping means for retaining the container and rotating it about its longitudinal axis and capable of rotating at high speeds to maintain the liquid material against the inner walls of the container by the centrifugal force; a filling means for introducing the liquid material into the container; a freezing means for freezing the liquid in the form of a liner of substantially uniform thickness against the inner walls of the container; and a means of transport for moving the next container or containers in the position for filling and freezing. By the fastening means is meant a means for retaining the firm container, while rotating about its longitudinal axis. Preferably, the liquid material is aqueous. By aqueous material is meant aqueous solutions, suspensions or the like, preferably pharmaceutical products such as antibiotics vaccine, chemical drugs, organics, enzymes or serum. However, the invention can be used to freeze material dissolved or dispersed in a solvent other than water. By substantially uniform thickness of the liner is meant in this way that the thickness varies less than about 5% of the average thickness from the top to the bottom of the container. By this it is meant that it includes the average thickness of the liner measured at the midpoint between any of the local peaks or valleys on the surface of the liner, caused for example by the dynamic interactions of the fluid between the liquid and the freezing gas during the freezing process. The invention (of the first and second aspect) can be applied to large containers of the liquid material, but preferably the containers are flasks or other such as small containers, such as of a diameter of about 10 to 40 mm and a plurality of these bottles are they fill and freeze simultaneously. This is the type of container used in the pharmaceutical industry to carry at least one unit dose of drug. The drug is then reconstituted in water before administration to the patient. The uniformity of the lining thickness is a function of the container angle and the rotation speed. It is preferred to rotate the container to approximately 45 ° from the horizontal, more preferably in a substantially horizontal position.

When the liquid material is introduced into the container while being rotated simultaneously, substantially around the horizontal (or up to 45 ° from the horizontal), a frozen liner product is obtained substantially free of frozen product at the base of the container. This seems to be the first time that this type of lining has been achieved, and forms a third aspect of the invention. All dry, liner product that can be obtained by the process and apparatus of the invention also forms this additional aspect of the invention. The rotational speed of the container must be controlled to keep the liquid material in a liner on the inner walls of the container by the action of the centrifugal force. If the rotation speed is too low, the liquid material will not be retained as a lining on the walls of the container. The rotation speed is a design consideration that depends on the density of the liquid material to be frozen and the size of the container and preferably about 2500 to 3500 revolutions per minute. Typically, they will be about 3000 revolutions per minute for a bottle of approximately 10 to 40 mm in diameter.

It has also been found that the liquid material is advantageously introduced into the container while simultaneously rotating at an angle at or close to the horizontal, then a greater amount of material can be introduced. That is, if a quantity of material greater than the normal "filling" is introduced, when the container is stationary and horizontal, some material will slide. This is less likely to occur if the container is spinning simultaneously when it is filling. The liquid material freezes in the form of a liner when subjected to freezing conditions. In a preferred embodiment of the invention this is achieved by injecting a controlled flow of inert freezing gas such as nitrogen into the container while simultaneously rotating in the container. The flow of the freezing gas is controlled in the sense that if it is injected at too high a pressure, it may break the lining of the aqueous material or it may cause an overflow. Injecting the freezing gas into the interior of the rotating container has the advantage of accelerating the freezing step. However, the freezing gas could be circulated around the outside of the container, but with this process it is important to minimize the contact points between the fastening means and the outer walls of the container to minimize any insulation of the liquid material by this contact. The method of the present invention readily provides the incorporation in a continuous or semi-continuous freeze drying process. In this process, the containers are kept in grids or tanks and move automatically through the various stages and include that they are subjected to vacuum drying conditions. A process for carrying out freeze drying according to the first aspect of the invention includes a freezing step, this process including the following steps: a) loading one or more grids or tanks with the containers to be filled; b) wash the containers, and the grids or tanks; c) sterilize the containers, and grids or tanks; d) filling the container with the liquid material to be frozen; e) freezing the liquid material according to the first aspect of the invention; f) subjecting the containers containing the frozen material to vacuum conditions; g) drying the frozen material; h) cover the containers; and i) unload the container and optionally cover and label the containers. In steps a) to c) and optionally in steps f) to h), the containers may optionally be retained in an inverted position, for example, in the grids or reservoirs. The containers should be inverted in step b) so that the wash water will drain. Additionally, in a preferred embodiment of the invention where the containers are retained by the base and the gas is injected through their open collars, then having the containers already inverted in step c) an additional handling step is saved. It will be readily appreciated that the containers could be discharged before plugging them. A fourth aspect of the present invention relates to the process for drying a dry liner material, and the fifth aspect refers to the apparatus for carrying out this drying operation.

Accordingly, a fourth aspect of the invention provides a process for freeze drying a frozen liquid material in the form of a liner on the interior walls of a container body, including the drying step for applying heat during a time interval radially inward from a heating medium to the liner in a vacuum chamber over a substantial surface area of the liner to dry the frozen lining material. In a fifth aspect of the invention, the apparatus for drying a frozen liquid material in the form of a liner on the inner walls of a container body is provided, the apparatus comprising: a vacuum chamber, a heating medium within the vacuum chamber designed to direct heat radially inward from the heating medium to the frozen liner material, and a conveying means for transporting the container through the vacuum chamber. The advantage of heating the container radially inwardly from the heating means is that the drying cycle time is greatly reduced as compared to conventional drying methods. Here, the base of the container is heated, such as on a heated shelf, and the heat transfer is axially towards the glass walls of the container. This causes a temperature difference between the length of the walls of the container, thereby causing a "drying front" in the frozen liner material. As a result, the drying cycle time is typically 30 hours for the frozen cap material compared to a drying cycle time according to the invention of 3 hours. Preferably, the heating means is in close proximity to the wall of the container, such as 5 mm or less, advantageously 3 mm or less. In a preferred embodiment of the invention (heating blocks), the distance between the wall of the container and the heating means is approximately 1 mm. Preferably, also the heating means extends substantially around the entire circumference of the container, and advantageously also extends substantially at the same height as the liner. In a particularly preferred embodiment, the heating means includes a heating chamber in which the container is received. Since the drying time is greatly reduced, the performance of the vacuum dryer is increased. Therefore, a similar production capacity can be achieved with a vacuum dryer much smaller than that used conventionally. It will be appreciated that although the first, second or fourth and fifth aspects of the invention can be used independently with conventional freezing or drying apparatuses, it is advantageous to use them together. In this way, as a consequence of the decreased freezing time, achieved by the first and second aspects of the invention together with the decreased drying time of the fourth and fifth aspects of the invention, the production capacity of the freeze drying apparatus, conventional can be achieved with a much smaller apparatus according to the present invention. Actually, the apparatus of the invention can be mobile, while the conventional freeze-drying apparatus is too large and bulky to move. With all aspects of the invention used together, a continuous or semi-continuous, automated process can also be designed with minimal or no contact with human operator. In this regard, the transport means is preferably the roll arrangement described hereinafter. The reservoir is also preferably of the design defined in the sixth aspect of the invention. Accordingly, in the sixth aspect of the invention, a reservoir comprising a tray having an upper and lower surface and having positioning openings is provided., equidistantly spaced apart, extending through the tray to place the necks of the bottles, each set of at least three positioning openings defining an area between them in which an air flow opening has been cut, and one or more butt joints adjacent each opening that trace the circumference of the base of a container about the vertical axis of the positioning opening to form a positioning flange in which the container can be placed in the vertical position. Preferably, the positioning openings are arranged in rows and columns and each set of four positioning openings define substantially the corners of a square, in which an air flow opening is provided. All aspects of the invention will now be described by way of example with reference to the following drawings, in which: Figure 1 is a side view, in cross-section, schematic showing the series of steps carried out in the continuous lyophilization process of the invention, which includes filling and freezing the aqueous material in a bottle transported in a tank and the drying of the material; Figure 2 is a schematic cross-sectional side view showing another embodiment of the process of the invention; Figure 3 is a perspective view of the top and side of the apparatus shown schematically in Figure 1; Figure 4 is a cross-sectional view through a bottle having a conventional cap of the lyophilized material in its base (4A) and a bottle having a liner of lyophilized material in the inner walls of the bottle according to the invention; Figure 5 is a perspective view, of the upper part of a reservoir used in the process of Figures 1 and 2; Figure 6 is a fragmentary plan view showing a corner portion of the reservoir shown in Figure 5; Figure 7 is a cross-sectional view through a portion of the reservoir of Figures 5 and 6, but showing a bottle in its position and a section of the roller conveyor below the reservoir; Figure 8 is a perspective view of the top and side of an automated apparatus including an automated arm which has fasteners for carrying out the filling and freezing steps, D and E, shown in Figures 1 and 2 ( that is, in the fill-turn-freeze chamber (FSF)); Figure 9 is a side view of the roller transport means for transporting the tanks and the bottles through the process; Figure 10 is a plan view of the part of the filling and freezing apparatus shown in Figure 8; Figure 11 is a cross-sectional view of the fasteners transported by the arm (not shown) of Figure 8; Figure 12 is a schematic side view of the arm and fasteners, but additionally showing a driving means for rotating the fasteners; Figure 13 is a schematic, cross-sectional view of a portion of the arm and fasteners; Figure 14 is a cross-sectional view through a bottle showing a nozzle inserted in the bottle; Figure 15 is a schematic longitudinal cross-sectional view of the FSF chamber shown in Figure 8; Figure 16 is another schematic plan view of a part of the filling and freezing apparatus of Figure 8, but additionally showing a verification weight station; Figure 17 is a perspective view of the top and side of the drying apparatus, automated for the drying step (H and I) shown in Figure 1; Figure 18 is a plan view, in cross section through a portion of the heating block used to dry the frozen material in the bottles; Figure 19 is a cross-sectional plan view through the heating walls which are an alternative embodiment to the blocks of Figure 15 for drying the frozen material in the bottles; and Figure 20 is a plan view of the drying vacuum tunnel housing the freezing apparatus. With reference to the process of Figures 1 and 2, the steps of one embodiment of the apparatus process of the invention are as follows. Loading step (A): the bottles (1) are loaded turned downwards in a tank (2), such that the neck of each bottle is located in an opening (3) of the tank (2). This loading step (A) takes place in a non-sterile environment and the bottles (1) can be loaded manually or automatically. The bottle (1) is transported through the entire process in the tank (2), which in turn is transported through the process on a conveyor in the form of roller conveyors (not shown in Figures 1 and 2), but shown in Figure 7). This is different from the previous processes of freeze drying, where the jars are placed loosely in metal trays. The specifically designed tanks (2) are shown more particularly in Figures 5 to 7. Washing step (B) and sterilization step (C): The bottles (1) are then washed both inside and outside, when injecting a washing solution in the inverted bottles (1) through their necks and spraying a washing solution on the outside of the bottles (1). The bottles (1) are then sterilized with hot air (step C) when passing them in a sterilization chamber (4-, see Figure 3)), where hot air is blown on the bottles (1). The sterilized tanks (2) filled with jars (1) are then transported by the transport means to a filling-turning-freezing section (FSF) (5) where the filling or filling steps take place (D) and freezing (E). The apparatus for carrying out these steps is shown more particularly in Figures 8 to 16. Filling step (D) and freezing step (E): In a filling and freezing operation, the bottles (1) and the deposits (2) enter the section (5) of FSF and allowed to cool to the internal temperature of FSF (typically around -50 ° C). The bottles (1) are removed from the tanks (2) one row at a time, (or feasibly two rows at a time) these are collected by an automaton arm (not shown in Figures 1 and 2) that transports a plurality of rotatable fastening means in the shape of the fastener (6) of several fingers. The bottles (1) are rotated horizontally and the robot arm rotates 90 ° to the side of the FSF chamber. The bottles (1) are rotated rapidly and filled with the required dose of the aqueous material, particularly a drug material such as a vaccine. Optionally, the bottles can be filled first, then rotated, but preferably filling or filling occurs while simultaneously rotating the bottle (1). The speed of rotation or rotation should not be less than that required to maintain the aqueous material in a liner (7) of substantially uniform thickness against the inner walls of the bottle (1). The bottles (1) then move on nozzles from which cold gas is blown (typically, nitrogen at about -150 ° C) to expose the aqueous material which rotates at sufficient freezing conditions to freeze the material in the liner (7) . The frozen liner (and finally the dry liner) will be of substantially uniform thickness, i.e., the thickness of the liner measured at any position along the axis of the bottle will not vary more than about 5%, providing that the thickness is measured as the average between any of the surface peaks or valleys that may result from fluid dynamics during the freezing process. After a preset time to determine the freezing, the rotation stops and the bottles (1) are returned to the tank (2). The temperature inside the enclosure is kept cold enough so that the linings do not melt. Weighing step (F): while a row of bottles (1) is filling and freezing, other bottles (1) are weighed by spreading the tank (2) back and forth on weight load cells (8) - Figure 1) . This allows all the bottles (1) to be weighed before and after filling to verify that the correct dose has been distributed. The cells (8) of the weight load are shown more particularly in Figure 16. Twist of the bottles (step G): After filling and freezing, the bottles (1) are rotated (optionally) from the set down to the right way up (see Figure 1). This is achieved by collecting the jars (1) (one row at a time) from a tank (2) and transferring them to the tank in the front. A transfer arm (9) that retains sufficient fasteners for a row of bottles holds the bottles (1) around its center and rotates them 180 ° about a horizontal axis through the direction of movement of the container (2). The bottles (1) are then released in the correct way upwards in the tank in the front (2). This optional step requires that there is always the equivalent of an empty deposit in the process, which is loaded at the start of production. In the process of Figure 2, this turning step does not occur and the bottles are loaded inverted backwards in the tank (2) before they are transported over the drying section of the process. Vacuum Tunnel - Entrance air lock (step H): once the material in the bottle (1) has been frozen, it is ready for drying. The deposit (2) enters an air lock chamber (10a) between the FSF chamber (4) and a vacuum drying tunnel (11). The outer door (12a) of the air lock (10a) is then closed and the air pressure is reduced thereto as the vacuum tunnel (11). The inner door (13a) then opens and the tank (2) enters the vacuum chamber (11). The outer door (12a) then opens list for the next deposit (2) . The reservoirs (2) in the vacuum tunnel (11) are moved by a conveyor means in a graduation movement a full length of deposit at the same time, typically, every 10 minutes. When the tanks (2) have been spaced to the new stations, the heating blocks (14) fall on the bottles (1). These direct heat substantially radially inwardly towards the bottle over substantially the entire surface area of the frozen liner material (7) and thereby provide the energy to completely sublimate the water and freeze the material (7). Immediately before the separation of the tanks (2), the heating blocks are raised to their first position to allow the tank (2) and the bottles (1) to pass below and move a tank length (2) to the next one. heater block (14). The heater blocks (14) are each adjusted to a different temperature, thus giving the profile and temperature necessary to achieve the correct drying conditions for the particular drug material being handled. The freeze-dried liner material (7) produced according to the invention is shown more clearly in Figure 4b. The dry, plug-like, conventional product is shown in Figure 4A. At the end of the vacuum tunnel there is a second air lock. It works in a manner similar to the intake air shutoff, allowing the jars to come out while maintaining the vacuum in the main tunnel.

Plugging (step J): there are two options for plugging. One is to carry out the plugging in the outlet air lock (10b). In this case, the plugs (15) would introduce the air lock (10a) as a tank (2) comes out. The plugs (15) would be pushed into the jars (1) before the outer door (12b) is opened; this allows plugging at any desired pressure and in any chosen gas. The second option is to cover after air closure (10b) in a sterile packing area (16) (see Figure 3). Conventional equipment could be used here but the size of the sterile area (16) would increase as a result. Putting caps (step K): The curling of the caps (17) on the plugs (15) could use normal equipment and is carried out in a clean area (but not necessarily sterile). The complete freeze drying process is operated from a central control operation, more particularly shown in Figure 4. Figures 5 to 7 show a tank (2) used to transport the bottles (1) through the process Complete drying by freezing. The reservoir (2) of Figure 5 comprises a tray (18) having an upper and lower surface and having eight rows of eight equally spaced positioning openings (19) extending through the tray (18) for place the necks of the jars. Each set of four positioning openings (19) defines the four corners of the square in which an air flow opening (20) has been cut. A concave butt joint (21) adjacent each opening traces the circumference of the base of a bottle (1) about the vertical axis of the positioning opening (19) to form a positioning flange (22) in which it can be place the bottle (1) in the vertical position. The bottles (1) are preferably kept in the inverted position as shown in Figure 7. This Figure also shows that the surface of the upper part of the neck of the bottle does not contact preferably with the tank (2), so that any of the particles that can be produced by the wear between the bottle (1) and the tank (2) at point A is unlikely to contaminate the inside of the bottle (1). The bottle is supported on its neck at point B. This design depends on the diameter of the bottle (1) that is greater than the diameter of the neck of the bottle.

The opening (19) for positioning in the tank (2) is preferably laminated as shown in Figure 6. The crenellations (23) allow a jet of water to be injected between the bottle (1) and the tank (2) during the washing process to remove any of the particles that have been trapped in the separation. The open area of the air flow opening (20) allows the free passage of air through the reservoir during sterilization with hot air and for cold laminar air flow in the section (5) of the FSF (see Figure 15). The positioning holes (24) towards the outer edge of the tank are preferably provided for precise positioning. The holes are circular on one side and elongated on the other side to allow placement in the position without overpressure. As shown more particularly in Figures 8 and 9, the means for transporting the reservoirs through the lyophilization process preferably comprises a plurality of parallel rollers (25) axially mounted near both ends of the rotatable shafts (26), corresponding which in turn are suspended between two lateral, parallel, long supports (27). Referring to Figure 7, each roller has a flange (28) extending outward and circumferentially, in which it rests and moves along in the tank. Also mounted on the rotatable shaft (26) adjacent to the roller is a drive gear wheel (29). The bottom side of the tank (2) has a grid with teeth (30) to mate with the teeth of the drive wheel (29) and space the tank (2) lengthwise. Through the entire process, the deposit (2) is supported on a series of these rollers (25), not all of which have drive teeth.

Additionally, not all the drive teeth will move at the same time, thus giving a controlled spacing of the tank through the process. For example, within the FSF chamber (5), the reservoir (2) is preferably spaced one row at a time, typically one row per minute. It also moves back and forth by one or two rows (as described later herein) above the check weighing cells (8). In the drying chamber (11), however, the tank (2) is preferably spaced by a full length of the tank at a time, a spacing every 8 minutes for example. Therefore, the rollers in the chamber (5) (FSF) will not be attached directly to those in the drying chamber (11). The transport rollers are nevertheless synchronized where necessary to provide a smooth transfer between the sections of the different rollers. Figure 9 shows a side view of the arrangement of drive rollers transporting the tanks (2) through the process. More particularly, the figure represents the movement from the region (5) of FSF towards the air lock (10) and the vacuum chamber (11) through the air lock doors (12a and 13). In order to move a reservoir from one region to another region, each set of rollers needs to be driven independently. The rollers (25) are connected together in groups by the drive shafts (31, 32, 33) and are driven by independent drive motors (34, 35 and 36). Each motor (34 to 36) is controlled in its position by central programming elements to provide the necessary movements of the synchronization movement between the adjacent groups during the transfer of the deposit from one group to another.

The transfer of the tank (2) and the bottles (1) throughout the process in the roller conveyor arrangement (25 to 36), preferred of the invention has a number of advantages for use particularly in a continuous process of freeze drying This is especially so in comparison with conventional drives which could be for example flat bed conveyors, as used in conventional freeze drying. They are as follows: 1. There is no contact bottle to bottle. This reduces the amount of particle generation caused by wear and reduces the chances of a broken jars. 2. The design of the tank is very open for the washing and sterilization process. The washing is better because the location or exact location of the bottle is known, therefore the washing jets can be directed to key parts of the bottle. The open spaces of the tank allow hot sterilization air to pass freely through the tank. 3. The open structure also allows good air flow in the FSF region where it is necessary to laminar air flow down to maintain very low levels of particles in the region of the flasks. The arrangement of the support rollers is also clean and simple and therefore aids in the flow of air. 4. The tanks and rollers themselves constitute a greatly reduced source of particles compared to conventional conveyors which tend to have large numbers of wear surfaces. 5. Since the tanks preferably pass through the entire process (rather than by short lengths of conveyors in each section) there is only a minimum of mechanical handling of the bottles. There is no need for any stage of handling bottles between the sterilizer and the FSF chamber for example, nor between the FSF chamber and the drying chamber. 6. Since the tanks preferably pass through the entire process (rather than by short lengths of conveyors in each section) they are repeatedly clean, ie, cleaned and sterilized in each route, while a conveyor contained within any machine element would not be cleaned and therefore would have the potential to cause a contamination from bottle to bottle. 7. The separate nature of the tanks allows them to pass through the air lock doors at the entrance and exit of the tunnel. This is possible because the air lock (slide) doors can be placed between two parallel rollers. 8. Since each bottle is placed in its individual location in the reservoir, the bottles can be easily placed when necessary, for example, for fastening by the FSF process, for heating in the drying chamber and for clogging . The conventional transport of jars generally requires a separate mechanism for the alignment of the jars before the handling stages. 9. Since each bottle is placed in its general location in the tank, it can be traced individually through the process for development purposes or to identify a particular bottle in the case of a process failure such as poor filling. A bottle that is identified by the verification weighing system as defective, can therefore be retrieved subsequently at any convenient stage in the process. With reference to Figure 8, the tanks (2) and the bottles (1) move through the FSF chamber (5) in the direction of the arrow from the rear end to the front thereof and then in the continuous tunnel vacuum drying (consisting of air closures (10a, 10b) and drying chamber (eleven) . An automaton (37) is located fixedly towards the front end of the FSF chamber (5) and next to the roller conveyor (25 to 36). An arm (38) having a plurality of equally spaced, rotatable, spacer means (39) extends perpendicular from the upper end of the automaton (37) and is controlled in this way. A filling or filling (40) and freezing station (41) are both located in the chamber (5) next to the roller conveyor (25 to 36) and to the back of the automaton driver (37). The filling station (40) consists of a row of needle nozzles (42) each having a connector (43) for connecting the outside of the FSF chamber to a reservoir of the aqueous material to be lyophilized (44, see Figure 9). The freezing station (41) also contains a row of needle nozzles (45) each also having an adapter (46) for connecting to a supply of gas (44) of freezing nitrogen also outside the FSF chamber. The nozzles (42) of the freezing station (40) are located directly below the nozzles (42) of the filling station (41) and both sets of nozzles (42, 45) are mounted in a sheath (47) at about the same height as the arm (38). The filler and gas reservoirs (44) are conveniently located outside the FSF chamber (5) so that the FSF chamber (5) can be kept as clean as possible (see Figure 9). The filling needles (42) are provided with either a heating means or thermal insulation to prevent freezing of the liquid material within the nozzle (42) during filling. Figure 11 shows the bottle holder means (6), rotatable in cross section. The bottle (1) is held in the concentrically moving nails (48) which are designed to retain the bottle (1) with its axis exactly concentric with the axis of rotation of the fastener (6). The nails (48) are accommodated and can move axially within an outer sheath (49) and have projections (50) that extend outwardly, which can be slidably received in complementary depressions (51) in the sheath ( 49) outside or vice versa. The bottle (1) is rotated to produce a liner (7) of the liquid drug inside the bottle (1). The bottle (1) is then transferred to a position that encloses the nozzle of the freezing gas to freeze the liner (7). This ensures that the frozen liner (7) has a substantially uniform wall thickness, and is an improvement over the winding while freezing. The nails (48) are controlled by a push rod (52) extending axially along the shaft (53) of the fastener connected between the base of the nails and a flange (55). The nails are opened by the movement of an actuator structure (54) (which is mounted inside the arm (37) automaton) in the direction of the arrows against the flange (55), thereby compressing a spring (56) against the tab (55) and a second tab (not shown). In the open position, the nails (48) are pushed axially out of the outer sheath (49) by the push rod (52) such that the projections (50) slide into the complementary depressions (51), thus allowing that the nails are opened. In the closed position, the force of the spring (56) pushes the nails (42) axially in the sheath (43) and the projections (50) slide out of the depressions (51) thus using the nails (48) to close, as with a necklace. This arrangement has the advantage that, in the event of power failure to the actuator (53) of the flange, the nails (48) will remain closed, clamped. In the open position, the structure actuator (54) is contiguous with the flange (55), but in the closed position they separate allowing free rotation of the complete fastening arrangement (6). Each rotatable fastening means (6) is designed with a beveled inlet conductor (57), sufficient that even a poorly formed flask (1) poorly located in a reservoir will still move smoothly in the fastener means (6) when lowered over The deposit . Figure 12 shows the drive arrangement (58, 59) by which the fastening means (6) is also rotated. There is an individual drive motor (58) attached to each shaft (53) of the fastener by a timing belt (59), serrated. As shown more particularly in Figure 13, since the atmosphere of FSF is about -50 ° C, the automaton arm (37) is covered by an outer sleeve (60) having an internal insulation (61). The arm (37) is maintained at room temperature by a thermostatically controlled heating element (62). The outer sleeve (60) contains a sliding seal (63) to allow rotation and the automaton handler (37) is provided with flexible bellows (64) to allow vertical movement relative to the reservoir (2). This arrangement means that the insulated outer sleeve (60, 61) provides thermal insulation between the cold atmosphere and the relatively hot mechanical components of the arm (38). The outer arm cover (60, 61) serves at least for two purposes. 1. To allow the arm mechanisms to operate at room temperature while the arm is mounted within the FSF enclosure. 2. To protect the clean environment of FSF from any of the particles generated by moving parts such as by the trees (53) of the rotating clamp by the drive belt (59). The air that is contained within the confinement will be extracted from the enclosure through the vent opening (64) and does not require any fan for the extraction since the enclosure is pressurized in a positive manner. This extraction will cause a relatively high air velocity in the narrow opening (65) between the turning clamping means (6) and the sheath (60) of the outer arm, which will tend to transport any of the particles generated in the density of the medium (6) fastening together with any of the particles generated within the inner atmosphere of the automaton arm (37) towards the vent opening (64) and therefore away from the clean area of the bottles (1). In a filling, turning, freezing cycle, the arm (37) is lowered vertically from a first position in which the clamping means (6) are placed perpendicular to the roller conveyor (from 25 to 36) and are separated from above of the bottles (1) transported therein, and a second position in which each holding means (6) holds the base of a bottle (1). Typically a row of bottles (1) is simultaneously removed from the tank (2). The arm (37) then rises to the first position and is rotated about 90 ° to a third position in which the clamping means are substantially parallel to the roller conveyor (from 25 to 36) and the bottles (1) are maintained substantially horizontally. The arm (37) then rotates about 90 ° in a horizontal plane at the front of the filling means, so that a nozzle (42) of the filling station (40) extends through the neck of a flask (1). ) correspondent. The bottles are then rotated at a high speed of approximately 3000 rpm and a metered dose of the aqueous material is injected simultaneously into the bottle (1), causing the material to remain in a liner (7) against the inner walls of the bottle (1). ) by the action of centrifugal force. The bottles (1) are then removed from the nozzles (42) of the filling or filling station (40) and the arm (38) is lowered to the height of the freezing station (41) and moved towards it, so that the nozzles (45) thereof are inserted into the bottles (1) and a controlled jet cold nitrogen (typically of a temperature of about -50 ° C) in the bottle (1), while simultaneously rotating to freeze the aqueous material in a liner (7) against the inner walls of the bottle (1). After a pre-set time to allow freezing (typically between 30 to 60 seconds) the rotation stops and the bottles (1) are returned to the tank (2). A main advantage that derives from the very short time of the freezing cycle is that the performance capacity of a conventional freeze drying apparatus can be adjusted on a much smaller scale of the apparatus. As a result, the process can be more easily automated and continuous, thus excluding human operators from the process and thus maximizing the sterility of the process. To achieve this, the inside of the process line must be insulated on the outside by "insulation technology." This requires both a barrier to the ingress of dirt or bacteria and also means internally, so that the chamber (4) can be cleaned and sterilize automatically, that is, it must be cleaned when it is sealed and must be sealed throughout the entire production of a batch, so preferably the complete freeze-drying process of the invention is designed For reliable mechanical handling, ie if a bottle (1) falls or breaks during the process then it is very hard to continue without an operator going inside the insulator to clean it.If this is necessary then the sterility is lost, the The product in the area should be discarded and the procedure for sterilization cleaning should be repeated before production can continue.This would be a costly and time consuming consumer, and Therefore, they are important reliable mechanisms. Figure 15 is shown as a sterile barrier is arranged in area (5) of FSF. The Figure is a cross section of the production line, looking in the direction of product flow. The barrier itself (66) is shown as a thick wall due to the need for thermal insulation (alternating temperature can be -50 ° C). The internal gas is circulated around the fan (67) in the direction of the various arrows. As the air passes through the filter ("HEPA" filter) (68) the fine particles and microorganisms are removed and the flow is also leveled, so that the flow and the region below the filter (68) is laminar, down. The downward flow of clean air ensures that the filling or filling process and the bottles (1) are in clean air and that any of the particles discharged in these or other regions are transported down and cleaned of the bottles. The injection of the freezing gas to form the liner is shown more particularly in Figure 14. Preferably, the freezing nozzle (42) has a plurality of holes (69) along its length through which it is formed. injects the freezing air. The substantially horizontal orientation of the bottle (1) mitigates the problem of producing a parabolic surface for the liner and helps form a liner of substantially uniform thickness. The rate of heat transfer from the gas to the product is increased by increasing the temperature difference (by having colder gas) and by increasing the relative viscosity between the gas and the liquid. Nevertheless, a very high gas velocity will break the liquid liner and cause a non-uniform frozen shape. The pattern or design of holes (69) in the side of the nozzle (62) (Figure 14) mitigates this problem by reducing any local peak in gas velocity. Since the bottle (1) can be rotated simultaneously and refilled, it is possible to fill the bottle beyond the limit where the aqueous material would spill on the neck if the bottles were not rotating. For sensitive drugs, it may be advantageous to fill or fill at a rotation speed lower than freezing, to minimize the effect of shear stress.It is advantageous to be able to weigh each bottle (1), so that the weight of the product filled in each bottle can be verified and any of the deviations of the process are indicated and corrected. This means, for example, that if one of the filling pumps is tending to fill slightly less than the target filling weight, then the pump could be adjusted to keep the filling weight under control. Any failure of the total filling for example, caused by an impediment would be recognized instantly. The weight cells (8) are placed in the area (5) of FSF under a row of bottles adjacent to the automaton arm (37) (Figure 16). The weight cells (8) are assembled in a structure (8a) such that when the structure (8a) is raised then all the bottles (1) in that row are lifted by the cells (8) of weight cleared from the tank (2). ) and their individual weights can be determined. The direction of the spreading of the deposit is shown by the arrow. The filling and weighing sequence is as follows: Row 1 is spread over the weight cells and weighed, empty.

The automaton arm (38) then gathers row 1, turns and fills and freezes it. During this time, the tank (2) moves so that the row 2 is spread over the cells (8) of weight and is weighed, empty. Row 1 is then returned to deposit (2). The automaton arm (38) then picks up row 2, rotates and refills and freezes it. During this time, the tank (2) is moved so that row 3 is spread over the weight cells (8) and weighed, empty and then row 1 is spread over the weight cells (8) and weighed, full. Row 2 is then returned to the deposit (2). The automaton arm (32) then collects row 3, rotates and refills it and freezes it. During this time, the tank is moved so that row 4 is spread over the weight cells (8) and weighed, empty and then row 2 is spread over the weight cells (8) and weighed, filled. Row 3 is then returned to the deposit (2).

This process is repeated until all the bottles (1) in the tank (2) have been weighed and filled. The next deposit (2) then spreads forward. It is preferable that each bottle (1) be weighed before and after filling as described, since the difference between the fill weights to be detected is less than the probable difference in the weights of the bottle (1). Preferably, also each bottle is weighed each time in the same cell (8) of weight so that variations between the cells (8) of weight will have no effect on the accuracy of the measurement. Drying (step I): The apparatus for drying the frozen liner material (7) is shown more particularly in Figures 17 to 20. The jars (1) pass through the vacuum tunnel (10a, 10b, 11) from the back to the front. The vacuum tunnel (10a, 10b, 11) comprises a vacuum, sealed, vacuum chamber (11) and the air closure chambers (10a, 10b) at the rear and front end of the drying chamber (11) . Each air lock (10a, 10b) has an interior door (13a, 13b) and an exterior door (12a, 12b). The reservoir (2) enters the frontal air closure (10a) between the FSF chamber (5) and a vacuum drying chamber (11). The outer door (12a) of the first air lock (10a) is then closed and the air pressure is reduced thereto as the vacuum drying chambers (11). The inner door (13a) of the front air lock (10a) is then opened and the tank (2) enters the vacuum drying chamber (11). The inner door (13a) then closes, the outer door (12a) of the front air lock (10a) then opens ready for the next tank (2). A conveyor means (not shown) preferably of the same arrangement of the roller conveyor (from 25 to 36) in the FSF chamber (5) is provided to move the reservoirs (2) of the bottles (1) through the vacuum tunnel (10a, 10b, 11). A series of heating blocks (70) are spread along the length of the vacuum chamber (11) above the conveying means (from 25 to 36) and the tanks (2). As shown more particularly in Figure 18 (showing the plan view of a portion of a heater block (70) and the jars), the heating blocks (70) comprise a plurality of heating chambers (71), tubular corresponding to the number of bottles (1) in each tank (2). Each chamber (71) is defined by a tubular wall (72) that extends at a height just above the top of the bottle (1), and the heating chamber (71) is optionally provided with an upper part (72). ) which may optionally have an opening (73) communicating with the drying chamber (11) to release water vapor from the chamber (71) (Figure 1). In the embodiment of Figure 2, there is no opening in the upper part between each heating chamber (71) but the bottle (1) is inverted and the water vapor escapes through the tank positioning opening (3) ( 2) . The lower end of each heating chamber is opened to receive the bottle (1). The heating blocks (70) can be turned vertically from a first position above the reservoirs (2) to a second position in which they are lowered so that the base of the heating block (70) rests on or is close to the upper surface of the tank (2) such that each bottle (1) fits comfortably in a heating chamber (71). In the embodiment of Figure 18, a small space is left between the body of each bottle (1) and the inner walls (72) of the corresponding heating chamber (71). In this position, the heat can pass radially inwardly from the heating block into the frozen liner material (7) over a substantial area of the liner (7) in the direction of the arrows (Figure 8). The heat is transferred by radiation and by conduction and convection through the waste gas leaving in the heating chamber (71) (vacuum). The vacuum space between the wall (72) of the heating chamber and the bottle body is important since it has an effect as efficient heat is transferred to the liner (7) of the material. Preferably, the possibility of the heating wall and the bottle (1) is about 5 mm or less, preferably about 3 mm or less. In the mode shown, the close distance is approximately 1 mm. The heating block (70) is constructed of a material with good thermal conductivity. Aluminum, for example, is suitable when it is provided to prevent the production of particles caused by the oxidation of the surface, for example, when anodizing. The temperature of the heater block (70) can be maintained by the passage of heating fluid through the element or tube (73) attached thereto, or a conduit (73) running through the heating block (70). Although the heating block (70) passes heat in the bottles (1), it is sometimes necessary that the block (70) be cooled in order to maintain the correct temperature (if for example, the heat gain from the environment to the block ( 70) is greater than the heat loss from the block (61) to the bottles (1). (Cooling is also necessary at the start of a batch.) For this reason, the blocks (70) are controlled by a fluid that can be heated or cooled and not only by an electric heating element, in particular, during primary drying the bottles (1) can be at -50 ° C and the heating blocks at -20 ° C. Figure 19 shows a medium of alternative heating to the heating blocks (70) of Figure 18. In this embodiment, extensive heating walls (74) are provided running in parallel along each side and down the middle (longitudinally) point of the medium conveyor (from 25 to 36) on which the tanks (2) rest. wall (74) is approximately the same height as the bottles (1) when they are resting in the tank (2). As with the heating blocks, the heating walls are preferably controlled by circulating a thermal liquid through an element (73) running through or attached to the walls (74). The walls (74) consist of separate sections, the temperature of which is progressively increased along the vacuum chamber (11) in the direction of the large arrow such that the temperature experienced by the frozen liner material 7 in each bottle (1) increases progressively as moves axially along the drying chamber (11). The heat path for heat transfer is again radially inward (as shown) by the arrows from the heating walls to the frozen liner material (3) over a substantial area of the liner, thereby drying the liner (7) much faster than previous methods in the art. Again, the heat transfer will be by a combination of conduction or convection, irradiation in the vacuum space between the heating walls (74), and the flasks (1). As before, the proximity between the heating walls (74) and the body of the bottles is preferably 5 mm or less, more preferably about 3 mm or less. The difference between the heating modes of Figures 16 and 17 is that the bottle (1) is passed between two heating walls (74) instead of being received in a heating chamber (70). As a result, it is no longer necessary to lift the heating blocks to allow the bottles (1) to move and therefore the embodiment of Figure 19 itself provides a more simplified design. However, the disadvantage is the longer thermal path and less efficient heat transfer from the heating walls (74) to the liner (7). By substantially enclosing the bottle with the heating means, such as with the heating chamber (71) of the heating block (7), a faster drying time is achieved. Both with the heating block (70) and the heating walls (74), because the heaters are controlled in the temperature individually, the product passing through the tunnel is put into a drying cycle, such as for example: one hour -25 ° C, 1/2 hour at + 5 ° C 1/2 hour at + 5 ° C, 1/2 hour at + 40 ° C, and 1/2 at + 40 ° C. Figure 20 shows a plan view of the arrangement of the vacuum pumps and condensers on the side of the vacuum chamber (11) and the air closures (10a, 10b). There is a separate vacuum pump (75) and a condenser (76) for each air lock (10a, 10b) and multiple vacuum pumps (75) are placed along the length of the tunnel. The vacuum will become progressively higher along the length of the tunnel (10a, 10b, 11) as the product becomes progressively drier. Insulating doors (77) therefore can be provided in intermediate positions in the tunnel to isolate a container, if it is found that the product is sensitive to the degree of vacuum that is applied during secondary drying. The condensers (76) will be progressively covered with ice as more product passes down the tunnel. For the purpose of thawing, the product in the run may be interrupted but preferably it should be a surplus of condensing capacity such that each condenser (76) can be isolated by means of the valve (78) to defrost after each time can be put back into service without interruption of production. In both of the illustrated modalities (Figures 16 and 17) of the heating means (i.e., using the heating blocks (61) and the heating walls (67)), the heat passes radially inward from the heating means to the frozen liner material at each jar. As a result, the product dries more quickly than in the conventional drying apparatus where the bottle rests on a heated shelf (and in this way only the base is heated directly).

In this case, the heat passes axially upwards from the base through the glass walls which causes a temperature gradient to increase the time required to dry the liner (7). Additionally, due to the efficient heat transfer conditions, the drying process and the apparatus of the invention are less energy demanding than the average process.

It is noted that in relation to this date, the best method known by the applicant to carry out the present invention is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property:

Claims (35)

1. A continuous or semi-continuous process to carry out freeze-drying of liquid material in a container, in which vessels are loaded at one end of the process and move automatically through the various stages and which includes subjecting to conditions of drying by vacuum, the process is characterized in that it comprises: a) loading gratings or tanks with containers to be filled, such that the containers are kept separate in individual locations in the grids or reservoirs; b) wash the containers and the grids or tanks, the containers that are in the inverted position so that the washing water will be drained; c) sterilizing the containers and grids or tanks; d) filling the containers with the liquid material to be frozen; e) rotating the containers containing the liquid material to be frozen at a speed no lower than that required to keep the liquid in a liner of substantially uniform thickness against the inner walls of the container by the action of the centrifugal force while subjecting the liquid to sufficient freezing conditions to freeze the material in the shape of the liner, where the containers are removed from the rack or tank and rotated out of the rack or tank and after a presetting time to complete the freezing, separates the rotation and the containers are returned to the grid or reservoir; And f) moving the grid or tank with the containers containing the frozen material, held in individual locations in and through a vacuum drying chamber to dry the frozen material.

2. A process according to claim 1, characterized in that the liquid material is introduced into each container while the container is being rotated simultaneously, the rotation being maintained during freezing.

3. A process according to claim 1 or 2, characterized in that each container is rotated about its axis, while being maintained in a substantially horizontal processor.

4. A process according to claims 1 to 3, characterized in that the liquid material is an aqueous drug and each container is a bottle of approximately 10 to 40 mm in diameter and has at least one unit dose of drug.

5. A process according to any of the preceding claims, characterized in that freezing is achieved by injecting a freezing gas into each container.

6. A process according to claim 5, characterized in that the gas is nitrogen gas at about -50 ° C.

7. A process according to claim 6, characterized in that the freezing cycle time is from 40 to 90 seconds.

8. A process according to any of the preceding claims, characterized in that the speed of rotation of the container is about 2500 to about 3500 revolutions per minute.

9. A process according to any of the preceding claims, characterized in that it also includes a weighing step (F) wherein each container while in the tank or grid is weighed in vacuum and then again after the liquid material has been frozen to verify that the correct dose is present inside the container.

10. A process according to any of the preceding claims, characterized in that within the vacuum drying chamber, heat is applied radially inwardly from a heating means over a substantial surface area of the lining of the frozen material.

11. A process according to claim 10, characterized in that the distance between the heating means and the lining of the frozen material is 5 mm or less.

12. A process according to any of the preceding claims, characterized in that the containers are washed by injecting washing water through the grids or tanks and through the neck of the inverted containers.

13. A process according to any of the preceding claims, characterized in that the containers are loaded with the upper side down on the rack or tank in step a) and then subsequently washed and sterilized in this inverted position according to the steps b) and c).

14. A process according to claim 13, characterized in that the containers are placed back with the upper side down in the rack or tank after the filling and freezing steps d) and e), and then they are returned to the correct way towards above a tank before they are subjected to the vacuum drying step.

15. Apparatus for freezing, continuous or semi-continuous drying of a liquid material contained in a sterilized container, in such a way that the liquid material forms a lining of substantially uniform thickness on the inner walls of the container and in which the filled containers at one end of the process they move automatically through the various stages and that includes subjecting them to vacuum drying conditions; the apparatus is characterized in that it comprises: grids or tanks that include individual locations for placing containers such that they are kept separate; a washing machine for washing and a sterilizer for sterilizing containers, grids or tanks; a pivotable fastening means for removing the containers from the grids or reservoirs and returning them back, and for retaining a container and rotating it about its longitudinal axis at high speeds to maintain the liquid material against the inner walls of the container by centrifugal force; a filling means for introducing the liquid material into the container; a freezing means for freezing the liquid in the form of a liner of substantially uniform thickness against the inner walls of the bottle; a vacuum drying chamber containing a heating means; and a means of transport for moving the tank or grid that holds the containers containing the frozen material in and through the vacuum freezing chamber, and moving the next rack or tank loaded with the containers in the position for filling or freezing .

16. The apparatus according to claim 15, characterized in that the means for freezing the liquid is a nozzle cooperating with a connector for connecting to a supply of freezing gas and designed to be inserted through the neck of each container while the container is rotating to introduce the freezing gas into the container.

17. The apparatus according to claim 16, characterized in that each freezing nozzle is provided with a plurality of orifices running along its length through which the freezing gas is injected.

18. The apparatus according to any of claims 15 to 17, characterized in that the filling means is a nozzle (42) cooperating with a connector for connecting to the liquid supply and designed to be inserted through the neck of the container to introduce the liquid in the container.

19. The apparatus according to any of claims 15 to 18, characterized in that it further includes a movable arm located next to, and adjacent to the conveyor means and the filling and freezing means, this arm having a plurality of fastening means, rotatable, spaced apart equidistantly along their length, and adapted to move a plurality of containers held in the fastener means between the fastener means and the filling and freezing means.

20. The apparatus according to claim 19, characterized in that the arm can move vertically from a first position in which the clamping means are substantially perpendicular separated above the conveyor means to a second position approximately one length of the container from the conveyor means for grasping the container, and a third position adjacent to the filling and freezing means for filling and freezing the container.

21. The apparatus according to claim 20, characterized in that a robot controller is cooperatively connected to the arm to control and move it, the handler which is fixedly located on and adjacent to the conveyor means, and the means, and the means of filling and freezing such that the arm can rotate through substantially 90 ° in a substantially horizontal plane between the first position in which the arm and the rotatable clamping means are substantially perpendicular to the conveying means and a third position in which the arm , and in the fastening means are placed substantially parallel and next to the conveyor means and adjacent to the filling and freezing means ready for filling and freezing.

22. The apparatus according to any of claims 15 to 21, characterized in that the rotatable fastening means comprises a drive shaft, nails connected to a base, and moving axially in and out of the cover, a resilient means, projections which extend outwards or depressions provided in the outer wall of the nails and slidably received in the complementary depressions or projections on the inner wall of the cover, such that the nails move axially outwardly from the cover against the force of the resilient medium and the projections are received in the depressions, thus allowing the nails to open and release a container, and move into the cover by virtue of the strength of the resilient medium, the projections and the depressions they slide out of the coupling, thereby forcing the nails to close around a container.

23. The apparatus according to claims 21 and 22, characterized in that the clamping means is provided with a drive shaft, which is additionally provided with a rotatable driving means comprising a driving motor and a driving belt, the band of drive that extends around the drive shaft and the drive motor to rotate the clamping means.

24. The apparatus according to any of claims 15 to 23, characterized in that the conveyor means comprises lateral, parallel support members; a plurality of parallel trees suspended between the support members; pivoting rollers mounted on the trees to support the tanks; and a drive means for driving the grids or reservoirs along the rollers.

25. The apparatus according to claim 24, characterized in that the drive means is a rotatable gear wheel, mounted on specific trees through the conveyor means, to hold the grate base or reservoir resting on the rollers and move them as far as possible. length of the conveyor medium.

26. The apparatus according to any of claims 15 to 22, characterized in that the reservoir comprises a tray having an upper and lower surface and having equally spaced positioning openings that hold through the tray to place the necks of the bottles , each set of at least three positioning openings defining an area between them in which an air flow opening has been cut, and one or more butt joints adjacent to each opening that traces the circumference of the base of a container about the vertical axis of the positioning opening to form a positioning flange in which the container can be placed in the vertical position.

27. The apparatus according to claim 25, characterized in that the teeth are provided on the underside of the grid or reservoir for coupling with the sprocket according to claim 24.

28. The apparatus according to any of claims 15 to 27, characterized in that the heating means inside the vacuum drying chamber is designed to direct heat radially inwardly from the heating means, towards the frozen lining material.

29. The apparatus according to claim 28, characterized in that the heating means is a heating block having at least one heating chamber for receiving and extending substantially around the entire circumference of a bottle, the wall (s) interior (s) of the heating chamber that emits heat radially inward toward the frozen lining material.

30. The apparatus according to claims 28 and 29, characterized in that the heating means comprises a series of heating blocks, all at different temperatures and separated from each other along the length of the vacuum chamber, such that the grids or deposits with the bottles are moved around the chamber by a conveyor means, the bottles are heated by successive heating blocks at an increasing temperature in order to dry the frozen lining material in this way.

31. The apparatus according to claim 30, characterized in that the heating means is parallel to the heated walls which extend substantially along the length of the conveyor means and which directs heat radially inward towards the frozen lining material, such that the material liner dries as the grid or reservoirs with the containers move along the conveyor means between the heated walls.

32. The apparatus according to claim 28 to 31, characterized in that the heating means has conduits running through it or elements attached thereto for transporting a liquid to control the heat and the heating means.

33. The apparatus according to any of claims 28 to 32, characterized in that the walls of the heating means are at a distance of 5 mm or less from the walls of the bottle during the drying cycle.

34. Apparatus for drying by semi-continuously or continuously freezing a frozen liquid material in the form of a liner on the inner wall of the body of a container, the apparatus is characterized in that it comprises: grids or reservoirs including individual locations for placing containers such that remain separate; a washing machine for washing and a sterilizer for sterilizing containers, grids or tanks; a rotatable fastening means, a filling means, a freezing means according to any of claims 15 to 22; a vacuum drying chamber comprising a heating means according to any of claims 28 to 33; a conveyor means for moving the containers through the different freeze-drying apparatus from the rear to the front of the same; an air lock to receive at least one reservoir of containers in the front of the vacuum drying chamber and an air lock in the rear of the vacuum chamber to maintain the vacuum in the drying chamber as the containers enter and they leave the camera at either end; and at least one condenser in communication with the vacuum drying chamber to move the water vapor generated by the drying of the frozen lining material.

35. A container characterized in that it comprises a lyophilized material in the form of a liner of the inner walls of the container, the liner that can be obtained by the freezing and drying process of the preceding claims.