Surgery – Container for blood or body treating material – or means used...
Reexamination Certificate
2003-02-11
2004-08-10
Michalsky, Gerald A. (Department: 3753)
Surgery
Container for blood or body treating material, or means used...
C383S038000, C604S408000, C604S410000
Reexamination Certificate
active
06773425
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention in its simplest form is a container for freeze-drying and storing pharmaceutical material. In its more expanded form it serves to collect, process, freeze-dry, store, reconstitute and utilize biological and/or pharmaceutical material solutions preferably under sterile conditions. In one preferred form the container can be collapsed to accommodate the volume of the freeze-dried product during storage and expanded to the volume corresponding to the rehydrated product. Hereinafter, the use is made of blood products, and the special needs associated with such product, as the lyophilized product is for description purposes and by no means should be taken as a limitation of the invention.
2. Description of the Related Art
Lyophilization is used to increase the shelf life of biological/pharmaceutical solutions by freezing the solution and then removing the solvent (usually water) by applying high vacuum. The rate of lyophilization is dependent on the vapor pressure of the drying mass, which in turns depends on the heat transferred by conduction from the shelf of the lyophilizer to the top of the frozen mass where evaporation occurs. The dehydrated frozen mass, or cake, is then stored until it is reconstituted by adding a solvent similar to that removed and then used as intended.
U.S. Pat. No. 4,973,327 of Goodrich et. al. of Cryopharm Corp discloses many of the desirable features of the present invention as described in the Abstract: “A lyophilization bag is provided in which a fluid, such as blood, may be introduced, lyophilized without collapsing the bag, stored, reconstituted and distributed from the bag without intermediate transfer of the useful contents from the bag”.
U.S. Pat. No. 5,257,983 discloses a container with its flexible peripheral walls reinforced with rigid structures to prevent its inward collapse and a bottom wall made of a rigid material. Samples of the last containers made by Cryopharm (obtained from Dr. Goodrich) were square rigid trays 1″ high 10″×10″ made of polyester film 0.020″ thick.
Bergmann's U.S. Pat. No. 5,309,649 discloses “a container for freeze drying materials under sterile conditions, wherein the sides of the container consist at least partly of a hydrophobic, porous, germ-impermeable, water vapor-permeable membrane.” Two forms of the container were described: a bag and a rigid rectangular tray both covered with the membrane. In 1995 W. L. Gore introduced the Lyoguard bag, a single-use sterilizable processing bag providing a protective barrier before, during and after bulk freeze drying (Flyer #LP001:03/08/95 and a brochure from W.L. Gore & Associates, Inc. Microfiltration Technologies Group, Elkton Md.) that looks very much like that shown by FIG. 2 of '649. The bag described by Pat. '649 and Gore's bag are open along one entire side to allow product introduction after which the open side of the bag is heat-sealed. Further, both are made with two layers, a floor and a roof, with the roof incorporating a hydrophobic membrane. Neither have sidewalls. Pat. '649 also illustrates a tray covered with a hydrophobic membrane, described as a “ . . . trough (tray) consists of liquid-impermeable synthetic resin and preferably has a wall thickness of 0.5 to 1 mm” (i.e. 0.020 to 0.040″ thick).
U.S. Des. Pat. Nos. D430,939 and D425,205 and resulting Lyoguard tray (W.L. Gore & Associates) illustrate a rigid wall container topped with a hydrophobic membrane with a flexible, transparent, thin-film bottom that closely conforms to the lyophilizer shelf for more efficient heat transfer. It also incorporates a large top port positioned above the floor of the tray.
Each of the prior art containers suggests useful features yet all can be improved. There are no prior art containers that provide a simple collapsible container having a flat bottom that conforms to the shelf of the lyophilizer or that provides the rectangular shape so useful for lyophilization. Some collapsible tray-shaped containers are complicated and require additional steps to receive and remove reinforcing members that allow the container to collapse or maintain its shape during lyophilization. Other trays used for lyophilization have a relatively heavy wall that results in at least two factors that reduce heat transfer between the shelf and the product. First, the thicker the floor of the tray, the greater the resistance to heat transfer. Second, and more importantly, it is almost impossible to maintain the bottom of a rigid thin plastic tray completely flat against the shelf of the lyophilizer. Though the product to be lyophilized weighs down the bottom of the tray downward towards the shelf, the weight of its thin layer (usually less than 10 mm) is insufficient. Thus, a bottom made of a noncompliant material will result in a non-conforming floor with some sections lifting off the shelf preventing said sections from having intimate shelf contact causing inefficient and non-uniform heat transfer. The latter, may result in non-uniform lyophilization of the product, which can lead to a final, less viable end product. Certainly, poor heat transfer would slow down the freezing and the warming of the product required for the process thereby increasing cost. A tray with a rigid wall also prevents reduction of the tray's volume prior to and/or after lyophilization. Since the product's volume relative to that of the tray is small before lyophilization and even smaller after lyophilization, it leads to unnecessary storage expenses especially when the lyophilized product has to be stored in a freezer.
Prior art bags designed for lyophilization, utilizing a hydrophobic membrane as the top wall, were made without side walls and without ports. Thus, when filled with a solution and placed on a lyophilizer shelf, the bag would have a cross-section that is tear-shaped, see
FIG. 1
a
. This shape of the prior art bags presents two drawbacks for lyophilization. First, the contacting surface of the bottom of the bag with the shelf is limited to the midsection, while the sides are raised above the shelf, see
FIG. 1
a
. As a consequence, less than 50% of the bottom surface may be available for direct heat transfer between the shelf and the product during both the freezing cycle and lyophilization (heating) cycle. The tear shaped cross-section also results in a non-uniform thickness of the product being lyophilized, which may cause product damage due to non-uniform freezing. Also, inefficient use of the lyophilizer is evident from the thinner sections drying much faster than the thicker midsection, and the tear-shaped tray results in lower product volume per foot print. Secondly, flexible containers without sidewalls are more likely to have the product contacting the membrane, resulting in, the product freezing against the membrane; the product would then dry against and plug up the membrane. Plugging of the membrane would result in reduction of the lyophilization rate. Furthermore, the lack of ports limits the usefulness of such bags, or requires complicated and expensive procedures to maintain sterility prior to lyophilization and when the product is to be used. The prior art also requires a heat sealer to seal the container once filled with product.
In general, molecules leaving any point along the top of a frozen mass can be viewed as a solid angle or a cone with its peak being the point on the surface of the product and its base, the perimeter of the membrane. The rate of evaporation depends on that solid angle. If part of the roof is blocked, the degree of blockage is dependent on the solid angle defined by the point on the surface and the external perimeter of the block. It is also possible to raise the membranous roof “far” above the product thereby decreasing the solid angle of blockage and increasing the chance of molecules “seeing” the hole. However, raising the roof above the product decreases the ratio of product volume to lyophilizer container volume, wastin
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