Patent Publication Number: US-11377276-B2

Title: Drying container

Description:
The present invention generally relates to containers for the drying of material. In particular, the invention relates to a lid of a drying container, said lid enabling to close the container body of the drying container so as to avoid i) contamination of the material to be dried inside the container and ii) solid and optionally liquid spills of said material from the container to the environment. The invention further provides drying containers comprising a container body and said lid, and methods for the drying of material. The containers and methods of the present invention are in particular suitable for freeze-drying of bulk material, such as biological material or pharmaceutical products. 
     Drying is a common step in many industrial processes, e.g. in the food, chemical, and pharmaceutical industry. The drying of bulk material such as slurries, suspensions, or liquid solutions is commonly carried out in open containers, e.g. in flat open trays. These are placed in a drying chamber, where evaporation of liquid occurs under appropriate conditions, usually at controlled pressure and temperature. The use of such open containers is however disadvantageous in that it bears the double risk of contaminating the material to be dried and of causing liquid or solid spills of said material to the surroundings. Hence, depending on the properties of the material to be dried, it is necessary to work in a clean room to avoid contamination of the dried product, and/or to perform extensive cleaning of the drying chamber. If the material is hazardous, as is the case for many active pharmaceutical ingredients, containment of the material in its wet or liquid state before drying as well as in its final dried state is essential for occupational safety. The containment of the dried product, which often forms fine powders or dust, is particularly challenging. 
     The above points apply in particular to methods of freeze drying or lyophilization. Freeze drying is widely used to improve the stability and handling of foods or pharmaceutical ingredients and compositions. The process comprises preparing and freezing the material to be dried followed by one or more drying steps. A primary drying step involves sublimation of the water/solvent at reduced pressure and temperature. A secondary drying step may involve gradual heating under low pressure conditions so as to remove residual water/solvent. To control the conditions the material is exposed to, it is preferable to precisely monitor temperature and pressure inside the lyophilization container. During lyophilization, evaporation of the solvent at reduced pressure and subsequent ventilation of the drying chamber may give rise to turbulences and cause spills of fine solid particles of the dried product. 
     The purpose of the present invention is to provide a flexible and resource-efficient container for the (freeze-)drying of material, which protects said material from contamination and, at the same time, enables containment of said material. Preferably, the container additionally allows to measure process parameters such as pressure and temperature in the immediate vicinity of the drying material during lyophilization. 
     Several closed or closable containers for bulk (freeze-)drying are known from the prior art. 
     U.S. Design Pat. Nos. D430,939 and D425,205 describe a lyophilization container marketed as Gore® Lyoguard®. It comprises a lyophilization tray with a flexible, thin-film bottom, rigid walls and a spout for filling positioned above the floor of the tray. The tray is topped with a hydrophobic membrane, which is fixed to the tray and cannot be removed without destroying the container. 
     U.S. Pat. No. 6,517,526 teaches a similar sealed lyophilization container comprising a tray with flexible floor, at least one fluid port, and a roof incorporating a hydrophobic membrane. 
     U.S. Pat. No. 5,309,649 describes a lyophilization tray made from a synthetic resin, which is tightly closed by an hydrophobic, porous, micro-organism impermeable, water vapor permeable membrane. 
     EP 2 157 387 describes a very similar container comprising a plastic tray, a water vapor permeable membrane, and an additional snap-on lid allowing to store the dried material inside the lyophilization tray. 
     Each of the above lyophilization containers is designed for single use and thus is resource intensive. Moreover, cutting the container open to recover the dry material bears the risk of introducing debris into the dried product. As the trays are made from synthetic resin, leachables and extractables may be an issue, depending on the solvents present in the material to be dried. There is a need for a more economic and flexible lyophilization container, allowing to select and independently combine the materials of the container body and the membrane. Moreover, there is a need to improve the unloading of closed lyophilization containers. 
     US 2008/0256822 discloses a container for freeze-drying and housing a freeze-dried article, comprising a container body and a cover removably attached to the container body. A nonporous moisture-permeable film is arranged on at least a portion of the cover. The document teaches the use of a O-ring or similar sealing member, but is otherwise silent on how to achieve a tight closure between the container body and the cover. Moreover, such elastic sealing elements are prone to wear and difficult to clean. 
     U.S. Pat. No. 9,278,790 discloses a lid assembly for covering and sealing a lyophilizer tray. The assembly comprises a first lid disposable to seal around the lip of the lyophilizer tray, a second lid positioned on top of the first lid, and a filter paper between both lids. The first lid comprises an opening covered by the filter paper and the second lid, wherein the second lid comprises holes positioned on top of the first lid&#39;s opening. Stoppers may be inserted into the holes to protect the contents of the tray from moisture after drying. The membrane area is small compared to the surface area of the tray, which hinders evaporation of solvent and results in high vapor pressure inside the container. This is undesirable because it may cause inhomogeneity of the resulting lyophilizate as well as leakage due to lifting of the lid, and brings about the need for slow lyophilization cycles to avoid product melt-back. The lid assembly seems to be simply put on top of the tray without any fastening means and keeps on the lyophilizer tray closed due to its weight. 
     There is a need for a robust, versatile and reusable lyophilization container with a large membrane area, which can be easily opened but provides a dust-tight seal in its closed state. Preferably, such a container should allow for the optimal choice and online monitoring of process parameters during drying, e.g. of pressure and temperature inside the container. Moreover, the container should preferably be adaptable to the requirements of good manufacturing practices (GMP). For use in a GMP setting, the container should not set free any leachables or extractables and allow for efficient cleaning of reusable parts. The drying container of the present invention addresses these needs. 
     DISCLOSURE OF THE INVENTION 
     A lid assembly for a drying container is proposed. The lid assembly comprises a lower frame F 1 , an upper frame F 2 , fastening means and a vapor permeable sheet, which is positioned between the two frames and forms a part of the lid&#39;s top wall. Preferably, the sheet is liquid impermeable. The lower frame F 1  and the upper frame F 2  are each shaped as an open box having a base area and at least one side wall. The lower frame F 1  and the upper frame F 2  are arranged such that a circumferential channel of preferably uniform width is formed, an outer side wall of the channel being formed by the side walls of the upper frame F 2 , an inner side wall of the channel being formed by the side walls of the lower frame F 1 , and a top wall of the channel being formed by a broad rim of the upper frame F 2 . The lower frame F 1  and the upper frame F 2  each comprise at least one opening in their respective base area, wherein the at least one opening in the lower frame F 1  at least partially overlaps with the at least one opening in the upper frame F 2 . The sheet covers the at least one opening in the lower frame F 1  and the sheet further covers at least a part of the top wall of the channel. Preferably, the sheet covers the complete top wall of the channel. The lower frame F 1 , the sheet, and the upper frame F 2  are aligned and held together by the fastening means. 
     The upper and the lower frame cooperate with the sheet to affect a tight seal of the container when the lid-assembly is placed on a container body. The sheet, which covers at least a part of the top channel wall, provides a gasket like effect so that no additional seal has to be included. The channel of the lid assembly provides for a relatively broad contact surface with the side walls of the container body and may be fixed to it by reversible fastening means. It was found that the lid assembly of the present invention provides a tight seal and eliminates the need for any elastomeric sealing elements. The width of the channel is chosen such that a mouth of a container body can engage in the channel. Preferably, the width of the channel is chosen from 0.5 to 5 cm, more preferably from 0.5 to 2 cm. 
     Optionally, the lid assembly may include an additional circumferential flat seal which may be inserted between the sheet and the upper frame F 2 . Alternatively or additionally, a flat circumferential flat seal may be inserted between the sheet and the lower frame F 1  and/or between the sheet and the mouth of the container body. 
     The open box-shape of the lower frame F 1  and/or the upper frame F 2  may be obtained by folding a flat plate. For example, a rectangular base area with adjacent flaps may be cut from a flat plate and the side walls are obtained by folding the flaps so that they are substantially at an angle of 90° with respect to the base area. 
     The open box-shape of the lower frame F 1  and/or the upper frame F 2  may preferably include gaps in the side walls, especially at the positions where two of the side walls meet. Such gaps may occur when the open box-shape is obtained by folding. The gaps are then between two adjacent flaps forming two of the side walls. Optionally, the gaps may be closed for example by welding. If the gaps are present, the frames F 1  and F 2  are more flexible and may better follow the shape of a buckled container body. 
     Alternatively, the open box-shape may for example be obtained by molding or deep-drawing. The height of the side walls of the open box-shape defines the depths of the channel. It is preferred that the height of the side walls of the lower frame F 1  and/or the upper frame F 2  are chosen in the range of from 0.5 to 3 cm. 
     The sheet is held between the lower frame F 1  and the upper frame F 2 . The lower frame F 1  and the upper frame F 2  are held together by fastening means. In order for the sheet to be replaceable, it is preferred that the connection between the two frames is releasable. It is preferred to use fastening means to keep the lower frame F 1 , the sheet and the upper frame F 2  aligned and firmly pressed together. Any type of screw, clamp, magnetic, or other fastening means may be used for this purpose. 
     Preferably, the fastening means comprise threaded rods attached to the lower frame F 1 , which extend through holes in the sheet and holes in the upper frame F 2 , and screw nuts screwed onto said threaded rods so as to press the upper frame F 2  and the sheet onto the lower frame F 1 . In order to replace the sheet, the nuts are unscrewed from the threaded rods and the upper frame F 2  is removed. The old sheet is removed and replaced with a fresh sheet. Afterwards, the upper frame F 2  is placed back into the lower frame F 1  and secured with the nuts screwed onto the threaded rods. 
     The lid assembly may be designed to have some flexibility, which allows it to adjust to slight distortions of the container body as can be observed, e.g., in a lyophilization tray. Preferably, the lid assembly is flexible such that the lid assembly fits tightly on top of the mouth of the drying container when a pressing force is applied to the lid assembly. 
     The pressing force may be applied through one or more fastening means to reversibly attach the container body to the lid assembly such as clamps, screws and magnetic fastening means. Said fastening means may be used in variable numbers and variable positions along the container body. 
     Both, the upper frame F 2  as well as the lower frame F 1  preferably comprise a broad rim. The width of the broad rim is preferably from 0.5 cm to 12 cm. The broad rim rims of the lower frame F 1  and the upper frame F 2  at least partially overlap and act as a clamp to securely hold the sheet between the two frames. In order to securely hold the sheet, it is preferred that the overlap region formed by the two broad rims has a width which is preferably from 0.5 to 10 cm, more preferably from 1 to 10 cm, and most preferably from 2 to 7 cm. 
     For an efficient freeze-drying of material covered using the proposed lid assembly, the exposed area of the sheet should be as large as possible during the drying process. A large exposed area of the sheet is important to enable the efficient transfer of vapor/solvent, thereby avoiding a high vapor/solvent pressure inside the drying container as compared to inside the drying chamber. The exposed area of the sheet is the area of the sheet, which is not in direct contact with either the lower frame F 1  or the upper frame F 2 . It should be noted that the exposed area of the sheet will usually vary between drying conditions and the conditions before or after the drying process: During the drying process, the pressure inside the container will usually be slightly higher than outside, due to the evaporating solvent. This typically results in some type of outward bulging of the sheet, thereby minimizing the contact area between the sheet and the lower frame F 1 . 
     The lower frame F 1  preferably comprises a broad rim and the at least one opening in the base area of the lower frame F 1 . Said opening may be formed as a single opening enclosed by the rim, or as a plurality of openings, the rim enclosing the plurality of openings, or as a plurality of holes, wherein the rim is free of holes. Likewise, the at least one opening in the base area of the upper frame F 2  is preferably formed as a single opening enclosed by the rim, or as a plurality of openings, the rim enclosing the plurality of openings. 
     In order to provide a large exposed area of the sheet, it is preferred to choose the size of the single opening or the combined size of the plurality of openings and/or holes as large as possible. The largest area is provided by a single opening which claims essentially the entire base area of the lower frame F 1  and of the upper frame F 2 , respectively. However, especially for large containers, the sheet should not span a large area unsupported in order to prevent the sheet from touching the contents of the lyophilization container. Likewise, supports should be provided to limit the outward bulging of the sheet so as to avoid it contacting the upper walls of the lyophilization chamber. Thus, arranging a plurality of openings at least in the lower frame F 1  is preferred. This allows for the arrangement of a support grid or support braces, which provide support for the sheet. It is preferred to arrange the support grid or support braces such that the exposed area of the sheet is maximized under drying conditions. An example of one such arrangement is shown in  FIG. 3 . 
     Further, there may be the need to minimize uncontrolled evaporation of explosive solvents and protect against electrostatic discharges, especially if the sheet is not electrically conducting. In order to provide for a good protection against electrostatic discharges, it is preferred to use a lower frame F 1  made from an electrically conducting material having a plurality of evenly distributed holes in the base area. Before drying, the exposed area of the sheet is small, because it contacts the lower frame F 1 , thereby minimizing evaporation of the solvent: Evaporation can occur only through those pores of the sheet which are positioned on top of one of the holes in the base area of the lower frame F 1 . However, under the conditions of (freeze-) drying, when a vacuum is applied outside the drying container and the sheet bulges outward, the exposed area of the sheet is markedly increased so as to enable efficient solvent removal. An example of this embodiment of the invention is shown in  FIG. 4 . The size and number of the holes in the base area of the lower frame F 1  is preferably chosen such that under the conditions of (freeze-) drying, the pressure difference between both sides of the sheet is larger than the pressure difference between both sides of the lower frame F 1 . This may be achieved, e.g., if the total area of the holes (=the sum of the holes&#39; areas) in the base area of the lower frame F 1  is at least three times the total area of the pores (=the sum of the pores&#39; areas) of the sheet. Each hole may have essentially the same diameter, e.g., a diameter of between 5 and 50 mm and the material between the holes preferably provides a dense network of electric conductors. 
     Preferably, the lower frame F 1  and/or the upper frame F 2  are made from a metal. A particularly suitable metal is stainless steel. 
     In principle, any vapor permeable sheet may be used with the present invention. As stated before, the sheet must be vapor permeable in order to allow for evaporation of the liquid during the drying process. The permeability of a given sheet may differ for different solvent vapours. It has been found that sheets allowing a passage of at least 10 l, preferably at least 50 l, of air per minute and dm 2  of membrane area at a transmembrane pressure of 200 Pa (&gt;10 l air/min/dm 2 , preferably &gt;50 l air/min/dm 2 ) are particular suitable for use with the present invention in that they enable efficient passage of water/solvent vapor. Hence, a preferred vapor permeable sheet allows the passage of at least 10 l, more preferably at least 50 l, of air per minute and dm 2  of membrane area at a transmembrane pressure of 200 Pa (&gt;10 l air/min/dm 2 , preferably &gt;50 l air/min/dm 2 ). 
     The sheet, which forms part of the lid&#39;s top wall and hence separates the container&#39;s content from the surroundings, will provide a barrier to particulate matter and optionally also to liquids. In the context of the present invention, “providing a barrier to particulate matter and/or to liquids” means that solid/and or liquid material is at least partially contained. Any sheet will do so, due to its sheet structure and its position within the lid assembly. 
     Particulate matter, especially airborne particulate matter, may emerge during drying or freeze-drying. The sheet is preferably constructed such that it is essentially impermeable for particles emerging during the drying or freeze-drying process, i.e. during the drying steps and subsequent steps such as ventilation of the drying chamber and resuspension of the material. Hence, in one embodiment, a vapor permeable sheet is used which provides a barrier to airborne solid particles emerging during the drying or freeze-drying process. Typically, the average size of such emerging particles is between 1 μm and 100 μm as measured by Focused Beam Reflectance Measurement (FBRM) technology. However, the particle size may be larger or smaller, depending on the specific dried product and drying protocol. 
     In practice, the sheet will usually be chosen such that a specific containment level is achieved for a specific drying process with a given drying container according to the invention. The sheet will be chosen such that the mass concentration of dried material in the air of the drying chamber is below a specific value after completion of the drying process with the maximally used load of material to be dried. The required level of containment depends on the nature of the material to be dried. Typical values are, e.g., selected from below 0.05 μg/m 3 , below 0.1 μg/m 3 , below 1 μg/m 3 , and below 10 μg/m 3 . Hence, in one preferred embodiment, a vapor permeable sheet is used, which allows containment of the dried material at a required level. For example, a vapor permeable sheet may be used which allows containment of the dried material such that its maximal concentration in the air of the drying chamber is below 10 μg/m 3 , below 1 μg/m 3 , below 0.1 μg/m 3 , or below 0.05 μg/m 3 . The skilled person will routinely carry out tests with different sheet materials to select an appropriate sheet for his/her specific purposes. Such tests may, e.g., be carried out as described in examples 1 and 2. 
     Preferably, a vapor permeable sheet is used, which is liquid repellent with respect to the liquid component of the sample to be dried, i.e. the sheet&#39;s surface will not be wetted or soaked by said liquid. For example, if the sample to be dried is an aqueous solution or suspension, a sheet with an apolar surface (e.g. from PTFE) will be liquid repellent: Water will not wet such a surface, but drip off, which helps to contain liquid spills caused by splashes. Vapor permeable sheets, which are repellent with respect to organic solvents, are likewise commercially available. 
     Depending on the specific use, not only the sheet&#39;s barrier function as detailed above, but also additional criteria may influence the selection of the sheet. For example, it may be desirable that the sheet is chemically stable, does not release extractables or leachables, and is certified for use in a certain setting. 
     Preferably, the sheet is selected from a) a microporous membrane, b) a nonporous, moisture permeable film, and c) a filter paper. A suitable microporous membrane may for example be made from a material selected from PTFE (polytetrafluoroethylene), expanded PTFE (polytetrafluoroethylene) or PET (polyethylene terephthalate), and composite materials comprising the above. Composite materials may comprise a membrane layer and a support layer. Preferably, the membrane&#39;s pore size is in the range from 0.2 to 100 micrometers, more preferably 1 to 25 micrometers, most preferably from 1 to 7 micrometers. A suitable non-porous, moisture permeable film may be for example selected from one or more copolyether ester elastomers such as DuPont™ Hytrel®. The expression “non-porous”, as used herein, refers to the absence of penetrating pores in both sides of the film as assessed by examination with an electron microscope at a magnification factor of 10,000. Microporous filters as the paper-like Tyvek® may likewise be suitable. In particularly preferred embodiments, the sheet is a PTFE (polytetrafluoroethylene) membrane with 1-2 μm pore size or a PET (Polyethylenterephthalate) membrane with 7 μm pore size. 
     Preferably, the sheet is arranged such that the edges of the sheet are folded back to form a double layer of the sheet within the circumferential channel. By folding the sheet to form a double layer the gasket-like effect of the sheet is enhanced. 
     The lid assembly may further comprise at least one port. 
     The port may be configured as a fixed port having a port opening in the lower frame F 1  and/or a port opening in the upper frame F 2 , and an opening in the sheet, the port openings and the opening in the sheet being aligned and surrounded by a connector arranged on the lower frame F 1  or the upper frame F 2 . The connector is fixed to the lower frame F 1  or to the upper frame F 2  for example by welding. When the port is not in use it is covered by a cap attached to the connector. 
     Alternatively, the port may be configured as a mobile port having a port opening in the lower frame F 1  and/or a port opening in the upper frame F 2 , the port openings being aligned and covered by the sheet prior to the use of the port. 
     The mobile port provides a possibility for arranging a port if needed. If the port is not needed, the sheet covers the openings in the lower frame F 1  and/or in the upper frame F 2  so that no further caps are required. In order to use the mobile port, the sheet is cut to provide a through opening in the lid assembly and a threaded nipple having a through hole and a flange-like lower end is pushed through the opening so that the flange-like structure abuts the respective frame. The nipple is then secured, e.g., by screwing a cap nut onto the nipple. The mobile port may be closed when not in use by attaching a cap to the nipple. 
     In one embodiment, the mobile and/or fixed ports are positioned in an area of the frame, which is depressed relative to the frame&#39;s rim. Such an arrangement is particularly preferred for use with fixed ports in the lower frame. As a result, when the lid is assembled, the fixed port&#39;s connector or mobile port&#39;s nipple will protrude less above the level of the upper frame F 2 &#39;s rim, as compared to an embodiment where the ports are positioned in an area of the frame, which is at level with the frame&#39;s rim. 
     A further aspect of the invention is to provide a drying container. The drying container comprises a container body having a bottom and at least one side wall, the side walls defining a mouth of the container body, the mouth having a contact surface enclosing said mouth, and one of the described a lid assemblies, wherein the contact surface engages the circumferential channel of the lid assembly. 
     The width of the contact surface is preferably chosen from 0.5 to 5 cm, more preferably from 0.5 to 2 cm. The width of the contact surface may be identical to the thickness of the side walls of the container. Alternatively, a rim may be arranged surrounding the mouth of the container in order to enlarge the contact surface. 
     Preferably, the drying container further comprises one or more fastening means to reversibly attach the container body to the lid assembly. The fastening means are preferably selected from clamps, screws and magnetic fastening means. 
     The container body is preferably made from a metal. A suitable metal is for example stainless steel. The container may for example be obtained by welding from a flat plate or by deep-drawing. 
     Typical drying containers have a width in the range of 20 to 40 cm, a length in the range of from 30 to 80 cm and a height of from 3 to 15 cm. It should be noted, however, that one advantage of the present invention is that the size and shape of the drying container is very flexible and can be adapted to the specific needs encountered, e.g. to allow for optimal use of space in a given drying chamber. 
     It is a further aspect of the invention to provide a method for drying of materials. The method comprises the following steps:
         a) introducing the material to be dried into a container body,   b) closing said container body by means of one of the described lid assemblies, and   c) exposing the closed drying container to conditions suitable to effect drying,   wherein steps a) and b) can be carried out in any order.       

     In step a) of the method, the material to be dried may be introduced prior to closing the container by means of a lid assembly. If the material is introduced after the container has been closed, it is preferred for the lid-assembly to comprise at least one port through which the material can be introduced. 
     Drying according to step c) may be effected by placing the container into a lyophilization chamber. 
     A further aspect of the invention is the use of one of the described lid assemblies or one of the described drying containers for the freeze-drying of material. 
     The embodiments of the invention described herein can advantageously be used to dry or freeze-dry bulk materials, in particular solutions comprising active pharmaceutical ingredients. 
     The present drying containers may be used for different purposes and uses. They are flexible in that the various embodiments of the lower frame F 1  and the upper frame F 2  can be combined with an appropriate sheet and container body to meet the requirements of a specific drying process. As a further advantage, they comprise only few single use parts, and most of the container parts can be continuously recycled. 
     The drying containers are assembled from cleaned multi-use parts (e.g. container body, frames F 1  and F 2 , spring clamps) and new single use parts (e.g. sheet, screw nuts, screw caps). Optionally, the assembly may be performed in a clean room, and assembled drying containers may be sealed in plastic film for storage. 
     The drying containers are then transferred to the drying chamber and the material to be dried is introduced. This may be done, in the case of liquid solutions, by pumping the liquid through one of the drying container&#39;s ports into the closed container, or by transferring the material onto the container body and closing the lid afterwards. 
     After completion of the drying program and venting of the drying chamber, the drying containers are removed from the drying chamber and transferred to an area suitable for unloading such as a glove box. The dried product is retrieved from the unloading area in suitably packaged from, e.g. in a bottle or a continuous liner. 
     After unloading of the drying containers, they are transferred, e.g. in a closed trolley, to a suitable area for disassembly and decontamination. This may likewise be a glove box. Single use parts are discarded and the decontaminated multi-use parts are transferred to a cleaning facility. After cleaning, the use cycle recommences. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         FIG. 1 a    shows an exploded view of one embodiment of the drying container of the present invention with a first embodiment of the lid assembly, 
         FIG. 1 b    shows a cross sectional view of the drying container, 
         FIG. 1 c    shows a cross sectional view of the drying container with a folded sheet, 
         FIGS. 2 a  to 2 h    show different embodiments of upper and/or lower frame, 
         FIG. 3 a    shows a top view of a second embodiment of the lid assembly, 
         FIG. 3 b    shows a cross sectional view of the second embodiment of the lid assembly 
         FIG. 4 a    shows a top view of a third embodiment of the lid assembly, 
         FIG. 4 b    shows a cross sectional view of the third embodiment of the lid assembly with the sheet resting on the lower frame F 1 , 
         FIG. 4 c    shows a cross sectional view of the third embodiment of the lid assembly during the drying process, 
         FIG. 5 a    shows an embodiment of a mobile port arranged on the lower frame F 1 , 
         FIG. 5 b    shows an embodiment of a mobile port arranged on the upper frame F 2 , 
         FIG. 5 c    shows an embodiment of a fixed port arranged on the lower frame F 1 , 
         FIG. 5 d    shows an embodiment of a fixed port arranged on the upper frame F 2 , 
         FIG. 6  shows the measurement of the pressure difference between both sides of the sheet of the drying container, 
         FIG. 7  shows the temperature measurement inside the drying container, 
         FIG. 8  depicts a material transfer though a port of the lid assembly, 
         FIG. 9  shows the transfer of liquid through a port of the lid assembly, 
         FIGS. 10 a  to 10 c    show a first embodiment of fastening means to fix the lid assembly to a container body, 
         FIGS. 10 d  to 10 e    show a second embodiment of fastening means to fix the lid assembly to a container body, 
         FIG. 10 f    shows a third embodiment of fastening means to fix the lid assembly to a container body, 
         FIGS. 11 a  and 11 b    show a fourth embodiment of fastening means to fix the lid assembly to a container body, 
         FIGS. 12 a  and 12 b    show a fifth embodiment of fastening means to fix the lid assembly to a container body, 
         FIGS. 13 a  and 13 b    show a sixth embodiment of fastening means to fix the lid assembly to a container body, and 
         FIG. 14  shows an exploded view of a second embodiment of the drying container. 
     
    
    
     The following figures, claims and examples, including the experiments conducted and the results achieved, are provided for illustrative purposes only and are not to be construed as limiting the scope of the claims. Container bodies and lid assemblies of any shape are possible and are not limited to the relative dimensions or the rectangular shape shown in drawings. 
       FIG. 1 a    shows an exploded view of one embodiment of the drying container  10  of the present invention with a first embodiment of the lid assembly  5 . The drying container  10  comprises a container body  1  having a bottom wall  20  and four side walls  21  defining a mouth  19  of the container body  1 . 
     The lid assembly  5  comprises a lower frame F 1   2 , a vapor permeable sheet  3 , and an upper frame F 2   4 , which are stacked in this order. The frames  2 ,  4  are each shaped like an open box with four side walls  17 ,  18 . Each of the frames  2 ,  4  has a rim  11  surrounding an opening  16 . The width of the rim  11  of the lower frame F 1   2  is marked with the reference numeral  6  and the width of the rim  11  of the upper frame F 2   4  is marked with the reference numeral  7 . The sheet  3  is positioned between the two frames  2 ,  4  such that it is clamped between the rims  11  of the two frames  2 ,  4 . 
     The lid assembly  5  is held together by means of threaded rods  12  attached to the lower frame F 1   2 . These threaded rods  12  extend through holes  14  in the sheet  3  and the upper frame  4 . After assembly of the lid assembly  5 , screw nuts (not shown) are put onto the threaded rods  12  to secure the lid assembly  5 . 
       FIG. 1 b    shows a cross sectional view of the drying container  10  as described in  FIG. 1   a.    
     The lid assembly  5  is shown in an assembled state with the sheet  3  securely held between the lower frame F 1   2  and the upper frame F 2   4 . The two frames  2 ,  4  define a circumferential channel  9  having a channel width  8 . The rim  11  of the upper frame F 2   4  defines a top wall of the channel  9 , the side walls  18  of the upper frame F 2   4  define outer walls of the channel  9  and the side walls  17  of the lower frame F 1   2  define inner walls of the channel  9 . 
     The container body  1  has a bottom wall  20  and side walls  21  which define a mouth  19  of the container body  1 . The mouth  19  has a contact surface  13  with a width which is chosen such that the mouth  19  may engage in the channel  9  when the lid assembly  5  closes the drying container  10 . The sheet  3  extends into the channel  9  and at least partially covers the top wall of the channel  9 . When the drying container  10  is closed, the part of the sheet  3  which is located inside the channel  9  serves as a gasket to seal the drying container  10 . 
       FIG. 1 c    shows a variation of the lid assembly  5  of the drying container  10  as described in  FIGS. 1 a  and 1 b   . The sheet  3  of the lid assembly  5  is arranged in the channel  9  such that the edges of the sheet  3  are folded back to form a double layer of the sheet  3  within the circumferential channel  9 . By folding the sheet  3  to form a double layer the gasket-like effect of the sheet is enhanced. 
       FIGS. 2 a  to 2 g    show several embodiments of plates which may be folded into a lower frame F 1  or an upper frame F 2  by folding the flaps  22  by 90°. The fold lines are shown as dashed lines in  FIGS. 2 a  to 2 g   . It should be noted that similar shapes of the lower and upper frames F 1  and F 2  can be obtained by other techniques such as deep drawing. 
     If the plate is used as lower frame F 1 , rods, e.g. threaded rods, may be attached to the plate. If the plate is used as upper frame F 2 , through holes may be drilled for attachment onto the rods of a lower frame F 1 . 
     In  FIG. 2 a    the plate has one single opening  16  which is surrounded by a rim  11 . Both the opening  16  and the rim  11  have a rectangular shape. Four flaps  22  abut the four sides of the rim  11  and may be folded by 90° to form side walls  17 ,  18  of the frames. 
       FIG. 2 b    shows an embodiment of the plate having six openings  16  arranged in three columns and two rows. The six openings  16  are surrounded by the rim  11 . The material of the plate between the openings  16  forms a support grid  24 . 
       FIG. 2 c    shows an embodiment of the plate having four openings  16  arranged in four columns and one row. The four openings  16  are surrounded by the rim  11 . The material of the plate between the openings  16  forms support braces  25 . 
       FIG. 2 d    shows an embodiment of the plate having a plurality of holes  15  which serve as openings  16 . The holes  15  are arranged in a regular pattern inside an area surrounded by the rim  11 . The rim  11  is free of holes  15 . 
       FIG. 2 e    shows an embodiment of the plate having support braces  25  with included port openings  26 . The port openings  26  may be used to attach a mobile port to the frame, and their shape may be chosen depending on the shape of the mobile port, e.g. from square, round, or oval. The width of the support brace  25  is larger in the area surrounding the port opening  26  in order to provide sufficient stability. Alternatively, a support grid  24  with included port openings  26  may be used. Another alternative is arranging a port opening  26  on a tab  29  which projects from the rim  11  into the space of the opening  16 . 
     The number and arrangement of port openings  26  on the plate may be varied. Further, the shape of the port openings  26  may be chosen as required. Examples for suitable shapes of a port opening  26  include circles, ovals and polygonal shapes such as squares or rectangles. 
       FIG. 2 f    shows a variant of the plate of  FIG. 2 e    wherein the port openings  26  are configured for welding of a connector to the port opening  26 . Cuts  31  are provided to compensate for warping due to the welding. 
       FIG. 2 g    shows a plate having six openings  16  and a support grid  24  similar to the embodiment of  FIG. 2 b   . Further, two port openings  26  are provided wherein one of the port openings is provided with cuts  31  to compensate for warping when a connector is welded to the port opening  26 . 
       FIG. 2 h   , panel (i) shows a plate having six openings  16  and a support grid  24  similar to the embodiment of  FIG. 2 b   . Further, a port opening  26  is provided wherein the port opening is located in a cup-like recess of the support grid, such that the port opening and the bottom  23  of the cup-like recess are lowered relative to the level of the rim  11 . Because the walls  27  of the cup-like recess limit warping, no cuts  31  are needed when a connector is welded to the port opening  26 . Panel (ii) shows a blow-up of the part of the support grid, which comprises the port opening. Panel (iii) shows a cross-section of this area in an embodiment where the port is configured as a fixed port with a welded connector  38 . 
       FIG. 3 a    shows a top view of a second embodiment of the lid assembly  5 . 
     The upper frame F 2   4  is configured with three support braces  25  as described with respect to  FIG. 2 c    and has four openings  16 . The lower frame F 1   2  is configured with four support braces  25 . The support braces  25  of the lower frame F 1   2  do not overlap with the support braces  25  of the upper frame F 2   4 . Thus, the lower frame F 1  has five openings  16  which partially overlap with the four openings  16  of the upper frame F 2 . 
       FIG. 3 b    shows a cross sectional view of the second embodiment of the lid assembly  5 . 
     In the situation shown in  FIG. 3 b    a freeze-drying operation is in progress. The sheet  3 , which is held between the lower frame F 1   2  and the upper frame F 2   4 , bulges outward due to a pressure difference. The outward bulging is limited by the support braces  25  of the upper frame F 2 . When there is no pressure difference, the sheet  3  rests on the support braces  25  of the lower frame F 1 . 
     By the alternating arrangement of the support braces  25  of the two frames  2 ,  4  most of the area of the sheet  3  is exposed during the freeze-drying process. Only the area covered by the support braces  25  of the upper frame F 2   4  is covered up. 
       FIG. 4 a    shows a top view of a third embodiment of the lid assembly  5 . 
     The lower frame F 1   2  is configured as described with respect to  FIG. 2 d    and the upper frame F 2   4  is configured as described with respect to  FIG. 2 a   . The sheet  3  is held between the two frames  2 ,  4  and rests on the lower frame F 1   2  when there is no pressure difference. 
       FIG. 4 b    shows a cross sectional view of the third embodiment of the lid assembly  5  with the sheet  3  resting on the lower frame F 1   2 . In the situation shown in  FIG. 4 b    there is no pressure difference between the inside of the drying container  10  and the outside. Thus, the sheet resets on the lower frame F 1   2  and the exposed area of the sheet is small, thereby limiting evaporation of the solvent. If a non-conductive sheet material is used, electrostatic charges may discharge over the material of the lower frame F 1   2  which is in close contact with the sheet  3 . 
       FIG. 4 c    shows a cross sectional view of the third embodiment of the lid assembly  5  when in use in a freeze-drying process. In the situation shown in  FIG. 4 c    there is a pressure difference between the inside of the drying container and the outside so that the sheet  3  bulges outwards. The sheet  3  is held between the rims of the two frames  2 ,  4  but does not rest on the lower frame F 1 . As can be seen in  FIG. 4 c   , nearly the entire area of the sheet  3  is exposed and may effectively be used in the freeze-drying process. 
       FIGS. 5 a  to 5 d    show different embodiments of ports  28 , all of which are drawn in a cross sectional view. 
       FIG. 5 a    shows an example of a mobile port arranged on a lower frame F 1   2 . 
     A threaded nipple  30  with a through hole and a projecting rim  37  at the lower end is inserted through the port opening  26  in the lower frame F 1   2 . The projecting rim  37 , which is not necessarily circumferential, keeps the threaded nipple  30  from slipping through the port opening  26  and/or provides a counter surface for an optional washer  32 . The sheet  3  rests on the lower frame F 1   2  under an optional second washer  32 . A seal  34  surrounds the nipple  30  and the threaded nipple  30  is secured using a screw cap or a screw nut (not shown). The cap may be closed or have a through hole. It should be noted that the outer circumference of the threaded nipple&#39;s lower end is not necessarily circular, but may be adjusted depending on the shape of the opening  26 . 
     In further embodiments a threaded nipple  30  with a lower section having a polygonal or oval shaped outer circumference may be used to provide a mobile port. Likewise, the port opening  26  has a matching polygonal or oval shape. When the lower section of the threaded nipple  30  is inserted in the corresponding port opening  26 , the threaded nipple  30  is secured against rotation. 
       FIG. 5 b    shows an example of a mobile port arranged on the upper frame F 2   4 . 
     A threaded nipple  30  with a through hole and a and a projecting rim  37  at the lower end is inserted through an opening in the sheet  3  and the port opening  26  in the upper frame F 2   4 . A washer  32  is placed between the projecting rim  37  and the sheet  3 . The sheet  3  rests on the washer  32 . A second washer  32  can be used to support the seal  34 . The seal  34  surrounds the nipple  30  and the threaded nipple  30  is secured using a screw cap or a screw nut (not shown). The cap may be closed or have a through hole. 
       FIG. 5 c    shows an example of a fixed port arranged on the lower frame F 1   2 . 
     A connector  38  having a thread is attached to the port opening  26  in the lower frame F 2   2  by welding. The sheet  3  has an opening through which the connector  38  extends. The sheet  3  rests on the lower frame F 1   2 . In order to close the port  28 , a seal  34  is placed over the connector  38  and a cap (not shown) is screwed onto the connector  38 . The cap may be closed or have a through hole. 
       FIG. 5 d    shows an example of a fixed port arranged on the upper frame F 2   4 . 
     The connector  38  is inserted through the port opening  26  in the upper frame F 2   4  and is fixed to the upper frame F 2   4  by welding. The upper frame F 2   4  is placed over the sheet  3 , wherein the connector  38  is inserted through an opening in the sheet  3 . A seal  34  which is secured with a screw nut  36  seals the side facing towards the inside of the container. 
     In order to close the port  28 , a seal  34  is placed over the connector  38  and a cap (not shown) is screwed onto the connector  38 . The cap may be closed or have a through hole. 
       FIG. 6  shows the measurement of pressure inside the drying container  10 . A differential pressure measurement device  42  is provided with a first tube  44  which is inserted through the port  28  into the drying container  10 . The drying container  10  is filled with material  58  to be dried and rests on a shelf  65  of the drying chamber  40 . A second tube  46  opens into the inside of the drying chamber  40 . In this arrangement, the pressure difference between the inside of the drying container  10  and the inside of the drying chamber  40  may be measured. The pressure measurement device  42  may be placed inside or outside the drying chamber  40 . 
       FIG. 7  shows the measurement of temperature inside the drying container  10 . A guide tube  47  with a narrower lower part and a closed, thin bottom is inserted into the port  28  of a drying container  10 . Preferably, the guide tube  47  is made from a material with good thermal conductivity. In order to provide a tight seal, a screw cap  50  with a through hole having a sealing lip  52  is arranged on the port  28 , which is shown in this example as a fixed port with a connector  38 . However, mobile ports may likewise be used. The sealing lip  52  forms a tight seal around the broader upper part of the guide tube  47 . A temperature probe  48  is inserted into the guide tube, such that its sensor contacts the guide tube&#39;s bottom. In order to measure the temperature, the guide tube  47  is pushed down, until its bottom contacts the bottom  20  of the container body. In this way, the temperature in the immediate vicinity of the drying material  58  can be monitored without contaminating the temperature probe or the content of the drying container. 
       FIG. 8  depicts a secure transfer of a sample of material  58  out of the drying container  10  through a port  28  of the lid assembly  5 . A bag  56  is secured to the port  28  by clamping the bag  56  between the sheet  3  and the seal  34  by means of a cap nut  57 . Material  58  may then transferred from the drying  10  container into the bag  56  without the danger of contamination of the surroundings. The bag  56  may then be safely removed, e.g., by applying commercially available safe seal clamps prior to separation with a cutting tool. The clamps will seal both the bag  56  itself and the reminder of the bag  56 , which is left at the port  28  after separation of the bag. The place where the clamps are to be applied is schematically indicated by a dot-and-dash line. 
       FIGS. 9 a  and 9 b    show two different embodiments enabling the transfer of liquid  59  through a port  28  of the lid assembly  5  into the drying container  10 . A hose  66  is attached to the port  28  and allows the transfer of liquid  59  onto the material  58  inside the drying container  10  without the danger of contamination of the surroundings. 
       FIG. 9 a    shows an example of a mobile port comprising a (treaded) nipple inserted in an opening of a lower frame  2 , a (screw) nut  57 , and seal  34 . 
       FIG. 9 b    shows an example of a fixed port comprising a connector  38  welded to the lower frame, seal  34 , and a screw cap  50  with a through hole having a sealing lip  52 . These configurations may either be used to dissolve or suspend the material  58  in the liquid  59  after completion of the drying process. Alternatively, the setup may be used to introduce the liquid material to be dried into the container  10 , i.e. the material  58  and the liquid  59  may be the same. 
       FIGS. 10 a  to 10 c    depict a first embodiment of fastening means to fix the lid assembly  5  to a container body  1 . The fastening means is constructed as a clamp  54  made out of a spring steel plate.  FIG. 10 a    depicts the clamp  54  after cutting the plate and before folding. The dashed lines mark the folds.  FIG. 10 b    depicts the clamp  54  after folding in a top view and  FIG. 10 c    depicts the clamp  54  after folding in a side view. 
       FIGS. 10 d  to 10 e    depict a second embodiment of fastening means to fix the lid assembly  5  to a container body  1 . The fastening means is constructed as a clamp  54  made out of a spring steel plate.  FIG. 10 d    depicts the clamp  54  after cutting the plate and before folding. The dashed lines mark the folds.  FIG. 10 e    depicts the clamp  54  after folding in a side view. 
       FIG. 10 f    depicts a third embodiment of fastening means to fix the lid assembly  5  to a container body  1 . The fastening means is constructed as a clamp  54  made out of a spring steel plate. FIG.  10   f  depicts the clamp  54  after cutting the plate and before folding. The dashed lines mark the folds and the fold angles are indicated. 
       FIGS. 11 a  and 11 b    show a fourth embodiment of fastening means to fix the lid assembly  5  to a container body  1 . The fastening means is constructed as a clamp  54  made out of a spring steel plate.  FIG. 11 a    depicts the clamp  54  after cutting the plate and before folding. The dashed lines mark the folds.  FIG. 11 b    depicts the clamp  54  after folding in a in a side view. 
       FIGS. 12 a  and 12 b    depict a fifth embodiment of fastening means to fix the lid assembly to a container body  1 . The fastening means are constructed as a clamp  54  and a locking block  55 .  FIG. 12 a    depicts the clamp  54  in a perspective view. The clamp  54  has through holes  53  for insertion of a screw bolt (not shown).  FIG. 12 b    depicts the locking block  55 , which is likewise provided with a through hole  53  for insertion of a screw bolt, in a perspective view. 
       FIGS. 13 a  and 13 b    show a sixth embodiment of fastening means to fix the lid assembly  5  to a container body  1 . The fastening means are constructed as magnetic fastening means having a flexible sheet  64  with two attached magnets  60 . The magnets  60  are not movable along the flexible sheet  64 . The magnetic fastening means are folded along fold lines  62  to secure the lid assembly  5  to the container body as shown in  FIG. 13 b   . The end if the flexible sheet  64  forms a little latch facilitating the separation of the magnets in order to open the container 
       FIG. 14  shows an exploded view of a second embodiment of the drying container  10 . 
     The drying container  10  comprises a container body  1  having a bottom wall  20  and four side walls  21  defining a mouth  19  of the container body  1 . 
     The lid assembly  5  comprises a lower frame F 1   2 , a vapor permeable sheet, and an upper frame F 2   4 , all of which are stacked in this order. 
     The lower frame F 1   2  is configured as shown in  FIG. 2 g    and has two ports  28 . One of the ports  28  is configured as a fixed port with a connector  38  welded to the lower frame F 1   2 . The upper frame F 2   4  is configured as shown in  FIG. 2 a    and has an opening  16  which overlaps with the six opening  16  in the lower frame F 2   2 . 
     The lid assembly  5  is held together by means of threaded rods  12  attached to the lower frame F 1   2 . These threaded rods  12  extend through holes  14  in the sheet  3  and the upper frame F 2   4 . 
     After assembly of the lid assembly  5 , screw nuts (not shown) are put onto the threaded rods  12  to secure the lid assembly  5 . 
     The lid assembly  5  is secured to the container body  1  by means of eight clamps  54  as described with respect to  FIGS. 11 a    and  11   b.    
     EXAMPLES 
     Example 1 
     To investigate the need for an elastomeric seal, 20 drying containers as depicted in  FIG. 14  were assembled with an additional silicone flat seal inserted between the sheet and frame F 2  of the lid. The container body, lower frame F 1 , upper frame F 2  and spring clamps were made from stainless steel, a PTFE (polytetrafluoroethylene) membrane with 1-2 μm pore size served as the sheet. The port incorporated into F 1  was closed by a screw cap. The drying containers were placed onto the shelfs of a lyophilization chamber. 
     Each drying container was filled with about 5 l of an aqueous paracetamol solution (10 g/l) using a peristaltic pump, whose outlet tube was connected to the drying container&#39;s port. After removal of the tube, a temperature sensor was inserted into the port, the lyophilization chamber was closed, and the lyophilization program started. 
     After the end of the lyophilization program and venting of the lyophilization chamber, swab tests were taken on the surface of the drying containers and inside the lyophilization chamber. The surface concentration of paracetamol ranged from below the detection limit of &lt;0.01 μg/dm2 to a maximum of 0.02 μg/dm 2 . The concentration of paracetamol in the room air as well as on the testing probes worn by the operator was likewise below the detection limit. 
     The experiment was repeated with 10 drying containers, which differed from the previously used containers only by omission of the silicone flat seal. 
     After the end of the lyophilization program and venting of the lyophilization chamber, swab tests were taken on the surface of the drying containers and inside the lyophilization chamber. The surface concentration of paracetamol was below the detection limit of &lt;0.01 μg/dm 2  in most samples and reached a maximum of 0.03 μg/dm 2 . The concentration of paracetamol in the room air as well as on the testing probes worn by the operator was likewise below the detection limit of &lt;0.01 μg/m 3 . It was therefore concluded that the design of the present drying container enables safe use without the need for an elastomeric seal. 
     Example 2 
     10 drying containers as depicted in  FIG. 14  were assembled and placed onto the shelfs of a lyophilization chamber. The container body, lower frame F 1 , upper frame F 2  and spring clamps were made from stainless steel, a PET (Polyethylenterephthalate) membrane with 7 μm pore size served as the sheet, and was folded back to form a double layer within the lid assembly&#39;s circumferential channel (cf.  FIG. 1 c   ). The port incorporated into F 1  was closed by a screw cap. 
     Each drying container was filled with about 5 l of an aqueous paracetamol solution (10 g/l) using a peristaltic pump, whose outlet tube was connected to the drying container&#39;s port. After removal of the tube, a temperature sensor was inserted into the port, the lyophilization chamber was closed, and the lyophilization program started. 
     After the end of the lyophilization program and venting of the lyophilization chamber, swab tests were taken on the surface of the drying containers and inside the lyophilization chamber. The surface concentration of paracetamol was below the detection limit of &lt;0.01 μg/dm 2  in most samples and reached a maximum of 0.02 μg/dm 2 . The concentration of paracetamol in the room air as well as on the testing probes worn by the operator was likewise below the detection limit of &lt;0.01 μg/m 3 . 
     
       
         
           
               
               
             
               
                   
               
             
            
               
                 1 
                 container body 
               
               
                 2 
                 lower frame F1 
               
               
                 3 
                 sheet 
               
               
                 4 
                 upper frame F2 
               
               
                 5 
                 lid assembly 
               
               
                 6 
                 rim width F1 
               
               
                 7 
                 rim width F2 
               
               
                 8 
                 channel width 
               
               
                 9 
                 channel 
               
               
                 10 
                 drying container 
               
               
                 11 
                 rim 
               
               
                 12 
                 threaded rod 
               
               
                 13 
                 contact surface 
               
               
                 14 
                 hole 
               
               
                 15 
                 holes 
               
               
                 16 
                 opening 
               
               
                 17 
                 side wall F1 
               
               
                 18 
                 side wall F2 
               
               
                 19 
                 mouth (container body) 
               
               
                 20 
                 bottom (container body) 
               
               
                 21 
                 side wall (container body) 
               
               
                 22 
                 flap 
               
               
                 23 
                 bottom (cup-like recess) 
               
               
                 24 
                 support grid 
               
               
                 25 
                 support braces 
               
               
                 26 
                 port opening 
               
               
                 27 
                 side wall (cup-like recess) 
               
               
                 28 
                 port 
               
               
                 29 
                 tab 
               
               
                 30 
                 nipple 
               
               
                 31 
                 cut 
               
               
                 32 
                 washer 
               
               
                 34 
                 seal 
               
               
                 36 
                 screw nut 
               
               
                 37 
                 projecting rim 
               
               
                 38 
                 connector 
               
               
                 40 
                 drying chamber 
               
               
                 42 
                 pressure measurement device 
               
               
                 44 
                 first tube 
               
               
                 46 
                 second tube 
               
               
                 47 
                 guide tube 
               
               
                 48 
                 temperature probe 
               
               
                 50 
                 screw cap with through hole 
               
               
                 52 
                 sealing lip 
               
               
                 53 
                 through hole 
               
               
                 54 
                 clamp 
               
               
                 55 
                 locking block 
               
               
                 56 
                 bag 
               
               
                 57 
                 screw nut 
               
               
                 58 
                 material 
               
               
                 59 
                 liquid 
               
               
                 60 
                 magnet 
               
               
                 62 
                 fold 
               
               
                 64 
                 flexible sheet 
               
               
                 65 
                 shelf 
               
               
                 66 
                 hose