Lyophilization promoting element

Abstract

A lyophilization promoting element to facilitate the transfer of heat between a lyophilizer and a pre-lyophilization solution. The element includes a base plate with a plurality of apertures. The base plate is made of a thermally conductive material and the apertures are regularly arranged within the base plate, each aperture being sized to receive a pharmaceutical vial container containing a pre-lyophilization solution. A method of lyophilizing includes inserting one or more pharmaceutical vial containers into the plurality of apertures of the lyophilization promoting element and placing the lyophilization promoting element holding the one or more pharmaceutical vial containers on a shelf of a lyophilizer.

Claims

1. A lyophilization promoting element comprising: a base plate comprising a plurality of apertures; the base plate comprising a thermally conductive material; the apertures being regularly arranged within the base plate, and each aperture being sized to receive a pharmaceutical vial container containing a pre-lyophilization solution; wherein the lyophilization promoting element facilitates a transfer of heat between a lyophilizer and the pre-lyophilization solution, and wherein the base plate comprises a hollow polymeric material and a fluid with a negative thermal expansion property.

2. The lyophilization promoting element of claim 1, wherein the base plate comprises aluminum or an oxide of aluminum.

3. The lyophilization promoting element of claim 1, wherein each of the plurality of apertures is cylindrical and has a diameter between 5 and 100 millimeters.

4. The lyophilization promoting element of claim 1, wherein each of the plurality of apertures comprises a circumferential wall and is sized to allow a tolerance of no more than 0.5 millimeters between the circumferential wall and an outer wall of an inserted pharmaceutical vial container.

5. The lyophilization promoting element of claim 1, wherein the base plate has a vertical thickness between 10 and 200 millimeters.

6. The lyophilization promoting element of claim 1, wherein the base plate comprises a surface area and the plurality of apertures occupy more than 50% of the surface area.

7. The lyophilization promoting element of claim 1, wherein at least one of the plurality of apertures extends entirely through a vertical thickness of the base plate.

8. The lyophilization promoting element of claim 1, wherein at least one of the plurality of apertures extends only partially through a vertical thickness of the base plate.

9. The lyophilization promoting element of claim 1, wherein each of the plurality of apertures further comprises a radial groove, the radial groove expanding outwardly from a circumferential wall of each aperture adjacent to a top surface of the base plate.

10. The lyophilization promoting element of claim 9, wherein each radial groove extends at an angle of approximately 45 degrees to a depth of approximately 0.5 to 10 millimeters from the top surface of the base plate down to the circumferential wall of each aperture.

11. A lyophilization promoting element comprising: a base plate comprising a plurality of apertures; the base plate comprising a thermally conductive material; the apertures being regularly arranged within the base plate, and each aperture being sized to receive a pharmaceutical vial container containing a pre-lyophilization solution; wherein the lyophilization promoting element facilitates a transfer of heat between a lyophilizer and the pre-lyophilization solution; wherein each of the plurality of apertures extends only partially through a vertical thickness of the base plate and the base plate further comprises a plurality of protrusions extending up from the base plate into each of the plurality of apertures.

12. The lyophilization promoting element of claim 11, wherein the base plate comprises a thermally conductive material with a thermal conductivity coefficient λ of about 0.1 to about 400.0 [W/mK] at 20° C. at 1 bar and a co-efficient of linear thermal expansion α of about 1 to about 25 [10.sup.−6° C..sup.−1] at normal temperature.

13. The lyophilization promoting element of claim 11, wherein the protrusions are sized and shaped to match an internal bore provided in a bottom of an inserted pharmaceutical vial container, said internal bore extending upwardly into an interior of said inserted pharmaceutical vial container.

14. The lyophilization promoting element of claim 1, wherein the base plate comprises a first portion comprised of a primary material and a second portion comprised of a secondary material, the second portion being located adjacent to a circumferential wall of each of the plurality of apertures.

15. The lyophilization promoting element of claim 1, wherein each of the plurality of apertures extends entirely through a vertical thickness of the base plate and further comprises a radial ridge, the radial ridge extending inwardly from a circumferential wall of each aperture adjacent to a bottom surface of the base plate.

16. The lyophilization promoting element of claim 15, wherein each radial ridge extends at an angle of approximately 45 degrees to a height of approximately 0.5 to 6 millimeters from the bottom surface of the base plate up into each aperture to meet the circumferential wall of each aperture.

17. The lyophilization promoting element of claim 1, wherein each of the plurality of apertures further comprises at least one side channel that permits the passage of air, said side channel having a width no greater than 10% of a perimeter of the aperture.

18. A method of lyophilization comprising steps of: providing a lyophilization promoting element comprising: a base plate comprising a plurality of apertures, the base plate comprising a thermally conductive material; the apertures being regularly arranged within the base plate; wherein the lyophilization promoting element facilitates the transfer of heat between a lyophilizer and the pre-lyophilization solution; providing one or more pharmaceutical vial containers containing a pre-lyophilization solution, the one or more pharmaceutical vial containers being half stoppered; inserting the one or more pharmaceutical vial containers into the plurality of apertures of the lyophilization promoting element; providing a tray; placing the lyophilization promoting element holding the one or more pharmaceutical vial containers on the tray; placing the tray and the lyophilization promoting element holding the one or more pharmaceutical vial containers on the shelf of the lyophilizer; removing the tray from between the shelf of the lyophilizer and the lyophilization promoting element, leaving the lyophilization promoting element holding the one or more pharmaceutical vial containers on the shelf of the lyophilizer; closing a door to the lyophilizer and initiating the lyophilization process, said lyophilization process comprising the steps of freezing, primary drying, and secondary drying; reinserting the tray between the lyophilizer shelf and the lyophilization promoting element and removing the tray and the lyophilization promoting element holding the one or more pharmaceutical vial containers from the lyophilizer upon completion of the lyophilization process; and fully stoppering and sealing the one or more pharmaceutical vial containers.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows a partial cross-sectional view from the side of a pharmaceutical vial loaded on the shelf of an exemplary, generally-known lyophilizer using methods known in the prior art.

(2) FIG. 2 shows a cross-sectional view from above of an exemplary, generally-known lyophilizer shelf filled with a plurality of vials using methods known in the prior art.

(3) FIG. 3a shows a front perspective view of a lyophilization promoting element according to exemplary embodiments of the present invention.

(4) FIG. 3b shows an orthogonal view from above of a lyophilization promoting element according to exemplary embodiments of the present invention as depicted in FIG. 3a.

(5) FIG. 3c shows a cross-sectional view from the side of a lyophilization promoting element according to exemplary embodiments of the present invention as depicted in FIGS. 3a and 3b.

(6) FIG. 4a shows an orthogonal view from above of a lyophilization promoting element according to exemplary embodiments of the present invention.

(7) FIG. 4b shows a cross-sectional view from the side of a lyophilization promoting element according to exemplary embodiments of the present invention as depicted in FIG. 4a.

(8) FIG. 4c shows a blown-up, front perspective view of a pocket of a lyophilization promoting element according to exemplary embodiments of the present invention as depicted in FIGS. 4a and 4b.

(9) FIG. 5 shows a schematic depiction of the installation of a lyophilization promoting element onto a lyophilizer shelf for processing according to exemplary embodiments of the present invention.

(10) FIG. 6a shows a cross-sectional view from the side of a bottom hollow pharmaceutical vial container according to exemplary embodiments of the present invention.

(11) FIG. 6b shows a cross-sectional view from the side of a bottom hollow pharmaceutical vial container according to exemplary embodiments of the present invention.

(12) FIG. 6c shows a cross-sectional view from the side of a bottom hollow pharmaceutical vial container according to exemplary embodiments of the present invention.

(13) FIG. 7 shows a series of cross-sectional views from the side of lyophilization promoting elements according to exemplary embodiments of the present invention loaded with bottom hollow pharmaceutical vial containers according to exemplary embodiments of the present invention as depicted in FIGS. 6a-6c.

(14) FIG. 8 shows an orthogonal view from above of a lyophilization promoting element according to exemplary embodiments of the present invention as depicted in FIG. 7.

(15) FIG. 9a shows a cross-sectional view from the side and an orthogonal view from above of a lyophilization promoting element according to exemplary embodiments of the present invention.

(16) FIG. 9b shows a close-up, cross-sectional view from the side of a pocket of the lyophilization promoting element depicted in FIG. 9a.

(17) FIG. 10 shows a cross-sectional view of a pharmaceutical vial container within a pocket of a lyophilization promoting element according to exemplary embodiments of the present invention.

(18) FIG. 11 shows a cross-sectional view of a pharmaceutical vial container within a pocket of a lyophilization promoting element according to exemplary embodiments of the present invention.

(19) FIG. 12 shows a cross-sectional view of a pharmaceutical vial container within a pocket of a lyophilization promoting element according to exemplary embodiments of the present invention.

(20) FIG. 13 shows a cross-sectional view of a pharmaceutical vial container within a pocket of a lyophilization promoting element according to exemplary embodiments of the present invention.

(21) FIG. 14a shows a front perspective view of a flat-bottom, short height pharmaceutical vial container according to exemplary embodiments of the present invention.

(22) FIG. 14b shows a front perspective view of a flat-bottom, short height pharmaceutical vial container according to exemplary embodiments of the present invention.

DETAILED DESCRIPTION

(23) Presently described herein is an efficient solution for an overall improved lyophilization process with efficient heat transfer, less vial-to-vial variation in the drying process, less risk of product spillage during transfer, and tracking of individual vial position in the lyophilizer.

(24) The term “lyophilization” (also known as freeze-drying, lyophilisation, or cryodesiccation) means a process of removal water or other solvents by freezing a material containing water and/or other solvents followed by reducing the surrounding pressure to allow the frozen water and/or other solvents in the material to sublimate directly from the solid phase to the gas phase.

(25) As contemplated herein, unless otherwise noted, lyophilization is meant to involve three phases: freezing, primary drying, and secondary drying.

(26) Lyophilization is performed within a lyophilizer. A variety of lyophilizers are commercially available and known in the art. The lyophilizer will have a lyophilizing chamber in which containers of product to be lyophilized are placed. The lyophilizing chamber contains one or more shelves on which the containers are placed. Typically, a plurality of shelves is used in the lyophilizing chamber during the lyophilization process.

(27) The lyophilizer is used to remove solvent from a pharmaceutical product solution. As used herein, “product solution” is meant to refer to any liquid mixture containing one or more pharmaceutical solids and a pharmaceutically acceptable solvent. The solid may be fully dissolved or dispersed within the solvent.

(28) Processes and apparatus for filling and loading vials into and out of a typical commercial, production-scale lyophilizer are described in. e.g., U.S. Pat. Nos. 9,522,752 and 10,781,003. It is envisioned that the elements, systems, and methods described herein may be used in conjunction with such processes and apparatus.

(29) FIGS. 1 and 2 depict vials in a lyophilization process according to known methods. FIG. 1 depicts a single pharmaceutical container 12 placed upon a shelf 14 within the lyophilizer. The container 12 contains a product solution 16 intended to undergo the lyophilization process. As depicted in FIG. 2, a plurality of containers 12 are placed upon the shelf 14 in the lyophilizer, surrounded by side walls 18, a back wall 20, and a front door 22. Many lyophilizers employ several shelves 14 to hold a plurality of containers 12 each, and the containers 12 are also surrounded by an additional shelf 14 above accordingly, as depicted in FIG. 1, or by the top of the lyophilizer (not depicted).

(30) To initiate the lyophilization process, the containers 12 are loaded into the lyophilizer upon the several shelves 14, and the door 22 to the lyophilizer is closed to create an enclosed space. The three steps of the lyophilization process are then performed—freezing, primary drying, and secondary drying—and the containers 12 are then removed from the lyophilizer and sealed for packaging and transport.

(31) The present invention improves upon the lyophilization process by encompassing the plurality of containers 12 with a lyophilization promoting element 24. As depicted in FIGS. 3a-3c, the element 24 includes one or more holes/openings or “pockets” 26 to accommodate each container 12 for lyophilization. The element is formed of a thermally conductive material having a thermal conductivity coefficient λ of about 0.1 to about 400.0 [W/mK] at 20° C. at 1 bar and a co-efficient of linear thermal expansion α of about 1 to about 25 [10.sup.−6° C..sup.−1] at normal temperature. The element is preferably made up of metal, most preferably aluminum (λ=239; α=23) or an oxide of aluminum, although other suitable materials falling with these ranges can be found on pages 131 and 265 of the Mechanical Engineer's Data Handbook by James Carvill (Butterworth Heinemann 1993), the contents of which are incorporated herein by reference.

(32) The height/depth of the pockets 26 may be about 5 mm to about 100 mm, or more preferably from about 10 mm to 80 mm and the width or diameter typically will be about 5 mm to about 30 mm, more preferably about 10 mm to about 25 mm. Most preferably, the height is about 20 mm to about 75 mm and diameter is about 15 mm to about 48 mm. Preferably, the pocket size is adapted to the size of container 12 and will allow a tolerance of about 0.05 mm to about 0.5 mm between the circumferential wall 30 of the pocket 26 and outer wall of container 12. The thickness of the element 24 is preferably about 10 mm to 200 mm, and more preferably between 20 mm and 100 mm. The area of the element 24 occupied by the pockets 26 is preferably more than 20% of total area when observed from above, more preferably more than 50%, and even more preferably more than 80%.

(33) In some preferable embodiments, the pockets 26 extend through the entire thickness of the element 24 such that a bottom edge of the container 12 is visible and accessible when the container 12 is installed within the element 24. In other preferable embodiments, the pockets 26 extend only partially through the thickness of the element 24, creating a lower surface of the pockets 26 upon which the bottom edge of the containers 12 may rest when the containers are installed within the element 24. In preferable embodiments, the pockets 26 are sized to provide a snug fit for containers 12 contained therein such that the containers 12 do not fall through the element 24 when the element 24 is lifted, regardless of which preferable embodiment is used.

(34) The container 12 will typically be a vial used to contain a liquid formulation and may be glass or glass-like vials or other suitably sterile transparent vials that are commercially available from various suppliers, including Nuova Ompi, Schott AG, or Daikyo Seiko, Ltd, for example. Pharmaceutical containers made from tubular glass are commercially available in a range of different sizes with dimensions according to the DIN/ISO 8362-1 standard. Molded glass vials are commercially available in a range of different sizes with dimensions according to the DIN/ISO 8362-4 standard. Particularly suitable glass containers are those described in 36 USP <660>/EP 3.2.1 Glass Containers for Pharmaceutical Use (2017). Glass has traditionally been the only choice for container material but problems with glass breakage, delamination, particulates due to glass-on-glass collisions, and stability of some products resulted in development and usage of suitable polymeric materials. One example of such polymeric material is TOPAS® cyclic olefin polymer. Vials made of polymeric materials are commercially available in size ranges and dimensions that typically closely mimic those of glass vials. Polymeric materials are significantly less scratch resistant than glass and existing aseptic processing equipment has not been redesigned to mitigate the risks of scratching. Scratched surfaces of containers are a serious concern for the perceived quality of the product, but also severely limits the inspection of the containers for particulates. Such inspection is typically a regulated requirement for good manufacturing practice. All such containers 12 are envisioned for use with the element 24. In some embodiments, the pocket 26 is adapted to contain a size 2R, 4R, 6R, 8R, 10R, 15R, 20R, 25R, 30R, 50R or 100R injection vial. The container 12 may further include a suitable stopper, such as commercially available elastomeric stoppers, e.g., those made or distributed by Daikyo Seiko, Ltd or West Pharmaceutical Services, Inc.

(35) It is desirable that the pocket 26 have a depth that allows it to envelope the side wall portion of container 12 containing the solution 16 at least up to the height of the solution. In some embodiments, the pocket will have a depth sufficient to envelope 25%, more preferably 50% to 75% of the height (excluding neck) of a vial. In preferable embodiments, the depth of the pocket 26 is sufficient to surround the body of a vial but does not cover the vial neck. In certain embodiment, the depth of the pocket 26 is substantially similar to a height (excluding neck) of a standard size injection vial. In other embodiment, the depth of the pocket 26 is substantially similar to the height (including neck) of a vial.

(36) In some embodiments, the element 24 of the present invention may be made up of polymeric material. The polymeric material can be hollow or filled with fluid having negative thermal expansion property, i.e., the fluid expands upon cooling, which can help to improve intimate contact of the element 24 and containers 12 placed within.

(37) Referring now to FIG. 4a, depicted is a preferable embodiment of the lyophilization promoting element 24 with a plurality of pockets 26 arranged in a 6×15, standard spaced arrangement. As will be appreciated by those of skill in the art, a rectangular, 6×15 arrangement is just one example of how the pockets 26 may be arranged in the element 24, and other shapes, sizes, and spacings are likewise available and are included in this disclosure. For instance, commercially available trays typically have 60-120 containers, the quantity varying with vial diameter. It is envisioned that the number and arrangement of pockets 26 can match the vial configurations of commercially available trays as well as nests/supporting structures disclosed in, e.g., U.S. Pat. Nos. 9,522,752 and 10,781,003 and/or commercially available from known vial suppliers.

(38) In the preferable embodiment depicted in FIG. 4a, the pockets 26 include a radial groove 28 extending outwardly from the outer circumference of the pockets 26. The radial groove 28 is cut out of the top surface of the element 24 and preferably extends radially and at a consistent angle from the top surface of the element, where the groove's 28 radius is largest, to the pocket's 26 outer circumference, where the groove's 28 radius is smallest and matches the pocket's 26 radius.

(39) As depicted in FIGS. 4b and 4c, the radial groove's 28 angle is preferably between 30 and 60 degrees, and more preferably approximately 45 degrees. The radial grooves 28 extend from the top surface of the element 24 to a preferable depth of between 0.5 and 10 millimeters, and more preferably to a depth of approximately 2.5 to about 6.5 millimeters. The radial grooves 28 accommodate smooth placement of the containers 12 into element 24 from any direction.

(40) FIG. 5 depicts the use of the preferable embodiment of the lyophilization promoting element 24 depicted in FIG. 4a to introduce a series of containers 12 into a lyophilizer. As depicted, the element 24 may be used in conjunction with a tray 32 to facilitate the installation and removal of the element 24 and containers 12 arranged therein. Containers 12 are first placed within the pockets 26 of element 24, with or without tray 32. The element 24 is then inserted into the lyophilizer and placed down upon the lyophilizer shelf 14. In preferable embodiments that use a tray 32, the tray 32 is then slid out from under the element 24 and containers 12 and removed from the lyophilizer while the element 24 and containers 12 remain resting on the lyophilizer shelf 14.

(41) The lyophilization process then occurs, and the element 24 and containers 12 are removed from the lyophilizer once complete, either by sliding tray 32 between the element 24 and lyophilizer shelf 14 or by simply removing the element 24 with inserted containers 12 on its own where no tray 32 is employed. As noted, preferable embodiments of the lyophilization promoting element 24 employ pockets 26 sized to accommodate containers 12 snugly such that they remain removably held within the element 24 when the element 24 is being removed, manipulated, and/or transferred even in preferable embodiments in which the pockets 26 extend through the entire thickness of the element 24.

(42) Referring next to FIG. 6, unique designs of pharmaceutical vial containers 12 are disclosed. Such unique containers 12, referred to herein as bottom-hollow containers 12, employ an internal bore 34 that extends up from the bottom edge of the container 12 into the container's interior 36. The internal bore 34 increases the contact surface area of the container's 12 outer surface and the lyophilization promoting element 24, improving the performance of heat transfer to and from the product solution 16 within the containers 12.

(43) Various shapes are available for the internal bore 34, including but not limited to those depicted in FIGS. 6a-6c—cone, cylinder, and cylinder with rounded top—among others. As those of skill in the art will appreciate, any internal bore 34 shape that increases the contact surface area between the container 12 and the element 24 will have the intended effect of increasing heat transfer to and from product solution 16.

(44) Referring now to FIG. 7, the unique containers 12 from FIGS. 6a-6c are depicted in use with a preferable embodiment of the lyophilization promoting element 24, which employs a protrusion 38 extending from the lower end of the pocket 26 up into pocket 26 and is preferably shaped to match the internal bore 34 provided in the unique container 12 design. Notably, the protrusion's 38 shape need not perfectly or even closely match the internal bore's 34 shape, but a more closely matching shape between the internal bore 34 and protrusion 38 will increase the contact surface area between the container 12 and element 24, as those of skill in the art will recognize. FIG. 8 depicts a top down view of the preferable embodiment of element 24 from FIG. 7c, wherein the containers 12 have been removed, and visible is element 24 with a plurality of pockets 26 employing radial grooves 28 and protrusions 38.

(45) Referring next to FIG. 9, depicted is a preferable embodiment of the lyophilization promoting element 24 with a primary portion 42 and a secondary portion 44. Such preferable embodiments preferably employ a first material for the primary portion 42, which makes up the vast majority of element 24, and a second material for the secondary portion 44, which is present only directly adjacent to the circumferential wall 30 of one or more of the pockets 26. By adding a secondary portion 44 comprising a second material directly adjacent to the circumferential wall 30 of pockets 26 (and thus to the containers 12 when installed), more costly materials more effective at direct conduction heat transfer may be employed efficiently and only where most effective, while the remaining primary portion 42 of the element 24 may be made of another, less costly material. Such preferable embodiments help to maximize the efficiency of heat transfer between the lyophilizer and the product solution 16 within the containers 12 during the lyophilization process.

(46) Referring now to FIGS. 10-13, a series of containers 12 containing product solutions 16 installed within preferable embodiments of lyophilization promoting elements 24 are depicted. FIG. 10 depicts a container 12 in element 24 with pocket 26 that does not extend through the entire thickness of element 24, thereby creating a lower surface of pocket 26 upon which container 12 rests. FIG. 11 depicts a similar arrangement, however the pocket 26 depicted in FIG. 11 does extend through the entire thickness of element 24, permitting access of the lyophilizer shelf to the bottom 48 of the container 12.

(47) Notably, while some preferable embodiments of the element 24 employ a plurality of pockets 26 all of which either extend entirely through the element's 24 thickness or do not, other embodiments may employ a plurality of both. In other words, some embodiments of the element 24 may include a plurality of pockets 26 that extend through the entire thickness of the element and a plurality of pockets 26 that do not, or any combination thereof, as those of skill in the art will appreciate.

(48) FIGS. 12 and 13 are similar to FIGS. 10 and 11, respectively, but also depict secondary portion 44 of element 24 comprising a second material directly adjacent to the installed containers 12. As noted with respect to FIG. 9, the secondary portion may be utilized to improve the efficiency of heat transfer between the lyophilizer and the product solution 16 within the containers 12 during the lyophilization process. With respect to FIGS. 11 and 13 specifically, depicted are lyophilization promoting elements 24 with pockets 26 extending through the elements' 24 entire thickness. This is notable because, as discussed above, element 24 is intended to facilitate moving the containers 12 as a group, and the containers 12 must accordingly fit snugly within pockets 26 to avoid dropping out of the bottom of elements 24 when the pockets 26 extend the entire length of the elements 24.

(49) Furthermore, in the preferable embodiments of the element 24 depicted in FIGS. 11 and 13, the pockets 26 employ a radial ridge 46 extending from the lower edge of the element 24 into the pockets 26. This radial ridge 46 is preferably sized and shaped to support the containers 12 from below when they are installed in the element 24. As depicted, the radial ridge 46 preferably extends at an angle from the lower edge of the element 24, at which point the radial ridge extends furthest into pocket 26, up into the pocket 26 a short distance, wherein it meets the circumferential wall 30 of the pocket 26. The radial ridge's 46 angle is preferably between 30 and 60 degrees, and more preferably approximately 45 degrees. The radial ridge 46 preferably extends no further than 0.5 millimeters to 6 millimeters from the element's 24 lower edge up into the pocket 26, and more preferably extends to a height of approximately 1.5 millimeters to 4 millimeters. Whatever the arrangement of radial ridge 46, the bottom 48 of the container 12 should preferably sit flush with or protrude slightly below the lower edge of the element 24, as depicted in FIGS. 11 and 13.

(50) In some preferable embodiments, the pockets 26 have side channels to permit air displacement while inserting the containers 12 into the pockets 26. The side channel feature is particularly useful in preferable embodiments in which the pockets 26 do not extend through the entire thickness of the element 24, creating a lower surface of the pockets 26 upon which the bottom 48 of the containers 12 may rest when the containers 12 are installed within the element 24. Such side channels preferably have a width of about 1% to 10% of the total perimeter of the pockets 26. The side channels may be cylindrical or cubical or any other shape that can assist with the passage of air, as will be understood by those of skill in the art.

(51) In some embodiments, the pockets 26 are numbered by engraving, printing, or embossing to locate the position of a container 12 on the shelf before lyophilization, and also after lyophilization. Such numbering can help in sampling or investigation.

(52) Referring lastly to FIG. 14, depicted are unique designs for pharmaceutical vial containers 12, referred to herein as flat-bottom, short-height containers 12. Such flat-bottom, short height containers 12 improve the effective heat transfer between the lyophilizer and the product solution 16 by increasing the contact surface area between the container 12 and the element 24 or the lyophilizer shelf 14, similar to the advantages provided by the bottom-hollow containers 12 depicted in FIGS. 6-7. Because the flat-bottom, short-height containers 12 have a large bottom surface area, the product solution 16 is more spread out and more effectively subjected to direct conduction heat transfer. Preferable embodiments of the flat-bottom, short height containers 12 may be used in conjunction with preferable embodiments of the lyophilization promoting elements 24 or may be placed directly upon the lyophilizer shelf 14 without losing any significant heat transfer effectiveness.

(53) While the present invention has been described with reference to particular embodiments and arrangements of parts, features, and the like, it is not limited to these embodiments or arrangements. Indeed, modifications and variations will be ascertainable to those of skill in the art, all of which are inferentially and inherently included in these teachings.