Patent Application
20090001042
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, or freeze-drying, is a process used in manufacturing various pharmaceutical, veterinary, medical, or diagnostic products. In a broad sense, a typical lyophilization process includes a material loading phase, a freezing phase, one or more drying phases, and a post-drying handling phase. In many lyophilization processes, 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.
In all three prior art closures, 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. In addition, 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, as set forth in U.S. patent application Ser. No. 11/702,472, 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.
In one aspect, 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 side vents define a fluid path between the cavity within the container and an atmosphere surrounding the container to facilitate nucleation of freezing of a material disposed within the cavity of the container upon depressurization of the atmosphere surrounding the container.
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.
The above and other aspects, features, and advantages of the present invention will be more apparent from the following, more descriptive description thereof, presented in conjunction with the following drawings, wherein:
The advanced lyophilization process described in U.S. patent application Ser. No. 11/702,472, and incorporated by reference herein, involves depressurization of the lyophilization chamber to controllably induce nucleation of freezing in the solution during lyophilization. Conventional container-closure designs tend to inhibit the efficacy of the depressurization method for inducing nucleation. The present container-closure systems, disclosed herein, allow the controlled nucleation via depressurization to occur with less interference and in a more precisely controlled manner.
Turning now to
Similar to conventional closures, the closure element or stopper 10 illustrated in
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. 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. Concurrently, 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.
In most commercial lyophilization processes, numerous individual container-closure systems are processed simultaneously within the freeze-dryer. 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.
As discussed 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. As depicted in
D
H=4A/P
where 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 (AE) of a side vent or a mouth vent as follows:
Since the side vents are often plural in number, it is also useful to define a “total side vent area” (AT,S) as follows:
AT,S=ΣN
where NS is the number of side vents. Likewise, the effective total side vent area (AET,S) can be defined as follows:
AET,S=ΣN
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. Alternatively, 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.
Turning now to
The closure shown in
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. As seen in the drawings, the protrusions 50 should be sufficiently long to accommodate the variability of mouth diameters for a given container style. Again, 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.
As can be appreciated when considering the embodiments described above, the shape and surface features of the closure element, and in particular, the closure legs, can be modified to enhance the stability of the container closure system in the open position and the sealing properties of the container closure system in the closed position while maintaining the desired effective vent areas.
Upon conclusion of the drying phase of the lyophilization process, 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
In the embodiment of
It has been found that suspending the closure element above the rim of the container typically eliminates most closure element inhibition effects on the depressurization method outlined in U.S. patent application Ser. No. 11/702,472. In fact, 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. Since 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. To exemplify this consideration, the closure in
The suspension device depicted in
The container closure systems depicted in
As seen in
It should be understood that the 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. However, more rigid polymers may face challenges in sealing appropriately with the container mouth. To overcome such challenges, another aspect of this invention is the addition of 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
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. To overcome this potential problem, 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 U.S. Pat. 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. To improve the efficacy of depressurization, 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. This design strategy is appropriate when one has no reason to increase the size of the vents beyond the standard requirements for drying; the resulting vents are in some cases too small to ensure reliable performance of the depressurization method for inducing nucleation during the freezing step of a lyophilization process.
All tests described herein were performed in a VirTis 51-SRC freeze-dryer having four shelves with approximately 1.0 m2 total shelf space and an internal condenser. This unit was retrofitted to hold positive pressures of up to about 15 psig. A 1.5″ diameter circular opening also was added to the rear wall of the freeze-drying chamber with 1.5″ diameter stainless steel piping extending from the hole through the rear wall insulation to emerge from the back of the freeze-dryer. Two 1.5″ full-port, air-actuated ball valves were attached to this tubing via sanitary fittings. One ball valve allowed gas to flow into the freeze-drying chamber and thereby provide positive pressures up to 15 psig. 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 NCOOL™-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 μm membrane. In addition to water, 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 μm 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 μm 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.
For the experimental conditions described herein and both lyophilization formulations studied, stochastic nucleation was typically observed to occur at vial temperatures between about −8° C. and −20° C. and occasionally as warm as −5° C. The vials could generally be held at temperatures warmer than −8° C. for long periods of time without nucleating. The onset of nucleation and subsequent crystal growth (i.e., freezing) was determined by temperature measurement as the point at which the vial temperature quickly increased in response to the exothermic latent heat of fusion. The initiation of freezing also could be visually determined through a sight-glass on the freeze-dryer chamber door or by opening the chamber door immediately after depressurization.
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 of ten 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
In each trial, 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° 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.
While the invention herein disclosed has been described by means of specific embodiments and processes associated therewith, numerous modifications and variations can be made thereto by those skilled in the art without departing from the scope of the invention as set forth in the claims or sacrificing all its material advantages.
This application claims priority to U.S. provisional patent application Ser. No. 60/937,232, filed on Jun. 26, 2007.
| Number | Date | Country | |
|---|---|---|---|
| 60937232 | Jun 2007 | US |
