Management of Empty Warfarin Containers or Acutely Hazardous Waste Pharmaceuticals
 William Kulas, MBA., Vaiyapuri Subramaniam, PharmD., John Lechman, CIH, CHMM
                                       
Abstract:
Objective:  The proper management of empty acutely hazardous waste pharmaceutical containers is a challenge to the healthcare industry including pharmacies, nursing homes, medical centers and hospitals.  This study (1) Solicited comments from the Environmental Protection Agency (EPA) to assist in the regulatory interpretation of empty Coumadin(R) (Warfarin) containers; (2) Quantified residual Warfarin in "empty" containers; (3) Developed a process to determine the weight of the residue generated and; (4) Analyzed the percentage of Warfarin in the residue to ensure proper waste characterization.  
Practice Description:  EPA regulates the residue remaining in empty containers of acutely hazardous waste found in pharmaceutical operations as a hazardous waste.  Facilities count the container weight and the remaining residue in their calculation to determine hazardous waste generator status.  This calculation frequently results in the facility being classified as a large quantity generator.  
Practice Innovation:  The Warfarin residue was quantified and found to be miniscule.  A practical method of quantifying residue was developed to ensure the empty Warfarin containers are properly classified and managed.    The percent of Warfarin in the residue was analyzed to determine if the residue would meet the definition of "p" listed waste or "u" listed waste in the hazardous waste regulations.  
Conclusion:  Implementing proper management controls for empty Warfarin containers can result in the determination of proper generator status for health care facilities, pharmacies and other areas that dispense Warfarin.  Many of these facilities are small quantity generators of hazardous waste versus large quantity generators of hazardous wastes when proper management controls are in place.
Introduction
The Department of Veterans Affairs (VA) Veterans Health Administration (VHA), has sought regulatory guidance for empty containers that previously held or contained pharmaceuticals that are on the "p" list of commercial chemical products identified in 40 CFR §261.33(e).  "P" listed wastes are acutely hazardous wastes when discarded.  This study focused solely on Warfarin due to the volume of prescriptions in the VA for it.  When a facility generates or accumulates more than 1 kg of acute hazardous waste per month, the generator is subject to the increased regulatory burden as a large quantity generator (40 CFR 262-270). 
This study sought a regulatory interpretation of how empty containers of "p" listed materials count towards the generator status of a facility, to quantify the warfarin residue in the different sized containers, strengths and formulations used in the VA and to  determine the percentage of Warfarin  in the residue to enable proper characterization of this waste stream.  
Objectives
This study reports the results of a quantitative analysis of the amount Warfarin residue in empty containers.  The steps taken were as follows:  (1) Review the regulations concerning the management of empty "p" listed containers, (2) Request letters of interpretation where the regulations were not clear, (3) Quantify the amount of residue left in empty containers to provide a conservative determination of generator status, and (4) Quantify the percentage of Warfarin in the residue to determine if it meets the characteristics of a "p" listed or "u" listed waste.
Methods
The VHA requested EPA's interpretation  on the proper management of empty Warfarin stock bottles on August 10, of 2011.  Specifically, clarification was requested on the following questions:
   * Should empty Warfarin stock bottles be managed as a hazardous waste?
   * Is the weight of the Warfarin stock bottle or only the warfarin residue therein counted toward monthly generator status?
   * Is the volume of the Warfarin stock bottle or only the warfarin residue therein counted toward the one quart limit for acutely hazardous waste at a satellite accumulation area?
Answers to those questions were provided on October 19, 2011, by EPA Region I and again on November 4, 2011, by EPA Headquarters.
Both interpretation letters stated that it is the residue's weight and not the container's weight that is regulated and counted towards generator status.  In the interpretation letter from EPA Region I, it recommended that a process should be developed to accurately and readily determine the amount of residues in such bottles.  Based upon the interpretation from the EPA the next part of this study was to quantify the amounts of residue left in various container sizes and doses to ensure that accurate monthly generator status calculations can be made.   
The "p" listing for warfarin is unusual in that it is concentration-based.  Warfarin and its salts at a concentration of >0.3 % are listed as a P001 in 40 CFR 261.33 (e) while warfarin salts at a concentration of <0.3% is listed as U248 in 40 CFR 261.33 (f).  The final part of the study was to analyze the percentage of Warfarin in the residue to determine if the residue remaining in these containers would carry the "p" listing or the "u" listing as hazardous wastes
An environmental lab, Bureau Veritas, was chosen to analyze the samples.  Seventeen different combinations of empty Warfarin containers with different dose and bottle sizes were collected from the VHA Pharmacy Benefits Management (PBM) Services' Consolidated Mail Outpatient Pharmacies (CMOPs).  Since all the potential warfarin containers generated by the VHA were not tested, the samples were weighted towards high count (1000 pill bottles) or high dose to the extent feasible.  Five or six replicates of each bottle size and dose were submitted to the laboratory from different CMOP locations between February 28, 2013 and May 24, 2013 to enable a statistical analysis.
Results
Regulatory Interpretation
The EPA issued a  regulatory interpretation in a Regional Letter on October 19, 2011, and a national letter on November 4, 2011.  It highlighted the regulatory status of Commercial Chemical Product residues that is specifically addressed in 40 CFR § 261.33 which states:
	"The following materials or items are hazardous wastes if and when they are discarded or intended to be discarded....
	(c) Any residue remaining in a container or in an inner liner removed from a container that has held any commercial chemical product or manufacturing chemical intermediate having the generic name listed in paragraphs (e ) or (f) of this section, unless the container is empty as defined in § 261.7(b)
The letter reiterates that it is only the residue in the non RCRA (Resource Conservation and Recovery Act) empty container that is considered a P-listed waste; the container itself is not a "p" listed hazardous waste.  Thus only the weight of the residue in the container needs to be counted towards generator status.
The interpretation letter from EPA Region I, however, further states that:
	"In order to determine the amount of P-listed hazardous waste or residue remaining in empty stock bottles for the purpose of monthly generator status determinations, the generator would need to develop a process by which the amount of waste or residue remaining in such bottles can be accurately and readily determined.  The process should adequately address how the amounts of waste or residue from different size bottles/containers of specific P-listed hazardous waste and form is determined so that the amount of waste residues generated from collected bottles/containers, possibly of various sizes, can be readily determined.... to ensure that accurate monthly generator status calculations are made.  
Based upon the EPA's interpretation, this study developed a process to quantify the amount of residue remaining in bottles/containers of various  sizes and dosage strengths.
The EPA Headquarters letter also stated that they "do not have, nor have we received, data regarding the concentration of warfarin in the residue remaining in fully dispensed containers of warfarin.  Generators have indicated that some doses of warfarin pills contain concentrations high enough to meet the "p" listing.  But if a generator conducted analysis on the warfarin residues remaining in a fully dispensed container and the concentration of the residues is <0.3 % warfarin, then the residues ..... would be regulated as U248 hazardous waste."  The last part of the study investigated the concentrations of warfarin in the residues to determine if a "p" or "u" listing was the most appropriate.
 Mass of Total Residue per Bottle 

Five or six samples of seventeen different products in either 100 or 1000 pill containers  were evaluated to determine the total residue of Warfarin.  Each bottle was triple rinsed with deionized water to remove any residue and to render the container "RCRA empty". The rinsates were combined in a weighed glass beaker and evaporated to dryness in a low temperature oven. The beaker was re weighed again to calculate the mass of total residue in each container.
Results for total residue are reported in Table 1 as the average mass of residue per product code and bottle type in milligrams. The one sided 95% upper confidence limit was calculated (milligrams) and used to provide a conservative figure for Warfarin residue. 
The results show that the most residue left in a 1000 pill empty container was the 85 mg found in the 6 mg dose of Product Code W0051.  A one sided, 95% upper confidence limit for the residue (mg) was calculated to be 125 mg.
 The most residue left in a 100 pill container was 7.8 mg in the 10 mg dose of Product Code W0037.  A one sided, 95% upper confidence limit for the residue (mg) was calculated to be 16 mg.  

Mass of Warfarin per Bottle 

Each bottle type was then evaluated for concentration of Warfarin in the residue to determine if the residue met the definition of  a "p" listed or "u" listed material.  Residues from three replicates of each bottle type were evaluated for Warfarin concentration. The residue was extracted in a 1:1 solution of methanol and water, and the extracts were analyzed using high pressure liquid chromatography (HPLC). 
The results of the Warfarin analysis are reported as an average mass of Warfarin per bottle (milligrams), and as the average concentration of Warfarin in the total residue (percentage). 
As all percentages are greater than 0.3% the "p" listing at P001 is the appropriate waste characterization.
Table 1

                              Sample Information
                              Total Residue (n=6)
                                Warfarin (n=3)
Product Code 
Warfarin Dose 
Tablet Count 
Average Mass 
(mg) 
One sided 95% upper confidence limit for the residue (mg) 
Average Mass 
(mg) 
Mass Warfarin per Mass Total Residue 
(%) 
W0051 
6 mg 
1000 
85 
125 
3.7 
5.1% 
W0050 
5 mg 
1000 
48 
74 
1.8 
4.1% 
W0049 
4 mg 
1000 
68 
109 
2.4 
3.0% 
W0048 
3 mg 
1000 
55 
69 
1.2 
2.1% 
W0046 
2 mg 
1000 
60 
81 
0.7 
1.1% 
W0044 
2.5 mg 
1000 
50 
60 
0.5 
1.0% 
W0039 
1 mg 
1000 
67 
80 
0.5 
0.8% 
W0038 
7.5 mg 
100 
7.8 
15 
0.1 
1.4% 
W0037 
10 mg 
100 
7.7 
16 
0.2 
2.7% 
W0017 
3 mg 
100 
3.4 
12 
0.02 
0.5% 
W0013 
4 mg 
100 
4.8 
6.6 
0.1 
1.7% 
W0009 
1 mg 
1000 
42 
70 
0.4 
0.7% 
W0005* 
7.5 mg 
100 
5.0 
7.1 
0.2 
3.9% 
W0004 
5 mg 
1000 
61 
91 
2.4 
3.9% 
W0003 
2 mg 
1000 
33 
43 
0.6 
1.7% 
W0002 
2.5 mg 
1000 
44 
57 
0.9 
1.9% 
W0001 
10 mg 
100 
4.2 
6.5 
0.2 
4.4% 
* Five replicates (n=5) for total residue for sample W0005

Quality Control Samples 

The method was evaluated by weighing duplicate known amounts of Warfarin sodium into a bottle. The bottle was triple rinsed, and the rinsates were combined in a weighed glass beaker and evaporated to dryness. The dried residue was extracted in a 1:1 solution of methanol and water and analyzed using HPLC. The results are reported in table 2 below.

Table 2

                            Quality Control Sample
                         Mass of Warfarin Sodium (mg)
                           Warfarin Recovery by HPLC
Laboratory Control Spike
                                     1.40
                                      99%
Laboratory Control Spike Duplicate
                                     1.73
                                     107%


Estimation of Bottle Accumulation to EPA Waste Rules 

We estimated, using the 95% confidence limit for the residue and the highest doses available, that it would take 7,602 empty warfarin 1000 pill containers or 60,320 empty warfarin 100 pill containers to meet the EPA regulatory limit of 2.2 pounds or 1 kg of warfarin residue.   We estimated the number of 55 gallon drums that could be filled with empty Warfarin bottles without exceeding the EPA threshold of 1 kilogram of total residue.  A facility could generate in any one month or accumulate at any one time 14 standard sized 55 gallon drums of 1000 pill empty containers or 26 standard sized 55 gall drums of 100 pill empty containers.  (See attachment 1 for the calculations)

Discussion
VHA Healthcare facilities and Consolidated Mail Order Pharmacies (CMOP) have been counting the weight of the container of empty "p" listed pharmaceuticals containers in calculating their generator status because there has not been a process developed that can accurately and readily determine the amount of residue that is found in the various sizes and dosages of collected bottles and containers.  Many of these facilities have exceeded the 1 kilogram threshold monthly generation/accumulation rate or total accumulation rate and have become Large Quantity Generators.  By developing a systematic process based upon test results of residues in bottles/containers of various sizes and dosages, healthcare and CMOP facilities now have data to quantify the amount of "p" listed residues that are generated.  In many cases this will allow the facility to change their regulatory status from Large Quantity Generator to Small or Conditionally Exempt Small Quantity Generator as  defined in 40 CFR 261.5.  
The results of this study will enable processes to be developed that can be used to calculate the actual amount of Warfarin remaining in empty containers, the actual amounts generated in any one month, or the actual amounts accumulated at any one time.
This study demonstrates that a facility can either generate or accumulate 7,602 containers or 14 (55 gallon) drums of empty Warfarin 1000 pill containers or 60,320 containers or 26 (55 gallon) drums of empty Warfarin 100 pill containers before reaching the 1 kg limit of a Small Quantity Generator. 
It is beneficial to the facility to manage these containers so that the facility does not reach these amounts at any time.   Facilities are required to calculate their generator status on a monthly basis.  By using the actual results of the warfarin remaining in empty pill containers facilities can potentially keep the facility under the limit of 1 kilogram.  A management option would be to separate the 1000 and 100 pill container sizes into separate drums and use 0.068 kg and 0.037 kg respectively for the amount of Warfarin contained in a 55 gallon drum. 
The Warfarin residue carries the "p" listing and not the "u" listing based upon the concentration of Warfarin found in the residue.

Limitations
Facilities may generate other acute hazardous wastes that, when combined with the "p" listed container residues, would cause the facility to exceed the 1 kg monthly threshold.  Facilities need to be aware of all wastes generated at the facility before the generator determination is made.  
Conclusion
Many Healthcare facilities and Consolidated Mail Order Pharmacies that have previously reported their generator status as Large Quantity Generator can now file as a Small Quantity Generator using the information provided in this study.
Accurate monthly generator status calculations are required.  The one-kilogram generation and accumulation threshold for P-listed acutely hazardous wastes may affect the regulatory status of many facilities.  Exceeding these thresholds subjects these generators to the large quantity generator requirements.  Documentation of the process used to make this determination should be maintained on site and be readily available for inspection.
Article Notes
Disclaimer:  The opinions expressed are those of the authors and do not represent the views of the Department of Veterans Affairs (VA).  No official support or endorsement by the VA is intended or should be inferred.

Attachment 1:
A standard 55 gallon drums has an inner dimensions of about 22.5 inches in diameter (11.25 inches in radius) and 33.5 inches in height, for an approximate volume of 13,320 cubic inches.
 
Volume of a cylinder = PI r ²  x h, where r = radius and h = height 

Volume a 55 gallon drum = PI x (11.25 inches) ² x 33.5 inches = 13,320 inches³ 

1000 Tablet Bottles 

There were two types of 1000 tablet bottles. The calculations are based on the smaller of the two bottles to present a worst-case scenario. 

The dimensions of the bottle were measured. The radius, r, was approximately 1.25 inches and the height, h, was 5 inches. The estimation of the volume was calculated in square inches, according to the calculation below. 

Estimated Volume = PI r²  x h = PI x (1.25 inches) ²  x 5 inches = 24.5 inches³/bottle 

The maximum number of bottles that could fit into a 55 gallon drum was calculated by dividing the volume of a 55 gallon drum by the volume of a bottle. 

      13,320 inches³     x       Bottle       =     543 bottle/drum
                  Drum                     24.5 inches

The total amount of pill residue in a 55 gallon drum filled with empty 1000 tablet Warfarin bottles was calculated by multiplying the maximum number of bottles per drum with the largest mass (one sided upper confidence limit) of pill residue (W0051) in a 1000 tablet bottle and converting to kilograms. The one sided upper limit of the largest mass was used to present a worst-case scenario.

	543 bottles	x	125 mg residue		x	1kg	         =0.068 kg residue/drum
                 Drum                                 bottle                             1,000,000 mg

Based on these calculations, 14 (55 gallon) drums of empty 1000 tablet Warfarin bottles could be stored on site without exceeding the limit of 1 kg of total residue.


100 Tablet Bottles

The same calculations were done for the 100 tablet bottles. There were two types of 100 tablet bottles. The calculations are based on the smaller of the two bottles to present a worst-case scenario. 

The dimensions of the bottle were measured. The radius, r, was approximately 0.75 inches and the height, h, was 3.25 inches. An estimation of the volume of the bottle was calculated in square inches, according to the calculation below.

Estimated Volume = PI r ²   x h = PI x (0.75 inches) ²   x 3.25 inches =5.74 inches³/bottle

The maximum number of 100 tablet bottles that could fit into a 55 gallon drum was calculated by dividing the volume of a 55 gallon drum by the volume of a bottle.

          13,320 inches³    x       bottle               =          2,320 bottles/drum
                 Drum                5.74 inches³ 


The total amount of pill residue in a 55 gallon drum filled with empty 100 tablet Warfarin bottles was calculated by multiplying the maximum number of bottles per drum with the largest mass (one sided upper confidence limit) of pill residue in a 100 tablet bottle (W0037) and converting to kilograms. The one sided upper limit of the largest mass was used to present a worst-case scenario.


    2,320 bottles     x     16 mg residue     x          1 kg          =     0.037 kg of residue/drum
          Drum                         bottle                  1,000,000

Based on these calculations, 26 (55 gallon) drums of empty 100 tablet Warfarin bottles could be stored on site without exceeding the limit of 1 kg of total residue.


References
   1.  Memorandum from Suzanne Rudzinksi, Director of Environmental Protection Agency Office of Resource Conservation and Recovery dated November 4, 2011 to RCRA Division Directors, EPA Regions 1-10.
   2.  Memorandum from Mary Sanderson, Chief Remediation and Restoration II Branch, Office of Site Remediation and Restoration (OSRR07-2), United States Environmental Protection Agency, Region 1, dated October 19, 2011 entitled Empty Warfarin Container Interpretation (warfarin stock bottles)
   3.  40CFR . § 261.7(b)
   4.  40 CFR § 261.33

