JPH0256896B2 - - Google Patents

Description

Claim 1: A method for manufacturing a sterile container for separately storing sterilized powder components and sterilized liquid components in a manner that provides for mixing and dosing of the powder and liquid components under aseptic conditions, comprising: , having at least two separate sealed compartments with a breakable connection therebetween, one compartment having a carrier liquid sealed therein and the other compartment being a closed chamber. sterilizing the flexible bag containing the carrier fluid compartment, the closed chamber and the breakable connection; and sterilizing the flexible bag while the flexible bag is in a sterile environment. opening one end of the chamber of the bag and inserting a sealed vial containing a sterile powder ingredient therein through the open end and into the chamber while the flexible bag is in a sterile environment; , the inserting step includes positioning the sealed vial such that when the seal is broken, the powder component enters the breakable connection between the carrier liquid compartment and the chamber; The method comprises sealing the open end of the chamber while the flexible bag is in a sterile environment, thereby sealing the vial within the chamber.

2. The method of claim 1, further comprising immersing the sealed vial in an immersion medium prior to inserting the sealed vial into the chamber.

3. The method of claim 1, further comprising encapsulating the entire outer surface of the sealed vial prior to inserting the sealed vial into the chamber.

4. The method of claim 1 further comprising encapsulating the sealed vial with a thermoplastic material prior to inserting the sealed vial into the chamber.

5. further comprising encapsulating the sealed vial in an immersion medium prior to inserting the sealed vial into the chamber;
2. The method of claim 1, wherein the immersion medium is a topical disinfectant.

6. The method of claim 1, comprising encapsulating the sealed vial in an immersion medium prior to inserting the sealed vial into the chamber, the immersion medium being a sterile light source.

7. The method of claim 1, comprising encapsulating the sealed vial in an immersion medium prior to inserting the sealed vial into the chamber, the immersion medium being a hot water wash.

8. The method of claim 1, wherein said closed chamber does not contain a carrier liquid therein during said sterilization step.

9 Prior to the step of opening one end of the chamber,
2. The method of claim 1, further comprising maintaining the flexible bag in a sterile condition.

10. The method of claim 9, wherein the step of maintaining comprises packaging the sterile flexible bag within an outer bag until the end of the chamber is opened in a sterile environment.

11. The method of claim 1, further comprising maintaining the outer surface of the flexible bag sterile after the step of sealing the vial within the chamber.

12. The method of claim 11, wherein said maintaining step comprises packaging the sealed flexible bag containing the vial into a barrier outer bag that prevents the transmission of light, gas, and water vapor into the flexible bag. .

13. The step of sterilizing the flexible bag includes autoclaving the flexible bag.
Section method.

14. The method of claim 1, further comprising subjecting the interior of the chamber to a sterilization process after the step of opening the chamber and before the step of sealing the vial within the chamber.

15. The method of claim 1, further comprising subjecting the outside of the sealed flexible bag to a sterilization process after the step of sealing the vial into the chamber.

16 A container for separately storing sterilized powder components and sterile liquid components in a manner that provides for mixing and dispensing of the powder and liquid components under aseptic conditions, the container having one compartment therein. at least two separate sealed compartments having a sealed sterile liquid component and the other compartment having a sealed vial therein having a sealed sterile powder component; a flexible bag having: a rupturable connector means for providing a sterile passageway between the liquid containing compartment and the vial containing compartment; and a rupturable connector means associated with the rupturable connector means for breaking the seal of the vial. and means for permitting passage of the liquid component and the powder component through the sterile passageway of the rupturable connector means, thereby mixing the liquid component and the powder component; and the mixed liquid and powder components. an outlet member opening into said one compartment for removing said bag from said flexible bag.

17. The container of paragraph 16, wherein said vial has an outer surface treated with an immersion medium.

18. The container of clause 16, wherein said vial has a peripheral encapsulation layer over its entire outer surface.

19. The container of clause 16, wherein said vial has a layer of thermoplastic material on its outer surface.

20. The container of clause 16, wherein said sealed chamber does not contain liquid therein.

21. The container of clause 16, wherein the container further includes an outer barrier bag over the flexible bag.

22. The container of clause 16, wherein said flexible bag is sterilized before said vial is sealed within said chamber.

23. The container of clause 16, wherein the chamber is sterilized prior to sealing the chamber.

24. The container of clause 16, wherein the exterior of the flexible bag is sterilized and the container further comprises a barrier outer bag over the sterilized flexible bag.

25. The sterilized liquid component is a carrier liquid,
17. The method of claim 16, wherein the sterilized powder ingredient is a pharmaceutically active ingredient.

26. The container of clause 16, wherein said rupturable connector means and said rupture means include a rupture cannula and a tapered syringe.

27. The container of clause 16, wherein the vial itself comprises only a rigid body having a neck opening and a breakable plug within the neck opening for closing the vial.

28. The container of paragraph 16, wherein said vial does not include an overcap member.

29. The container of paragraph 16, wherein said flexible bag has unbroken, substantially smooth inner and outer surfaces.

30. The container of clause 16, wherein the container further includes an outer barrier bag over the flexible bag, and wherein the outer barrier bag is made of non-autoclavable material.

BACKGROUND AND DESCRIPTION OF THE INVENTION The present invention generally relates to methods and products for separately storing sterile powder components and sterile liquid components in a single sterile unit container. More particularly, the invention provides for two separate chambers to be provided in a unit container or bag, the separate chambers being interconnected by a sterile breakable connector providing a closed connection between the chambers. related to methods and products. Such a closed connection is manually opened when it is desired to mix the liquid and the powder to create a solution of the powder in the liquid, the liquid being sterile and capable of being dispensed from the container in liquid form. .

With regard to the administration of pharmaceuticals, it is often desirable to provide the pharmaceutically active ingredient in powder form, and to administer the pharmaceutical by intravenous means, eg, in a liquid carrier. Exemplary carrier liquids include saline, dextrose solutions, and sterile water. Frequently, such pharmaceutical powders undergo deterioration upon prolonged storage in the carrier liquid, so that it is desirable to keep the powder component separate from the liquid component until shortly before actual use by a physician or paramedical staff. In such cases, before, during or after the liquid or powder ingredients are mixed,
It is typically desirable to avoid possible contamination of the liquid-powder mixture. In addition to concerns about staying clean, it is often desirable to avoid exposing physicians, paramedical staff, or pharmacists to certain unusually active agents, such as those used in chemotherapy.

Powdered drugs are normally sterilized by the pharmaceutical manufacturer in sterile vials, typically made of glass. Such vials have caps that are easily pierced to permit removal of their sterile powder contents into a carrier liquid or the like. Although these vials are usually provided as clean as possible, their external features provide a potential source of mold or bacteria growth on the outside of the vial. Such potential sources include stoppers and overcaps for sealing the mouths of the vials, informational labels affixed to the outside of the vial, and the adhesives used to affix the labels thereto. Nevertheless, since such vials have gained wide acceptance throughout the pharmaceutical industry and enjoy a degree of uniformity, it is likely that the use of these vials in this manner will become obsolete in the near future. There is no gender.

Mold or bacterial growth on non-porous containers or bags often occurs when such bags are stored for a significant period of time in the outer bag, which serves as a barrier to gas, light and water vapor transmission to the bag within the outer bag. be observed. Because such a barrier is not absolute, or because some residual moisture remains between the bag and the bag when the bag is sealed over the bag, moisture and bacteria are highly conducive to mold or bacterial growth, especially when the bag is sealed over the bag. Because of the temperature conditions that normally exist between the bag and the outer bag, or at other locations such as at the interface between a glass vial and its support means, mold growth can often occur.

Thus, both the powder drug and its intended carrier liquid are maintained in a sterile condition, while at the same time substantially eliminating the possibility of mold or bacterial growth between contact surfaces of packaging for such sterile drug products. There is a demand for a system that does this. There is also a need for an integrated device for separately packaging carrier liquids and powdered drugs that does not require direct contact by the physician, pharmacist, or paramedical staff with the rigid vial containing the powdered drug or its contents. be. These demands require that the liquid ingredients in the flexible container or bag be first sterilized under relatively harsh conditions, that the vials containing the sterile powder be maintained sterile, and that is satisfied by the present invention through the use of several steps, by being inserted into and sealed within.

It is therefore a general object of the invention to provide a combined device for the separate storage of powders and liquids.

Another object of the invention is to provide a means for using vials of powdered medicament within a system that avoids potential sources of contamination emanating from the vials.

Another object of the present invention is a product and method for its manufacture in which a sterile liquid and a sterile powder are packaged separately in a single unit in a manner that provides for aseptic mixing of the liquid and powder.

Another object of the invention is to package sterile liquid carriers and powdered medicaments in a manner that minimizes the possible introduction of sources of bacteria, mold, etc. into or outside the liquid container or container of powdered ingredients. This is an improvement method.

Another object of the invention is an improved product and method for its manufacture that is packaged in such a way that all external surfaces of the powder container are rendered sterile and that sterility is maintained.

Another object of the invention is an improved method and product by which rigid vials are sterilely encapsulated.

These and other objects of the invention will become apparent from the following detailed description, taken in conjunction with the accompanying drawings. In the drawings: FIG. 1 is a perspective view illustrating aspects relevant to the sterilization of a flexible container and a liquid solution therein prior to insertion of a powder-containing vial therein; FIG. 2 is a perspective view of the flexible container of FIG. 1 illustrating access to the vial receiving chamber of the instrument; FIG. FIG. 2A is a longitudinal sectional view of FIG. 2. 2nd B
The figure is a cross-sectional view of FIG. 2. FIG. 3 is a diagram illustrating a preferred process for immersing a vial to sterilely encapsulate the vial. Fourth
1 is a perspective view of the flexible container of FIG. 1 illustrating insertion of a vial into an opened chamber; FIG.
FIG. 5 is a perspective view of the flexible container of FIG. 1 illustrating the completed device with the opened chamber resealed with the vial. FIG. 6 is a front view illustrating the final protective outer bag of the completed device.
FIG. 7 is a partially cutaway plan view of the device shown in FIG. 5. FIG. 7 is a longitudinal sectional view of FIG.

The device according to the invention has a compartment 22 in which the carrier liquid is sealed, and a closed chamber 23 free of carrier liquid and dimensioned to seal a standard sized rigid vial therein. Contains bug 21. Generally 2
A breakable connector designated 5 enters both the liquid compartment 22 and the closure chamber 23. The bag and its liquid contents are sterilized.

Often, the bag 21 in the condition shown in FIG.
If the bag is sterilized at some time before other operations to be carried out later, it is then necessary to maintain the sterility of the bag 21 until such later operation begins. As such, an outer bag 2 may be obtained, either sized to fit into a single bag 21 as shown, or sized to hold large stacks and/or storage of such bags 21.
4 can be achieved.

A rupturable connector 25 enters both the liquid containing compartment 22 and the closure chamber 23, the rupturable connector 25 being of known construction including means for blocking passage between the compartment and the closure chamber 23. This blocking means can be removed when desired to provide a sterile passageway for direct liquid and powder passage communication between compartment 22 and closure chamber 23. Such a rupturable connector 25 typically includes a rupturable cannula 26 and a rubber tipped syringe 27, both of known construction. Batsugu 21
further includes an outlet member 28 whereby the solution within the compartment 22 can be removed therefrom by opening the outlet member 28.

The steps illustrated in Figures 2, 2A and 2B may be carried out in a clean environment, such as a so-called clean room, or in a known environment which strictly prevents the passage of potential contaminants into such spaces, but still provides an accessible space. The structure is implemented within a laminar flow unit. Normally any such clean environment would ensure maintenance of a bacterial count of approximately ¹⁰³ , which is the bacterial count typically present on the external surface of vials of commercially prepared powdered drugs. . Within this environment, as shown in FIG. 2, when the distal end 29 of the bag is opened by cutting, tearing or otherwise, the chamber 23 forms an open bag 21a. This step is performed under clean conditions to avoid adding significant contamination that could lead to future mold or bacterial growth on the outer surfaces or within the chamber 23.

With distal end 29 open, clean vial 32 is inserted into chamber 23 while bag 21a and clean vial 32 are in a clean environment. See Figure 4. Thereafter, to provide a completed bag 21b having a sealed clean vial 32 in its enclosed chamber 23 and a sterile liquid in its compartment 22, as illustrated in FIG. The open end 29 is resealed to form a seal 33, such as by heat sealing. Such a completed bag 21b is the vial 3
2 without sterilizing the vial with harsh sterilization conditions such as high temperatures that would be expected to induce deterioration or damage of the powder within.

To enhance the maintenance of a clean outer surface of the finished bag 21b, such bag 21b exhibits particularly good barrier properties with respect to light, gas and/or water vapor transmission to the outer bag 24, to other outer bags like it, or to other outer bags like it. The barrier bag 34 is preferably inserted into a barrier bag 34, which may be any other type of outer bag.

Clean vial 32 is provided in an environment that maintains vial 32 in an environment that maintains a sterile or clean condition of vial 32, particularly its outer surface, after vial 32 has been sterilized or otherwise subjected to sanitary treatment. By maintaining the vial 32, a clean vial 32 can be provided. Since most powdered pharmaceutical products cannot be subjected to autoclave conditions, the contents of vial 32 are sterilized by so-called dry methods, such as the well-known freeze-drying sterilization technique.

In another aspect of the invention, the clean nature of the vial is generally maintained, and typically enhanced, by the dipping operation illustrated in FIG. This soaking operation is particularly useful when it is used to encapsulate the entire vial 32 in the soaking medium with any mold, bacteria or other contaminants that may remain on the outside surface of the vial 32. It is valid. Contaminants are most likely to collect under or within the label 35 or under the cap of the vial 32. Labels, which are typically made of cellulosic materials, present difficult problems with maintaining sterile conditions. For example, such labels tend to absorb and retain moisture, thereby providing highly favorable conditions for mold growth.

This dipping operation can take various forms.
Preferably, such soaking operation increases the surface temperature of the vial to help reduce the amount of mold or bacterial material remaining on the surface, while also reducing the entire vial and remaining bacterial material to a cured thermoplastic. Serves as a seal within the material. It involves immersion in a molten thermoplastic material that solidifies or hardens upon cooling. This sealing severely inhibits, if unchecked, any bacterial growth, while at the same time freeing any remaining bacteria from inside the vial 32, inside the chamber 23, or anywhere else inside or outside the bag 21. would prevent movement to. Suitable thermoplastic materials include synthetic rubbers and polymers such as polyvinyl chloride, silicone rubber, and copolymers, including block polymers, whether of the cotton or cyclic type. Any number of these types of thermoplastic materials may be used, but any such material should preferably be relatively transparent to the extent that the information contained on label 35 can be read therethrough.

Other soaking agents can be used including topical disinfectants such as Betadine® and the like. This type of dipping material is less preferred due to the fact that it tends to stain the label 35, which is usually made of cellulosic material. The usefulness of these types of soaking agents is limited by the extent to which they render such dye label information unobtainable.

The soaking operation can include passing through sterilizing light, such as a UV source, or by a Pasteurization type cleaning operation. Because these operations do not encapsulate the entire vial in the strict sense that thermoplastic materials do, and they do not function to prevent the migration of residual bacterial content from the external surface of the vial 32, they are typically Less desirable.

Although it is preferable to use containers that have been in use for many years due to their proven effectiveness in avoiding contamination and deterioration of powder components, the present invention provides a Modifications to these traditional vials can be made by eliminating the overcap, which in many cases is typically a metal cap that has a means of providing easy access to the shaft. This is illustrated in FIGS. 7 and 7A, in which a clean vial 32 is inserted into a rupturable plug 3.
It has an opening 36 which is closed only by 7. Because of the complete circumferential encapsulation 32 molded over the entire vial 32, including the outer flange of the rupturable plug 37, no overcap is required to secure the rupturable plug 37 in place.

Such elimination of the overcap, which is a potential source of contamination, is possible even when a complete circumferential encapsulation is not the thermoplastic material that serves to provide functional assistance in keeping the rupturable plug 37 in place. Chamber 32 is completely surrounded,
and so closely covers the vial 32 that the powder within the vial 32 remains as long as the breakable plug 37 is slightly oversized with respect to the neck opening 36 to form a frictional engagement between the breakable plug 37 and the neck opening 36. There is no chance that the rupturable plug 37 will escape from the neck opening 36 of the vial 32, which could result in spillage and waste.

The elimination of overcaps for any embodiment of the present invention is such that the closed chamber 23 itself is a closed clean environment, whereby vials 32 from sources inside or outside the closed chamber are
It is further possible in view of the fact that it prevents contamination of the powder inside. Additionally, the closed chamber 32 does not provide accessible structures such as narrow pockets or crevices that have the potential for contamination or moisture retention introduced during cleaning of the closed chamber prior to sealing. In addition, all compartments of the finished bag 21b are
Since it is closed and sealed, including the chamber 23, the entire outer surface of the finished bag 21b also has pockets or crevices that can lead to undesirable retention of contaminants and/or moisture prior to its insertion into the barrier outer bag 34. Not yet.

Regarding details of method aspects of the invention, please refer to Bug 2.
1 within an autoclave outer bag 24, typically made of a material such as high density polyolefin.
It is usually sterilized by steam overcapping at about 25°C. These materials, including high density polyethylene and polypropylene, can be exceptionally thin, for example 1.5 mils, depending on the length of time that initial over-bagging protection is needed. Such materials rarely have dimensions greater than 10 mils.

When the vial 32 is to be inserted into the bag 21,
Outer bag 24 is removed from bag 21 in a clean environment and distal end 29 of chamber 23 is opened. The interior of chamber 23 must still be sterile or at least sterile after this operation. If desired, the open chamber 23 can be cleaned with water, for example at about 110 to about 180 degrees Celsius, air dried and, if necessary, ultraviolet treatment. Vial 32 is then subjected to immersion if desired, dried if necessary, and sealed into chamber 23. This work is performed in a clean environment.

If the finished bag 21b is sealed within the barrier outer bag 34, the outer surface of the bag 21b can be clean enough to avoid mold or bacterial growth during long-term storage. Sterility can be promoted by one or more of hot water washing at about 110 to 180 °C, air drying with filtered air, and ultraviolet treatment. The interior of the barrier outer bag 34 itself may be subjected to such type of treatment to ensure its sterility in order to minimize the possibility of mold or bacterial growth at the interface between the finished bag 21b and the barrier outer bag 34. can be subject to.

Since the outer barrier bag 34 is not subjected to steam sterilization operations, the outer barrier bag 34 need not be made of an autoclavable material. The most important property for such a barrier outer bag 34 is its barrier effectiveness, i.e., its ability to minimize the transmission of light, gas, and moisture through it in order to protect sensitive products therein. be. If convenient, the previously removed autoclavable outer bag 24 can be used as the barrier outer bag 34, although the additional handling involved in such an operation can be avoided during rough handling of the thin high-density polyolefin material. This increases the risk that the barrier may rupture due to prone bending crack pinholes. When using a completely separate barrier outer bag 34, possible materials for it are Saran-polypropylene laminate, vinyl film or laminates containing vinyl film, and exceptionally good barriers such as metal foil on one side. It includes an outer bag made of an opaque material and the other side made of a transparent material which may not be an exceptional barrier. For example, such other side panels may be made of thin high-density polyolefin on the order of 5 mils or more, since an absolute barrier panel halves the effective permeability through the other panel when considered as a whole outer bag. can do.

It will be obvious to those skilled in the art that the present invention can be embodied in various other ways.
Accordingly, the invention should be construed and limited only by the scope of the claims.