Method and device for optimized freeze-drying of a pharmaceutical product

Abstract

A method for lyophilizing a substance is provided which may include placing at least one vial containing the substance in a lyophilization chamber, the at least one vial having an opening in which a stopper is inserted in a closed state not allowing gas exchange between the interior and exterior of the vial; providing mechanical means external to the stopper and arranged at the opening for restricting an upward movement of the stopper; lowering the temperature within the lyophilization chamber to a predefined value below the freezing temperature of the substance and reducing the pressure within the lyophilization chamber to a predefined pressure at a predefined temperature, the predefined pressure being chosen such that the force exerted by it on the stopper lifts the stopper from the closed state to an exchange state in which the stopper is only partly inserted in the opening of the vial allowing gas exchange between the interior and exterior of the vial, wherein the lowering of the temperature within the lyophilization chamber to the predefined value is performed before reducing the pressure within the lyophilization chamber to the predefined pressure and wherein lifting the stopper from the closed state abruptly lowers the pressure within the at least one vial which initiates nucleation in the substance within that vial. In addition, mechanical means is provided which may be used in order to perform the method for lyophilizing a substance.

Claims

1. A method for lyophilizing a substance comprising the steps of: placing at least one vial containing the substance in a lyophilization chamber, the at least one vial having an opening in which a stopper is inserted in a closed state in which the stopper does not allow gas exchange between the interior and exterior of the at least one vial; providing mechanical means external to the stopper and arranged at the opening for restricting an upward movement of the stopper; lowering the temperature within the lyophilization chamber to a predefined value below the freezing temperature of the substance; and reducing the pressure within the lyophilization chamber to a predefined pressure, the predefined pressure being chosen such that the force exerted by it on the stopper lifts the stopper from the closed state to an exchange state in which the stopper is only partly inserted in the opening of the at least one vial allowing gas exchange between the interior and exterior of the at least one vial; wherein the lowering of the temperature within the lyophilization chamber to the predefined value is performed before reducing the pressure within the lyophilization chamber to the predefined pressure; and wherein lifting the stopper from the closed state abruptly lowers the pressure within the at least one vial which initiates nucleation in the substance within the at least one vial.

2. The method for lyophilizing according to claim 1, wherein the mechanical means define a maximum portion of the stopper which can protrude outwardly from the opening of the at least one vial in the exchange state.

3. The method for lyophilizing according to claim 1, wherein the mechanical means are configured to prevent the stopper from falling off the opening of the at least one vial when the stopper is lifted from the closed state.

4. The method for lyophilizing according to claim 1, wherein providing the mechanical means external to the stopper for restricting the upward movement of the stopper includes positioning of shelves within the lyophilization chamber at a predefined distance from each other.

5. The method for lyophilizing according to claim 1, wherein providing the mechanical means external to the stopper for restricting the upward movement of the stopper includes providing a closure device on a neck of the at least one vial which encloses a space above the opening of the at least one vial thereby being configured to restrict the upward travel of the stopper when it is lifted from the closed state into the exchange state.

6. The method for lyophilizing according to claim 5, further comprising the step of: forcing the stopper into and securing it in the closed state after the lyophilization process by pressing the closure device onto the neck of the at least one vial.

7. The method for lyophilizing according to claim 1, wherein providing the mechanical means external to the stopper for restricting the upward movement of the stopper includes placing the at least one vial into the lyophilization chamber in a tray package having a container and a lid, the lid being held at a predefined distance from the container by dynamic elements, the lid being configured to restrict the upward travel of the stopper when it transitions from the closed state into the exchange state.

8. The method for lyophilizing according to claim 1, wherein the predefined pressure corresponds to a pressure value of 800 mbar or less.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a flow chart depicting the method for lyophilizing a substance according to an embodiment of the present invention.

(2) FIG. 2 is a flow chart describing a process of preparing a pharmaceutical substance which includes the method for lyophilizing a substance according to an embodiment of the present invention.

(3) FIG. 3 is a perspective side view showing an empty tray package according to an embodiment of the present invention;

(4) FIG. 4 is a side view perspective view of side view of a tray package according to an embodiment of the present invention containing two vials; and

(5) FIGS. 5A to 5D show the technical implementation of the method for lyophilizing a substance according various embodiments using a closure device as disclosed herein.

DETAILED DESCRIPTION OF THE INVENTION

(6) Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings.

(7) FIG. 1 shows a flow chart 100 depicting the method for lyophilizing a substance according to an embodiment of the present invention in its basic implementation. In a first step 102, the method according to various embodiments may include placing at least one vial containing the substancei.e. the substance to be lyophilizedin a lyophilization chamber, the at least one vial having an opening which is closed by a stopper. In other words, the stopper is in the closed state not allowing gas exchange between the interior and exterior of the vial. In a next step 104, the method may include providing the mechanical means external to the stopper and arranged at the opening of the vial for restricting an upward movement of the stopper. It is to be noted that step 104 may carried out prior to step 102, e.g. if the tray package with the lid is used as mechanical means external to the stopper to secure the stopper in the exchange state. In that case, the at least one vial may be placed in the tray package before the tray package is then placed in the lyophilization chamber. If, on the contrary, the movable shelving plate within a lyophilizer is used as mechanical means external to the stopper to secure the stopper in the exchange state, the shelving plate may be lowered to its predefined position above the at least one vial and thereby fulfill the role of the mechanical means external to the stopper after the at least one vial has been placed in the lyophilization chamber. Thus, the actual chronological order of step 102 and step 104 is irrelevant from the point of view of the inventive concept and is rather determined by practicality. The method according to various embodiments as depicted in FIG. 1 relies on the mechanical means external to the stopper being in place before step 106 is performed. However, prior to step 106, in step 105 the temperature within the lyophilization chamber is lowered to a predefined value below the freezing temperature of the substance. This step may be advantageously performed before the following step 106 in which the pressure within the lyophilization chamber is reduced to a predefined pressure, the predefined pressure being chosen such that the force exerted by it on the stopper is capable of lifting the stopper from the closed state to the exchange state. In the exchange state, the stopper is only partly inserted in the opening of the vial allowing gas exchange between the interior and exterior of the vial. As can be realized, the chronological order of step 102 and step 104 depends on the actual implementation of the mechanical means external to the stopper. The inventive concept embodied by the method as explained may be seen to rely on the mechanical means external to the stopper being fully operational before the stopper of the at least one vial can be lifted from the closed state into the exchange state by underpressure (or, put differently, by a relative overpressure present within the closed vial).

(8) The method disclosed herein may be particularly advantageous in the sense that it is designed for vials which may be placed in a freeze drier in a closed state, i.e. in a state in which the stopper is preventing gas exchange between the interior and the exterior of the vials. This may be advantageous since the vials may be transported into the freeze drier in the closed state, i.e. safely preventing contamination of the interior of the vial. Once the freeze drier is closed, the vials may opened by lowering the pressure within the freeze drier.

(9) A further embodiment of the method for lyophilizing is depicted in the flow chart 200 shown in FIG. 2 in a more extended form. The flow chart 200 depicts a process which may be applied in order to prepare a pharmaceutical substance which includes the method for lyophilizing a substance according to various embodiments of the invention. In the following, the method for lyophilizing as outlined in the flow chart 200 will be described on the basis of a number of vials assuming a highly industrialized process. However, it is to be understood that the process as such is applicable to a single vial as well and does not rely on the presence of a multitude of vials.

(10) The method for lyophilizing a substance according to various embodiments may begin with step 202 in which the vials are filled with the substance to be lyophilized. The filling may be performed according to a standard liquid filling line using an isolator or a reduced access barrier system (RABS).

(11) In a next step 204, each of the vials may be closed with a stopper. The closing process may directly follow the filling process such that the risk of contamination of the substance inside the vials is minimized. A vial may be closed by pushing the corresponding stopper into the neck portion of the vial such that there is no gas exchange between the interior and the exterior of the vial.

(12) After the filling process is finished, the vials may be placed in a lyophilization chamber in step 206. In addition, as an optional step, a closure device of the kind described above may be attached to or placed on the neck portion of the closed vial. If the closure device is designed appropriately as discussed above, then placing the closure device on each vial may be seen as providing mechanical means external to the stopper and arranged at the opening of a vial for restricting an upward movement of the stopper. The closure device may be placed on the vials either immediately after filling or at any subsequent time prior to placing the vials in the lyophilization chamber. Since the vials are closed when they are extracted from the filling line, their transfer to the lyophilization chamber is less critical under the aspect of sterility. Several possibilities exist for placing the vials in the lyophilization chamber. In one embodiment, the vials may be placed in standard loading systems as known from state of the art in the form of racks, e.g. steel racks, before being placed in the freeze drier to improve their handling. In another embodiment, the vials may have already been placed in a special holding container, such as a container of a tray package according to various embodiments, before being filled with a substance to be lyophilized in the filling line. A tray package according to various embodiments may allow the vials to remain therein during the entire filling process and subsequently during the entire freeze-drying process. In addition, the tray package according to various embodiments may include a movably supported lid which may be seen to correspond to the mechanical means external to the stopper and arranged above the opening of a vial for restricting an upward movement of the stopper. The movably supported lid may be attached to the container of the tray package at a distance therefrom at any time. In yet another embodiment that may be used to restrict the movement of the stoppers when the vials are opened via vacuum in the freeze drier the vials may be placed in a rack inside the freeze drier and the distance between the shelves or shelving plates within the freeze drier may be adjusted to define a maximum travel by which the stoppers may be lifted from the vials. This option, however, is only viable if the freeze drier offers this specific functionality.

(13) After the freeze drier has been loaded with the filled and closed vials, there are generally two different freezing patterns which may be applied in order to transform the previously liquid substance into a solid lyophilisate.

(14) First, step 208 will be described which comprises opening of the vials by underpressure. Here, the chamber of the freeze drier is evacuated down to a pressure which exerts enough force to pull the stoppers which close the vials into their exchange states. Optionally the temperature of the freeze dryer may be lowered to a temperature above the thermodynamic freezing temperature of the substance before evacuation, for example to a temperature between approximately 5 C. and 10 C. above the thermodynamic freezing temperature of the substance. By doing so situations may be prevented in which the substance boils which would lead to a highly inhomogeneous ice structure within the frozen substance. This step may also prevent boiling of the substance during the subsequent steps.

(15) After all stoppers have taken their exchange positions (which may take a certain time since the opening time of a vial is a stochastic process), the temperature within the freeze drier may be lowered to a freezing temperature well below the thermodynamic freezing temperature and well below the glass transition temperature, e.g. to 45 C. for aqueous solutions, in order to induce conventional freezing of the substance to be lyophilized in step 212. Since the temperature at which the supercooled solution contained in a vial spontaneously forms ice is a randomly distributed parameter, the substance in each of the vials freezes at a different temperature in the freezing step 212 and hence at a different point in time. Due to the stochastic spread of the nucleation temperatures, choosing the freezing temperature to lie well below the standard freezing temperature of the substance to be lyophilized is essential in order to eventually obtain frozen lyophilisate in each of the vials.

(16) The random distribution of nucleation temperatures may cause the content of each vial to nucleate at a different temperature which may result in different ice crystal structure, prolonged drying time and batch inhomogeneity. However, independent of those circumstances, after the vials have been exposed to a temperature well below the standard freezing temperature of the lyophilisate for a certain time, at the end of step 208 the substances to be lyophilized in all vials are frozen and ready for the next stage in the lyophilization process.

(17) As an alternative to step 208, step 210 may be executed after the vials with stoppers in stealing state have been placed in the lyophilization chamber in step 206. In step 210, the order of lowering the temperature and opening of the vials is reversed as compared to step 208. In step 210, before opening the vials by underpressure, the temperature within the lyophilization chamber is lowered to a temperature slightly below the standard freezing temperature of the lyophilisate, for example to 5 C. or 10 C. for aqueous solutions. As can be seen, this temperature is significantly higher that the temperature which is set in the lyophilization chamber in step 208. Due to the high purity of the solution, it remains liquid in a supercooled state in each vial, even though that temperature is chosen to lie below the standard freezing temperature of the solution. The vials may be left to rest at that temperature until they are all equilibrated at that same temperature. Next, the pressure in the lyophilization chamber is lowered to a predefined value, e.g. to 200 mbar. One of the factors defining the predefined pressure value may be the force required to move the stoppers from their closed state into the exchange state. Even though the pressure required for this to happen may be calculated, the actual pressure at which a respective stopper pops out of the vial into the exchange state is subject to stochastic variations. In other words, the time it takes for each vial to be opened is randomly distributed and, depending on the size of the batch of processed vials, may last anything from a few minutes to a few tens of minutes.

(18) Once a vial is opened by the stopper moving to the exchange state, the pressure inside the vial drops abruptly to the predefined value prevailing in the lyophilization chamber. This sudden drop of pressure which may be assumed to be on the order of the ambient pressure minus the predefined pressure prevailing in the lyophilization chamber acts as a nucleation impulse and thus triggers nucleation in the substance to be lyophilized, i.e. the formation of nucleation seeds from fog formation in the atmosphere above the solution within the vial due to over-saturation. Still, it cannot be predicted when a respective vial is opened and consequently when the subsequent formation of ice in a respective vial takes place. The fundamental difference to step 208 is, however, that the nucleation in each of the vials takes place at the same precisely defined temperature, namely the temperature which is prevailing in the lyophilization chamber (e.g. for aqueous solutions the temperature of 5 C. or 10 C. mentioned above) and at which all of the vials have equilibrated. The advantage of this mode of operation may be seen in that the content in each vial nucleates at the same relatively high temperature i.e. slightly below the thermodynamic freezing point of the substance. In other words, independent of the point in time at which the nucleation in a respective vial may take place, the nucleation process in step 210 always takes place at the temperature prevailing in the lyophilization chamber. In that sense, the nucleation in step 210 may be seen to take place in a controllable manner. The advantages of controlled nucleation in respect to product quality, batch uniformity, process time and process cost saving are well described in the literature, for example in Controlled ice nucleation in the field of freeze-drying: Fundamentals and technology review by R. Geidobler and G. Winter in European Journal of Pharmaceutics and Biopharmaceutics 85 (2013), pages 214-222.

(19) Independent of the actual implementation of the step in which the vials are opened by means of underpressure, i.e. either according to step 208 or step 210, in each of those steps the mechanical means external to the stopper and arranged at the openings of the vials for restricting an upward movement of the stopper may be applied or may become effective in order to prevent the stoppers from popping out too far from the vial and falling off the vial. When the mechanical means are applied, it may be guaranteed that the stopper will not fall off the neck portion of the vial.

(20) Independently of the actual implementation of the opening process of the vials (i.e. conventional opening according to step 208 or opening with controlled nucleation according to step 210), subsequently the freezing step 212 is performed. The freezing process in step 212 is a conventional thermodynamic process in which the substance transitions from liquid phase into solid phase.

(21) After the drying step 214 which is performed after the freezing step 212, the frozen and dried lyophilisate, i.e. the end product, is enclosed within the vial in step 216 by pushing the stopper from the exchange state into the closed state. This may be performed by lowering a shelving plate within the freeze drier towards the neck portions of the vials just enough to push the stoppers back into the necks of the vials such that they take the closed state again. It is to be noted that the lowering of a movable shelving plate within the lyophilization chamber works in combination with any of the mentioned means external to the stopper and arranged at the openings of the vials for restricting an upward movement of the stoppers. In the case of the movable shelving plate itself fulfilling the role of the external mechanical means, the shelving plate may be trivially just lowered further until the stoppers have reached their final state (closed state). In the case of the closure device being provided on the neck of each vial, the shelving plate may exert a pushing force on the closure device which in turn pushes down on the stopper. In the last case of the lid of the tray package according to various embodiments fulfilling the role of the eternal mechanical means, the shelving plate is lowered and exerts a pushing force on the lid which in turn exerts a force on the stoppers. The tray package and its use will be described in more detail below.

(22) In the last step 218 of the method depicted in the flowchart 200, the vials can be unloaded from the freeze drier. Since the vials are hermetically closed, the risk of contaminating the end product is eliminated.

(23) In the state of the art, a lyophilization method is known in which a lyophilization chamber is first pressurized, for example to a pressure of approximately 2 bar, and then a ventilation valve is opened to abruptly reduce the pressure in the lyophilization chamber to induce nucleation in the materials to be lyophilized. In other words, this method relies on a buildup of overpressure which is quickly released to generate a strong pressure drop which acts as nucleation trigger. However, in order to apply this method, a common lyophilization apparatus has to be fitted subsequently with the ventilation valve and an extra input which may be used to pressurize the lyophilization chamber. Both measures are time consuming and incur costs.

(24) The method for lyophilizing a substance according to various embodiments can be applied without pressuring the chamber. As has been described with regard to step 210, the pressure drop is generated by the sudden transition of the stopper from the closed state to the exchange state. This transition takes place practically instantaneously and thus generates a steep pressure drop inside the vial, wherein the pressure drop rate is given by the difference of the pressure within the vial (e.g. approximately 1 bar) and the pressure within the lyophilization chamber (e.g. 100 mbar or e.g. 200 mbar) at the point of vial opening, divided by the time need for reaching this state. The opening of the closed vial which is practically an instantaneous process may be safely assumed to take place on a timescale of less than a second, e.g. between a few tens of milliseconds and a few hundreds of milliseconds. In other words, in the method for lyophilizing a substance as disclosed herein the nucleation process is controlled or initiated locally, i.e. by an event that affects each vial individually and independently, namely the lifting of a stopper to the exchange state in a respective vial resulting in extremely high pressure drop rates due to spontaneous opening of single each single vial. The solvent vapour saturation of the gas atmosphere above the solution of each closed vial is reliably in an equilibration state. The extremely high rate of pressure loss by promptly lifting the stopper ensures adiabatic cooling with generation of the ice fog providing instantly nucleation seeds for initiating freezing which spreads from the surface of the solution into the solution. In contrast thereto, in the method known from the state of the art, the nucleation is initiated by a global event, i.e. simultaneously for the whole batch of vials, by venting the lyophilization chamber which results in much lower pressure drop rates due to principal technical limitations and therefore to less reliable adiabatic cooling.

(25) A further advantage may be seen in the fact that common lyophilization devices may be used to perform the method disclosed herein without any costly and time consuming upgrades or modifications. A yet further advantage may be seen in the fact that the venting of the vials takes place in a hermetically sealed and sterilized environment (i.e. the lyophilization chamber). Therefore, neither can the content of the vials be contaminated with pollutants from outside of the lyophilization chamber, nor can toxic evaporates from the vials contaminate the ambient air outside of the lyophilization chamber, e.g. the space surrounding the cleanroom area.

(26) As mentioned above, in order to perform the method for lyophilizing a substance as described herein with a high success rate, the stoppers need to be pushed back into the closed state after the vials have been freeze dried. As already outlined above, various kinds of mechanical means external to the stopper and arranged at the opening for restricting an upward movement of the stopper may be provided to prevent the stoppers falling off the neck or neck portions of the vials.

(27) In FIG. 3, the tray package 300 according to various embodiments is shown which includes the mechanical means external to the stopper. The tray package 300 includes a container 302, a holding element 304 arranged within the container 302 and having at least one opening 306 therein for holding a vial. The holding element 304 may be configured as a tray with openings 306 for accommodating vials such that the vials may processed and/or safely transported without the risk of bumping against each other and breaking. The form/diameter of the openings 306 may be adapted to the form of the vials to be placed therein. The tray package 300 further includes a lid or a cover 308 which is movably supported at a predefined distance from the container 302. In FIG. 2, the lid 308 is indicated as a seemingly transparent parallelogram with a dashed contour in order to be able to show the structure of the tray package 300 that would in real life would be obscured by the lid 308.

(28) The tray package 300 may further include at least one dynamic element 310 which may be configured to enable movement of the lid 308. In some embodiments of the tray package 300 according to various embodiments, the at least one dynamic element 310 may be a deformable element such as a rubber cylinder or a spring. The deformable element may be one that deforms elastically, i.e. reversibly, or plastically, i.e. irreversibly. In FIG. 3, four dynamic elements 310 are shown (only two of the four carrying the corresponding label), each arranged in a corner of the container 302. Even though this configuration may be mechanically favorable, other configurations in which, for example, a dynamic element 310 is provided somewhere, e.g. in the middle, of each of the four sides of the container 302 are conceivable as well. The lid 308 and/or the dynamic elements 310 are configured such that in the quiescent position the distance between the inner surface of the lid 308 and the container 302 is such that the stoppers from vials (not shown in FIG. 3) placed in the container 302 cannot be completely lifted from the necks or neck portions of the vials and fall off. This aspect will be described in more detail with reference to the next figure. In further embodiments, the dynamic elements 310 may be configured as adjustable mechanical means which provide movability to the lid 308 by passive or active adjustment without being deformed. For example, at least one of the dynamic elements 310 may be configured as motor based (active) lifting device and the remaining dynamic elements 310 may be configured as passive lifting devices which act passively based on the action of the motor based (active) lifting device.

(29) A side view of a simplified tray package 300 including only two vials 405, 406 carrying a substance to be lyophilized 410 inside is shown in FIG. 4. Elements corresponding to elements of the tray package 300 already explained based on FIG. 3 carry the same reference numbers and will not be described again.

(30) In the embodiment of the tray package 300 shown in FIG. 4, the dynamic elements 310 are configured as springs. The tray package 300 is shown in its quiescent state where no force (except the weight force of the lid 308) is acting on the dynamic elements 310 and thus the lid 308 is in its quiescent position. The left vial 405 is shown in a closed state, i.e. with the left stopper 403 in the closed state. Since the stopper is completely inserted into the neck portion 414 of the left vial 405, no gas exchange between the inside and the outside of the left vial 405 can take place. The right vial 406 is shown in the exchange state, i.e. with the right stopper 404 in the exchange state, such that the vial 406 is partially stoppered and ventilation openings extend above the right vial 406. It is to be mentioned that even though only a lyo (lyo: abbreviation for lyophilization) stopper 403, 404 of the two leg type is illustrated in FIG. 4, stoppers of the iglu type as well as other types of lyo stoppers may also be used. Consequently, in the case of the right vial 406, gas exchange between the inside and the outside of the vial can take place. The lid 308 may further comprise optional protrusions on its inner side (not shown in FIG. 4). The protrusions may be used in order to fine tune the distance between the inner surface of the lid 308 and the container 302 or the upper rims 416 of the vials 405, 406 provided therein to the required value. However, instead of providing the protrusions this distance may be adjusted by modifying the dynamic elements 310. The optional protrusions may take any shape such as trapezoidal, quadratic or cylindric and may be, for example, formed by embossing, i.e. by deforming the originally flat lid 308 locally such that the thickness of the lid 308 substantially remains the same. In general, the material of the lid may be different from the material of the protrusions. For example, while the lid 308 may comprise a metal, the protrusions may include a soft material which will not scratch or damage the upper rims of the vials 405, 406 when it comes in contact with those.

(31) The distance between the inner surface of the lid 308 and the container 302 or the upper rims 416 of the vials 405, 406 provided therein in the quiescent state of the lid 308 is configured such that the upper surface of the stopper 404 in the exchange state may touch the inner surface of the lid 308 as shown in the case of the right vial 406 in FIG. 4.

(32) The embodiment of the tray package 300 shown in FIG. 4 further comprises optional guiding elements 412 which restrict the motion of the lid 308 to a one-dimensional movement, i.e. along the axis defined by the guiding elements 412. In this embodiment the guiding elements 412 are configured as rods which extend from the inner surface of the lid 308 downwards into hollow ducts (not explicitly shown in FIG. 4) which are provided in the sidewalls of the 302 just below the guiding elements 412. During movement of the lid 308, the guiding elements 412 slide into the hollow ducts and confine the motion of the lid 308 to a uniaxial motion. Here, the guiding elements 412 are implemented into the dynamic elements 310, i.e. provided as one unit. In other embodiments, the guiding elements 412 may be provided separately from the dynamic elements 310. For example, while the springs 310 in FIG. 4 are provided at corner positions, each of the guiding elements 412 may be provided at some position along any one side of the container 302. The number of guiding elements 412 may be generally different from the number of dynamic elements 310. For example, three guiding elements 412 of the kind shown in FIG. 4 will suffice to guarantee a uniaxial motion of the lid 308, i.e. without any torsion and/or shifts of the lid 308 to the sides.

(33) The guiding elements 412 in FIG. 4 simultaneously fulfill the role of spacer elements, defining a maximum distance between the lid 308 and the box 308 or the upper rims 416 of the vials. The length of the guiding elements 412 (or the depth of the hollow ducts, respectively) may be configured such that the guiding elements 412 hit the bottom of the hollow ducts once a desired end position of the lid 308 has been reached. Thus, in the embodiment of the tray package 300 shown in FIG. 4 the guiding elements 412 may be additionally seen as safety elements which prevent the lid 308 from being pushed too far towards the container 302 and damaging the vials 405, 406. Depending on the actual implementation of the dynamic elements 310, the guiding elements 412 and the spacer elements, the spacer elements may be provided as separate elements which are independent from the other two.

(34) In FIGS. 5A to 5D, the technical implementation of the method for lyophilizing a substance according various embodiments based on a closure device 504 as disclosed herein is depicted. In each of the figures, a different stage of the lyophilization process is shown. In each of the figures a vial 405 filled with the substance to be lyophilized 410 is shown which is arranged on a lower shelf or shelving plate 502. Above the vial 405, an upper shelf or shelving plate 308 is provided which was already shown in FIG. 4. In the simplified application example shown in FIGS. 5A to 5D, the tray package is omitted and the view is focused on one vial only, the one exemplary vial shown being representative of a batch of vials which are processed in a lyophilization chamber. However, the lower portion of the tray package including at least the container and the holding element for secure holding of vials may be of course provided. The lid may be omitted as its function is provided by the closure device 504 arranged on the neck of the vial 405.

(35) FIG. 5A shows a stage of the lyophilization process in which the vial 405 is located in the lyophilization chamber. The stopper 403 is in the closed state, preventing a gas exchange between the interior and exterior of the vial 405. The closure device 504 is arranged at the opening of the vial 405. As can be seen, at this stage there is a hollow space 508 above the stopper 403 which is enclosed by the closure device 504. In other words, the closure device 504 is configured such that, when placed on the neck of the vial 405, it encloses a hollow space 508. The closure device 504 may include fastening means 510 by which the closure device 504 may be attached to the rim of the vial 405.

(36) FIG. 5B shows a stage of the lyophilization process in which the stopper 403 has been moved from the closed state as shown in FIG. 5A into the exchange state. As described previously, this can be done by creating a vacuum in the lyophilization chamber. The resulting buildup of a relative overpressure inside the vial 405 causes the stopper 403 to be pushed out of the opening of the vial 405 at some point during buildup of the vacuum. As can be seen in FIG. 5B, after the stopper 403 has been pulled out of the opening of the vial 405, it advances into the hollow space 508. The closure device 504 may be configured such that the hollow space 508 is explicitly adjusted to the stopper 403, e.g. the upper part of the stopper 403, in the sense that the stopper 403, when being lifted from the closed state, may advance into the hollow space 508 without any hindrance from the closure device 504. At this stage of the process, the stopper 403 is in the exchange state and permits a gas exchange between the interior and exterior of the vial 405. It goes without saying that the closure device 504 is configured such that in its unsealing state (i.e. as shown in FIG. 5A) it does not form a hermetic seal around the opening of the vial 405. In other words, the closure device 504 includes openings or channels which, in the unsealing state thereof, permit gas exchange between the interior of the vial 405, the hollow space 508 and the surrounding atmosphere.

(37) FIG. 5C shows a stage of the lyophilization process in which the upper shelf 308 has been collapsed towards the lower shelf 502 and thereby towards the upper portion of the closure device 504, as indicated by the arrow 506. This step may be performed after the lyophilisate has been frozen and subsequently dried. The lowering of the upper shelf 308 from its position shown in FIG. 5B towards the vial 405 is used to exert pressure on the closure device 504. The closure device 504 is constructed such that it may be collapsed and thus the upper shelf 308 ultimately pushes the stopper 403 into the opening of the vial 405. In other words, in this step the vial 405 is closed by bringing the stopper 403 into the closed state back again. The closure device 504 may have an outer part and an inner part which are movable with respect to one another when pressure is applied to at least one of the parts. In this example, when pressure is applied to the outer part of the closure device 504, i.e. the part indicated by the two antenna-like portions at each side of the closure device 504, the fastening means 510 may be configured to unlock by the relative movement of the outer part of the closure device 504 towards the inner part of the closure device 504 such that eventually the whole closure device 504, while being arranged on the neck portion of the vial 405, is pushed downwards. It may be seen that during this process the hollow space 508 is collapsed by the closure device 504 advancing downwards on the neck portion of the vial 405. In the final state of the closure device 504 as shown in FIG. 5C, i.e. when the stopper 503 has been pushed into the opening of the vial 405, the closure device 504 may be configured to form a hermetic seal around the opening of the vial 405.

(38) Finally, in FIG. 5D, the final stage of the lyophilization process is shown in which the upper shelf 308 is lifted back up to its default position as indicated by the arrow 512. The closure device 504 remains in its sealing state arranged around the opening of the vial 405 which is hermetically sealed and may be unloaded from the freeze drying chamber.

(39) While preferred embodiments of the invention have been described and illustrated above, it should be understood that these are exemplary of the invention and are not to be considered as limiting. Additions, omissions, substitutions, and other modifications can be made without departing from the scope of the present invention. Accordingly, the invention is not to be considered as being limited by the foregoing description, and is only limited by the scope of the appended claims.