Patent Application
20210316918
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'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.
A lid assembly for a drying container is proposed. The lid assembly comprises a lower frame F1, an upper frame F2, fastening means and a vapor permeable sheet, which is positioned between the two frames and forms a part of the lid's top wall. Preferably, the sheet is liquid impermeable. The lower frame F1 and the upper frame F2 are each shaped as an open box having a base area and at least one side wall. The lower frame F1 and the upper frame F2 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 F2, an inner side wall of the channel being formed by the side walls of the lower frame F1, and a top wall of the channel being formed by a broad rim of the upper frame F2. The lower frame F1 and the upper frame F2 each comprise at least one opening in their respective base area, wherein the at least one opening in the lower frame F1 at least partially overlaps with the at least one opening in the upper frame F2. The sheet covers the at least one opening in the lower frame F1 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 F1, the sheet, and the upper frame F2 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 F2. Alternatively or additionally, a flat circumferential flat seal may be inserted between the sheet and the lower frame F1 and/or between the sheet and the mouth of the container body.
The open box-shape of the lower frame F1 and/or the upper frame F2 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 F1 and/or the upper frame F2 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 F1 and F2 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 F1 and/or the upper frame F2 are chosen in the range of from 0.5 to 3 cm.
The sheet is held between the lower frame F1 and the upper frame F2. The lower frame F1 and the upper frame F2 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 F1, the sheet and the upper frame F2 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 F1, which extend through holes in the sheet and holes in the upper frame F2, and screw nuts screwed onto said threaded rods so as to press the upper frame F2 and the sheet onto the lower frame F1. In order to replace the sheet, the nuts are unscrewed from the threaded rods and the upper frame F2 is removed. The old sheet is removed and replaced with a fresh sheet. Afterwards, the upper frame F2 is placed back into the lower frame F1 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 F2 as well as the lower frame F1 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 F1 and the upper frame F2 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 F1 or the upper frame F2. 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 F1.
The lower frame F1 preferably comprises a broad rim and the at least one opening in the base area of the lower frame F1. 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 F2 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 F1 and of the upper frame F2, 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 F1 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
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 F1 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 F1, 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 F1. 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
Preferably, the lower frame F1 and/or the upper frame F2 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 dm2 of membrane area at a transmembrane pressure of 200 Pa (>10 l air/min/dm2, preferably >50 l air/min/dm2) 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 dm2 of membrane area at a transmembrane pressure of 200 Pa (>10 l air/min/dm2, preferably >50 l air/min/dm2).
The sheet, which forms part of the lid's top wall and hence separates the container'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/m3, below 0.1 μg/m3, below 1 μg/m3, and below 10 μg/m3. 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/m3, below 1 μg/m3, below 0.1 μg/m3, or below 0.05 μg/m3. 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'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'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'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 F1 and/or a port opening in the upper frame F2, 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 F1 or the upper frame F2. The connector is fixed to the lower frame F1 or to the upper frame F2 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 F1 and/or a port opening in the upper frame F2, 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 F1 and/or in the upper frame F2 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'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's connector or mobile port's nipple will protrude less above the level of the upper frame F2'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'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:
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 F1 and the upper frame F2 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 F1 and F2, 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'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.
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.
The lid assembly 5 comprises a lower frame F12, a vapor permeable sheet 3, and an upper frame F24, 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 F12 is marked with the reference numeral 6 and the width of the rim 11 of the upper frame F24 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 F12. 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.
The lid assembly 5 is shown in an assembled state with the sheet 3 securely held between the lower frame F12 and the upper frame F24. The two frames 2, 4 define a circumferential channel 9 having a channel width 8. The rim 11 of the upper frame F24 defines a top wall of the channel 9, the side walls 18 of the upper frame F24 define outer walls of the channel 9 and the side walls 17 of the lower frame F12 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.
If the plate is used as lower frame F1, rods, e.g. threaded rods, may be attached to the plate. If the plate is used as upper frame F2, through holes may be drilled for attachment onto the rods of a lower frame F1.
In
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.
The upper frame F24 is configured with three support braces 25 as described with respect to
In the situation shown in
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 F24 is covered up.
The lower frame F12 is configured as described with respect to
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 F12. 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 F12 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'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.
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 F24. 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.
A connector 38 having a thread is attached to the port opening 26 in the lower frame F22 by welding. The sheet 3 has an opening through which the connector 38 extends. The sheet 3 rests on the lower frame F12. 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.
The connector 38 is inserted through the port opening 26 in the upper frame F24 and is fixed to the upper frame F24 by welding. The upper frame F24 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.
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 F12, a vapor permeable sheet, and an upper frame F24, all of which are stacked in this order.
The lower frame F12 is configured as shown in
The lid assembly 5 is held together by means of threaded rods 12 attached to the lower frame F12. These threaded rods 12 extend through holes 14 in the sheet 3 and the upper frame F24.
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
To investigate the need for an elastomeric seal, 20 drying containers as depicted in
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'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 <0.01 μg/dm2 to a maximum of 0.02 μg/dm2. 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 <0.01 μg/dm2 in most samples and reached a maximum of 0.03 μg/dm2. 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 <0.01 μg/m3. It was therefore concluded that the design of the present drying container enables safe use without the need for an elastomeric seal.
10 drying containers as depicted in
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'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 <0.01 μg/dm2 in most samples and reached a maximum of 0.02 μg/dm2. 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 <0.01 μg/m3.
| Number | Date | Country | Kind |
|---|---|---|---|
| 16182931.2 | Aug 2016 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2017/066964 | 7/6/2017 | WO | 00 |
