Apparatus and methods for making, storing, and administering freeze-dried materials such as freeze-dried plasma

A freeze-dried material is stored in a first chamber of a container along with a reconstituting liquid for the freeze-dried material, which is stored in a second chamber of the container. A sealing wall within the container forms a barrier between the first chamber and the second chamber preventing contact between the freeze-dried material and the reconstituting liquid. At least one valve assembly in the sealing wall selectively opens a region of the sealing wall to establish fluid flow communication between the first and second chambers, allowing the freeze dried material to be reconstituted. The reconstituted freeze-dried material can be administered from the same container to a recipient.

FIELD OF THE INVENTION

The present invention relates to methods, systems, and apparatuses for manufacturing, storing and administering freeze-dried materials, such as single donor units of freeze-dried human plasma.

BACKGROUND OF THE INVENTION

First aid is critical for the survival of a person that has suffered a serious injury, such as a trauma victim. For instance, initial treatment of a severely wounded person in combat situations can often mean the difference between life and death. While it is necessary to treat the wounds and stop the bleeding of the person, it is also important to ensure that the person's body is capable of properly functioning. Thus, it is necessary to take steps to ensure that the person's body is properly hydrated after losing fluids due to the injury. The present invention addresses these issues.

Previously, fluids were replenished within the patient by delivering saline intravenously. While effective, research has indicated that delivery of plasma to the patient is even more effective in replenishing fluid to the patient than the use of saline. However, delivery and storage of the plasma is critical to prevent contamination of the plasma. An ideal way of delivering the plasma is to deliver the plasma in a freeze dried form and reconstituting the plasma when it is administered to a person.

SUMMARY OF THE INVENTION

The invention provides methods, systems, and apparatuses for manufacturing, storing and administering freeze-dried materials, such as single donor units of freeze-dried human plasma.

According to one aspect of the invention, a freeze-dried material, e.g., freeze-dried human plasma, is stored in a first chamber of a container along with a reconstituting liquid for the freeze-dried material, e.g., de-gassed water. The reconstituting liquid is stored in a second chamber of the container. A sealing wall within the container forms a barrier between the first chamber and the second chamber preventing contact between the freeze-dried material and the reconstituting liquid. At least one valve assembly in the sealing wall can be manipulated to selectively open at least one region of the sealing wall to establish fluid flow communication between the first and second chambers. This allows the freeze dried material to be reconstituted within the container. The reconstituted freeze-dried material can also be administered directly from the same container to a recipient.

In one arrangement, the valve assembly includes a pressure sensitive valve, e.g., a flap valve. The valve is operative between a normally closed condition, normally resisting fluid flow communication between the first and second chambers, and an opened condition, establishing fluid flow condition communication between the first and second chambers. The pressure sensitive valve can be placed in its open condition in response to establishing a pressure differential across the valve, e.g., by preferentially squeezing a chamber of the container.

In one arrangement, the valve assembly includes a normally closed septum. The septum is operative in a normally closed condition, maintaining closure between the first and second chambers, and an opened condition establishing fluid flow communication between the first and second chambers in response to at least a partially tearing of the septum. The septum can, e.g., include a tear member coupled to a pulling member to at least partially tear open the septum.

The pressure sensitive valve and the septum can be arranged serially to provide a redundant valve assembly. In this arrangement, the normally closed septum is operative in a normally closed condition, maintaining closure between the first and second chambers, independent of the valve and an opened condition establishing fluid flow communication between the first and second chambers in response to at least a partially tearing of the septum and a pressure differential applied across the valve.

In one arrangement, an outer skirt is provided that overlays an exterior wall of the container in a region of the sealing wall. The outer skirt can include a tear member coupled to a pulling member to tear open the outer skirt for removal.

Another embodiment of the invention provides a method that provides a flexible container as above generally described, with first and second chambers. The first chamber holds a freeze-dried material, such as freeze-dried human plasma, in a dry state. The second chamber holds a reconstituting liquid for the freeze-dried material. An interior sealing wall within the container is sized and configured to form a barrier between the first chamber and the second chamber preventing contact between the freeze-dried material and the reconstituting liquid. At least one valve assembly in the sealing wall is operative by manipulation to open at least one region of the sealing wall to establish fluid flow communication between the first and second chambers. According to this aspect of the invention, the valve assembly is manipulated to open the region, and the reconstituting liquid is expressed from the second chamber through the valve assembly into the first chamber into contact with the freeze-dried material.

In one arrangement, an outer skirt overlays an exterior wall of the container in a region of the sealing wall and blocking manipulation of the valve assembly. In this arrangement, the outer skirt is removed to expose the valve assembly to manipulation prior to manipulating the valve assembly to open the region in the sealing wall.

In another arrangement, the reconstituted freeze-dried plasma is administered directly from the container to a recipient.

According to another aspect of the invention, a freeze-dried material comprising freeze-dried human plasma is prepared and stored, transported, reconstituted, and administered using a container as just generally described in any of the foregoing paragraphs. In one arrangement, liquid human plasma is loaded in molds. The molds are cooled until they reach approximately −45° C. The plasma is dried so the moisture content is below 5% w/w, thereby forming the freeze-dried human material that can be stored, transported, reconstituted, and administered using a container.

These and other areas of importance and significance will become apparent from following description.

DESCRIPTION OF THE PREFERRED EMBODIMENT

I. Device for Storing and Reconstituting Freeze-Dried Plasma

FIGS. 1 and 2show a device10for storing and administering a freeze-dried material. The device10comprises a flexible bag having a first collapsible chamber12and a second collapsible chamber14.

The first chamber12, also referred to as the dry chamber, contains an aliquot of a freeze-dried material16. The nature and type of freeze-dried material16can vary. In the illustrated embodiment, the freeze-dried material comprises human plasma, and the aliquot is a single donor unit of human plasma.

The second chamber14, also referred to as the wet chamber, contains a reconstituting liquid18for the freeze-dried material16. The nature and type of the reconstituting material18can vary. In the illustrated embodiment, the reconstituting material18comprises degassed, sterile water. In use, the sterile water in the wet chamber14is mixed with the freeze-dried plasma in the dry chamber12to provide plasma for transfusion. The plasma is reconstituted and administered on site using the device10.

The first chamber12is sized and configured to maintain the freeze-dried material16, prior to its reconstitution, in a vacuum packed, aseptic, moisture-free and low concentration oxygen environment, preferably accommodating long term storage, e.g., at least 2 years at room temperature. Stored in this environment, the freeze-dried material16retains its desired qualities for transfusion.

The second chamber12is sized and configured to maintain the reconstituting liquid18, prior to its mixing with the freeze-dried material16, in an aseptic environment and at a low gas concentration, preferably accommodating long term storage, e.g., at least 2 years at room temperature.

The volume of each of the chambers12and14is preferably approximately 50% larger than the volume of the freeze-dried material16in the first chamber12. This provides ample volume within the device10for mixing the freeze-dried material16and reconstituting liquid18, either in the first chamber12or the second chamber14, as will be described in greater detail later.

The device10may be made, e.g., of an inert medical grade plastic material, such as polyvinyl chloride, polyethylene, polypropylene, or high density polyethylene. The device10can comprise a multi-laminate of polymer layers for greater durability, e.g., to resist tearing and puncturing that could be encountered in normal handling.

The material of the device10can be selected to be transparent, if desired, to allow visual inspection of the contents of the chamber12and14. The material in the first chamber12can be selected to provide a gas-impermeable barrier, such as a metallized, reduced gas-permeability coating, or a metal laminate. In this case, the wall of the first chamber may be opaque.

Furthermore, the device10may be enveloped prior to use by a vacuum sealed over-wrap20(shown in phantom lines inFIG. 1), made, e.g., a metallized, gas impermeable material. The over-wrap20enhances shelf-stability.

An interior sealing wall22(seeFIG. 1) compartmentalizes the device10into the first and second chambers12and14(see alsoFIG. 5A). The sealing wall22provides a barrier between the first chamber12and the second chamber14, which normally prevents contact between the freeze-dried material16and the reconstituting liquid18during storage, up to the instant of use.

As FIGS.5A/B and7show, one or more regions24of the sealing wall22may be selectively opened by a caregiver, as will be described in greater detail later. The region(s)24, when opened, make possible fluid communication between the two chambers12and14. The fluid communication makes it possible to mix the reconstituting liquid18with the freeze-dried material16, as will further be described in greater detail later.

The region(s)24of the sealing wall22may be opened in various ways. In a representative embodiment (seeFIG. 5), the sealing wall22includes a normally closed valve assembly26associated with each region24where the sealing wall22is to be opened. InFIG. 5A, a single region24is shown, so a single valve assembly26is shown. As shown inFIG. 5B, where multiple regions24aand24bare provided, each region24aand24bwould include its own dedicated valve assembly26aand26b, respectively.

In the representative embodiment (seeFIGS. 5A and 5B), each valve assembly26includes a primary, pressure sensitive valve28. The valve28can take the form, e.g., of a short duck bill or two way flap valve. The primary valve28is sized and configured to normally resist flow communication between the two chambers12and14.

In the representative embodiment, each valve assembly26also includes a normally closed septum30between the valve28and the wet chamber14. The septum30maintains closure between the two chambers12and14, independent of the valve28. Independent of the valve28, the septum30prevents unintended passage of material between the two chambers12and14, thereby maintaining the separate integrity of the freeze-dried material16and the reconstituting liquid18within the device10prior to use.

The septum30includes an integrated tear member32that is incorporated within the septum30. The integrated tear member32is coupled to a pull string34that extends through a fluid sealed pass-through or septum36in the wall of the second chamber14. AsFIG. 1shows, the pull string terminates outside the device10at a pull tab38.

AsFIGS. 6 and 7show, the tear member32is sized and configured to open the septum30when a caregiver pulls on the tab38. The pass-through or septum26seals around the pull string34, and also seals close after passage of the pull string34from the interior of the chamber14, maintaining in integrity of the second chamber14. Opening the septum30in this manner forms the open region24(seeFIG. 7). The open region24places the first and second chambers12and14into communication through the valve28.

With the region24opened (seeFIG. 7), the primary valve28still serves to normally resist flow communication between the two chambers12and14. However, when the region24is opened, the valve28is sized and configured to resiliently yield in response to a difference in fluid pressure between opposite sides of the valve38(seeFIGS. 11 and 14). In response to the pressure differential, the valve28opens in the direction of the fluid pressure differential, from the region of higher pressure toward the region of lower pressure.

As will be described in greater detail later (as shown, respectively, inFIGS. 10 and 13), the caregiver creates the fluid pressure differential across the valve28by selectively squeezing one chamber and not the other chamber. Fluid is expelled in response to the fluid pressure differential through the valve28from the chamber that is squeezed into the chamber that is not squeezed.

The multi-component valve assembly26provides a redundant sealing capability, to assure that the chambers12and14remain separated until it is desired to reconstitute the freeze-dried material16.

In a representative embodiment (seeFIGS. 1 and 2), the device10further includes an outer tear-away skirt40, which provide further redundancy. AsFIGS. 1 and 2show, the skirt40overlays the device10in the region of the sealing wall22. The skirt40serves to overlay and protect the components of the valve assembly26associated with the sealing wall22.

At least one region of the skirt40is circumferentially attached about an exterior wall of the device, e.g., by adhesive, either in the region of the first chamber, the second chamber, or both. Furthermore, as the skirt40is installed about the device10, the exterior wall of the device is desirably plicated or pleated or otherwise bunched together (asFIGS. 1 and 2show). Alternatively, the placations can be performed in the wall of the container.

The placations relieve wall stress in the region of the sealing wall22. The skirt40, once attached, maintains these placations or pleats, and thereby serves to relieve or distribute wall stresses in the region of sealing wall22and the components of the valve assembly26associated with the sealing wall22. Such wall stresses can arise, e.g., due to the weight of the reconstituting liquid18contained in the second chamber14, and/or by virtue of handling during transport and manipulation prior to use. The presence of the overlaying skirt40also serves to isolate the components of the valve assembly26associated with the sealing wall22from unintended contact during transport and prior to use.

AsFIG. 1shows, the skirt40includes an integrated tear member42. The integrated tear member42includes a pull string44that terminates with a pull tab46, that depends outside the skirt40. The tear member42is sized and configured to tear open the skirt40when a caregiver pulls on the tab46(asFIG. 3shows). Upon removal of the skirt40, the placations of the walls of the bags12and14are relieved (asFIGS. 4A and 4Bshow), placing the components of the valve assembly26associated with the sealing wall22into condition for manipulation.

It should be understood that reference to the first chamber12and the second chamber14is done to distinguish one chamber from the other, and not to limit either chamber to a specific spatial relationship. For example, the chambers12and14may be arranged face to face, having vertical edges in contact.

The technical features of the device10includes separate chambers or compartments that are separated by sealing means that will allow for eventual interconnection and intercommunication, between the chambers, which can be accomplished in various ways. Furthermore, reference to a bag or chambers should not be limited to any specific structure or shape but should be understood to refer any container capable of carrying and mixing the contents16and18.

II. Preparing and Packaging the Freeze Dried Material and Reconstituting Liquid

Preparing and packaging the freeze-dried material16and reconstituting liquid18comprises two main processing steps: (i) freeze-drying the material16, and (ii) packaging the material16and the reconstituting liquid18within the chambers12and14.

A. Preparation of Freeze-Dried Plasma

In a representative embodiment, the freeze-dried material16comprises plasma. A description of an illustrative way of preparing freeze-dried plasma for packaging in the device10therefore follows.

Preparation and manufacturing of the plasma will take place in a sterile setting. Preferably, manufacturing and preparation procedures will be done in an ISO Class 5 clean room (or better) with ISO Class 3 bio-containment hoods for aseptic handling of human plasma. Freeze drying will be done aseptically in a CIP/SIP freeze dryer.

Human plasma is collected from a single donor in a conventional way, e.g., by collecting a unit of whole blood from the donor in a closed system collection bag, followed by centrifugal separation of the plasma and its collection in an integrally connected transfer bag (containing one plasma unit of about 250 ml). Each unit (contained in the transfer bag) will be handled individually in the bio-containment hood. Between handling one single donor unit and another unit single donor unit from a different donor, there will be a line clearance protocol for change-over in the bio-containment hood. This protocol will address removal of all tools and materials associated with the previous handling. It will also address the thorough wash down of the containment work area and work area instruments (mass balances) to ensure no residues of the previous handling were left in place. The identification of single donor samples will be maintained by bar coding and other tagging of the single donor human plasma containers.

As shown inFIG. 17A, prior to freeze drying, the 250 ml human plasma unit is dispensed from the transfer bag48into a sterile, pyrogen free, rectangular mold50(e.g., 4 cm×10 cm×12.5 cm—d×w×l). The mold50can be stainless-steel; however it can also be composed of metal with good thermal transfer properties such as aluminum, aluminum alloy, titanium or gold. The mold50may be coated on its inside surfaces with a tough, inert barrier film with good release properties such as PTFE or diamond.

As shown inFIG. 17B, the mold50containing the human plasma is then placed inside a water-impermeable, vapor-permeable, sterile, heat sealable bag52with bar coding and tagging54indicative of the human plasma identification (source, blood type, date of collection, etc.). This vapor permeable bag52would typically be manufactured using microporous PTFE membrane material (e.g. Gore-Tex™) or microporous HDPE membranes (e.g. Tyvek™).

The bag52is heat sealed to contain the mold50and human plasma. The bag52is designed to neatly contain the mold50and its contents without any bunching or sagging of the bag material below the surface of the interior mold wall edge or at the base of the mold.

As shown inFIG. 17C, the mold50inside the containment bag52is then placed inside a freeze dryer56on an aseptic freeze dryer shelf surface58. The freeze dryer56used for the lyophilization will be a validated clean in place, steam in place freeze dryer with shelf area of near 200 square feet or more. Such a freeze dryer56can accommodate at least 500 molds when it is fully loaded.

Once loaded, the freeze dryer cycle is started. This cycle generally cools the human plasma to near −45° C. and freezing for 2 to 8 hours, followed by cooling of the freeze dryer condenser and application of vacuum to start the freeze drying cycle. A freeze-dried human plasma cake60is formed.

In the primary freeze drying cycle, the temperature of the human plasma cake60needs to remain below −33° C. (the collapse temperature) to maintain its integrity. When the moisture content of the cake60is below 5% weight per weight (w/w), a secondary drying cycle (the elevated temperature) is used to further lower the moisture content. Generally the combined primary and secondary freeze drying cycles will take at least 72 hours. At the conclusion of the freeze drying cycle, the freeze dryer vacuum is opened to an atmosphere of an oxygen-free, high purity inert gas such as nitrogen or argon.

As shown inFIG. 17D, the freeze dried cakes60in their molds50and containment bags52are removed to an aseptic containment cart62whose environment may be maintained under a nitrogen or argon blanket to exclude moisture and oxygen. The containment cart62may couple to the front of the freeze dryer to allow for transfer of the freeze dryer contents under a controlled inert gas blanket.

The containment carts62may be used to store human freeze dried plasma cakes (each cake within a mold50and enclosed within a bag52) as well as allow cakes to be transferred to a device loading area, which allows loading of the freeze dried plasma cake60into the device10, as will be described in greater detail later.

B. Packaging Freeze-Dried Plasma and Water into the Device

As shown inFIG. 1, the device10comprises a first aseptic vacuum port64, which communicates with the first chamber12, and a second aseptic vacuum port66, which communicates with the second chamber14. The vacuum ports64and66are sized and configured for connection to various tubing T during final assembly (seeFIGS. 18 to 21) to facilitate packaging of the freeze-dried plasma material16and reconstituting liquid18(e.g., water) within the device10.

An administration port68is also heat sealed in communication with the second chamber14. The administration port68is used during the packaging process to convey the reconstituting liquid18into the second chamber14, as will be described in greater detail later. After the reconstituting liquid18is packaged within the chamber14, the administration port68is sealed with a conventional septum or frangible membrane assembly or a convention screw-lock luer fitting70, to accommodate its coupling to an administration set72to the port28at time of transfusion, as shown inFIG. 16.

The device10also comprises a heat sealable aseptic flange74(seeFIG. 1), which allows a freeze-dried plasma cake60to be inserted into the first chamber12, as shown inFIG. 18, and then sealed in a sterile fashion, as shown inFIG. 19.

A slot76may be pre-formed on the flange74. The slot76makes it possible to hang the device10at a desired gravity head height for administering reconstituted plasma to an individual, asFIG. 16shows.

Individual single donor human plasma freeze dried cakes60are aseptically loaded into the device10(seeFIG. 18) through the flange74. The device loading area may be, e.g., a bio-containment hood that excludes significant oxygen and moisture contamination by inert gas blanketing. Also the device loading area may be an aseptic glove-box system with an inert gas environment.

FIGS. 18 and 19depict a representative loading process. The bag52is opened, and the plasma cake60removed from the mold50. The plasma cake60is loaded through the open flange74into the first chamber12. As shown inFIG. 17E, it is anticipated that the plasma cake60can be transferred into the chamber12directly from the mold50(after removal of the bag52) using a single-use, aseptic, clear-plastic applicator tool78, similar to a large open-ended spatula. Once the chamber12is loaded, the flange74can be sealed closed using various conventional aseptic techniques, e.g., dielectric welding or heat sealing.

The loading of the plasma chamber12can be through an “oyster style” opening that comprises approximately 50% of the flange74of the chamber12, which can be readily sealed close after loading. An oyster opening would allow loading of the plasma cake60without concerns of damaging the first chamber12or the freeze-dried plasma during the process. In the case of the oyster opening, there would be sufficient excess overlay of the edge seam to allow for straightforward edge-seam alignment and contact during the sealing process.

Preferably, after loading and sealing of the chamber12, an aseptic vacuum is applied through tubing T connected to the vacuum port64on the first chamber12(seeFIG. 19). Upon achieving near 100 mTorr of pressure, the vacuum port64is heat sealed and the tubing T removed. This evacuation process provides for the eventual ability to mix and reconstitute the human freeze dried plasma without introduction of bubbles and without foaming. The vacuum would also cause the plasma cake60to be compacted to a fine powder, forming the freeze-dried material16within the chamber12.

To maintain a direct traceable link between the source plasma and the material16packaged into the chamber12, the device10preferably includes a bar coding and tagging54′ (seeFIG. 1), which is indicative of the human plasma identification (source, blood type, date of collection, etc.), and which replicates or is otherwise linked to the bar coding and tagging54placed on the bag52enveloping the mold50at the time of freeze-drying. In this way, the device10maintains a traceable link back to the human donor source.

To assist in the reconstitution of the freeze dried plasma material16, an aseptic dense sphere of an inert material such as, but not limited to, glass, polyvinyl chloride or high density polyethylene may be added to the inside of the chamber12prior to its closure.

The reconstituting liquid18(in the representative embodiment, gas-free water) is introduced into the second chamber14. The vacuum port66and administration port68are connected to feed lines80and82, respectively, asFIG. 20shows. Gas in the chamber14is removed by application of aseptic vacuum.

The vacuum port66is sealed and the tubing80is removed. The required aliquot (e.g., approximately 250 ml) of degassed water for injection is added to the chamber14through the administration port68. The tubing82is removed and the administration port68is then sealed with the conventional septum or frangible membrane assembly or a convention screw-lock luer fitting70, which accommodate coupling of the administration set68to the port68at time of transfusion.

To assist in the reconstitution of the freeze dried plasma, an aseptic dense sphere of an inert material such as, but not limited to, glass, polyvinyl chloride or high density polyethylene may be present inside the second chamber14.

AsFIG. 21shows, after packaging the freeze-dried material16and the reconstituting liquid18in the manner just described, the wall of the device10is plicated in the region of the sealing wall22, as previously described, and the outer skirt40attached. The overwrap20can be applied, as shown inFIG. 1, if desired.

The device10is ready for storage, transport, and use

III. Reconstitution and Administration of the Freeze-Dried Material

The device10makes possible a purposeful two step manipulation in anticipation of reconstituting the freeze-dried material16.

In the first step (shown inFIG. 8), the tear member42is pulled to open and remove the skirt40, which places the sealing wall22of the device10in the ready for use configuration shown inFIG. 6. In the second step (shown inFIG. 9), the tear member32is pulled to open the septum20(whichFIG. 7shows in greater detail). The region24of the sealing wall22is thereby opened.

When the region24is opened, the caregiver can apply pressure to the second chamber14to express the reconstituting liquid18from the second chamber14into the first chamber12(seeFIGS. 10 and 11), thereby beginning the reconstitution of the freeze-dried material16. More particularly, with the region24opened, the caregiver can apply pressure to the second chamber14(asFIG. 10shows) and not the first chamber12. AsFIGS. 10 and 11show, the pressure differential between the second chamber14and the first chamber12expels the liquid18from the second chamber14, through the valve28(which yields in response to the pressure differential to open in the direction of the first chamber12, asFIG. 11shows), and into the first chamber12. The expelled liquid18mixes with the freeze-dried material16in the first chamber12, beginning the reconstitution.

AsFIG. 12show, shaking the device10accelerates the mixing of liquid18and freeze-dried material18in the first chamber12.

When the region24is opened, the caregiver can subsequently apply pressure to the first chamber12to express the material16, now at least partially reconstituted in the liquid18, from the first chamber12into the second chamber14(seeFIGS. 13 and 14). Reconstitution of the freeze-dried material16is advanced. More particularly, asFIG. 13shows, the caregiver can now apply pressure to the first chamber12(asFIG. 13shows) and not the second chamber14. AsFIGS. 13 and 14show, the pressure differential between the first chamber12and the second chamber14expels the mixture of the liquid18and the freeze-dried material16from the first chamber12, through the valve28(which yields in response to the pressure differential to open in the direction of the second chamber14, asFIG. 14shows), and back into the second chamber14. The expelled liquid18continues to mix with the freeze-dried plasma material18, furthering the reconstitution of the material18.

AsFIG. 15shows, shaking the device10further accelerates the mixing of water and freeze-dried plasma in the second chamber14.

The material16reconstituted in the liquid18can be passed back and forth between the two chambers12and14by alternating pressure on the chambers12and14, with intermediate shaking, until the desired degree of mixing occurs, at which time the mixture is ready for transfusion. More particularly, the caregiver can proceed to squeeze one chamber and not the other, to expel the mixture of the liquid18and freeze-dried material18back and forth between the chambers12and14, with periodic shaking, until the desired degree of mixing and reconstitution of the plasma is accomplished.

At this point (asFIG. 16shows), the caregiver can couple the administration fitting70of the device10to the fluid administration set72. The reconstituted plasma is transfused by gravity flow through a phlebotomy needle84into the circulatory system of an individual.

The administration fitting70can further include a static mixing tube86(as shown inFIG. 16), to assist in continued reconstitution of plasma aliquot5with water7during transfusion.

The device10as described provides:

i) long term stable containment of a freeze-dried material such as freeze-dried human plasma;

ii) eventual rapid reconstitution of the freeze-dried material with a reconstituting liquid for injection; and

iii) eventual delivery of the reconstituted freeze dried material to a trauma victim in a safe, sterile manner.

IV. Other Representative Embodiments

A. Dual Containers With Intermediate Valve Passage

FIG. 22shows another representative embodiment of a device100for storing an administering a freeze-dried material. The device100comprises a first collapsible container102and a second collapsible container104, joined by an intermediate normally closed valve assembly106.

The device100shares many of the technical features of the device shown inFIG. 1, albeit the particular structure differs. The first container102comprises the dry chamber12as previously described, and is sized and configured to contains an aliquot of a freeze-dried material16, such as a freeze-dried single donor unit of human plasma.

The second container104comprises the wet chamber14, as previously described, and is sized and configured to contain a reconstituting liquid18for the freeze-dried material16. As before described, the reconstituting material18can comprise, e.g., degassed, sterile water.

In use, the sterile water in the wet chamber14is mixed with the freeze-dried plasma in the dry chamber12to provide plasma for transfusion. The plasma is reconstituted and administered on site using the device10.

As before described, the first container102is sized and configured to maintain the freeze-dried material16, prior to its reconstitution, in a vacuum packed, aseptic, moisture-free and low concentration oxygen environment, preferably accommodating long term storage, e.g., at least 2 years at room temperature. Stored in this environment, the freeze-dried material16retains its desired qualities for transfusion.

As also before described, the second container104is sized and configured to maintain the reconstituting liquid18, prior to its mixing with the freeze-dried material16, in an aseptic environment and at a low gas concentration, preferably accommodating long term storage, e.g., at least 2 years at room temperature.

The volume of each of the containers102and104is preferably approximately 50% larger than the volume of the freeze-dried material16in the first chamber12. This provides ample volume within the device10for mixing the freeze-dried material16and reconstituting liquid18, either in the first container102, or the second container104, as will be described in greater detail later.

The containers102and104may be made, e.g., of an inert medical grade plastic material, such as polyvinyl chloride, polyethylene, polypropylene, or high density polyethylene. One or both of the container102and104can comprise a multi-laminate of polymer layers for greater durability, e.g., to resist tearing and puncturing that could be encountered in normal handling.

The material of the containers102and104can be selected to be transparent, if desired, to allow visual inspection of the contents of the chamber12and14. The material in the first container102can be selected to provide a gas-impermeable barrier, such as a metallized, reduced gas-permeability coating, or a metal laminate. In this case, the wall of the first chamber may be opaque.

As before described, the device100may be enveloped prior to use by a vacuum sealed over-wrap20(shown in phantom lines inFIG. 22), made, e.g., a metallized, gas impermeable material. The over-wrap20enhances shelf-stability.

In the alternative representative embodiment shown inFIG. 22, the valve assembly106includes a pressure sensitive valve108enclosed within a flexible tubular valve passage110, which extends between the two containers102and104. The valve108can take the form, e.g., of a short duck bill or two way flap valve. The valve108is sized and configured to normally resist flow communication between the two containers102and104. However, the valve108is sized and configured to resiliently yield in response to a difference in fluid pressure between opposite sides of the valve108(in the same manner as the valve28shown inFIGS. 11 and 14). In response to the pressure differential, the valve108, like the valve28, opens in the direction of the fluid pressure differential, from the region of higher pressure toward the region of lower pressure.

The regions of the wall of the containers to which the valve passage11Q is joined normally close communication between the containers102and104through the valve passage110.

An outer tear-away skirt112is wrapped around the mid-regions of the containers102and104and the intermediate valve passage110. The skirt112serves to overlay and protect the components of the valve assembly106prior to use. At least one region of the skirt112is circumferentially attached about an exterior wall of each container102and104, e.g., by adhesive, either in the region of the first chamber, the second chamber, or both.

AsFIG. 23shows, within the outer skirt112, the mid-regions of the containers102and104, and the valve passage110itself, are desirably plicated or pleated or otherwise bunched together, shortening the length of each container102and104and the valve passage110. Alternatively, the placations can be performed in the walls of the containers102and104and/or valve passage110. The presence of the overlaying skirt112serves to isolate the valve passage100from unintended contact during transport and prior to use.

AsFIG. 23shows, the walls of each container102and104that overlay opposite ends of the valve passage110each includes an integrated tear member112. AsFIG. 23shows, each integrated tear member112is coupled by an internal pull string114to an adjacent side wall of the respective container102and104. The internal pull string114is normally held in slight tension when the device100is in the plicated condition shown inFIG. 22(i.e., when the mid-regions of the containers102and104, and the valve passage110itself, are plicated and held in this condition by the outer shirt112). When the device100is in the plicated condition, the tension on the internal pull string114is not sufficient to affect the tear member112. The walls of each container102and104that overlay opposite ends of the valve passage110remain closed. When the device100is in the plicated condition, the chambers12and14and their contents remain isolated and separated prior to use.

AsFIG. 24shows, the skirt112can be torn and removed by operation of an integrated tear member116(in the manner shown inFIG. 3), to place the device100in the condition shown inFIG. 24. AsFIG. 24shows, upon removal of the skirt112, the placations of the walls of the containers102and104and valve passage110are relieved, and the device100lengthens.

AsFIG. 25shows, when the device100lengthens, tension on the internal pull string114is increased. The increased tension is sufficient to activate the tear member112, tearing open regions116of the walls on opposite ends of the valve passage110(asFIG. 25shows). The open regions116place the first and second chambers12and14into communication through the valve passage110.

With the regions116opened, the caregiver can proceed to manipulate the device100in the same manner previously described with respect to device10(as shown inFIGS. 10 to 16). The caregiver creates the fluid pressure differential across the valve108by selectively squeezing one container and not the other container. Fluid is expelled in response to the fluid pressure differential through the valve108from the container that is squeezed into the container that is not squeezed to mix and reconstitute the freeze-drive material for administration. Transfer of materials in opposite directions between the chambers12and14through the valve passage110as a result of the manipulation of the containers102and104is shown inFIGS. 26 and 27.

B. Alternative Ways to Package the Reconstituting Liquid

FIGS.28A/B and29A/B shows alternative ways to package the reconstituting liquid18in a device10or device100as previously described. In these alternative ways, it is not necessary to use the administration port68to convey the reconstituting liquid18, but can be closed and sealed in a pre-packaging operation.

In one alternative representative embodiment (see FIG.28A/B), the wet chamber14includes two packaging ports120and128. In use (seeFIG. 28A), the first port120is coupled to a source124of the reconstituting liquid18via a first inline valve122. The second port128is coupled to a vacuum source125via a second inline valve126.

As shownFIG. 28A, the first valve122is closed and the second valve126is opened. A vacuum is applied to the interior of the chamber14. As shown inFIG. 26B, the first valve122is opened and the second valve126is closed. The reconstituting liquid18is conveyed by gravity flow into the chamber14. Both packaging ports120and128are sealed.

In another alternative representative embodiment (see FIGS.29A/B), the wet chamber14includes a single packaging port130. In use (seeFIG. 29A), the port130is coupled to a source132of the reconstituting liquid18and a vacuum source134through a two way valve136.

As shownFIG. 29A, the two way valve136is operated to close communication with the liquid source132and to open communication with the vacuum source134. A vacuum is applied to the interior of the chamber14. As shown inFIG. 29B, the two way valve136is operated to open communication with the liquid source132and to close communication with the vacuum source134. The reconstituting liquid18is conveyed by gravity flow into the chamber14. The packaging port130is sealed.

In both arrangements, the administration port68can be inserted and sealed close in a pre-packing operation.

The administration port68is not used until it is time to administer the reconstituted freeze-dried material, as shown inFIG. 16.