Method of reconstituting a hazardous material in a vial, relieving pressure therein, and refilling a dosage syringe therefrom

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This invention relates to the packaging of hazardous material and more particularly to the packaging of such materials which enable a user to mix a diluent with the hazardous material and then fill a syringe with the solution in such a way as to substantially prevent the hazardous material from entering the immediate atmospheric environment.

While the present invention is applicable to hazardous materials in general, the specific example of hazardous materials to which the invention is particularly applicable are freeze dried or powdered cytotoxic drugs such as are used extensively in chemotherapy treatment of cancer patients and radiographic materials.

Freeze dried or powdered cytotoxic drugs are usually contained within a vial of the type which is open ended and has an elastomeric stopper assembly disposed in sealing relation within the open end so as to enable the freeze dried or powdered cytotoxic drug to be sealingly contained therein. The elastomeric stopper assembly is adapted to receive therethrough a needle of a diluent containing syringe. The amount of freeze dried or powdered cytotoxic drug within the vial is an amount such that when dissolved in a proper amount of diluent within the vial the solution has a volume substantially less than the volume of the sealed interior of the vial. Nevertheless, when the diluent is injected into the vial through the needle by the operation of the diluent containing syringe there is sufficient volume of solution within the vial to displace the gas therein into a smaller volume and hence to increase its pressure. It is generally well known that this increase in pressure may cause an aerosol effect when the needle is removed. This aerosol effect may result in the passage outwardly through the elastomeric stopper assembly of portions of the cytotoxic drug in the form of aerosol or droplets. This aerosoling action presents a highly dangerous situation to the nurse or other personnel reconstituting the cytotoxic material with a diluent.

The extent to which this aerosoling will occur is basically determined by whether or not the diluent syringe which is utilized to inject the diluent into the vial is used as the injectate syringe as well and, if so, whether or not the injectate syringe is to be filled with injectate before being withdrawn from the vial. The minimal extent of aerosoling is presented in the case of the one dosage vial where the injection of the diluent into the vial, the subsequent mixing of the diluent with the powder in the vial, and the subsequent refilling of the mixture of the diluent and powder back into the syringe all take place without the necessity to remove the syringe needle from the elastomeric stopper of the vial until after the single dosage has been refilled into the syringe chamber. The procedure inevitably results in leaving some liquid in the vial so that the pressure in the vial does not completely reduce to atmospheric pressure after refilling. Consequently, even under these most advantageous circumstances small existing pressure at the time of needle removal after refilling can result in some aerosoling. The usual procedure to accomplish this most favorable operation is to penetrate the needle through the elastomeric stopper while the vial is upright and then press on the syringe plunger. As the diluent is injected into the vial the pressure in the vial as well as the pressure acting on the plunger increases. To accomplish the mixing operation, the operator has two options, he can keep the plunger depressed so as to maintain the increased pressure condition or he can allow the plunger to retract to fill the syringe chamber with gaseous fluid. In either event, it may become necessary to shake the vial to achieve full mixing. The term "gaseous fluid" as used in the present context means the air and/or other gas in the vial container above the liquid solution after the diluent has been added and any hazardous material suspended in the air in the form of particulate solids, vapor and/or liquid and any associated diluent similarly suspended.

After mixing has been accomplished, refilling of the syringe chamber with the reconstituted liquid medicament solution requires that the syringe plunger be fully engaged within the syringe chamber and that the syringe and vial be inverted so that the liquid in the vial is above the open end of the syringe needle extending just through the elastomeric stopper. Another favorable aspect of this most advantageous manner of proceeding is that the increased pressure conditions within the vial above the liquid materially aids in filling the syringe chamber. That is, it is not necessary for the operator to draw the liquid out of the vial with the syringe, rather, the positive pressure within the vial tends to cause the liquid to flow into the syringe chamber without pulling back on the plunger. Nevertheless between the time that extrusion of the diluent into the vial takes place and the time when refilling is complete, the syringe and vial are manipulated at times when maximum pressure conditions exist in the vial with the resultant possibility of leakage between the exterior periphery of the syringe needle and the interior periphery of the elastomeric stopper accommodating the needle penetration.

There are many situations where this most favorable method of operation cannot be utilized. For example, in many hospital situations, the reconstituting of the drug must be performed in the pharmacy remote from and at a time prior to the actual use of the reconstituted drug in the ward or patient's room. Thus, in any situation where reconstitution is divorced from subsequent use, the possibility exists that reconstitution will be accomplished by simply withdrawing the syringe needle from the elastomeric stopper with the plunger fully engaged within the syringe chamber so that pressure conditions within the vial are maximum at the time of withdrawal. This needle withdrawal under maximum pressure conditions is sometimes avoided by simply relaxing the plunger prior to withdrawal and allowing the syringe chamber to fill with the gaseous fluid on top of the liquid in the upright vial. This practice heretofore has been a source of contamination when the gaseous fluid contents of the syringe are subsequently discharged into the immediate environment in cases where the syringe is to be reused.

In the case of multidosage vials, almost by definition the reconstituting procedures are divorced from the use procedures. Consequently, all of the problems of effecting a separate reconstituting procedure with a single dosage vial are simply multiplied.

Another handling procedure which presents a potential cytotoxic material contact with the user exists when the injecting syringe is finally prepared for injecting. The actual step of filling the injecting syringe with cytotoxic material solution almost inevitably results in the inclusion of some air being taken within the syringe. In the more common usage wherein the cytotoxic material solution is to be injected into an i.v. bag, the expelling of this air before injection is not critical. Where the hazardous material is to be directly injected into the patient, particularly intravenously (e.g. some radiographic materials) air should be expelled or extruded from the syringe before the actual injection is performed. The air is extruded by operating the syringe with the needle end uppermost in a direction to extrude the contents. Here again, it is almost inevitable that some of hazardous material solution will be extruded from the needle end of the syringe along with the last pocket of air.

Recent studies have shown that the effects of exposure to anti-neoplastic drugs including cytotoxic agents can be quite severe. Particularly this is true when the exposure is on a day-to-day basis over an extended period. A definite cause and effect relationship between exposure and fetal loss has been observed in a study reported in the Nov. 7, 1985 issue of The New England Journal of Medicine entitled "A Study of Occupational Exposure to Antineoplastic Drugs and Fetal Loss in Nurses" (Vol. 311, No. 19, pages 1173-1178). See also the Editorial in the same edition, pages 1220-1221.

Presently, there is only one procedure available for protecting the user to the extent of enabling the user to accomplish both the reconstituting and air expelling operations without exposing the cytotoxic drugs to the immediate atmospheric environment. This method involves the use of the so-called glove box where the user inserts his hands into gloves so that the user can manipulate the syringe or syringes and the vial with the gloves within an enclosed space. This procedure is bothersome and somewhat cumbersome to perform.

A second presently available procedure which is capable of preventing aerosoling is to use a dispensing pin of the type disclosed in U.S. Pat. No. 4,211,588. The dispensing pin constitutes a separate device which functions to enable diluent to be extruded into the vial and hazardous material solution to be aspirated out of the vial while the interior of the vial is maintained at atmospheric pressure. The use of the dispensing pin obviates the problem of aerosoling since the elastomeric stopper of the vial is never pierced by a needle but rather only by a pin having two parallel passages extending therethrough. One of the passages functions to maintain the interior pressure within the vial substantially at atmospheric pressure by venting the one passage to atmosphere through a filter. The other passage functions as a conduit for conducting diluent into the vial and hazardous material solution out of the vial.

The exterior end of the other passage is formed with an interior luer lock fitting which detachably sealingly engages an exterior luer lock fitting on the injecting syringe with a needle after filling it and removing it from the luer lock of the dispensing pin. After the needle has been secured on the filled injecting syringe, as by engaging the interior luer lock fitting of the needle with the exterior luer lock fitting of the syringe, the user must now operate the syringe to extrude the air from within it with the almost inevitable extrusion of hazardous material solution after the last pocket of air is expelled, as aforesaid. The usual procedure for handling any hazardous material extruded in this procedure is to catch the extrudite in a cloth or other absorbent material and thereafter safely dispose of the soiled cloth or other material. This procedure is cumbersome and inherently fraught with the hazard of environmental and/or accidental exposure to the user.

In addition to the commercially available apparatus described above, the patent literature discloses several other proposed solutions to the problem presented. The expired patented literature; namely, U.S. Pat. No. 2,364,126 discloses an outer cap assembly for securement over a vial closure assembly, the outer cap assembly providing a control chamber over the central elastomeric portion of the closure assembly. Needle access to the chamber can be obtained through a septum provided by the outer cap assembly. The disclosure does not contemplate filtering the chamber to atmosphere nor does it make any reference to the procedure for aspirating air from the syringe used with the outer cap assembly.

U.S. Pat. No. 3,882,909 discloses in FIG. 7 an apparatus similar to that disclosed in U.S. Pat. No. 4,211,588 noted above except that the dual passage pin is straight and the upper ends of the pin and passages are surrounded by a chamber having a septum in the upper end thereof and a parallel vent with a filter therein. U.S. Pat. No. 4,588,403 discloses a functionally similar apparatus with a different structural arrangement.

U.S. Pat. No. 4,564,054 discloses the equivalency between a communicating chamber vented through a filter and a communicating chamber vented to a bladder (see also U.S. Pat. No. 4,600,040). This patent also discloses an embodiment in FIG. 14 wherein a simple exterior non-communicating chamber similar to that provided in expired U.S. Pat. No. 2,364,126 is provided with a filtered vent. Stated differently, the FIG. 14 embodiment is the same as U.S. Pat. No. 2,364,126 with the chamber vented through a filter to atmosphere, as disclosed in U.S. Pat. No. 3,882,909.

U.S. Pat. No. 4,619,651 discloses in FIG. 7 an exterior chamber vented to atmosphere through a filter. However, there are many other embodiments described in this patent in which the chamber provided is simply a closed chamber either exteriorly of or within the neck of the vial. Other pertinent patent literature disclosures may be found in U.S. Pat. Nos. 4,552,277 (telescoping closed chamber), 4,576,211 (telescoping closed chamber with special needle), and 4,582,207 (simple closed chamber).

In summary, it can be stated that in those instances where a continuously communicating chamber is provided, aerosoling is minimized by insuring an interior atmospheric pressure within the vial whenever the needle is withdrawn from the elastomeric stopper; however, the advantages of loading the syringe under pressure are lost. Where a non-communicating chamber is provided, the advantages of loading under pressure are retained; however, the chamber must be operable to accommodate aerosoling when the needle is removed from the vial and thereafter prevent aerosoling when the needle is removed from the chamber. Where the chamber is a simple closed chamber, the pressure within the chamber will increase in response to aerosoling when the needle is withdrawn from the vial so that the withdrawal of the needle from the chamber will take place with the chamber contaminated and under pressure so that aerosoling to the atmospheric environment becomes a likelihood. The use of a filtered vent in the chamber prevents an elevated chamber pressure so long as the filter does not become blocked. Efforts to make the chamber expansible so as to prevent an elevated pressure within the chamber are severely limited by the extent of the expanded volume which can be practically accommodated.

An object of the present invention is to provide apparatus which achieves the advantages of pressure filling while at the same time providing for controlled needle withdrawal from the control chamber under atmospheric pressure conditions by virtue of a filtered vent opening therein while at the same time positively preventing the filtered vent opening from coming into contact with the saturated vapor of the gaseous fluid which may aerosol when the needle is withdrawn from the vial. In accordance with the principles of the present invention, this objective is accomplished by providing apparatus which includes a vial container having hazardous material therein in a condition requiring a diluent to be mixed therewith to form a liquid solution. An assemblage is carried by the vial container which provides (1) a sealed medicament chamber within the vial container withi