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WO2009002991A1 - Système de fermeture de contenant pour utilisation dans des applications de lyophilisation - Google Patents

Système de fermeture de contenant pour utilisation dans des applications de lyophilisation Download PDF

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Publication number
WO2009002991A1
WO2009002991A1 PCT/US2008/068074 US2008068074W WO2009002991A1 WO 2009002991 A1 WO2009002991 A1 WO 2009002991A1 US 2008068074 W US2008068074 W US 2008068074W WO 2009002991 A1 WO2009002991 A1 WO 2009002991A1
Authority
WO
WIPO (PCT)
Prior art keywords
container
closure
legs
opening
closure element
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2008/068074
Other languages
English (en)
Inventor
Robert Sever
Balazs Hunek
Nigel Grinter
Gurjit Baring
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Praxair Technology Inc
Original Assignee
Praxair Technology Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Praxair Technology Inc filed Critical Praxair Technology Inc
Publication of WO2009002991A1 publication Critical patent/WO2009002991A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D51/00—Closures not otherwise provided for
    • B65D51/24—Closures not otherwise provided for combined or co-operating with auxiliary devices for non-closing purposes
    • B65D51/241—Closures not otherwise provided for combined or co-operating with auxiliary devices for non-closing purposes provided with freeze-drying means
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D41/00—Caps, e.g. crown caps or crown seals, i.e. members having parts arranged for engagement with the external periphery of a neck or wall defining a pouring opening or discharge aperture; Protective cap-like covers for closure members, e.g. decorative covers of metal foil or paper
    • B65D41/02—Caps or cap-like covers without lines of weakness, tearing strips, tags, or like opening or removal devices
    • B65D41/28—Caps combined with stoppers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D51/00—Closures not otherwise provided for
    • B65D51/002—Closures to be pierced by an extracting-device for the contents and fixed on the container by separate retaining means
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14—Details; Accessories therefor
    • A61J1/1468—Containers characterised by specific material properties
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D2251/00—Details relating to container closures
    • B65D2251/0003—Two or more closures
    • B65D2251/0006—Upper closure
    • B65D2251/0015—Upper closure of the 41-type
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D2251/00—Details relating to container closures
    • B65D2251/0003—Two or more closures
    • B65D2251/0068—Lower closure
    • B65D2251/0075—Lower closure of the 39-type
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D2539/00—Details relating to closures arranged within necks or pouring openings or in discharge apertures, e.g. stoppers
    • B65D2539/001—Details of closures arranged within necks or pouring opening or in discharge apertures, e.g. stoppers
    • B65D2539/005—Details of closures arranged within necks or pouring opening or in discharge apertures, e.g. stoppers provided with slits or gaps for increasing the elasticity

Definitions

  • the present invention relates to a container closure system for use in lyophilization applications, and more particularly, to vial or container stoppers useful in advanced lyophilization processes.
  • Lyophilization is a process used in manufacturing various pharmaceutical, veterinary, medical, or diagnostic products.
  • a typical lyophilization process includes a material loading phase, a freezing phase, one or more drying phases, and a post-drying handling phase.
  • the material to be lyophilized is a solution placed into a container such as a glass vial or bottle.
  • This container is generally equipped with a special closure, or stopper, that provides both a path for solvent removal during the drying phases of the lyophilization process and a method for sealing the container during the post-drying phase to protect the lyophilized material from contamination or degradation during its specified shelf- life.
  • Closures are often manufactured out of polymeric materials that provide a flexible seal capable of conforming to potential irregularities in the container dimensions and being penetrated by a needle to reconstitute the lyophilized material or withdraw the reconstituted material.
  • the combination of a container and a closure is commonly referred to as a "container-closure system.”
  • the container-closure system is generally supplemented by an aluminum crimp seal that overlays the junction between the container and closure.
  • Fig. IA depicts a prior art stopper or closure whereas Fig. IB and Fig. 1C show the prior art container-closure system using the closure of Fig. IA. As seen therein, the stopper or closure is a two-leg configuration.
  • Fig. IB open or unsealed position
  • Fig. 1C closed or sealed position
  • Fig. 2 depicts a prior-art one-leg closure configuration
  • Fig. 3 illustrates a three-leg closure configuration also found in the prior art.
  • the closure includes a vertical sealing surface located above the legs that seals against the inside wall of the container mouth when the closure is oriented in the closed position.
  • each of the closures also includes a continuous horizontal sealing surface disposed above the vertical sealing surface. The horizontal sealing surface provides a seal that is pressed against the rim of the container mouth when the closure is oriented in the closed position.
  • the size and shape of the closure legs and the manner in which they are positioned relative to the container dictate the size and shape of the openings through which fluids may enter or leave the container (e.g., solvent vapor being removed during drying). These openings are commonly referred to as the vents.
  • Most container-closure systems used for lyophilizing various pharmaceutical, veterinary, medical, or diagnostic products are designed such that the vents do not present a significant resistance to vapor flow out of the container during the primary or secondary drying processes.
  • Conventional lyophilization container- closure systems are designed to minimize the size of the vents without significantly impeding the upper range of solvent vapor flow rates that are typically encountered in the drying phases of lyophilization.
  • the vents are traditionally minimized in an effort to control manufacturing costs, reduce product contamination risks when the container closure system is in the open position, and ensure an acceptable seal when the container closure system is oriented in the closed position.
  • a recent advancement in lyophilization processes involves changes in the pressure in the lyophilization chamber during the freezing phase so as to initiate nucleation of the solution to be lyophilized in a controlled and uniform manner.
  • What is needed is an improved closure or stopper for use in lyophilization processes that optimizes the vent area yet does not present significant resistance to changes in the lyophilization environment during either the freezing phase or the drying phases of lyophilization processes, and ensures an acceptable seal when the container closure system is oriented in the closed position.
  • the present invention may be characterized as a container- closure system comprising: a container having an upper section defining an opening having a cross-sectional area and the container having a top surface and an interior surface adjacent to the opening; the container further comprising a body section defining a cavity in fluid communication with the opening; a closure element disposed proximate to the container and adapted for sealing the opening of the container when in a closed position, the closure element having a first sealing surface adapted for sealably contacting the interior surface of the container when in the closed position, the closure element having a second sealing surface adapted for sealably contacting the top surface of the container when in the closed position, and the closure element having a plurality of closure legs extending from the first or second sealing surface toward the body section; wherein the closure legs define a plurality of side vents between each of the closure legs when the container closure system is in an open position and the cumulative area of the side vents is greater than or equal to 50% of the cross-sectional area of the opening; and wherein the
  • the invention may also be characterized as a lyophilization stopper comprising: a sealing element defining an annular sealing surface; a cap section disposed adjacent to the sealing element and having a second sealing surface disposed in an orthogonal orientation relative to the annular sealing surface; and a plurality of closure legs extending from the annular sealing surface, each of the closure legs further defining an outwardly facing surface and the plurality of closure legs further defining a plurality of side vents between each of the closure legs; wherein the cumulative area of the plurality of side vents is equal to or greater than the cumulative area of the outwardly facing surfaces of the closure legs.
  • Fig. IA is a perspective view of a prior art stopper used in lyophilization applications
  • Fig. IB is a cross-sectional view of a container with the stopper of Fig. IA shown in the open or unsealed position;
  • Fig. 1C is a cross-sectional view of a container with the stopper of Fig. IA shown in the closed or sealed position;
  • FIG. 2 is a perspective view of another prior art stopper typically used in lyophilization applications
  • FIG. 3 is a perspective view of yet another prior art stopper typically used in lyophilization applications
  • FIG. 4 is a side view of a container-closure arrangement in accordance with an embodiment of the present invention.
  • FIG. 4A is a cross-sectional view of the container-closure arrangement of
  • FIG. 4B is a cross-sectional view of the container-closure arrangement of
  • FIG. 5 is a side view of a container-closure arrangement in accordance with another embodiment of the present invention.
  • FIG. 5A is a cross-sectional view of the container-closure arrangement of
  • Fig. 5 taken along line A-A.
  • FIG. 5B is a cross-sectional view of the container-closure arrangement of
  • FIG. 5 taken along line B-B.
  • Fig. 6 is a side view of a container-closure arrangement in accordance with another embodiment of the present invention.
  • FIG. 6A is a cross-sectional view of the container-closure arrangement of
  • FIG. 6B is a cross-sectional view of the container-closure arrangement of
  • FIG. 7 is a side cross-sectional view of a container-closure arrangement employing a suspension device in accordance with yet another embodiment of the present invention.
  • FIG. 8 is a side cross-sectional view of a container-closure arrangement employing a suspension device in accordance with still another embodiment of the present invention.
  • FIG. 9 is a side cross-sectional view of a container-closure arrangement employing a suspension device in accordance with still another embodiment of the present invention.
  • FIG. 10 is a side view of a container-closure arrangement in accordance with yet another embodiment of the present invention.
  • Fig. 1OA is a cross-sectional view of the container-closure arrangement of
  • FIG. 11 is a side view of a container-closure arrangement in accordance with still another embodiment of the present invention.
  • Fig. HA is a cross-sectional view of the container-closure arrangement of
  • Fig. HB is a cross-sectional view of the container-closure arrangement of
  • Fig. 1 IA detailing area B-B.
  • the container closure system includes a closure element or stopper 10 adapted for sealing a container 12 when depressed into the top mouth or opening 13 of the container 12.
  • the container 12 includes a generally cylindrical body section 14 adapted to contain a solution to be lyophilized, a neck portion 15 which defines an opening 16 into the body section 14, and a rim section 17 adapted for sealably engaging the closure or stopper 10 when the container 12 is sealed.
  • Collectively the neck portion 15 and rim section 17 of the container 12 are referred to as the top section 18 of the container 12.
  • the rim section 17 includes a rim inner surface 21, a rim outer surface 22, and a top surface 23.
  • the rim section 17 also defines an opening or mouth 13 of the container 12 having a prescribed diameter.
  • the neck portion 15 of the container 12 also defines a neck inner surface 24 generally aligned with the rim inner surface 21 and adapted to receive and guide the closure element 10 into place during sealing.
  • the neck portion 15 also includes a neck outer surface 26 that defines an annular shoulder 28 that facilitates handling the container 12 with and without the closure element 10.
  • the closure element or stopper 10 illustrated in Figs. 4, 4A, and 4B possesses a set of legs 30; a first, vertically or nearly vertical oriented sealing surface 32; and a cap section 34 that defines a second, horizontally or nearly horizontal oriented sealing surface 36 and a top surface 38.
  • the closure legs 30 function to align and stand the closure element 10 inside the rim section 17 of the container 12 in an open position during the lyophilization process.
  • the closure legs 30 also function as guides when pushing or pressing the closure element 10 into the closed position after lyophilization is complete.
  • the vertically or nearly vertical oriented sealing surface 32 of the closure element 10 is an annular surface located above the closure legs 30 and beneath the cap section 34.
  • the horizontally or nearly horizontal oriented sealing surface 36 of the cap section 34 is adjacent to and generally orthogonal to the annular vertically oriented sealing surface 32.
  • the closure element 10 When the container-closure system is oriented in the open position, the closure element 10 stands upright within the container mouth 13 and is held in such stationary position as a result of the friction forces between the legs 30 and the inside surface 21 of the rim section 17 of the container 12.
  • the vertical sealing surface 32 When the container-closure system is oriented in the closed position, the vertical sealing surface 32 functions to seal the closure against the inside surface 21 of the rim section 17 proximate the mouth 13 of the container 12.
  • the horizontal sealing surface 36 forms a seal against the top surface 23 of the rim section 17 of the container 12 proximate the mouth 13 of the container 12.
  • the containers are loaded onto temperature-controlled shelves within the freeze- dryer with the container-closure system placed in the open position.
  • the container-closure systems are maintained in the open position during the freezing and drying phases of the lyophilization process. Upon completion of the drying phase, the container-closure systems are moved from the open position to the closed position.
  • Most commercial freeze-dryers are equipped with automatic closure systems that push or depress the closure elements into the container mouth once the lyophilization process is complete.
  • the closure step generally occurs in the presence of an inert gas like nitrogen between approximately 10 mTorr and atmospheric pressure. Automatic closure is typically accomplished by raising or lowering the shelves so that all closures on a given shelf are pushed into their respective containers by contact with the shelf above.
  • the size and shape of the closure legs and the position of the closure element relative to the container define the size and shape of openings through which fluids may enter or leave the container when the container-closure system is in the open position.
  • FIGs 4, 4A, and 4B there are shown two different vents created by the engagement of the closure legs 30 with the container 12.
  • side vents 40 are the openings between each of the closure legs 30 above the rim section 17 of the container 12 and below the annular vertical sealing surface 32.
  • the mouth vent is the generally circular opening of the container mouth 13 that is not obstructed by the closure legs 30.
  • the size, shape, and number of the side vents 40 together with the size and shape of the mouth vent are important features of the present container-closure system.
  • D R hydraulic diameter
  • A is the open area of a vent at its minimum cross-section and P is the linear perimeter of the vent at its minimum cross-section.
  • the hydraulic diameter characterizes an effective vent area (A E ) of a side vent or a mouth vent as follows:
  • a ⁇ ,s total side vent area
  • a T 7 .,S , V i—i ⁇ s A where Ns is the number of side vents.
  • the effective total side vent area (AET, S ) can be defined as follows:
  • the present container-closure systems are characterized in that both the effective total side vent area and the effective mouth vent area are maximized and each are preferably at least 50% of the cross-sectional area of the mouth of the container.
  • the length, thickness, number, and shape of the legs are chosen to produce an effective total side vent area that is greater than the cumulative surface area of the outwardly facing surface of the closure legs.
  • Preferred embodiments of the present container closure system include one or more vents.
  • FIG. 5 Fig. 5A, and Fig. 5B there is shown another embodiment of the present container-closure system.
  • Many of the elements of the container and the upper portion of the closure element are the same or similar to the embodiment described with reference to Fig. 4 and will not be repeated here.
  • the difference in this embodiment is that the cross-sectional shape of the closure element 10 is non-uniform along the length of the closure legs 30.
  • the four legs 30 are relatively thin to provide greater effective total side vent area 40.
  • the four legs transition into an annular lower ring 48 that provides a very stable base to support the closure element 10 or stopper standing in the container 12 when the container closure system is in the open position.
  • the lower ring 48 is dimensioned so as to maximize the effective mouth vent area and, in particular maintain the effective mouth vent area greater than 50% of the container mouth area.
  • the closure shown in Fig. 6, Fig. 6A, and Fig. 6B differ from the closures previously described by the shape and features of the closure legs.
  • the illustrated container-closure system maintains the effective total side vent area 40 and sealing features of the previously described designs including a set of four closure legs 30 and the annular vertically oriented sealing surface 32 and the horizontally oriented sealing surface 36 above the legs 30 necessary to provide a pharmaceutically acceptable seal with the container-closure system.
  • many of the elements of the container and the upper portion of the closure element are the same or similar to the embodiments described with reference to Fig. 4 and Fig. 5 and thus will not be repeated here.
  • the illustrated closure element 10 includes one or more outwardly directed protrusions 50 located at or near the distal end 46 of the closure legs 30. These protrusions 50 enable the closure element 10 to sit or rest on the top surface 23 of the rim section 17 of the container 12 when the container closure system is in the open position.
  • the protrusions 50 and legs 30 are pushed through the mouth 13 and into the neck portion 15 of the container 12 so the vertical or nearly vertical sealing surface 32 can sealably mate with the inner surface 21 of the rim section 17 and the horizontal or nearly horizontal sealing surface 36 can sealably mate with the top surface 23 of the rim section 17 of the container 12.
  • the material and dimensions of the protrusions 50 and legs 30 are selected to allow them to properly compress upon entering the mouth 13 of the container 12 during the closure process.
  • the protrusions 50 should be sufficiently long to accommodate the variability of mouth diameters for a given container style.
  • the length, thickness, number, and shape of the legs and protrusions are chosen to optimize the effective total side vent area 40 and an effective mouth vent while maintaining stability of the container closure system when in the open position.
  • Fig. 7, Fig. 8, and Fig. 9 show a container-closure system with a stopper or closure element 70, 80, 90 respectively coupled or mounted to a container 12 with the aid of a suspension device 74, 84, 94 respectively.
  • Fig. 7 illustrates a container-closure system in an open position with the closure element 70 partially engaged into the mouth 13 of the container 12 and held in place by collapsible arms 75.
  • FIG. 8 illustrates a container-closure system in an open position with the closure 80 suspended above the container 12 and also held in place by a suspension device 84 such as collapsible arms 85.
  • Fig. 9 illustrates a container- closure system in an open position with the closure 90 suspended above the container 12 and held in place within a suspension device 94, namely a hollow cylindrical sleeve 96.
  • the annular suspension device 74, 84, 94 i.e. collapsible arms or sleeve
  • the annular suspension device 74, 84, 94 is also attached at the second end 78, 88, 98 to the outside surface of the top section 18 of the container 12.
  • the suspension device 74, 84, 94 collapses or moves under the closing force to allow the closure element 70, 80, 90 to move downward and seal the container 12 at the generally vertical and horizontal sealing surfaces.
  • the embodiment of Fig. 7 employs the suspension device 74 partially within the mouth 13 of the container 12 to provide enhanced stability of the container-closure system while in the open position.
  • the length, thickness, number, and shape of the legs are chosen to produce an effective total side vent area and an effective mouth vent area greater than 50% of the container mouth area.
  • the embodiments of Fig. 8 and Fig. 9, on the other hand, employ a suspension device 84, 94 that suspends the closure 80, 90 above the container 12, helping maximize the effective vent areas while still providing a facile means of sealing the container 12.
  • the suspension device 94 takes the form of a hollow cylindrical sleeve 96 where one end, namely the mouth end 102, is open and has an inner diameter designed to fit over the rim section 17 of the container 12 and where the other end, the closure end 104, is open or closed and has an inner diameter sized to hold a closure by friction.
  • the inside wall of the closure end 104 could include grooves or flanges that supplement or replace frictional forces to hold the closure 90 in place.
  • the body 106 of the sleeve 96 between the mouth end 102 and the closure end 104 could take any number of forms as long as side vents 108 are provided with an effective total side vent area greater than 50% of the container mouth area.
  • the mouth end 102 of the cylindrical suspension device 94 would be mounted proximate the container mouth 13 to hold the closure 90 above the container mouth 13.
  • the closure 90 could be sealed within the container mouth 13 by pushing the combined sleeve- closure assembly down until the stopper 90 mates with the mouth 13 at its horizontal and vertical sealing surfaces.
  • the closure 90 only could be pushed down within the sleeve 96 until the closure 90 mates with and seals the container mouth 13.
  • the additional vent area created by suspending the closure element above the rim of the container can even enable conventional lyophilization closures to work successfully with the depressurization method for most lyophilization applications.
  • suspension devices such as the ones described herein hold the closure in the open position, the closure does not strictly require legs, but only the horizontal and vertical sealing surfaces.
  • the closure in Fig. 9 is depicted without legs.
  • the suspension device depicted in Figs. 7, 8, and 9 need not be bound to the container, as illustrated, but could instead be bound to some part of the freeze- dryer system, such as the shelves.
  • Built-in suspension systems may take the form of a grid holding the containers in set positions on a shelf, a corresponding grid on the underside of the shelf above holding the closure elements in positions aligned with the containers below, and a means of releasing the closures after they are pushed into the containers during the closure process. Still other configurations or designs for a suspension device can be conceived without departing from the scope of the teachings herein.
  • the container closure systems depicted in Fig. 10 and Fig. 1OA represent an alternate approach to maximizing the effective vent area.
  • the closure element 110 includes an annular vertical sealing surface 112 and a horizontal sealing surface 114, but now these components are disposed in the mouth 13 of the container 12 and define an interior cavity 116.
  • the closure lid 120 includes a circular cap 122 and a plug 124 attached thereto adapted to fit into the interior cavity 116.
  • the illustrated embodiment of the closure element 110 has no legs (and thus no side vents) as the sealing surfaces are always in contact with the rim section 17 of the container 12 proximate the mouth 13. Rather, the lid 120 is disposed in a hinged coupling 128 with the sealing surfaces 112, 114 of the closure element 110 such that the plug 124 can be inserted into the interior cavity 116 when the container closure system is in the closed position or pulled away from the interior cavity 116 and mouth 13 of the container 12 when the container closure system is in the open position.
  • the open and closed positions are defined by the position of the cap 122 and plug 124 relative to the interior cavity 116.
  • the lid 120 is preferably maintained at an acute angle with respect to the vertical axis of the container 12 to allow automatic closure systems to push the cap 122 and plug 124 into sealing engagement after the drying phase of lyophilization is complete.
  • the interior cavity 116 is preferably sized to produce an effective mouth vent area sufficient to allow the depressurization method of inducing nucleation to proceed uninhibited.
  • Other arrangements for sealing the interior cavity are also contemplated including a compression fit or press fit of a stand-alone plug or even a threaded plug and cavity to facilitate closure via rotational motion.
  • closure elements described herein can be composed of any material that meets the basic demands of a lyophilization process with regards to moisture migration and absorption, oxygen migration, product absorption and adsorption, leaching, coring, fragmentation, reseal, sprayback, handling properties, etc.
  • the material may be a flexible polymer, such as the various butyl rubber formulations employed conventionally.
  • the material may also be a more rigid polymer, such as polytetrafluoroethylene. It may also include polymer blends, block copolymers or coated polymers as well. More rigid polymers may be easier to stabilize in the open position considering the relatively long and thin legs that may be necessary to achieve the vent areas disclosed herein.
  • a narrow sealing flange 135 to the vertical sealing surface 132 above the legs 130 of the closure 140 and below the horizontal sealing surface 136 as shown in Fig. 11, Fig. HA, and Fig. HB.
  • the sealing flange 135 should be sized to accommodate the variability of inner mouth diameters for a given container style and to allow the tip of the flange to be compressed during the closure process to achieve the proper seal. All the design concepts disclosed herein permit the addition of such a sealing flange 135, and all accommodate the conventional aluminum crimp to supplement the container- closure seal.
  • Suspension devices such as the ones described herein can be made of any pharmaceutically acceptable material and should not need to meet the product contact requirements of conventional closure materials.
  • More rigid polymers may also prevent injection of needles to directly reconstitute the lyophilized material in the container or withdraw the reconstituted material from the container.
  • all the closure elements disclosed herein may be executed as composite designs wherein the majority of the closure structure is composed of a rigid polymer for good stability, while a portion of the horizontal surface above the container mouth is composed of a flexible polymer that permits needle injection.
  • All of the closure concepts disclosed herein can be coupled to a filter material to minimize any contamination risks associated with the large vent areas as generally disclosed in United States Patent No. 5,732,837.
  • the filter material should not significantly affect the flow of gases between the container and its environment, but should prevent the ingress of bacteria or other non-gaseous contaminants into the vial.
  • the filter material should be positioned within the closure so that anything passing through the vents must pass through the filter material prior to entering the container.
  • the novel lyophilization closures disclosed herein overcome the limitations associated with closure elements known in the prior art and significantly extend the range of applicability for using the depressurization method to induce nucleation.
  • the size of the vents presented by the closure in the open position must be expanded substantially beyond the conventional ranges.
  • Conventional lyophilization closures are designed to minimize the size of the vents without significantly impeding the upper range of solvent vapor flow rates that are typically encountered in lyophilization practice.
  • the vents are traditionally minimized to control manufacturing costs, reduce contamination risks when the closure is in the open position, help the closure sit more stably in the open position, and ensure an acceptable seal when the closure is in the closed position.
  • the second ball valve allowed gas to flow out of the freeze-drying chamber and thereby reduce chamber pressure to atmospheric conditions (0 psig). All refrigeration of the freeze-dryer shelves and condenser was accomplished via circulation of Dynalene MV heat transfer fluid cooled by liquid nitrogen using the Praxair NC00LTM-HX system.
  • All solutions were prepared in a class 100 clean room.
  • the freeze-dryer was positioned with the door, shelves, and controls all accessible from the clean room while the other components (pumps, heaters, etc.) were located in a non- clean room environment.
  • All solutions were prepared with HPLC grade water filtered through 0.5 ⁇ m membrane.
  • each solution contained a single bulking agent, either mannitol or sucrose, at a concentration of approximately 5 wt%.
  • the final solutions were filtered through a 0.22 ⁇ m membrane prior to filling the vial containers.
  • the argon gas used to pressurize the chamber was supplied via cylinders and was filtered through 0.22 ⁇ m filters to remove particulates.
  • the 5 and 10 mL glass vials were obtained from Wheaton Science Products and pre-cleaned for particulates by a third party (ThermoFisher Scientific). The above steps were taken to ensure the materials and methods met conventional pharmaceutical manufacturing standards for particulates, which act as nucleating agents.
  • Table 1 summarizes the results for a set of experimental trials that demonstrate how container-closure systems with vents possessing the features described herein improve the efficacy of the depressurization method for inducing nucleation of the freezing transition in a solution near or below its thermodynamic freezing point.
  • Each tabulated result is based on a minimum often vials loaded in close proximity to one another on a freeze-dryer shelf. The temperatures of the vials were monitored using surface mounted thermocouples.
  • the closure style labeled as "prior art” is a traditional, two-legged lyophilization closure supplied by West Pharmaceutical Services, Inc. of Lionville, PA that resembles the closure depicted in Fig. IA.
  • the closure style labeled as Sample A is a four-legged closure similar to the closure element depicted in Figs. 4, 4A, and 4B.
  • the closure style labeled as Sample B is a four-legged closure similar to the closure element depicted in Figs. 6, 6A, and 6B.
  • the closure style labeled as Sample C is a four-legged suspension device that holds a conventional legless stopper above the container similar to the closure element depicted in Figs. 9, 9A, and 9B.
  • the freeze-dryer was pressurized in an argon environment to about 14 psig.
  • the freeze-dryer shelf was cooled to obtain vial temperatures of between approximately -1°C and -3 0 C (+/-1°C measurement accuracy of the thermocouples).
  • the freeze-dryer was then depressurized from about 14 psig to about atmospheric pressure in less than five seconds to attempt to induce nucleation of the solution within the vials.
  • the set of depressurization conditions used for the trials summarized in Table 1 were intentionally chosen to provide cases where nucleation efficacy was relatively low for conventional container- closure systems, so the improvement obtained with the container-closure systems disclosed herein could be more obvious.

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  • Engineering & Computer Science (AREA)
  • Mechanical Engineering (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)
  • Closures For Containers (AREA)

Abstract

L'invention concerne un système de fermeture de contenant (10, 12) pour une utilisation dans des procédés de lyophilisation employant la décompression pour initier une nucléation. Le présent système de fermeture (10) de contenant (12) comprend un contenant et un élément de fermeture disposé à proximité et adapté pour sceller l'ouverture du contenant. L'élément de fermeture (10) comprend une première surface d'étanchéité (32) adaptée pour mettre en contact de manière étanche une surface intérieure du contenant et une seconde surface d'étanchéité (36) adaptée pour mettre en contact de manière étanche la surface supérieure du contenant lorsque le système de fermeture de contenant est dans une position fermée. L'élément de fermeture (10) comprend également une pluralité de traverses de fermeture (10) s'étendant depuis la seconde surface d'étanchéité qui définissent une pluralité d'évents latéraux (40) entre chacune des traverses de fermeture lorsque le système de fermeture du contenant est dans la position ouverte. La longueur, l'épaisseur, le nombre et la forme des traverses (30) sont choisis pour produire une zone d'évent latéral totale efficace qui est d'au moins 50 % de la zone de l'ouverture de contenant. En variante, la longueur, l'épaisseur, le nombre et la forme des traverses sont choisis pour produire une zone d'évent latéral totale efficace qui est supérieure à la surface cumulative de la surface faisant face vers l'extérieur des traverses de fermeture.
PCT/US2008/068074 2007-06-26 2008-06-25 Système de fermeture de contenant pour utilisation dans des applications de lyophilisation Ceased WO2009002991A1 (fr)

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US93723207P 2007-06-26 2007-06-26
US60/937,232 2007-06-26
US12/144,872 2008-06-24
US12/144,872 US20090001042A1 (en) 2007-06-26 2008-06-24 Container-closure system for use in lyophilization applications

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