EPA/600/R-14/167 / December 2014 / www.epa.gov/research
United States
Environmental Protection
Agency
Evaluation of P-Listed
Pharmaceutical Residues
in Empty Pharmaceutical
Containers
Prepared for:
U.S. Environmental Protection Agency
Office of Research and Development
Waste Management Branch,
National Risk Management Research Laboratory
Cincinnati Ohio
Prepared by:
Pegasus Technical Services
Cincinnati, OH
Under EPA Contract No. EP-C-11-006
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Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers EPA/600/R-14/167
Notice
This research was funded by the National Risk Management Research Laboratory (NRMRL) of the U.S.
Environmental Protection Agency (EPA), Office of Research and Development (ORD) and the EPA's
Office of Resource Conservation and Recovery (ORCR) under the Safe and Healthy Communities
Research Program. This report was prepared by Pegasus Technical Services (PTS) under EPA Contract
EP-C-11-006.
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Foreword
The US Environmental Protection Agency (US EPA) is charged by Congress with protecting the Nation's
land, air, and water resources. Under a mandate of national environmental laws, the Agency strives to
formulate and implement actions leading to a compatible balance between human activities and the ability
of natural systems to support and nurture life. To meet this mandate, US EPA's research program is
providing data and technical support for solving environmental problems today and building a science
knowledge base necessary to manage our ecological resources wisely, understand how pollutants affect
our health, and prevent or reduce environmental risks in the future.
The National Risk Management Research Laboratory (NRMRL) is the Agency's center for investigation
of technological and management approaches for preventing and reducing risks from pollution that
threaten human health and the environment. The focus of the Laboratory's research program is on
methods and their cost-effectiveness for prevention and control of pollution to air, land, water, and
subsurface resources; protection of water quality in public water systems; remediation of contaminated
sites, sediments and ground water; prevention and control of indoor air pollution; and restoration of
ecosystems. NRMRL collaborates with both public and private sector partners to foster technologies that
reduce the cost of compliance and to anticipate emerging problems. NRMRL's research provides
solutions to environmental problems by: developing and promoting technologies that protect and improve
the environment; advancing scientific and engineering information to support regulatory and policy
decisions; and providing the technical support and information transfer to ensure implementation of
environmental regulations and strategies at the national, state, and community levels.
This publication has been produced as part of the Laboratory's strategic long-term research plan. It is
published and made available by US EPA's Office of Research and Development to assist the user
community and to link researchers with their clients.
Cynthia Sonich-Mullin, Director
National Risk Management Research Laboratory
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Table of Contents
Notice 1
Foreword 2
Table of Contents 3
List of Figures 4
List of Tables 5
List of Appendices 5
1 Abbreviations and Acronyms 6
2 Executive Summary 7
3 Project Objective 8
4 Approach 9
4.1 Experimental Approach 9
4.2 Experimental Steps 9
5 Results and Discussion 13
5,1 Control Samples 13
5.1.1 Cotton Piece 13
5.1.2 Warfarin Sodium Swabbed 13
5.1.3 Nicotine Swabbed 14
5.1.4 Physostigmine Salicylate Swabbed 15
5.2 Warfarin Sodium Medications 16
5.2.1 Warfarin Sodium Tablets, Img 16
5.2.2 Warfarin Sodium Tablets, 5mg 17
5.2.3 Warfarin Sodium Tablets, lOmg 19
5.2.4 Warfarin Sodium Tablets, 2mg 21
5.3 Jantoven 23
5.3.1 Jantoven Tablets, Img 23
5.3.2 Jantoven Tablets, lOmg 24
5.4 Nicotine 25
5.4.1 Nicorette Gum (Fruit Chill), 2mg 25
5.4.2 Nicorette Gum (Fruit Chill), 4mg 27
5.4.3 Nicotine Polacrilex Gum, 2mg 28
5.4.4 Nicotine Polacrilex Gum, 4mg 29
5.4.5 Nicorette Mini Lozenge, 2mg 31
5.4.6 Nicorette Lozenge, 4mg 33
5.4.7 Nicotine Transdermal System (Patch), 7mg 35
5.4.8 Nicotine Transdermal System (Patch), 14mg 37
5.4.9 Nicotine Transdermal System (Patch), 21mg 39
5.4.10 Nicotrol NS (nicotine nasal spray), lOmg/ml 40
5.4.11 Nicotrol Inhaler (nicotine inhalation system), lOmg/cartridge 42
5.5 Physostigmine Salicylate Medications 43
5.5.1 Physostigmine Salicylate, (Img/ml) 43
6 Quality Control 45
6.1 Accuracy (bias) 45
6.2 Representativeness 46
6.3 Completeness 46
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6,4 Comparability 47
7 Conclusions 48
8 Appendix A 57
9 Appendix B 75
10 Appendix C 92
11 Appendix D 94
12 Appendix E 140
List of Figures
Figure 1. Cotton tip applicator and empty plastic containers 11
Figure 2. TGA Sample Pan 11
Figure 3. Thermogravimetric Analyzer (TGA) 11
Figure 4. Components of the TGA instrument 12
Figure 5. TGA results of cotton piece (control) 13
Figure 6. TGA results of Warfarin Sodium 14
Figure 7. TGA results of pure Nicotine 15
Figure 8. TGA results of pure Physostigmine Salicylate 15
Figure 9. TGA results of Warfarin Sodium 1 mg, plastic containers 16
Figure 10. TGA results of non-rinsed containers of Warfarin Sodium 1 mg versus Warfarin
Sodium 17
Figure 11. TGA results of Warfarin Sodium 5 mg, plastic containers 18
Figure 12. TGA results of non-rinsed containers of Warfarin Sodium 5 mg versus Warfarin
Sodium 19
Figure 13. TGA results of Warfarin Sodium 10 mg, plastic containers 20
Figure 14. TGA results of non-rinsed containers of Warfarin Sodium 10 mg versus Warfarin
Sodium 21
Figure 15. TGA results of Warfarin Sodium 2 mg, blister packs 22
Figure 16. TGA results of Jantoven (Warfarin Sodium) 1 mg, blister packs 23
Figure 17. TGA results of Jantoven (Warfarin Sodium) 10 mg, blister packs 25
Figure 18. TGA results of Nicorette gum 2 mg, blister packs 26
Figure 19. TGA results of Nicorette gum 4 mg, blister packs 27
Figure 20. TGA results of Nicotine Polacrilex gum 2 mg, blister packs 29
Figure 21. TGA results of Nicotine Polacrilex gum 4 mg, blister packs 30
Figure 22. TGA results of Nicorette mini lozenges 2 mg, plastic containers 31
Figure 23. TGA results of Nicorette mini lozenges 2 mg plastic containers versus pure nicotine 32
Figure 24. TGA results of Nicorette lozenges 4 mg, plastic containers 33
Figure 25. TGA results of Nicorette lozenges 4 mg, plastic containers versus pure nicotine 34
Figure 26. Picture of the Nicotine patches 35
Figure 27. TGA results of Nicotine Transdermal Patches 7 mg, plastic wrap 36
Figure 28. TGA results of Nicotine Transdermal Patches 14 mg, plastic wrap 37
Figure 29. TGA results of Nicotine Transdermal Patches 21 mg, plastic wrap 39
Figure 30. TGA results of Nicotine nasal spray lOmg/ml, glass vial 41
Figure 31. TGA results of Nicotine nasal spray 10 mg/ml, glass vial versus pure Nicotine 41
Figure 32. TGA results of Physostigmine Salicylate 1 mg/ml, glass vial 43
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Figure 33. TGA results of Physostigmine Salicylate 1 mg/ml, glass vial versus pure
Physostigmine Salicylate 44
List of Tables
Table 1. List of medications and package types 9
Table 2. Summary of QA/QC checks for accuracy 45
Table 3. Temperature calibrations of the TGA 46
Table 4. Temperature for maximum weight loss for pure pharmaceutical compounds 46
Table 5. Completeness of the measurements 47
Table 6. Summary of the results and limitations of analysis 51
List of Appendices
Appendix A 57
Appendix B 75
Appendix C 92
Appendix D 94
Appendix E 139
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1 Abbreviations and Acronyms
DI Deionized Water
DQO Data Quality Objectives
EPA Environmental Protection Agency
OSWER Office of Solid Waste and Emergency Response
QAPP Quality Assurance Project Plan
RCRA Resource Conservation and Recovery Act
Tmaxwt loss Temperature at which the peak in weight loss occurs for the residuals
TGA Thermal Gravimetric Analysis
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2 Executive Summary
Under the Resource Conservation and Recovery Act (RCRA), some discarded pharmaceuticals are
considered acute hazardous wastes because their sole active pharmaceutical ingredients are P-listed
commercial chemical products (40 CFR 261.33). Hospitals and other healthcare facilities have struggled
with RCRA's empty container requirements when it comes to the disposal of visually empty warfarin and
nicotine containers, and this issue is in need of investigation. For example, nicotine gums, patches and
lozenges are hazardous wastes because nicotine and its salts are listed as P075, and Coumadin (also
known as warfarin) is hazardous because warfarin and its salts are listed as P001 (when warfarin is
present at concentrations greater than 0.3%).
Therefore, when unused nicotine-based smoking cessation products (e.g., patches, gums and lozenges)
and Coumadin are discarded, they are classified as acute hazardous wastes, and must be managed in
accordance with all applicable RCRA regulations. Furthermore, due to additional management
requirements for P-listed wastes, any acute hazardous waste residues remaining in containers (and
therefore the container itself) must be managed as hazardous unless the container has been rendered
"RCRA empty" either by triple-rinsing with an appropriate solvent or by another method proven to
achieve equivalent removal.
The primary objective of the current study was to answer the research question "Is there a difference
between empty P-listed pharmaceutical containers that are triple-rinsed and those that are not triple-
rinsed?" The study objective was accomplished via two tasks: 1) calculating the "maximum possible
weight of residual drug/total residual /container" for each compound and packaging combination to infer
an upper limit for the amount of active pharmaceutical compound in the total residue remaining in the
container and 2) evaluating, qualitatively, the presence of active pharmaceutical ingredient in the residues.
The experimental test program included the use of a sensitive balance to determine the total amount of
residues in the empty pharmaceutical containers and a thermal gravimetric analysis to qualitatively
evaluate the presence of the active pharmaceutical compounds in the residues. The P-listed
Pharmaceuticals evaluated in the study were nicotine, Coumadin, and physostigmine.
The results of the study indicated the following: 1) all the medications in liquid form (Nicotrol nasal spray
10 mg/ml and Physostigmine salicylate 1 mg/ml) as well as the Nicotine inhaler (lOmg/ cartridge)
showed a difference between triple-rinsed containers and those that were not triple-rinsed because the
residues in the not-triple-rinsed ones contained the active pharmaceutical ingredient; 2) the TGA results
for the medications in solid form (i.e., tablet (caplet form), gum, and lozenge) and patches showed no
difference between triple-rinsed containers and those that were not triple-rinsed. However, this conclusion
is based on a qualitative analysis by thermal gravimetric analysis (TGA) that is limited by the sensitivity
of the TGA. Other analytical techniques (e.g., gas chromatography or liquid chromatography equipped
with mass spectrometer) may be needed to verify the TGA results for these medications, and to
quantitatively determine the amount of the active pharmaceutical compounds present in the residues (if
any); 3) the medications packaged in blister packs and plastic wraps contained minimal residuals, within
the range of the error of the balance used in the study, after removing the drugs; 4) medications packaged
in plastic containers contained measurable amount of residuals (using balance data) after removing the
drugs (except for Nicorette 2 mg and 4 mg lozenges, for which the balance data were inconclusive); and
5) a theoretical "maximum possible weight of residual active compound/total residual /container" was
calculated and presented for each compound and packaging combination.
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3 Project Objective
The primary purpose of this study is to evaluate if simply removing the drug (specifically nicotine,
Coumadin and physostigmine) from its container is equivalent to triple rinsing the container. The
secondary purpose of this study was to determine whether the active pharmaceutical ingredient is present
in the residues remaining in the containers. The U.S. Environmental Protection Agency (EPA) Office of
Solid Waste and Emergency Response (OSWER) plans to address the issue of rendering these
pharmaceutical packages RCRA empty through a rulemaking. The objectives of this study were achieved
as follows:
• Measure the amount of total residuals in pharmaceutical containers containing warfarin, physostigmine
and nicotine medications after removing the drugs.
• Calculate the "maximum possible weight of residual drug/total residual /container" for each compound
and packaging combination. This calculated result may be used to infer an upper limit for the amount
of active pharmaceutical compound in the total residue remaining in the container.
• Use thermal gravimetric analysis (TGA) technique to qualitatively evaluate the presence of active
pharmaceutical ingredient in the residuals after removing the drug from the rinsed pharmaceutical
containers.
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4 Approach
4,1 Experimental Approach
The investigated medications and package types are summarized in Table 1.
Table 1. List of medications and package types
Medication
Warfarin
Nicotine
Physostigmine Salicylate
Form and Dose
Warfarin sodium tablets (caplet), 1 mg
Warfarin sodium tablets (caplet), 5 mg
Warfarin sodium tablets (caplet), 10 mg
Warfarin sodium tablets (caplet), 2 mg
Jantoven tablets (caplet), 1 mg
Jantoven tablets (caplet), 10 mg
Nicorette gum, 2 mg
Nicorette gum, 4 mg
Nicotine polacrilex gum, 2 mg
Nicotine polacrilex gum, 4 mg
Nicorette mini lozenge, 2 mg
Nicorette lozenge, 4 mg
Nicotine transdermal patch, 7 mg
Nicotine transdermal patch, 14 mg
Nicotine transdermal patch, 21 mg
Nicotrol nasal spray, 10 mg/ml
Nicotine inhaler, 10 mg/cartridge
Physostig-mine salicylate, 1 mg/ml
Package Type
Plastic container
Plastic container
Plastic container
Blister pack
Blister pack
Blister pack
Blister pack
Blister pack
Blister pack
Blister pack
Plastic container
Plastic container
Plastic wrap (peel off)
enclosed in foil wrap
Plastic wrap (peel off)
enclosed in foil wrap
Plastic wrap (peel off)
enclosed in foil wrap
Glass vial
Plastic container
Glass ampule
Drugs were purchased from TriHealth outpatient pharmacy located in Cincinnati, OH. The drugs were
purchased under a license issued from the Ohio Board of Pharmacy to the U.S. EPA. The license number
is LR. 022271550.
The instruments utilized to determine the amount of residual drug and identify if these residuals contain
the active pharmaceutical ingredient are:
1. Thermal Gravimetric Analysis (TGA) (model 2950, TA instruments)
2. Microbalance (AB 104S-Mettler Toledo)
4,2 Experimental Steps
The medication (tablets, pills, lozenges, etc.) was removed from the container in a way to simulate actual
use. The discarded medication was disposed as hazardous waste. For the Plastic Wrap peel offs, only the
plastic peel was tested. The external foil wrap packaging was not tested because the active side of the
nicotine patch is only in contact with the plastic wrap that is facing it, preventing the release of the drug to
other surfaces. The drug can only release when the internal plastic wrap is peeled off. Therefore, the
external foil package is not expected to contain residues as it is not in contact with the patch, and
therefore it was not experimentally tested.
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1. The empty containers were then exposed to one of three treatment conditions:
A. No rinse
B. Single triple rinse (30 seconds per rinse) with deionized water (DI)
C. Double triple rinse (30 seconds per rinse) with organic solvent (methanol) to prepare clean
containers (negative controls, because unused, empty containers could not be obtained)
2. Triplicate containers were evaluated under each one of the above three treatment conditions
(Appendix A).
3. The amount of total residuals in each container was measured.
A. Using a microbalance, the weight of the empty container was measured before and after
treatment, and the difference in weight represented the amount of total residuals (i.e., the
combined weights of the active pharmaceutical ingredient plus all the inactive ingredients).
To dry the containers between triple-rinses, the container were kept upside down in a
desiccator for a minimum of 12 hours.
B. The balance readability is 0.1 mg
4. The maximum amount of active pharmaceutical ingredient that could theoretically be contained
in the residuals of any of the tested medication was calculated as follows:
A. It was assumed that the active pharmaceutical ingredient is homogenously distributed in the
medication (e.g., tablet, lozenge, gum, etc.). This assumption represents the worst case
scenario. Most likely, the outer layer of the medication is mainly composed of a different
chemical coating that is needed to prevent the loss of the drug until the medication reaches
the location where it should be delivered in the body. In the case of liquid medications
(solutions), the active pharmaceutical ingredient is homogeneously distributed in the
residuals.
B. Based on the above assumption, information on the concentration of the active
pharmaceutical ingredient in the medication (e.g., % drug per tablet is calculated from the
labeled drug concentration provided by the manufacturer), and the experimentally determined
weight of total residuals, the maximum amount of active pharmaceutical ingredient that could
theoretically be contained in the residuals was calculated. The detailed calculations for each
medication/package are presented in Appendix A.
5. The TGA was used to qualitatively evaluate the presence of the active pharmaceutical compounds
(warfarin sodium, nicotine, and physostigmine salicylate) in the residuals.
6. The residuals were collected from the empty containers after each treatment using a cotton tip
applicator that was used to swab the container walls (Figure 1).
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Figure 1. Cotton tip applicator and empty plastic containers
7. The cotton piece was then detached from the wooden stick and loaded into the TGA sample pan.
6
Figure 2. TGA Sample Pan
C. The weight loss of the cotton piece (loaded with residual, if any) as a function of temperature
was measured using TGA (Figure 3). The TGA was programmed to heat the sample at a rate
of20°C/minto600°C.
a. The TGA balance readability is 0.1 ug
Figure 3. Thermogravimetric Analyzer (TGA)
D. The TGA is a technique in which the loss of mass of a substance is monitored as a function of
temperature or time as the sample specimen is subjected to a controlled temperature program
in a controlled atmosphere. The TGA instrument consists of a sample pan that is supported by
a precision balance and a furnace (Figure 4). The sample pan containing the sample is heated
to a specified temperature. The loss of the sample weight is monitored as a function of
temperature. TGA relies on a high degree of precision in three measurements: weight,
temperature, and temperature change. As a result of heating the sample to a high enough
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temperature, some residuals decompose into gas, which disperses into the air. To prevent
decomposition gases from entering the balance chamber, nitrogen gas was purged all the time
at a rate of 100 ml/min. The TGA analysis generates a plot of % weight (Y-axis) and
temperature (X-axis). The temperature at which the peak in weight loss (Tmaxwtioss) occurs for
the collected residual from the empty drug container will be compared to that of the active
pharmaceutical compound. If the Tmaxwtioss for both the residual and the compounds are
similar, then the residuals contain the active ingredient. It should be noted that the TGA data
is qualitative, which means that the TGA results are not used to quantify the amount of active
pharmaceutical ingredient in the residuals.
Figure 4. Components of the TGA instrument
The following controls were also analyzed in triplicates using the TGA:
a. Clean cotton piece
b. Negative control: clean empty containers cleaned with methanol
c. Positive control: the active pharmaceutical compounds which are warfarin sodium,
nicotine and physostigmine salicylate. The specifications of these compounds are
presented in Table C2 (Appendix C).
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5 Results and Discussion
5.1 Control Samples
5.1.1 Cotton Piece
The average Tmaxwt ioss of the cotton piece was 427 °C as presented by the first derivative of the profile of
the weight loss as a function of temperature (Figure 5).
120
100 -
80 -
•+J
JS
•£ 60 -
40 -
20 -
427 °C
Cotton Piece-Control
1st Derivative of Weight Loss
100
200
500
300 400
Temperature (°C)
Figure 5. TGA results of cotton piece (control)
- 1.8
- 1.6
- 1.4
-1.2 P
g,
-1.0 +T
.0)
-0.8 |
Q
- 0.4
- 0.2
- 0.0
600
5.1.2 Warfarin Sodium Swabbed
The pure warfarin sodium had a distinct weight loss peak (Tmax wt ioss) at 313 °C in addition to the peak that
corresponds to the weight loss of the cotton piece (Figure 6). According to the Quality Assurance Project
Plan (QAPP) for this study, the Tmaxwtioss of the residuals represents warfarin sodium if it occurs within ±
5 °C of the Tmaxwt ioss of the pure warfarin sodium (313 °C).
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120
Pure Warfarin Sodium on Cotton Piece
Cotton Piece Only
100 -
100
200 \ 300 / 400 500
Temperature (°C)
Figure 6. TGA results of Warfarin Sodium
- 0.0
600
It is noted that the weight loss profile and consequently its 1st derivative are somewhat noisy. The TGA
analysis of the pure compounds (only warfarin and physostigmine) was performed after moving the TGA
instrument inside a fume hood because of the very dangerous compounds that can emit from heating those
compounds to elevated temperatures. Because the TGA balance is very sensitive, the air flow in the fume
hood resulted in a somewhat noisy signal. Nonetheless, the overall profile was good and two distinct
weight loss peaks were identified (one corresponds to the cotton piece and the other corresponds to the
pure compound). Also, the Tmaxwtioss of the cotton piece was within the acceptable limit for the cotton
piece (Appendix C).
5.1.3 Nicotine Swabbed
The pure nicotine had a distinct weight loss peak at 217 °C in addition to the peak that corresponds to the
weight loss of the cotton piece (Figure 7). According to the QAPP for this study, the Tmaxwtiossof the
residuals represents nicotine if it occurs within ± 5 °C of the TmaxwtiossOf the pure nicotine (217 °C). It is
noted that the weight loss profile and consequently its 1st derivative were NOT noisy because the pure
nicotine analysis was conducted while the TGA was outside the fume hood so there was no air flow
disturbance as happened for warfarin sodium and physostigmine salicylate.
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120
100 -
80 -
20 -
Pure Nicotine on Cotton Piece
Cotton Piece Only
- 1.8
- 1.6
- 1.4
- 1.2
- 1.0
- 0.8
- 0.6
- 0.4
- 0.2
.5"
5J
&
- 0.0
100
500
600
\ 200 / 300 400
\ /
/' Temperature (°C)
Figure 7. TGA results of pure Nicotine
5.1.4 Physostigmine Salicylate Swabbed
The pure physostigmine salicylate had a distinct weight loss peak at 236 °C in addition to the peak that
corresponds to the weight loss of the cotton piece (Figure 8). According to the QAPP for this study, the
TmaxwtioSSof the residuals represents physostigmine if it occurs within ± 5 °C of the Tmaxwtiossof the pure
physostigmine (236 °C). It is noted that the weight loss profile and consequently its 1st derivative are
somewhat noisy for the reasons stated in section 5.1.2.
120
Pure Physostigmine on Cotton Piece
Cotton Piece Only
- 1.5
2.0
f
0)
Q
0.0
100
500
400
Temperature (°C)
Figure 8. TGA results of pure Physostigmine Salicylate
600
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5.2 Warfarin Sodium Medications
5.2.1 Warfarin Sodium Tablets, 1mg
Medication: Warfarin Sodium Tablets, 1 mg
Active compound: Warfarin Sodium
Manufacturer: Taro Pharmaceutical Industries Ltd
Form: Tablets
Package: Plastic Container
Lot#: 124368
Expiration Date: 10/2015
Date Received: 03/25/2013
5.2.1.1 Thermogravimetric Results
The average Tmaxwtiossforthe residuals was 245 °C for the non-rinsed containers (Figure 9). This peak
does not correspond to warfarin sodium which has a Tmax wt ioss of 313 ± 5 °C (Figure 10). This indicates
that the majority of the residue (if not all) represents other chemical compounds that are likely used as a
capping layer to encapsulate the dose of active pharmaceutical compound within the tablet until the time
of use. The overlay plot of all treatments is presented in Appendix B (Figure B-l).
o>
100
200
600
Temperature (°C)
Figure 9. TGA results of Warfarin Sodium 1 mg, plastic containers
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120
Warfarin Sodium Img-Plastic Container
No Rinse
Pure Warfarin Sodium
100 -
80 -
.2? 60 -
40 -
20 -
100
200
300
400
500
600
Temperature (°C)
Figure 10. TGA results of non-rinsed containers of Warfarin Sodium 1 mg versus Warfarin Sodium
5.2.1.2 Mass Results
The amount of residuals/container =19.8 ± 0.9 mg (detailed calculations are presented in Appendix A,
Table A-l). The calculated upper limit for the amount of warfarin sodium in empty container residue is
0.0900 ± 0.0039 mg (Table A-2, Appendix A). This amount is calculated assuming that the drug is
homogenously distributed in the tablets. This assumption represents the worst case scenario. In reality, the
outer layer of the medication probably does not contain the drug; rather, it may be a coating that is needed
to prevent the loss of the drug until the medication reaches the location where it should be delivered in the
body.
5.2.2 Warfarin Sodium Tablets, 5mg
Medication: Warfarin Sodium Tablets, 5 mg
Active compound: Warfarin Sodium
Manufacturer: Taro Pharmaceutical Industries Ltd
Form: Tablets
Package: Plastic Container
Lot#: 124320
Expiration Date: 08/2015; Date Received: 03/25/2013
Warfarin Sodium
Tablets, USP Crystals
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5.2.2.1 Thermogravimetric Results
The average Tmaxwtioss for the residuals was 239 °C for the non-rinsed containers (Figure 11). This peak
does not correspond to warfarin sodium, which has a Tmaxwt ioss of 313 ± 5 °C (Figure 12). This indicates
that the majority of the residues (if not all) represents other chemical compounds that are probably used as
a capping layer to encapsulate the dose of active pharmaceutical compound within the tablet until the time
of use. The overlay plot of all treatments is presented in Appendix B, Figure B-2.
120
100 -
80 -
.2? 60 -
40 -
20 -
100
Warfarin Sodium Sing-Plastic Container
No Rinse
Triple Dl Rinse
Methanol Cleaned
O
•2-.
vP
OJ
'o>
200
500
600
300 400
Temperature (°C)
Figure 11. TGA results of Warfarin Sodium 5 mg, plastic containers
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120
Warfarin Sodium Smg-Plastic Container
No Rinse
Pure Warfarin Sodium
0
100
200
500
600
300 400
Temperature (°C)
Figure 12. TGA results of non-rinsed containers of Warfarin Sodium 5 mg versus Warfarin Sodium
5.2.2.2 Mass Results
The amount of residuals/container =17.5 ± 1.1 mg (detailed calculations are presented in Appendix A,
Table A-3). The calculated upper limit for the amount of warfarin sodium in empty container residue is
0.3887 ± 0.0246 mg (Table A-4, Appendix A). This amount is calculated assuming that the drug is
homogenously distributed in the tablets. This assumption represents the worst case scenario. In reality, the
outer layer of the medication probably does not contain the drug; rather, it may be a coating that is needed
to prevent the loss of the drug until the medication reaches the location where it should be delivered in the
body.
5.2.3 Warfarin Sodium Tablets, 10mg
Medication: Warfarin Sodium Tablets, 10 mg
Active compound: Warfarin Sodium
Manufacturer: Taro Pharmaceutical Industries Ltd
Form: Tablets
Package: Plastic Container
Lot#:123976
Expiration Date: 08/2015
Date Received: 03/25/2013
19
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
5.2.3.1 Thermogravimetric Results
The average Tmaxwtioss for the residuals was 231 °C for the non-rinsed containers (Figure 13). This peak
does not correspond to warfarin sodium, which has a Tmaxwt ioss of 313 ± 5 °C (Figure 14). This indicates
that the majority of the residues (if not all) represents other chemical compounds that are likely used as a
capping layer to encapsulate the dose of active pharmaceutical compound within the tablet until the time
of use. The overlay plot of all treatments is presented in Appendix B, Figure B-3.
OK
120
100 -
80 -
60 -
40 -
20 -
100
Warfarin Sodium 10mg-Plastic Container
No Rinse
Triple Dl Rinse
Methanol Cleaned
200
500
600
300 400
Temperature (°C)
Figure 13. TGA results of Warfarin Sodium 10 mg, plastic containers
o
o
0)
i
o
Q
20
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
120
Warfarin Sodium 10mg-Plastic Bottle
No Rinse
Pure Warfarin Sodium
100
200
300 400
Temperature (°C)
500
Figure 14. TGA results of non-rinsed containers of Warfarin Sodium 10 mg versus Warfarin
Sodium
5.2.3.2 Mass Results
The amount of residuals/container =19.8 ± 1.2 mg (detailed calculations are presented in Appendix A,
Table A-5). The calculated upper limit for the amount of warfarin sodium in empty container residue is
0.8895 ± 0.0543 mg (Table A-6, Appendix A). This amount is calculated assuming that the drug is
homogenously distributed in the tablets. This assumption represents the worst case scenario. In reality, the
outer layer of the medication probably does not contain the drug; rather, it may be a coating that is needed
to prevent the loss of the drug until the medication reaches the location where it should be delivered in the
body.
5.2.4 Warfarin Sodium Tablets, 2mg
Active compound: Warfarin Sodium
Manufacturer: Taro Pharmaceutical Industries Ltd
Form: Tablets
Package: Blister Pack
Lot#: 123247
Expiration Date: 09/2014
Date Received: 03/25/2013
21
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
5.2.4.1 Thermogravimetric Results
There was no Tmax wt ioss peak for the residuals in the non-rinsed containers (Figure 15). The overlay plot
of all treatments is presented in Appendix B, Figure B-4.
120
Warfarin Sodium 2mg-Blister Pack
- 1.8
No Rinse
Triple Dl Rinse
Methanol Cleaned
100 200 300 400 500
Temperature (°C)
Figure 15. TGA results of Warfarin Sodium 2 mg, blister packs
5.2.4.2 Mass Results
The amount of residuals per one individual blister pack =0.3 ± 0.0 mg (detailed calculations are presented
in Appendix A, Table A-7). This amount of residuals is within the range of the error of the balance.
The calculated upper limit for the amount of warfarin sodium in empty container residue is 0.0026 ±
0.0002 mg (Table A-8, Appendix A). This amount is calculated assuming that the drug is homogenously
distributed in the tablets. This assumption represents the worst case scenario. In reality, the outer layer of
the medication probably does not contain the drug; rather, it may be a coating that is needed to prevent the
loss of the drug until the medication reaches the location where it should be delivered in the body.
22
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
5.3 Jantoven
5.3.1 Jantoven Tablets, 1mg
Oose, 100 Tablets
Carts/10 Tabfels Each) Ri o(il«
Medication: Jantoven, Img
Active compound: Warfarin Sodium
Manufacturer: UPSHER-SMITH
Form: Tablets
Package: Blister Pack
Lot#: 307762
Expiration Date: 04/2014
Date Received: 03/25/2013
5.3.1.1 Thermogravimetric Results
There was no Tmax wt ioss peak for the residuals in the non-rinsed containers (Figure 16). The overlay plot of
all treatments is presented in Appendix B, Figure B-5.
120
Jantoven (Warfarin Sodium) Img-Blister Pack
100 -
80 -
I 60 H
40 -
20 -
100
No Rinse
Triple Dl Rinse
Methanol Cleaned
200
600
Temperature (°C)
Figure 16. TGA results of Jantoven (Warfarin Sodium) 1 mg, blister packs
23
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
5.3.1.2 Mass Results
The amount of residuals per one individual blister pack =0.3 ± 0.0 mg (detailed calculations are presented
in Appendix A, Table A-9). This amount of residuals is within the range of the error of the balance. The
calculated upper limit for the amount of warfarin sodium in empty container residue is 0.0012 ± 0.0001
mg (Table A-10, Appendix A). This amount is calculated assuming that the drug is homogenously
distributed in the tablets. This assumption represents the worst case scenario. In reality, the outer layer of
the medication probably does not contain the drug; rather, it may be a coating that is needed to prevent the
loss of the drug until the medication reaches the location where it should be delivered in the body.
5.3.2 Jantoven Tablets, 10mg
Medication: Jantoven, lOmg
Active compound: Warfarin Sodium
Manufacturer: UPSHER-SMITH
Form: Tablets
Package: Blister Pack
Lot#:308312
Expiration Date: 06/2014
Date Received: 03/25/2013
5.3.2.1 Thermogravimetric Results
There was no Tmax wt ioss peak for the residuals in the non-rinsed containers (Figure 17). The overlay plot of
all treatments is presented in Appendix B, Figure B-6.
5.3.2.2 Mass Results
The amount of residuals per one individual blister pack =0.2 ± 0.0 mg (detailed calculations are presented
in Appendix A, Table A-l 1). This amount of residuals is within the range of the error of the balance.
The calculated upper limit for the amount of warfarin sodium in empty container residue is 0.0084 ±
0.0008 mg (Table A-12, Appendix A). This amount is calculated assuming that the drug is homogenously
distributed in the tablets. This assumption represents the worst case scenario. In reality, the outer layer of
the medication probably does not contain the drug; rather, it may be a coating that is needed to prevent the
loss of the drug until the medication reaches the location where it should be delivered in the body.
24
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
120
Warfarin Sodium 10 mg- Blister Pack
100 -
80 -
I 60 H
40 -
20 -
- 1
- 1
- 1
- 1
- 1
- 0
- 0
- 0
- 0
o .s>
•!
R <"
6 Q
4
2
0
100
200
300 400
Temperature (°C)
500
No Rinse
Triple Dl Rinse
Methanol Cleaned
600
Figure 17. TGA results of Jantoven (Warfarin Sodium) 10 mg, blister packs
5.4 Nicotine
5.4.1 Nicorette Gum (Fruit Chill), 2mg
Medication: Nicorette Gum, 2mg
Active compound: Nicotine
Manufacturer: Glaxo SmithKline (GSK)
Form: Gums
Package: Blister Pack
Lot#: 12C28N
Expiration Date: 02/2015
Date Received: 03/25/2013
corette
lorr.iB.-3wr, 2-nq rtapvnoUneod
5.4.1.1 Thermogravimetric Results
There was no Tmax wt ioss peak for the residuals in the non-rinsed containers (Figure 18). The overlay plot of
all treatments is presented in Appendix B, Figure B-7.
25
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
120
Nicorette Gum 2 mg-Blister Pack
100
200
500
- 2.0
No rinse
Triple Dl Rinse
Methanol Cleaned
- 0.0
300 400
Temperature (°C)
Figure 18. TGA results of Nicorette gum 2 mg, blister packs
600
O
g>
I
0)
Q
5.4.1.2 Mass Results
The amount of residuals per one individual blister pack =0.3 ± 0.2 mg (detailed calculations are presented
in Appendix A, Table A-13). This amount of residuals is within the range of the error of the balance.
The calculated upper limit for the amount of nicotine in empty container residue is 0.0005 ± 0.0002 mg
(Table A-14, Appendix A). This amount is calculated assuming that the drug is homogenously distributed
in the gums. This assumption represents the worst case scenario. In reality, the outer layer of the
medication probably does not contain the drug; rather, it may be a coating that is needed to prevent the
loss of the drug until the medication reaches the location where it should be delivered in the body.
26
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
5.4.2 Nicorette Gum (Fruit Chill), 4mg
Nicorette
,um
» \
Medication: Nicorette Gum, 4mg
Active compound: Nicotine
Manufacturer: GlaxoSmithKline (GSK)
Form: Gums
Package: Blister Pack
Lot#: 12L14N
Expiration Date: 10/2015
Date Received: 03/25/2013
5.4.2.1 Thermogravimetric Results
There was no Tmax wt ioss peak for the residuals in the non-rinsed containers (Figure 19). The overlay plot of
all treatments is presented in Appendix B, Figure B-8.
120
100 -
80 -
I 60 H
40 -
20 -
100
Nicorette Gum 4 mg-Blister Pack
No Rinse
Triple Dl Rinse
Methanol Cleaned
200
O
g>
I
0)
Q
0.0
600
Temperature (°C)
Figure 19. TGA results of Nicorette gum 4 mg, blister packs
27
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
5.4.2.2 Mass Results
The amount of residuals per one individual blister pack =0.3 ±0.1 mg (detailed calculations are presented
in Appendix A, Table A-15). This amount of residuals is within the range of the error of the balance.
The calculated upper limit for the amount of nicotine in empty container residue is 0.0008 ± 0.0002 mg
(Table A-16, Appendix A). This amount is calculated assuming that the drug is homogenously distributed
in the gums. This assumption represents the worst case scenario. In reality, the outer layer of the
medication probably does not contain the drug; rather, it may be a coating that is needed to prevent the
loss of the drug until the medication reaches the location where it should be delivered in the body.
5.4.3 Nicotine Polacrilex Gum, 2mg
Medication: Nicotine Polacrilex Gum, 2mg
Active compound: Nicotine
Manufacturer: Rugby Laboratories
Form: Gums
Package: Blister Pack
Lot#: 571893
Expiration Date: 08/2014
Date Received: 03/25/201
5.4.3.1 Thermogravimetric Results
There was no Tmax wt ioss peak for the residuals in the non-rinsed containers (Figure 20). The overlay plot of
all treatments is presented in Appendix B, Figure B-9.
5.4.3.2 Mass Results
The amount of residuals per one individual blister pack =0.1 ± 0.1 mg (detailed calculations are presented
in Appendix A, Table A-17). This amount of residuals is within the range of the error of the balance.
The calculated upper limit for the amount of nicotine in empty container residue is 0.0002 ± 0.0002 mg
(Table A-18, Appendix A). This amount is calculated assuming that the drug is homogenously distributed
in the gums. This assumption represents the worst case scenario. In reality, the outer layer of the
medication probably does not contain the drug; rather, it may be a coating that is needed to prevent the
loss of the drug until the medication reaches the location where it should be delivered in the body.
28
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
120
Nicotine Polacrilex Gum 2mg-Blister Pack
100 -
80 -
60 H
40 -
20 -
No Rinse
Triple Dl Rinse
Methanol Cleaned
2.0
- 1.8
- 1.6
- 1.4
- 1.2
- 1.0
- 0.8
- 0.6
- 0.4
- 0.2
0.0
100
200
500
600
300 400
Temperature (°C)
Figure 20. TGA results of Nicotine Polacrilex gum 2 mg, blister packs
5.4.4 Nicotine Polacrilex Gum, 4mg
Medication: Nicotine Polacrilex Gum, 4mg
Active compound: Nicotine
Manufacturer: Rugby Laboratories
Form: Gums
Package: Blister Pack
Lot#: 508965
Expiration Date: 04/2014
Date Received: 03/25/2013
o
1
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
120
Nicotine Polacrilex Gum 4mg-Blister Pack
100 -
Sf
'S
80 -
60 -
40 -
20 -
No Rinse
Triple Dl Rinse
Methanol Cleaned
100
200
600
Temperature (°C)
Figure 21. TGA results of Nicotine Polacrilex gum 4 mg, blister packs
5.4.4.2 Mass Results
The amount of residuals per one individual blister pack =0.1 ±0.1 mg (detailed calculations are presented
in Appendix A, Table A-19). This amount of residuals is in the range of the error of the balance.
The calculated upper limit for the amount of nicotine in empty container residue is 0.0003 ± 0.0002 mg
(Table A-20, Appendix A). This amount is calculated assuming that the drug is homogenously distributed
in the gums. This assumption represents the worst case scenario. In reality, the outer layer of the
medication probably does not contain the drug; rather, it may be a coating that is needed to prevent the
loss of the drug until the medication reaches the location where it should be delivered in the body.
30
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
5.4.5 Nicorette Mini Lozenge, 2mg
Nicorette
Medication: Nicorette Mini Lozenge, 2mg
Active compound: Nicotine
Manufacturer: GlaxoSmithKline (GSK)
Form: Lozenge
Package: Plastic Container
Lot#: 14149
Expiration Date: 04/2015
Date Received: 08/13/2013
5.4.5.1 Thermogravimetric Results
The average Tmaxwtioss for the residuals was 306 °C for the non-rinsed containers (Figure 22). This peak
does not correspond to nicotine, which has a Tmax wt ioss of 217 ± 5 °C (Figure 23). This indicates that the
majority of the residues (if not all) represents other chemical compounds that are likely used as a capping
layer to encapsulate the dose of active pharmaceutical compound within the lozenge until the time of use.
The overlay plot of all treatments is presented in Appendix B, Figure B-l 1.
01]
'3
120
Nicorette mini Lozenges 2mg-Plastic Container
100 -
80 -
60 -|
40 H
20 -
100
No Rinse
Triple Dl Rinse
Methanol Cleaned
\ /
200 300 400
Temperature (°C)
500
2.5
- 2.0
oo
- 1.5 S
*ri
O)
1
MJO >
C
(!)
Q
- 0.5
0.0
600
Figure 22. TGA results of Nicorette mini lozenges 2 mg, plastic containers
31
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
120
Nicorette Mini Lozenges 2mg-Plastic Container
o -\
100
200 300 400
Temperature (°C)
500
600
Figure 23. TGA results of Nicorette mini lozenges 2 mg plastic containers versus pure nicotine
5.4.5.2 Mass Results
The amount of residuals/container =0.2 mg (detailed calculations are presented in Appendix A, Table A-
21). This amount of residuals is within the range of the error of the balance. It is noted that residuals could
be visually seen in the empty containers after the disposal of the lozenges. But the weight of the residual
was negligible as compared to the relatively large container weight, and thus, the residuals were not
detectable by the balance. The density of the residuals could also be very low which may be also part of
the problem. The presence of peaks for the residuals from the TGA analysis supports the presence of a
significantly larger quantity of residuals as compared to the weight obtained by the balance.
Therefore, the balance results for this medication are misleading and should not be used. Only duplicate
samples were tested from this medication for each treatment. This was a result of the limited quantity of
medication from the vendor.
32
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
5.4.6 Nicorette Lozenge, 4mg
Nicorettel
nicotine polocrilex lozenge, 4mg • ito^nok^r
ozenge
Medication: Nicorette Lozenge, 4mg
Active compound: Nicotine
Manufacturer: Glaxo SmithKline (GSK)
Form: Lozenge
Package: Plastic Container
Lot#: 13674
Expiration Date: 05/2014
Date Received: 03/25/2013
5.4.6.1 Thermogravimetric Results
The average Tmaxwtioss for the residuals was 324 °C for the non-rinsed containers (Figure 24). This peak
does not correspond to nicotine, which has a Tmax wt ioss of 217 ± 5 °C (Figure 25). This indicates that the
majority of the residues (if not all) represents other chemical compounds that are likely used as a capping
layer to encapsulate the dose of active pharmaceutical compound within the lozenge until the time of use.
The overlay plot of all treatments is presented in Appendix B, Figure B-12.
120
Nicorette Lozenge 4 mg-Plastic Container
100 -
80 -
60 H
No Rinse
Triple Dl Rinse
Methanol Cleaned
40 H
20 -
100
200
600
Temperature (°C)
Figure 24. TGA results of Nicorette lozenges 4 mg, plastic containers
33
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
120
Nicorette Lozenge 4 mg-Plastic Container
o
0.0
100
200
500
600
300 400
Temperature (°C)
Figure 25. TGA results of Nicorette lozenges 4 mg, plastic containers versus pure nicotine
5.4.6.2 Mass Results
The amount of residuals/container =0.0 ± 0.0 mg (detailed calculations are presented in Appendix A,
Table A-22). This amount of residuals is within the range of the error of the balance. It is noted that
residuals could be visually seen in the empty containers after the disposal of the lozenges. But the weight
of the residual was negligible when compared to the relatively large container weight, and thus, the
residuals were not detectable by the balance. The density of the residuals could also be very low, which
may be also part of the problem. The presence of peaks for the residuals from the TGA analysis supports
the presence of a significantly larger quantity of residuals as compared to the weight obtained by the
balance. Therefore, the balance results for this medication are misleading, and should not be used.
34
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
5.4.7 Nicotine Transdermal System (Patch), 7mg
Clear
Nicotine
Transdermal System
7 mg delivered over 24 hours
STOP SMOKING AID
7 mg
Medication: Nicotine Transdermal System, 7mg
Active compound: Nicotine
Manufacturer: Rugby Laboratories
Form: Patch
Package: Plastic Wrap (peel off)
Lot#: 40660
' Expiration Date: 05/2014
Date Received: 03/25/2013
Nicotine
Transdermal
System
." W
21 mg
R9nME»
MOTBK
STEP
ONE
•^^^^•^^^^^^»—
Nicotine
Transdermal
System
7mg
STEP
THREE
—
I4mg
Figure 26. Picture of the Nicotine patches
5.4.7.1 Thermogravimetric Results
There was no Tmax wt ioss peak for the residuals in the non-rinsed containers (Figure 27). The overlay plot of
all treatments is presented in Appendix B, Figure B-13.
35
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
Nicotine Transdermal Patch 7mg-Platic Wrap
120 -i r 1.8
No Rinse
Triple Dl Rinse
Methanol Cleaned
100
200
500
- 0.0
600
300 400
Temperature (°C)
Figure 27. TGA results of Nicotine Transdermal Patches 7 mg, plastic wrap
5.4.7.2 Mass Results
The amount of residuals/container =0.1 ± 0.2 mg (detailed calculations are presented in Appendix A,
Table A-23). This amount of residuals is within the range of the error of the balance. The calculated upper
limit for the amount of nicotine in empty container residue was 0.0011± 0.0026 mg (Table A-24,
Appendix A). This amount was calculated assuming that the drug is distributed evenly across the surface
of the patch along with other chemicals that ensure the active ingredient's slow release over a 24-hour
time period.
36
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
5.4.8 Nicotine Transdermal System (Patch), 14mg
Nicotine Transdermal System
•\A-r-S~tt M tioun
•VU LnSTOP SMOKING AID
Medication: Nicotine Transdermal System, 14mg
Active compound: Nicotine
Manufacturer: Habitrol
Form: Patch
Package: Plastic Wrap (peel off)
Lot#: 121356
Expiration Date: 08/2014; Date Received: 03/25/2013
5.4.8.1 Thermogravimetric Results
There was no Tmax wt ioss peak for the residuals in the non-rinsed containers (Figure 28) . The overlay plot of
all treatments is presented in Appendix B, Figure B-14.
120
Nicotine Transdermal Patch 14mg-Platsic Wrap
100 -
80 -
• 60 H
40 -
20 -
0
No Rinse
Triple Dl Rinse
Methanol Cleaned
100
200
500
600
300 400
Temperature (°C)
Figure 28. TGA results of Nicotine Transdermal Patches 14 mg, plastic wrap
37
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers EPA/600/R-14/167
5.4.8.2 Mass Results
The amount of residuals/container =0.0 ± 0.0 mg (detailed calculations are presented in Appendix A,
Table A-25). This amount of residuals is within the range of the error of the balance. The calculated upper
limit for the amount of nicotine in empty container residue is 0.0000 ± 0.0000 mg (Table A-26, Appendix
A). This amount is calculated assuming that the drug is distributed evenly across the surface of the patch.
38
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
5.4.9 Nicotine Transdermal System (Patch), 21 mg
Medication: Nicotine Transdermal System, 21mg
Active compound: Nicotine
Manufacturer: Rugby Laboratories
Form: Patch
Package: Plastic Wrap (peel off)
Lot#: 40703
ONE Expiration Date: 05/2015
Date Received: 03/25/2013
Clear
Nicotine
Transdermal System
21 mg delivered ove' 24 tours
STOP SMOKING AID asF,,
21 mg
Nicotine
Transderma!
Svster/
Includes Behavior
5.4.9.1 Thermogravimetric Results
There was no Tmaxwtioss peak for the residuals in the non-rinsed containers (Figure 29). The overlay
all treatments is presented in Appendix B, Figure B-15.
Nicotine Transdermal Patch 21mg-Plastic Wrap
plot of
120
100 -
80 -
wo
'S 60 -
40 -
20 -
100
No Rinse
Triple Dl Rinse
Methanol Cleaned
200
500
- 0.0
600
300 400
Temperature (°C)
Figure 29. TGA results of Nicotine Transdermal Patches 21 mg, plastic wrap
O
o
O)
'3
cu
O
39
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
5.4.9.2 Mass Results
The amount of residuals/container =0.0 ±0.1 mg (detailed calculations are presented in Appendix A,
Table A-27). This amount of residuals is within the range of the error of the balance. The calculated upper
limit for the amount of nicotine in empty container residue is 0.0000 ± 0.0010 mg (Table A-28, Appendix
A). This amount is calculated assuming that the drug is evenly distributed across the surface of the patch.
5.4.10 Nicotrol NS (nicotine nasal spray), 10mg/ml
Medication: Nicotrol NS, 10 mg/ml
Active compound: Nicotine
Manufacturer: Pfizer
Form: Liquid
Package: Glass Vial
Lot#:PHlllG
Expiration Date: 08/2014
Date Received: 03/25/2013
5.4.10.1 Thermogravimetric Results
The average Tmaxwtioss forthe residuals was 217 °C for the non-rinsed containers (Figure 30). This peak
corresponds to pure nicotine, which has a Tmaxwtioss of 217 ± 5 °C (Figure 31). The overlay plot of all
treatments is presented in Appendix B, Figure B-16.
It must be noted that in the case of the non-rinsed containers, the residuals of this medication were in
liquid form. The Tmaxwtioss forthe cotton piece of the non-rinsed containers (used as a QA/QC) was 410
°C, which is not within the acceptable range (427 ± 5 °C). This deviation was not due to a calibration
problem because the triple-rinsed and the clean containers were analyzed on the TGA right after the non-
rinsed containers and the Tmax wt ioss for the cotton piece were within the specified range. The deviation that
occurred for these samples may be a result of a reaction between the residual liquid and the cotton piece,
which may have resulted in changes in the properties of the cotton piece. Therefore, the TGA results of
this medication are inconclusive. Nonetheless, the fact that this medication is in liquid from and contains
40
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
67.8 (ig of nicotine based on the theoretical calculations suggests that the detected TGA peak at 217 °C
represents nicotine.
120
100 --
80 -
I 60 H
40 -
20 -
100
Nicotine Nasal Spray 10mg/ml-Glass Vial
No Rinse
Triple Dl Rinse
Methanol Cleaned
2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
L 0.0
0°
O)
I
0)
Q
200
300
400
500
600
Temperature (°C)
Figure 30. TGA results of Nicotine nasal spray 10 mg/ml, glass vial
120
Nicotine Nasal Spray 10mg/ml-Glass Vial
o
r 1.2
100
200
500
600
300 400
Temperature (°C)
Figure 31. TGA results of Nicotine nasal spray 10 mg/ml, glass vial versus pure Nicotine
41
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
5.4.10.2 Mass Results
The amount of residuals/vial =67.8 ± 36.9 mg (detailed calculations are presented in Appendix A, Table
A-29). The high standard deviation in this case is a result of the nature of the medication. The medication
is in liquid form, and therefore, when removing the medication from the container, the remaining liquid is
expected to have significant differences from one container to the other when emptying the container
when trying to simulate the use. The calculated amount of nicotine in empty container residue is 0.6780
mg (Appendix A). This amount is calculated assuming that the drug is homogenously distributed in the
glass vial, which is highly likely since the sample is in liquid form.
5.4.11 Nicotrol Inhaler (nicotine inhalation system), 10mg/cartridge
iMne inhalation
'system)
lOmg/earfridge
i.:
168 Cartridges
Medication: Nicotrol Inhaler,
10 mg/cartridge
Active compound: Nicotine
Manufacturer: Pfizer
Form: Cartridge
Package: Plastic Container
Lot#: PA068A
Expiration Date: 01/2015
Date Received: 03/25/2013
The amount of residuals/cartridge =6 mg. This value is not experimentally determined for two reasons:
1. The manufacturer already mentioned on the package that every cartridge contains 10 mg nicotine,
with 4 mg of the drug delivered (please see the above picture).
2. Simulation of the use of this medication was not possible in the laboratory.
Therefore, no experiments (balance or TGA) were conducted on this medication because it is already
known how much nicotine will be in the residuals. It should be noted that at temperatures higher than
room temperatures, more nicotine can be released from the cartridge. Nonetheless, 6 mg is a conservative
upper estimate for the level of nicotine residue in the cartridge.
42
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Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
5.5 Physostigmine Salicylate Medications
5.5.1 Physostigmine Salicylate, (1mg/ml)
Medication: Physostigmine Salicylate injection, Img/ml
Active compound: Physostigmine Salicylate
Manufacturer: Akron Inc.
Form: liquid for injection
Package: Glass Ampoule
Lot#:101402
Expiration Date: 10/2014
Date Received: 03/25/2013
5.5.1.1 Thermogravimetric Results
The average Tmaxwtioss for the residuals was 103 °C for the non-rinsed containers (Figure 32). This peak
does not correspond to physostigmine Salicylate, which has a Tmaxwtioss of 236 ± 5 °C (Figure 33). The
overlay plot of all treatments is presented in Appendix B, Figure B-17.
^hysostigmine Salicylate
Injection (1mg/mL)
120
Physostigmine Salicylate 1mg/ml-Glass Vial
r 2.0
L 0.0
100
200
300 400
Temperature (°C)
500
600
No Rinse
Triple Dl Rinse
Methanol Cleaned
Figure 32. TGA results of Physostigmine Salicylate 1 mg/ml, glass vial
43
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Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
Physostigmine Salicylate 1mg/ml-Glass Vial
100 -
80 -i
%
•53 60 -
£
£
40 -
20 -
10
Pure Physostigmine
103 °C - - - *. ^ l\
N > \
^' \
>\
_/\'
236 °C / \\V
,«^ ^*^ >•*-••
0 200 300 400 500 6(
- 2.0
- 1.5
- 1.0
- 0.5
i- o.u
DO
o
O)
1
_
o>
Q
Temperature (°C)
Figure 33. TGA results of Physostigmine Salicylate 1 mg/ml, glass vial versus pure Physostigmine
Salicylate
5.5.1.2 Mass Results
The amount of residuals/vial =73.0 ± 2.2 mg (detailed calculations are presented in Appendix A, Table A-
30). This means that the volume of residuals equals ~ 73 uL. Thus, if the concentration of the active drug
is Img/ml, then the amount of physostigmine in the residual per vial is = 0.0730 ± 2.2000 mg.
44
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Evaluation of P-Listed Pharmaceutical Residues
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6 Quality Control
6,1 Accuracy (bias)
The current study was conducted under a Quality Assurance Project Plan (QAPP) that was approved by
the U.S. EPA with a QA ID # L18039-QP-1-5 (Appendix D). A summary of the required QA/QC checks
for accuracy and whether or not the accuracy was met are presented in Table 2.
For the measurements of the weight of residuals, the accuracy checks for the balance AB104-S (Mettler
Toledo) as well as the TGA balance were conducted as specified in Table 2 and were recorded in the
project laboratory notebook CH 276.
The accuracy of the TGA (TA 2950) temperature measurements were verified for each of the analyzed
samples by checking that the Tmaxwt ioss for the cotton piece for each sample was within the range specified
in the QAPP (427 ± 5 °C). The TmaxwtioSS values of the cotton piece of all the analyzed samples on the
TGA are presented in Table C-l (Appendix C). The Tmaxwtiossof the cotton piece was in the acceptable
range for all samples except the triplicate samples of the non-rinsed containers of nicotine nasal spray 10
mg/ml. This discrepancy was not a result of a calibration issue because cotton peaks of the triple rinsed
samples of nicotine nasal spray were in agreement with the specified range though they were analyzed
right after the analysis of the non-rinsed samples on the same day (August 20, 2013). The reason for this
discrepancy may be a result of some chemical in the residual liquid (the residual of this sample was in
liquid form) that reacted with the cotton piece and changed its characteristics. Therefore, the results of
this medication should be used with caution.
Table 2. Summary of QA/QC checks for accuracy
Parameter
Weight of
residuals
Presence of
active
pharmaceutical
ingredient in
residuals
Measurement
Weight
Temperature
Weight
QC Check
Accuracy
(bias)
Temperature
calibration
Calibration
Check
Accuracy
(bias)
Method
Measure a
standard
weight
1 point
calibration
2 point
calibration
Measure a
standard
weight
Frequency
Once per day
before conducting
the measurements
Initially (once at
start of the project
data collection)
and as needed**
Initially (once at
start of the project
data collection)
and as needed
Once per day
before and after
conducting the
measurements
Acceptance
Criteria
±0.1mg of
the actual
weight
± 5 of the
curie
temperature of
the standard
metal
±0.1 mgof
the actual
weight
±0.1 mgof
the actual
weight
Accuracy
Met?
Yes
Yes
Yes
Yes
** As needed: temperature calibration is needed when the temperature of the peak weight loss of the
cotton piece is not in the range of 427 ± 5 °C.
The temperature calibrations of the TGA using Nickel standard are presented in Table 3.
45
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Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
Table 3. Temperature calibrations of the TGA
Date
05/20/2013
05/29/2013
08/10/2013
Curie point of the
Nickel standard (°C)
358.28
Actual measured
Curie point (°C)
358.43
355.65
359.56
Acceptance
Criteria
± 5 of the curie
temperature of
the standard
Comment
Accepted
Accepted
Accepted
The temperature at which the maximum weight loss occurs was used to qualitatively evaluate the
presence of the active pharmaceutical compounds in the residuals. This was achieved through comparing
the temperature at which the maximum weight loss occurs for the pure pharmaceutical compounds (Table
4) to that of the residuals.
Table 4. Temperature for maximum weight loss for pure pharmaceutical compounds
Pure Compound
Warfarin Sodium
Physostigmine Salicylate
Nicotine
CAS#
129-06-6
57-64-7
54-11-5
Temperature for maximum
weight loss on TGA (°C)
313
236
217
Acceptance
Criteria (°C)
±5
±5
±5
6.2 Representativeness
Representativeness is the extent to which measurements actually depict the true condition or population
being evaluated. The measurement of the residuals in the pharmaceutical containers was conducted using
the container as a whole and not on portions of it. This ensures a high representativeness of the
measurement. With regards to the TGA analysis on the residuals, a cotton piece was used to swab all the
internal walls of the containers in order to ensure the representativeness of the measurement for the actual
residuals in the containers.
6,3 Completeness
Completeness is number of data points meeting all data quality objectives (DQO)/total number data
points. A completeness of 90 % is required for this project. The completeness (C) was calculated as
follows and the results are presented in Table 3:
o/0c = V- x 100
Where: v = the number of data points meeting DQO
T= the number of data points
46
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Evaluation of P-Listed Pharmaceutical Residues
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EPA/600/R-14/167
Table 5. Completeness of the measurements
Measurement
Parameter
Weight of residuals
Temperature for
maximum weight
loss
Number of data
points meeting
DQO
153
150
Number of data
points
153*
153**
Completeness
(%C)
100%
98%
Acceptance
criteria
(90%)
Accepted
Accepted
* 17 medications experimentally tested x 3 treatments (triple rinsed with DI, cleaned with methanol,
cleaned with another organic solvent) x 3 (triplicate) = 153
** 17 medications experimentally tested x 3 treatments (not rinsed, triple rinsed with DI, cleaned with
methanol) x 3 (triplicate) = 153. The TGA tests that failed the DQO were the triplicate nicotine nasal
spray 10 mg/ml samples.
6.4 Comparability
Comparability is the extent to which data from one study can be compared to past data from the current
project or data from another study. Data comparability was maintained through the use of defined and
consistent sampling and analytical procedures. The standard operating procedures (SOPs) defined in the
study QAPP were systematically followed each time a sample was being processed.
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Evaluation of P-Listed Pharmaceutical Residues
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7 Conclusions
The current study aimed at evaluating if removing the P-listed drugs of warfarin sodium, nicotine, and
physostigmine salicylate from their containers is equivalent to triple rinsing the containers. The study was
conducted using thermal gravimetric analysis and weight measurements using a microbalance. The TGA
was used to qualitatively evaluate the presence of the active pharmaceutical ingredient in the residuals
after removing the drug from the rinsed pharmaceutical containers by comparing the Tmaxwtioss of the
residuals to that of the pure active pharmaceutical compound. The total amount of residuals in
pharmaceutical containers containing warfarin, physostigmine salicylate and nicotine medications after
removing the drugs were measured using a microbalance. The theoretical "maximum possible weight of
residual drug/total residual /container" was calculated for each compound and packaging combination.
This calculated result may be used to infer an upper limit for the amount of pharmaceutical compound in
the total residue remaining in the container. A total of 18 drug/packaging combinations were evaluated in
the study. The results obtained in the study are summarized in Table 6, and indicate the following:
• For the medications in liquid form (Nicotrol nasal spray 10 mg/ml and Physostigmine
salicylate 1 mg/ml), there is a difference between triple-rinsed containers and those that are
not triple-rinsed. The residues in the not triple-rinsed containers contain the active
pharmaceutical ingredient. It should be noted that the tested liquid medications were solutions
(not suspensions) and there was no mention of a requirement or recommendation to shake the
medication before use on the drug package.
• For Nicotine inhaler 10 mg/cartridges, there is a difference between triple-rinsed containers
and those that are not triple-rinsed. The residues in the not-triple-rinsed containers contain the
active pharmaceutical ingredient. The amount of nicotine in the residue was not calculated
based on experimental results; rather, it was calculated based on information provided by the
manufacturer. On the package, it was stated that every cartridge contained 10 mg nicotine and
only 4 mg out of the 10 mg will be delivered, and thus, 6 mg nicotine will be retained in each
used cartridge.
• For the medications in solid form (i.e., tablet, gum, and lozenge) and patches, the TGA results
showed no difference between triple-rinsed containers and those that are not triple-rinsed.
However, this conclusion is based on a qualitative analysis by TGA that is limited by the
TGA sensitivity. Other analytical techniques (e.g., gas chromatography or liquid
chromatography equipped with mass spectrometer) are needed to verify the TGA results for
these medications and to quantitatively determine the amount of the active pharmaceutical
compounds present in the residues (if any).
The above conclusions present the straight answer to the main research question of the study which was
"Is there a difference between triple-rinsed P-listed pharmaceutical containers and those that are not
triple-rinsed?" Additional conclusions are presented below and highlight other findings obtained herein as
well as limitations of the analysis:
The medications packaged in blister packs and plastic wraps contained minimal residuals, in the
range of the error of the balance used in the study, after removing the drugs. Although the
sensitivity of the balance did not allow for determining the actual amount of total residues in
these package types, the results infer an upper limit for the total amount of residues in these
packages.
All medications packaged in plastic containers contained measurable amount of residuals (using
balance data) after removing the drugs. An exception happened for two medications, Nicorette
lozenges 2 mg and Nicorette lozenges 4 mg. Although residues were visually present in the empty
48
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Evaluation of P-Listed Pharmaceutical Residues
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containers of these two medications and were detected by TGA, the amount of residues detected
by the balance was within the range of the balance error. The balance results in this case were
inconclusive.
The theoretical "maximum possible weight of residual active compound/total residual /container"
was calculated for each compound and packaging combination (Table 5). The calculated amounts
may be used to infer an upper limit for the amount of active pharmaceutical compound in the total
residue remaining in the container.
Any medication in liquid form must contain the active pharmaceutical ingredient in the residuals.
This is because the active pharmaceutical ingredient is highly likely to be homogenously
distributed in the liquid. Therefore, for any liquid medication, the actual amount of drug in the
residuals can be calculated by knowing 1) the weight of residuals, and 2) the concentration of the
active pharmaceutical ingredient in the medication as stated by the manufacturer. Despite this
fact, the TGA results for physostigmine medication did not show the presence of the
physostigmine compound in the residuals although the calculated amount of physostigmine in the
residue in each ampule was 73 (ig. The reason for the negative TGA results in this case could be
explained by the limited capacity of the cotton piece to absorb all the amount of liquid residue in
the empty ampule. This means that only a fraction of the total residue was loaded on the cotton
piece, and thus, only a fraction of the 73 (ig of physostigmine was available to be detected by the
TGA. It should be noted that the majority of residue absorbed by the cotton piece was liquid
water as indicated by the Tmaxwt ioss at 103 °C.
The nicotine nasal spray 10 mg/ml was the only medication to have positive TGA results (active
pharmaceutical drug was detected in the residuals) as the residues had a TmaXwtioSS at 217 °C that is
representative of nicotine. But the Tmaxwtioss for the negative control (cotton piece) was shifted in
this case, which may be attributed to a reaction between the residual liquid and the cotton piece
that caused changes in the properties of the cotton piece. Nonetheless, the fact that this
medication is in liquid from and contains 67.8 (ig of nicotine based on the theoretical calculations
suggests that the detected TGA peak at 217 °C represents nicotine.
For the blister packs and nicotine patches, the calculated upper limit for the amount of active
pharmaceutical compound in the total residue was relatively low and ranged from 0 to 8 (ig.
These amounts are upper limits, and the actual amounts of active compounds in the residues are
more than likely lower because the outer layer of the medication acts as a coating to prevent the
loss of the drug until the medication reaches the target location in the body and thus, this layer
does not probably contain the drug. The balance and upper limit results support the TGA results,
which were negative for these pharmaceutical packages.
For the plastic containers encompassing warfarin tablets (1,5, and 10 mg), detectable quantities
of residues were found in the empty containers. The TGA results for the same containers showed
clear peaks for these residues; however, the peaks did not correspond to the warfarin and thus,
they most likely represent the coating materials. These data support the aforementioned
assumption that the residues in these cases are mainly composed of coating materials.
Nonetheless, having negative TGA results do not eliminate the possibility of the presence of the
active pharmaceutical compound in the residues. However, if it is present, it represents a
relatively small fraction.
Conclusions 5, 6, and 7 highlight the importance of considering the balance results and TGA
results collectively rather than individually when analyzing the data.
49
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Evaluation of P-Listed Pharmaceutical Residues
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50
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Evaluation of P-Listed Pharmaceutical Residues
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EPA/600/R-14/167
Table 6. Summary of the results and limitations of analysis
Medication
Warfarin
Nicotine
Dose
Warfarin
sodium
tablets, 1 mg
Warfarin
sodium
tablets, 5 mg
Warfarin
sodium
tablets, 10 mg
Warfarin
sodium
tablets, 2 mg
Jantoven
tablets, 1 mg
Jantoven
tablets, 10 mg
Nicorette
gum, 2 mg
Nicorette
gum, 4 mg
Nicotine
polacrilex
gum, 2 mg
Nicotine
polacrilex
gum, 4 mg
Package
Type
Plastic
container
Plastic
container
Plastic
container
Blister
pack
Blister
pack
Blister
pack
Blister
pack
Blister
pack
Blister
pack
Blister
pack
TGA Results
1 max wt loss
for
Residues
245 °C
239 °C
231°C
None
None
None
None
None
None
None
1 max wt loss
for Pure
Compound
313°C
313°C
313°C
313°C
313°C
313°C
217 °C
217 °C
217 °C
217 °C
Results
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Limitation
of Analysis
Qualitative
Qualitative
Qualitative
Qualitative
Qualitative
Qualitative
Qualitative
Qualitative
Qualitative
Qualitative
Total weight of residues
Weight
(mg)
19.8
17.5
19.8
0.3
0.3
0.2
0.3
0.3
0.1
0.1
Limitation of
Analysis
NA
NA
NA
Within range
of error
Within range
of error
Within range
of error
Within range
of error
Within range
of error
Within range
of error
Within range
of error
Calculated Upper
Limit for Amount
of Active
Pharmaceutical
Ingredient (|ig)
90
390
890
3
1
8
0.5
0.8
0.2
0.3
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Evaluation of P-Listed Pharmaceutical Residues
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EPA/600/R-14/167
Table 6. Summary of the results and limitations of analysis (Cont'd)
Medication
Nicotine
Physostig-
mine
salicylate
Dose
Nicorette
mini lozenge,
2mg
Nicorette
lozenge, 4
mg
Nicotine
transdermal
patch, 7 mg
Nicotine
transdermal
patch, 14 mg
Nicotine
transdermal
patch, 21 mg
Nicotrol nasal
spray, 10
mg/ml
Nicotine
inhaler, 10
mg/cartridge
Physostig-
mine
salicylate,
1 mg/ml
Package
Type
Plastic
container
Plastic
container
Plastic
wrap (peel
off)
Plastic
wrap (peel
off)
Plastic
wrap (peel
off)
Glass vial
Plastic
container
Glass
ampule
TGA Results
1 max wt loss
for
Residues
306 °C
324 °C
None
None
None
217 °C
NA
103 °C
1 max wt loss
for Pure
Compound
217 °C
217 °C
217 °C
217 °C
217 °C
217 °C
NA
236 °C
Results
Negative
Negative
Negative
Negative
Negative
Positive
NA
Negative
Limitation
of Analysis
Qualitative
Qualitative
Qualitative
Qualitative
Qualitative
Uncertainty
with the
negative
control
Qualitative
Qualitative
Total weight of residues
Weight
(mg)
0.2
0.0
0.1
0.0
0.0
67.8
NA
73
Limitation of
Analysis
Uncertainty of
measurement a
Uncertainty of
measurement a
Within range
of error
Within range
of error
Within range
of error
NA
NA
NA
Calculated Upper
Limit for Amount
of Active
Pharmaceutical
Ingredient (|ig)
NA
NA
1.0
0.0
0.0
67.8
6000 b
73
a Although residues were visually present in the empty container and were detected by TGA, the amount of residues detected by the balance was
within the range of the balance error. The balance results in this case were inconclusive.b This value was not calculated based on experimental
results, rather it was calculated based on information provided by the manufacturer. On the package, it was stated that every cartridge contain 10
mg nicotine and only 4 mg out of the 10 mg will be delivered when used.
52
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Evaluation of P-Listed Pharmaceutical Residues
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EPA/600/R-14/167
8 Appendix A
Appendix A
Summary of the Residual Weight Results and Calculations
Table A-l: Warfarin Sodium Tablets Img (Item # 830-612), plastic bottles
Treatment
Triple rinse with
DI water
Cleaned with
methanol
(negative control)
Weight before
treatment (g)
9.6249
9.5810
9.4592
9.5256
9.5666
9.4594
Weight after
first triple
rinse (g)
9.6110
9.5654
9.4430
9.5105
9.5526
9.4455
Weight after
second triple
rinse (g)
Not Applicable
9.5048
9.5473
9.4401
Weight of
residuals (g)
0.0139
0.0156
0.0162
0.0208
0.0193
0.0193
Average weight of
residuals (gm)
(W)
0.0152
0.0198*
Stdev weight of
residuals (g) (S)
0.0012
0.0009**
* Average weight of residuals (W) used in the calculations of the upper limit for the amount of active ingredient in container residue
** Stdev of residuals (S)
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Evaluation of P-Listed Pharmaceutical Residues
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Table A-2: Calculated upper limit for the amount of active ingredient warfarin sodium in container residue (Warfarin Sodium Tablets Img)
Weight of
randomly
selected
tablets(gm)
A
0.2180
0.2244
0.2184
0.2213
0.2175
Average
weight
(g)
B
0.2199
Stdev
weight
(g)
C
0.0029
%
drug/Tablet
D
As per
manufacturer
0.4547
Number of
tablets/Container
E
100
Total
weight
of all
tablets
(g)
F
F=B*E
21.9920
Weight of
drug/Container
(g)
G
G=D*F
0.1000
**Maximum possible
weight of residual
drug/Total
residual/container
(mg)
H
H=W*(D/100)
0.0900
Stdev
I
i=(S/iooo)*
(D/100)
0.0039
** Assuming that the drug is homogenously distributed so it will have the same concentration in the residual as in the medication. This assumption
represents the worst case scenario. In reality, the outer layer of the medication does not probably contain the drug; rather it may be a coating to
prevent the loss of the drug until the medication reaches the location where it should be delivered in the body.
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Evaluation of P-Listed Pharmaceutical Residues
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Table A-3: Warfarin Sodium Tablets 5mg (Item # 824-896), plastic bottles
Treatment
Triple rinse with
DI water
Cleaned with
methanol
(negative control)
Weight before
treatment (g)
9.4004
9.4616
9.5951
9.4118
9.5228
9.4059
Weight after
first triple rinse
(g)
9.3888
9.4455
9.5770
9.3932
9.5053
9.3897
Weight after
second triple
rinse (g)
Not Applicable
9.3933
9.5052
9.3896
Weight of
residuals (g)
0.0116
0.0161
0.0181
0.0185
0.0176
0.0163
Average weight of
residuals (g)
(W)
0.0153
0.0175*
Stdev weight of
residuals (g)
(S)
0.0033
0.0011**
*Average weight of residuals (W) used in the calculations of the upper limit for the amount of active ingredient in container residue, ** Stdev. of
residuals (S)
Table A-4: Calculated upper limit for the amount of warfarin sodium in empty container residue (Warfarin Sodium Tablets 5mg)
Weight of
randomly
selected
tablets (g)
A
0.2278
0.2235
0.2260
0.2243
0.2218
Average
weight
(g)
B
0.2247
Stdev
weight
(g)
C
0.0023
%
drug/Tablet
D
As per
manufacturer
2.2254
Number of
tablets/Container
E
100
Total
weight
of
tablets
(g)
F
F=B*E
22.4680
Weight of
drug/Container
(g)
G
G=D*F
0.5000
**Maximum
possible weight of
residual
drug/Total
residual/container
(mg)
H
H=W*(D/100)
0.3887
Stdev
I
i=(S/iooo)*
(D/100)
0.0246
** Assuming that the drug is homogenously distributed so it will have the same concentration in the residual as in the medication.
This assumption represents the worst case scenario. In reality, the outer layer of the medication does not probably contain the drug; rather
it may be a coating to prevent the loss of the drug until the medication reaches the location where it should be delivered in the body.
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Evaluation of P-Listed Pharmaceutical Residues
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Table A-5: Warfarin Sodium Tablets IQmg (Item # 822-965), plastic bottles
Treatment
Triple rinse with
DI water
Cleaned with
methanol (negative
control)
Weight before
treatment (g)
9.3765
9.4651
9.4116
9.4285
9.3187
9.6159
Weight after
first triple
rinse (g)
9.3622
9.4509
9.3931
9.4121
9.3047
9.6014
Weight after
second triple
rinse (g)
Not Applicable
9.4073
9.2998
9.5965
Weight of
residuals (g)
0.0143
0.0142
0.0185
0.0212
0.0189
0.0194
Average weight of
residuals (g)
(W)
0.0157
0.0198*
Stdev weight of
residuals (g)
(S)
0.0025
0.0012**
*Average weight of residuals (W) used in the calculations of the upper limit for the amount of active ingredient in container residue, **
Stdev. of residuals (S)
Table A-6: Calculated upper limit for the amount of warfarin sodium in empty container residue (Warfarin Sodium Tablets 10 mg)
Weight of
randomly
selected
tablets(g)
A
0.2227
0.2234
0.2253
0.2214
0.2221
Average
weight
(g)
B
0.2230
Stdev
weight
(g)
C
0.0015
%
drug/Tablet
D
As per
manufacturer
4.4847
Number of
tablets/Container
E
100
Total
weight
of
tablets
(g)
F
F=B*E
22.2980
Weight of
drug/Container
(g)
G
G=D*F
1.0000
**Maximum
possible weight of
residual
drug/Total
residual/container
(mg)
H
H=W*(D/100)
0.8895
Stdev
I
i=(S/iooo)*
(D/100)
0.0543
** Assuming that the drug is homogenously distributed so it will have the same concentration in the residual as in the medication.
This assumption represents the worst case scenario. In reality, the outer layer of the medication does not probably contain the drug; rather
it may be a coating to prevent the loss of the drug until the medication reaches the location where it should be delivered in the body.
60
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Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
Table A-7: Warfarin Sodium 2mg (Item # 580-516), blister packs
Treatment
Triple rinse with DI
water
Cleaned with
methanol (negative
control)
##Weight before
treatment (g)
3.5586
3.5459
3.5101
3.5285
3.5108
3.5386
## Weight
after first
triple rinse (g)
3.5559
3.5433
3.5085
3.5257
3.5082
3.5364
## Weight after
second triple
rinse (g)
Not Applicable
3.5256
3.5079
3.5361
Weight of
residuals (g)
0.0003
0.0003
0.0002
0.0003
0.0003
0.0003
Average weight of
residuals (gm)
(W)
0.0002
0.0003*
Stdev weight of
residuals (gm)
(S)
0.0001
0.0000**
## Weight of the whole empty card which contains 10 individual blister packs. Thus the weight of residuals was calculated as the
difference between the weights before and after rinse divided by 10. This measurement has been conducted this way because the amount
of residuals in individual packs is too small to be detected by the utilized balance.
* Average weight of residuals (W) used in the calculations of the upper limit for the amount of active ingredient in container residue, **
Stdev. of residuals (S)
61
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
Table A-8: Calculated upper limit for the amount of warfarin sodium in em
Weight of
randomly
selected
tablets(g)
A
0.2168
0.2202
0.2181
0.2147
0.2151
Average
weight
(g)
B
0.2170
Stdev
weight
(g)
C
0.0023
%
drug/Tablet
D
As per
manufacturer
0.9217
Number of
tablets/Container
E
1
Total
weight
of
tablets
(g)
F
F=B*E
0.2170
pty container residue (Warfarin Sodium 2 mg)
Weight of
drug/Container
(g)
G
G=D*F
0.0020
**Maximum
possible weight of
residual
drug/Total
residual/container
(mg)
H
H=W*(D/100)
0.0026
Stdev
I
i=(S/iooo)*
(D/100)
0.0002
** Assuming that the drug is homogenously distributed so it will have the same concentration in the residual as in the medication.
This assumption represents the worst case scenario. In reality, the outer layer of the medication does not probably contain the drug; rather
it may be a coating to prevent the loss of the drug until the medication reaches the location where it should be delivered in the body.
62
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
Table A-9: Jantoven (Warfarin Sodium) Img (Item # 015-920), blister packs
Treatment
Triple rinse with
DI water
Cleaned with
methanol
(negative control)
##Weight
before
treatment (g)
3.0942
3.1217
3.0691
3.0748
3.0626
3.0526
## Weight
after first
triple rinse
(g)
3.0918
3.1195
3.0668
3.0721
3.0602
3.0497
## Weight
after second
triple rinse
(g)
Not
Applicable
3.0721
3.0602
3.0497
Weight of
residuals (g)
0.0002
0.0002
0.0002
0.0003
0.0002
0.0003
Average weight of
residuals (g)
(W)
0.0002
0.0003*
Stdev weight
of residuals
(g)
(S)
0.0000
0.0000**
## Weight of the whole empty card which contains 10 individual blister packs. Thus the weight of residuals was calculated as the
difference between the weights before and after rinse divided by 10. This measurement has been conducted this way because the amount
of residuals in individual packs is too small to be detected by the utilized balance.
*Average weight of residuals (W) used in the calculations of the upper limit for the amount of active ingredient in container residue, **
Stdev. of residuals (S)
Table A-10: Calculated upper limit for the amount of warfarin sodium in empty container residue (Jantoven 1 mg)
Weight of
randomly
selected
tablets(g)
A
0.2226
0.2224
0.2223
0.2257
0.2283
Average
weight
(g)
B
0.2243
Stdev
weight
(g)
C
0.0027
%
drug/Tablet
D
As per
manufacturer
0.4459
Number of
tablets/Container
E
1
Total
weight
of
tablets
(g)
F
F=B*E
0.2243
Weight of
drug/Container
(g)
G
G=D*F
0.0010
**Maximum
possible weight of
residual
drug/Total
residual/container
(mg)
H
H=W*(D/100)
0.0012
Stdev
I
i=(S/iooo)*
(D/100)
0.0001
** Assuming that the drug is homogenously distributed so it will have the same concentration in the residual as in the medication. This
assumption represents the worst case scenario. In reality, the outer layer of the medication does not probably contain the drug; rather it
may be a coating to prevent the loss of the drug until the medication reaches the location where it should be delivered in the body
63
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
Table A-ll: Jantoven (Warfarin Sodium) IQmg (Item # 014-528), blister packs
Treatment
Triple rinse with DI
water
Cleaned with
methanol (negative
control)
##Weight before
treatment (g)
3.0737
3.0453
3.0268
3.0484
3.0589
3.0465
## Weight
after first rinse
(g)
3.0714
3.0434
3.0250
3.0464
3.0569
3.0448
## Weight after
second rinse (g)
Not Applicable
3.0464
3.0569
3.0448
Weight of
residuals
(g)
0.0002
0.0002
0.0002
0.0002
0.0002
0.0002
Average weight of
residuals (gm)
(W)
0.0002
0.0002*
Stdev
weight of
residuals (g)
(S)
0.0000
0.0000**
## Weight of the whole empty card which contains 10 individual blister packs. Thus the weight of residuals was calculated as the
difference between the weights before and after rinse divided by 10. This measurement has been conducted this way because the amount
of residuals in individual packs is too small to be detected by the utilized balance.
* Average weight of residuals (W) used in the calculations of the upper limit for the amount of active ingredient in container residue, **
Stdev. of residuals (S)
64
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
Table A-12: Calculated upper limit for the amount of warfarin sodium in empty container residue (Jantoven 10 mg)
Weight of
randomly
selected
tablets(g)
A
0.2255
0.2238
0.2265
0.2249
0.2255
Average
weight
(g)
B
0.2252
Stdev
weight
(g)
C
0.0010
%
drug/Tablet
D
As per
manufacturer
4.4397
Number of
tablets/Container
E
1
Total
weight
of
tablets
(g)
F
F=B*E
0.2252
Weight of
drug/Container
(g)
G
G=D*F
0.0100
**Maximum
possible weight of
residual
drug/Total
residual/container
(mg)
H
H=W*(D/100)
0.0084
Stdev
I
i=(S/iooo)*
(D/100)
0.0008
** Assuming that the drug is homogenously distributed so it will have the same concentration in the residual as in the medication.
This assumption represents the worst case scenario. In reality, the outer layer of the medication does not probably contain the drug; rather
it may be a coating to prevent the loss of the drug until the medication reaches the location where it should be delivered in the body
65
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
Table A-13: Nicorette Gum (fruit Chill) 2mg (Item #151579), blister packs
Treatment
Triple rinse with
DI water
Cleaned with
methanol (negative
control)
Weight before
treatment (g)
0.2531
0.2427
0.2501
0.2433
0.2536
0.2569
Weight after
first triple
rinse (g)
0.2529
0.2424
0.2499
0.2430
0.2534
0.2564
Weight after
second triple
rinse (g)
Not Applicable
Not Applicable
Weight of
residuals (g)
0.0002
0.0003
0.0002
0.0003
0.0002
0.0005
Average weight
of residuals (gm)
(W)
0.0002
0.0003*
Stdev weight
of residuals
(g)
(S)
0.0001
0.0002**
*Average weight of residuals (W) used in the calculations of the upper limit for the amount of active ingredient in container residue, **
Stdev. of residuals (S)
Table A-14: Calculated upper limit for the amount of nicotine in empty container residue (Nicorette Gum (fruit Chill) 2mg)
Weight of
randomly
selected
tablets(g)
A
1.2842
1.2976
1.2920
1.2702
1.2878
Average
weight
(g)
B
1.2864
Stdev
weight
(g)
C
0.0103
%
drug/Tablet
D
As per
manufacturer
0.1555
Number of
tablets/Container
E
1
Total
weight
of
tablets
(g)
F
F=B*E
1.2864
Weight of
drug/Container
(g)
G
G=D*F
0.0021
**Maximum
possible weight of
residual
drug/Total
residual/container
(mg)
H
H=W*(D/100)
0.0005
Stdev
I
i=(S/iooo)*
(D/100)
0.0002
** Assuming that the drug is homogenously distributed so it will have the same concentration in the residual as in the medication.
This assumption represents the worst case scenario. In reality, the outer layer of the medication does not probably contain the drug; rather
it may be a coating to prevent the loss of the drug until the medication reaches the location where it should be delivered in the body
66
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
Table A-15: Nicorette Gum (fruit Chill) 4mg (Item #151542), blister packs
Treatment
Triple rinse with
DI water
Cleaned with
methanol (negative
control)
Weight before
treatment (g)
0.2661
0.2695
0.2501
0.2482
0.2571
0.2521
Weight after
first triple
rinse (g)
0.2660
0.2692
0.2500
0.2479
0.2569
0.2518
Weight after
second triple
rinse (g)
Not
Applicable
Not
Applicable
Weight of
residuals (g)
0.0001
0.0003
0.0001
0.0003
0.0002
0.0003
Average weight of
residuals (g)
(W)
0.0002
0.0003*
Stdev weight
of residuals
(g)
(S)
0.0001
0.0001**
*Average weight of residuals (W) used in the calculations of the upper limit for the amount of active ingredient in container residue, **
Stdev. of residuals (S)
Table A-16: Calculated upper limit for the amount of nicotine in empty container residue (Nicorette Gum (fruit Chill) 4mg)
Weight of
randomly
selected
tablets(g)
A
1.2831
1.3006
1.2822
1.3152
1.2337
Average
weight
(g)
B
1.2830
Stdev
weight
(g)
C
0.0307
%
drug/Tablet
D
As per
manufacturer
0.3118
Number of
tablets/Container
E
1
Total
weight
of
tablets
(g)
F
F=B*E
1.2830
Weight of
drug/Container
(g)
G
G=D*F
0.0040
**Maximum
possible weight of
residual
drug/Total
residual/container
(mg)
H
H=W*(D/100)
0.0008
Stdev
I
i=(S/iooo)*
(D/100)
0.0002
** Assuming that the drug is homogenously distributed so it will have the same concentration in the residual as in the medication.
This assumption represents the worst case scenario. In reality, the outer layer of the medication does not probably contain the drug, rather
it may be a coating to prevent the loss of the drug until the medication reaches the location where it should be delivered in the body
67
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
Table A-17: Nicotine Gum Polacrilex 2mg (Item #753-121), blister packs
Treatment
Triple rinse with
DI water
Cleaned with
methanol (negative
control)
Weight before
treatment (g)
0.2444
0.2577
0.2533
0.2584
0.2566
0.2605
Weight after
first triple
rinse (g)
0.2442
0.2576
0.2533
0.2582
0.2565
0.2605
Weight after
second triple
rinse (g)
Not
Applicable
Not
Applicable
Weight of
residuals (gm)
0.0002
0.0001
0.0000
0.0002
0.0001
0.0000
Average weight of
residuals (g)
(W)
0.0001
0.0001*
Stdev weight
of residuals
(g)
(S)
0.0001
0.0001**
*Average weight of residuals (W) used in the calculations of the upper limit for the amount of active ingredient in container residue, **
Stdev. of residuals (S)
Table A-18: Calculated upper limit for the amount of nicotine in empty container residue (Nicotine Gum Polacrilex 2mg)
Weight of
randomly
selected
tablets(g)
A
0.9546
0.9663
0.9777
0.9658
0.9607
Average
weight
(g)
B
0.9650
Stdev
weight
(g)
C
0.0085
%
drug/Tablet
D
As per
manufacturer
0.2072
Number of
tablets/Container
E
1
Total
weight
of
tablets
(g)
F
F=B*E
0.9650
Weight of
drug/Container
(g)
G
G=D*F
0.0020
**Maximum
possible weight of
residual
drug/Total
residual/container
(mg)
H
H=W*(D/100)
0.0002
Stdev
I
i=(S/iooo)*
(D/100)
0.0002
** Assuming that the drug is homogenously distributed so it will have the same concentration in the residual as in the medication.
This assumption represents the worst case scenario. In reality, the outer layer of the medication does not probably contain the drug; rather
it may be a coating to prevent the loss of the drug until the medication reaches the location where it should be delivered in the body
68
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
Table A-19: Nicotine Gum Polacrilex 4mg (Item #753-133), blister packs
Treatment
Triple rinse with
DI water
Cleaned with
methanol (negative
control)
Weight before
treatment (g)
0.2511
0.2556
0.2520
0.2543
0.2554
0.2651
Weight after
first triple
rinse (g)
0.2511
0.2555
0.2519
0.2542
0.2554
0.2650
Weight after
second triple
rinse (g)
Not Applicable
Not Applicable
Weight of
residuals (g)
0.0000
0.0001
0.0001
0.0001
0.0000
0.0001
Average weight of
residuals (gm)
(W)
0.0001
0.0001
Stdev weight
of residuals
(g)
(S)
0.0001
0.0001
*Average weight of residuals (W) used in the calculations of the upper limit for the amount of active ingredient in container residue, **
Stdev. of residuals (S)
Table A-20: Calculated upper limit for the amount of nicotine in empty container residue (Nicotine Gum Polacrilex 4mg)
Weight of
randomly
selected
tablets(g)
A
0.9748
0.9648
0.9574
0.9633
0.9292
Average
weight
(g)
B
0.9579
Stdev
weight
(g)
C
0.0172
%
drug/Tablet
D
As per
manufacturer
0.4176
Number of
tablets/Container
E
1
Total
weight
of
tablets
(g)
F
F=B*E
0.9579
Weight of
drug/Container
(g)
G
G=D*F
0.0040
**Maximum
possible weight of
residual
drug/Total
residual/container
(mg)
H
H=W*(D/100)
0.0003
Stdev
I
I=(S/1000)*
(D/100)
0.0002
** Assuming that the drug is homogenously distributed so it will have the same concentration in the residual as in the medication.
This assumption represents the worst case scenario. In reality, the outer layer of the medication does not probably contain the drug; rather
it may be a coating to prevent the loss of the drug until the medication reaches the location where it should be delivered in the body
69
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
Table A-21: Nicorette mini Lozenges 2mg (Item #030256), blister packs
Treatment
Triple rinse with
DI water
Cleaned with
methanol (negative
control)
Weight before
treatment (g)
12.8935
12.8906
**
13.0467
12.9654
**
Weight after
first triple
rinse (g)
12.8934
12.8906
**
13.0463
12.9654
**
Weight after
second triple
rinse (g)
Not Applicable
**
Not Applicable
**
#Weight of
residuals (g)
0.0001
0.0000
**
0.0004
0.0000
Average weight of
residuals (g)
0.0000
0.0002
# It is noted that residuals could be visually seen in the empty containers after disposing of the lozenges. But the weight is
negligible as compared to the relatively large container weight. So the residuals were not detectable by the balance. But these
residuals were detected by the TGA.
** Only duplicate samples were tested
Table A-22: Nicorette Lozenges 4mg (Item #002-089), blister packs
Treatment
Triple rinse with
DI water
Cleaned with
methanol
(negative control)
Weight before
treatment (g)
28.0900
27.8721
28.1864
27.8877
27.8521
27.8813
Weight after
first triple
rinse (g)
28.0900
27.8720
28.1864
27.8877
27.8521
27.8813
Weight after
second triple
rinse (g)
Not
Applicable
Not
Applicable
#Weight of
residuals (g)
0.0000
0.0001
0.0000
0.0000
0.0000
0.0000
Average weight of
residuals (g)
0.0000
0.0000
Stdev weight of
residuals (g)
0.0001
0.0000
# It is noted that residuals could be visually seen in the empty containers after disposing of the lozenges. But the weight is negligible as
compared to the relatively large container weight. So the residuals were not detectable by the balance. But these residuals were detected by
the TGA
* * Only duplicate samples were tested
70
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
Table A-23: Nicotine Transdermal Patch 7mg (Item #414-944), patch (plastic wrap to peel)
Treatment
Triple rinse with
DI water
Cleaned with
methanol (negative
control)
Weight before
treatment (g)
0.1041
0.1038
0.1040
0.1046
0.1052
0.1043
Weight after
first triple
rinse (g)
0.1040
0.1038
0.1040
0.1044
0.1051
0.1044
Weight after
second triple
rinse (g)
Not Applicable
Not Applicable
Weight of
residuals (g)
0.0001
0.0000
0.0000
0.0002
0.0001
-0.0001
Average weight of
residuals (g)
(W)
0.0000
0.0001*
Stdev weight
of residuals
(g)
(S)
0.0001
0.0002**
*Average weight of residuals (W) used in the calculations of the upper limit for the amount of active ingredient in container residue, **
Stdev. of residuals (S)
Table A-24: Calculated upper limit for the amount of nicotine in empty container residue (Nicotine Transdermal Patch 7mg)
Weight of
randomly
selected
tablets(g)
A
0.4146
0.4145
0.4137
0.4148
0.4135
Average
weight
(g)
B
0.4142
Stdev
weight
(g)
C
0.0006
%
drug/Tablet
D
As per
manufacturer
1.6899
Number of
tablets/Container
E
1
Total
weight
of
tablets
(g)
F
F=B*E
0.4142
Weight of
drug/Container
(g)
G
G=D*F
0.0070
**Maximum
possible weight of
residual
drug/Total
residual/container
(mg)
H
H=W*(D/100)
0.0011
Stdev
I
i=(S/iooo)*
(D/100)
0.0026
** Assuming that the drug is homogenously distributed so it will have the same concentration in the residual as in the medication.
This assumption represents the worst case scenario. In reality, the outer layer of the medication does not probably contain the drug; rather
it may be a coating to prevent the loss of the drug until the medication reaches the location where it should be delivered in the body
71
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
Table A-25: Nicotine Transdermal Patch 14mg (Item #722-285), patch (plastic wrap to peel)
Treatment
Triple rinse with
DI water
Cleaned with
methanol (negative
control)
Weight before
treatment (g)
0.5232
0.5289
0.5461
0.5134
0.5384
0.5385
Weight after
first triple
rinse (g)
0.5232
0.5289
0.5461
0.5134
0.5384
0.5385
Weight after
second triple
rinse (g)
Not Applicable
Not Applicable
Weight of
residuals (g)
0.0000
0.0000
0.0000
0.0000
0.0000
0.0000
Average weight of
residuals (g)
(W)
0.0000
0.0000*
Stdev weight of
residuals (g)
(S)
0.0000
0.0000**
*Average weight of residuals (W) used in the calculations of the upper limit for the amount of active ingredient in container residue, **
Stdev. of residuals (S)
Table A-26: Calculated upper limit for the amount of nicotine in empty container residue (Nicotine Transdermal Patch 14mg)
Weight of
randomly
selected
tablets(g)
A
1.3442
1.3486
1.3465
1.3506
1.3479
Average
weight
(g)
B
1.3476
Stdev
weight
(g)
C
0.0024
%
drug/Tablet
D
As per
manufacturer
1.0389
Number of
tablets/Container
E
1
Total
weight
of
tablets
(g)
F
F=B*E
1.3476
Weight of
drug/Container
(g)
G
G=D*F
0.0140
**Maximum
possible weight of
residual
drug/Total
residual/container
(mg)
H
H=W*(D/100)
0.0000
Stdev
I
i=(S/iooo)*
(D/100)
0.000
** Assuming that the drug is homogenously distributed so it will have the same concentration in the residual as in the medication.
This assumption represents the worst case scenario. In reality, the outer layer of the medication does not probably contain the drug; rather
it may be a coating to prevent the loss of the drug until the medication reaches the location where it should be delivered in the body
72
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
Table A-27: Nicotine Transdermal Patch 21mg (Item #414-969), patch (plastic wrap to peel)
Treatment
Triple rinse with
DI water
Cleaned with
methanol
(negative control)
Weight before
treatment (g)
0.3020
0.3015
0.2987
0.2989
0.3050
0.3054
Weight after
first triple
rinse (g)
0.3019
0.3015
0.2987
0.2989
0.3050
0.3053
Weight after
second triple
rinse (g)
Not Applicable
Not Applicable
Weight of
residuals (g)
0.0001
0.0000
0.0000
0.0000
0.0000
0.0001
Average weight of
residuals (g)
(W)
0.0000
0.0000*
Stdev weight of
residuals (g)
(S)
0.0001
0.0001**
*Average weight of residuals (W) used in the calculations of the upper limit for the amount of active ingredient in container residue, **
Stdev. of residuals (S)
Table A-28: Calculated upper limit for the amount of nicotine in empty container residue (Nicotine Transdermal Patch 21mg)
Weight of
randomly
selected
tablets(g)
A
1.2216
1.2275
1.2264
1.2272
1.2269
Average
weight
(g)
B
1.2259
Stdev
weight
(g)
C
0.0024
%
drug/Tablet
D
As per
manufacturer
1.7130
Number of
tablets/Container
E
1
Total
weight
of
tablets
(g)
F
F=B*E
1.2259
Weight of
drug/Container
(g)
G
G=D*F
0.0210
**Maximum
possible weight of
residual
drug/Total
residual/container
(mg)
H
H=W*(D/100)
0.0000
Stdev
I
i=(S/iooo)*
(D/100)
0.0010
** Assuming that the drug is homogenously distributed so it will have the same concentration in the residual as in the medication.
This assumption represents the worst case scenario. In reality, the outer layer of the medication does not probably contain the drug, rather
it may be a coating to prevent the loss of the drug until the medication reaches the location where it should be delivered in the body
73
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Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
Table A-29: Nicotrol NS Nasal Spray 10 mg/ml (Item # 500948), glass vial
Treatment
Triple rinse with
DI water
Cleaned with
methanol (negative
control)
Weight before
treatment (g)
11.1850
11.2278
11.1780
11.0927
11.1898
11.3298
Weight after
first triple
rinse (g)
11.1489
11.1558
11.1444
11.0469
11.0795
11.2826
Weight after
second triple
rinse (g)
Not Applicable
11.0469
11.0794
11.2826
Weight of
residuals (g)
0.0361
0.0720
0.0336
0.0458
0.1104
0.0472
Average weight of
residuals (g)
0.0472
0.0678
# Stdev weight
of residuals (g)
0.0215
0.0369
# The high standard deviation in this case is a result of the nature of the medication. The medication is in liquid form and therefore, when
removing the medication from the container, the remaining liquid is expected to have significant differences from one container to the
other when emptying the container when trying to simulate the use.
Volume of liquid per vial 10 ml
Nicotine Concentration in the vial 10 mg/ml
Total nicotine per vial 100 mg
Average total amount of residual nicotine per vial 0.6780 mg
Stdev of the total amount of residual nicotine per vial 0.3690 mg
Table A-30: Physostigmine Salicylate Ampules Img/ml (Item # 003-012), glass ampule
Treatment
Triple rinse with DI
water
Cleaned with
methanol (negative
control)
Weight before
treatment (g)
1.8730
1.9563
1.9636
1.9289
1.9280
1.9602
Weight after
first triple rinse
(g)
.8499
.8862
.8614
.8497
.8796
.8700
Weight after
second triple
rinse (g)
Not Applicable
1.8492
1.8796
1.8694
Weight of
residuals (g)
0.0231
0.0701
0.1022
0.0797
0.0484
0.0908
Average weight of
residuals (g)
0.0651
0.0730
Stdev weight
of residuals
(g)
0.0398
0.0220
Drug concentration is 1 mg/ml
Volume of drug /ampule is 2 ml
Total weight of drug/ampule is 2mg
Average actual residual drug/ampule is 0.0730 mg
Stdev of actual residual drug/ampule is 0.0220 mg
74
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Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
9 Appendix B
Appendix B
Overlay of TGA Plots for the Treatments of Each Medication Containers
TGA Analysis-All Plots Overlay
120
100 -
80 -
.Sf
I 60 -
40 -
20 -
100
Warfarin Sodium 1mg-Plastic Container
r 2.0
- 1.5
O
>
- 0.5
L o.o
200
300 400
Temperature (°C)
500
600
No Rinse
Triple Dl Rinse
Methanol Cleaned
Pure Warfarin Sodium
Cotton Swab-Control
Figure B-l: Warfarin Sodium 1 mg, plastic container
75
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Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
120
0
100
Warfarin Sodium Smg-Plastic Container
200
r 1.8
L 0.0
300 400
Temperature (°C)
500
600
No Rinse
Triple Dl Rinse
Methanol Cleaned
Pure Warfarin Sodium
Cotton Swab-Control
Figure B-2: Warfarin Sodium 5 mg, plastic container
76
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Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
120
Warfarin Sodium 10mg-Plastic Container
o
- 0.0
100
200
300 400
Temperature (°C)
500
600
No Rinse
Triple Dl Rinse
Methanol Cleaned
Pure Warfarin Sodium
Cotton Swab-Control
Figure B-3: Warfarin Sodium 10 mg, plastic container
77
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Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
120
Warfarin Sodium 2mg-Blister Pack
o
100
0)
200
300 400
Temperature (°C)
500
600
No Rinse
Triple Dl Rinse
Methanol Cleaned
Pure Warfarin Sodium
Cotton Swab-Control
Figure B-4: Warfarin Sodium 2 mg, blister packs
78
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Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
120
100 -
80 -
!§>60 -
40 -
20 -
0
Jantoven (Warfarin Sodium) Img-Blister Pack
100
J1"^
2.0
- 1.8
- 1.6
- 1.4 0
o
-1.2 a
- 0.8
- 0.6
- 0.4
- 0.2
0.0
200
300 400
Temperature (°C)
500
600
No Rinse
Triple Dl Rinse
Methanol Cleaned
Pure Warfarin Sodium
Cotton Swab-Control
Figure B-5: Jantoven (Warfarin Sodium) 1 mg, blister packs
79
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Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
120
Jantoven (Warfarin Sodium) 10 mg- Blister Pack
100
200
300 400
Temperature (°C)
500
600
No Rinse
Triple Dl Rinse
Methanol Cleaned
Pure Warfarin Sodium
Cotton Swab-Control
Figure B-6: Jantoven (Warfarin Sodium) 10 mg, blister packs
80
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Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
120
Nicorette Gum 2 mg-Blister Pack
o
O)
'53
o
100
200
300 400
Temperature (°C)
500
600
No rinse
Triple Dl Rinse
Methanol Cleaned
Pure Nicotine
Cotton Swab-Control
Figure B-7: Nicorette gum 2 mg, blister packs
81
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Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
120
100
Nicorette Gum 4 mg-Blister Pack
o
100
200
300 400
Temperature (°C)
500
No Rinse
Triple Dl Rinse
Methanol Cleaned
Pure Nicotine
Cotton Swab-Control
Figure B-8: Nicorette gum 4 mg, blister packs
82
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Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
120
Nicotine Polacrilex Gum 2mg-Blister Pack
100
200
300 400
Temperature (°C)
500
600
No Rinse
Triple Dl Rinse
Methanol Cleaned
Pure Nicotine
Cotton Swab-Control
o
O)
'53
Figure B-9: Nicotine Polacrilex gum 2 mg, blister packs
83
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Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
120
100 -
Nicotine Polacrilex Gum 4mg-Blister Pack
o -g
100
200
300 400
Temperature (°C)
500
No Rinse
Triple Dl Rinse
Methanol Cleaned
Pure Nicotine
Cotton Swab-Control
Figure B-10: Nicotine Polacrilex gum 4 mg, blister packs
84
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Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
Nicorette mini Lozenges 2mg-Plastic Container
120
- 1.0
- 0.5
o
OJ
'53
0.0
100
200
300 400
Temperature (°C)
500
600
No Rinse
Triple Dl Rinse
Methanol Cleaned
Pure Nicotine
Cotton Swab-Control
Figure B-l 1: Nicorette mini lozenges 2mg, plastic
85
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Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
120
Nicorette Lozenge 4 mg-Plastic Container
100
200
300 400
Temperature (°C)
500
No Rinse
Triple Dl Rinse
Methanol Cleaned
Pure Nicotine
Cotton Swab-Control
Figure B-12: Nicorette mini lozenges 4mg, plastic container
86
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Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
120
Nicotine Transdermal Patch 7mg-Platic Wrap
0
100
200
300 400
Temperature (°C)
500
600
No Rinse
Triple Dl Rinse
Methanol Cleaned
Pure Nicotine
Cotton Swab-Control
Figure B-13: Nicotine Transdermal Patch 7mg, plastic wrap
87
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Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
Nicotine Transdermal Patch 14mg-Platsic Wrap
120
100 -
100
200
300 400
Temperature (°C)
500
No Rinse
Triple Dl Rinse
Methanol Cleaned
Pure Nicotine
Cotton Swab-Control
Figure B-14: Nicotine Transdermal Patch 14mg, plastic wrap
-------
Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
Nicotine Transdermal Patch 21mg-Plastic Wrap
120
I
O
O)
'53
100
200
300 400
Temperature (°C)
500
No Rinse
Triple Dl Rinse
Methanol Cleaned
Pure Nicotine
Cotton Swab-Control
Figure B-15: Nicotine Transdermal Patch 21mg, plastic wrap
89
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Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
120
Nicotine Nasal Spray 10mg/ml-Glass Vial
o
100
200
300
400
500
Temperature (°C)
600
No Rinse
Triple Dl Rinse
Methanol Cleaned
Pure Nicotine
Cotton Swab-Control
O
OJ
'53
Figure B-16: Nicotine nasal spray 10 mg/ml, glass vial
90
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Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
120
Physostigmine Salicylate 1mg/ml-Glass Vial
200
300 400
Temperature (°C)
500
0.0
600
— No Rinse
Triple Dl Rinse
Methanol Cleaned
Pure Physostigmine
Cotton Swab-Control
Figure B-17: Physostigmine Salicylate 1 mg/ml, glass vial
91
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Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
10 Appendix C
Appendix C
Table C-l: Summary of the Tmax wt loss for the pure compounds and the residuals in the medication containers
Active
Compound
Nicotine
Warfarin Sodium
Physostigmine
salicylate
Medication
Nicorette Gums 4 mg fruit chill
Nicorette Gums 2 mg
Nicorette lozenges 4mg
Nicorette mini lozenges 2mg*
Nicotine gum polacrilex 2mg
Nicotine gum polacrilex 4mg
Nicotine nasal spray 10 mg/ml##
Nicotine transdermal patch 7 mg
Nicotine transdermal patch 14 mg
Nicotine transdermal patch 21 mg
Nicotine Inhaler $$
Jantoven 1 mg
Jantoven 10 mg
Warfarin sodium 1 mg tablets
Warfarin sodium 5 mg tablets
Warfarin sodium 10 mg tablets
Warfarin sodium 2 mg blister packs
Physostigmine Salicylate
Tmax wt loss (°C) * * Tmax Wt Loss (°C)
No Rinse Triple Rinse with Water
Residuals QC Check Triple Rinse QC Check Pure QC Check
(Cotton piece) with Water (Cotton piece) Compound (Cotton piece)
o±o
o±o
424±2
425±0.6
324±0.7 426±2
306
o±o
o±o
217±18
o±o
o±o
o±o
No
o±o
o±o
245±4
239±2
231±2
o±o
427
425±0.8
424±2
410±2
426±0.4
426±0.6
428±3
experiments were
423±2
422±2
425±1
423±0.7
425±1
427±1
o±o
o±o
o±o
0
o±o
o±o
o±o
o±o
o±o
o±o
conducted for this
o±o
o±o
o±o
o±o
o±o
o±o
423±1
424±1
427±0.9
427
427±0.3
427±3
430±2
422±0.2
425±3
428±3
medication
423±1
424±0.4
426±0.4
425±0.9
425±2
426±0.9
217±3
431±1
313±3
43 Oil
* Duplicate samples only were analyzed. The Tmaxwtioss (°C)
triple rinse with DI samples.
** The temperature at which the peak in weight loss occurs
103±0.4 424±0 0±0 425±2 236±3
for the residuals were 307 and 305 for non-rinse samples and were 0 and 0 for the
431±1
92
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Evaluation of P-Listed Pharmaceutical Residues
in Empty Pharmaceutical Containers
EPA/600/R-14/167
## Results are inconclusive. This residuals were in liquid form. All samples (non-rinsed, triple rinsed with DI and cleaned with methanol) were
analyzed same day August 20, 2013 and there was no issue with the rinsed samples with regards to the cotton piece QC check. Therefore, it is not
a calibration issue because the triple rinsed samples cotton peaks were in agreement with the specified range. The discrepancy observed here may
be a result of some chemicals in the residual liquid that reacted with the cotton piece and changed its characteristics. Therefore, the results of this
medication should be used with caution.
$$ The amount of residuals/cartridge =6 mg. This value is not experimentally determined. The manufacturer already mentioned on the package
that every cartridge contain 10 mg and 4 mg delivered
Note:
TmaxwtioSS temperature values were obtained from the TGA plot of each replicate and given values are the average of n=3 measurements, with
uncertainty expressed as the standard deviation of n=3 measurements for each medication (except for Nicorette mini lozenges 2mg*).
Table C-2: Specifications of the pure active pharmaceutical compounds
Warfarin Sodium
Formula: Ci9Hi5NaO4
CAS#: 129-06-6
Lot#: TKUB-RD
Molecular Weight: 330.31
Purity:>98%
Company: TCI
Nicotine
Formula: L-Nicotine
CAS#:54-ll-5
Lot#: A0315876
Code: 181420050
Purity: 99+ %
Company: Acros Organics
Physostigmine Salicylate
Formula: CisHjiNsCh.CyHe
CAS#: 57-64-7
Lot#: GG01-FFOL
Molecular Weight: 413.47
Purity: >98%
Company: TCI
93
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Date: December 4, 2013
Revision No.: 1
Page 94 of 165
11 Appendix D
Appendix D
Quality Assurance Project Plan
for
Evaluation of P-Listed Pharmaceutical Residues in Empty Pharmaceutical Containers
Prepared by:
Pegasus Technical Services
Cincinnati, OH
Prepared under:
EPA Contract No. EP-C-11-006
94
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Date: December 4, 2013
Revision No.: 1
Page 95 of 165
QUALITY ASSURANCE PROJECT PLAN
CATEGORY II MEASUREMENT PROJECT
Evaluation of Methods for Disposal of P-Listed Pharmaceutical Containers to
be Considered RCRA Empty
QUALITY
ASSURANCE
PROJECT PLAN
APPROVAL LIST
U.S. Environmental Protection Agency Contract No. EP-C-11-006
Work Assignment 3-17
Prepared for:
Thabet Tolaymat, Ph.D.
Work Assignment Manager
U.S. Environmental Protection Agency
Office of Research and Development
National Risk Management Research Laboratory
Land Remediation and Pollution Control Division
Prepared by:
Amro El Badawy, Ph.D.
Pegasus Technical Services Inc.
Cincinnati, OH 45219
Revision 1
December 4, 2013
95
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Date: December 4, 2013
Revision No.: 1
Page 96 of 165
Pegasus Technical Services, Inc. Concurrences:
1. Amm K\ Badau-y. Ph.D.. Work Alignment Leader
Mahendranath Aramhcwela. Ph.D., Peeasus On-Sitc Stuff
Signature
2.
Steven Jones. ASQ CQA/CQfc. Contract Quality Assurance Manager
Dare
Signature
_C4/07/20:14
Date
3. Raghuraman Venkatapaihy. Ph.D.. On-Site Technical Manager
1
Signatu/e
U.S. Environmental Protection Agency Approval for Implementation:
Thabei
D;itc
OSy/2£/ 4_
Date
ijtrtature
2. Jim Voit, LRPCD Quality Assurance Manager
Signature
List of Acronyms
Date
TABLE OF CONTENTS
96
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Date: December 4, 2013
Revision No.: 1
Page 97 of 165
1. Project Description and Objectives
1.1 Proj ect Description
1.2 Proj ect Obj ectives
2. Organization and Responsibilities
2.1 Responsibilities of Project Participants
2.2 Project Organization and Distribution List
2.3 Project Schedule
3. Scientific Approach
3.1 Sample Collection
3.2 Methodology
4. Sampling Procedures
4.1. Sampling Strategy
4.2. Sample Handling and Storage
4.3. Sample Labeling
5. Measurement Procedures
6. Quality Matrices (QA/QC Checks)
7. Assessment and Oversight
7.1 Assessment and Responses Actions
8. Data Review, Verification, and Validation
8.1 Data Reporting
8.2 EPA Data Review, Verification and Validation
7
7
9
9
9
11
12
12
12
19
19
19
20
21
22
25
25
26
26
26
97
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Date: December 4, 2013
Revision No.: 1
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8.3 Pegasus Data Review, Verification and Validation 27
8.4 Data Qualification 28
8.5 Reconciliation with User Requirement 30
8.4 Data Summary, Analysis and Storage 30
9. Reporting 32
9.1 Periodic Reports 32
9.2 Final Report 32
References 33
Appendix A 34
98
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Date: December 4, 2013
Revision No.: 1
Page 99 of 165
LIST OF TABLES
Table 2.1. Project Contacts and Distribution List
Table 2.2. Project Schedule
Table 3.1. Temperature of Maximum Weight Loss
Table 4.1. Sampling Schedule
Table 4.2. Sample Containers, Preservation and Hold Times
Table 5.1. Outline of Analysis Methods
Table 6.1. Summary of QA/QC Checks
Table 7.1. Reporting Units
Table 8.1. Data Descriptor
Table 8.2 Data Qualifiers
9
11
17
19
19
21
24
26
29
29
LIST OF FIGURES
Figure 2.1 Project Organization Chart
Figure 3.1 Picture of the cotton tip applicator
Figure 3.2 Picture of the TGA sample pan
Figure 3.3 Schematic of sample preparation for TGA analysis
Figure 3.4 TGA components
Figure 3.5 TGA analysis of clean cotton piece
Figure 3.6 TGA analysis of pure nicotine loaded on cotton piece
Figure 3.7 TGA analysis of residuals of nicotine lozenges as compared to pure
nicotine
10
13
14
14
14
16
16
17
99
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Date: December 4, 2013
Revision No.: 1
Page 100 of 165
LIST OF ACRONYMS
AWBERC Andrew W. Breidenbach Environmental Research Center
NRMRL National Risk Management Research Laboratory
ORD Office of Research and Development
SOP Standard Operating Procedure
QA Quality Assurance
QC Quality Control
QAPP Quality Assurance Proj ect Plan
RCRA Resource Conservation and Recovery Act
CFR Code of Federal Regulations
OSWER Office of Solid Waste and Emergency Response
TGA Thermal Gravimetric Analysis
PI Principal Investigator
RSD Relative Standard Deviation
RPD Relative Percent Difference
WA Work Assignment
100
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Date: December 4, 2013
Revision No.: 1
Page 101 of 165
• PROJECT DESCRIPTION AND OBJECTIVES
o Project Description
Under the Resource Conservation and Recovery Act (RCRA), some pharmaceuticals are
considered acute hazardous wastes since their sole active pharmaceutical ingredients are P-listed
commercial chemical products (40 Code of Federal Regulations [CFR] Part 261.33). Hospitals
and other healthcare facilities have struggled with RCRA requirements for empty containers
when it comes to disposal of visually empty warfarin and nicotine containers. For example,
nicotine and its salts that are used in nicotine gums, patches and lozenges are considered
hazardous wastes and listed as P075; warfarin (when present at concentrations greater than 0.3%)
and its salts that are used in Coumadin are also considered hazardous waste and listed as POOL
When unused nicotine-based smoking cessation products (e.g., patches, gums and lozenges) and
Coumadin are discarded, they must be managed as acute hazardous wastes in accordance with all
applicable RCRA regulations. Furthermore, due to additional management requirements for P-
listed wastes, any acute hazardous waste residues remaining in containers must be managed as
hazardous unless the container has been rendered "RCRA empty" either by triple rinsing with
water or by another method proven to achieve equivalent removal. Rendering empty pill bottles
and other pharmaceutical containers (e.g., blister packs, ampoules, protective peel strips and
packaging from medicinal patches, etc.) as "RCRA empty" is better than managing them as
hazardous waste which is difficult and costly for the healthcare facilities, and it may not be
necessary if the amount of residues is sufficiently small. However, in order to make any changes
to the current P-listed empty container requirements for pharmaceuticals, more information is
needed on residual wastes remaining in the empty containers after removal of the drug to
determine if triple rinsing of the container is needed.
o Project Objectives
The purpose of this study is to ascertain if simply removing the drug (specifically nicotine,
Coumadin and physostigmine) from its container is equivalent to triple rinsing the container. The
U.S. Environmental Protection Agency (EPA) Office of Solid Waste and Emergency Response
(OSWER) plans to address the issue of rendering these pharmaceutical packages RCRA empty
through a rulemaking. Therefore, the objective of this study is to evaluate if the residues in fully
dispensed (but not triple rinsed) containers and packaging contain the pharmaceutical active
ingredient. In other words, to determine if simply removing the drug from its container (without
rinsing) is equivalent to triple rinsing the container with water or other appropriate solvents. This
objective will be achieved through the following steps:
• Measure the amount of residuals in pharmaceutical containers containing warfarin,
physostigmine and nicotine medications after removing the drugs (no rinsing) and after
triple rinsing the empty container.
101
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Date: December 4, 2013
Revision No.: 1
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Use thermal gravimetric analysis (TGA) technique to verify the presence of active
pharmaceutical ingredient in the residuals in a weight above the detection limit of the TGA
balance (0.1 ug).
102
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ORGANIZATION AND RESPONSIBILITIES
o Responsibilities of Proj ect Participants
Mr. Michael Moeykens serves as the EPA Project Officer for EPA Contract No. EP-C-11-006.
Dr. Thabet Tolaymat is the EPA Principal Investigator (PI) responsible for technical direction,
project goals, and the quality of the data generated. Ms. Kristin Fitzgerald of the Office of Solid
Waste Emergency Response (OSWER) is the data end user. Mr. Jim Voit is the EPA Land
Remediation and Pollution Control Division (LRPCD) Quality Assurance (QA) Manager
responsible for review and approval of the quality assurance project plan (QAPP).
Dr. Karen Koran is the Pegasus Technical Services, Inc. (Pegasus) Project Manager. Dr.
Raghuraman Venkatapathy is the Pegasus On-Site Technical Manager responsible for
supervision of the Pegasus Team staff. Mr. Steven Jones, ASQ CQA/CQE, with Shaw
Environmental & Infrastructure, Inc., is the Pegasus Contract QA Manager responsible for
oversight of Pegasus Quality Program implementation, QA review of quality documents and
deliverables, and project assessments. Dr. Amro El Badawy, Pegasus On-Site WA Leader, with
the help of Dr. Mahendranath Arambewela, Pegasus On-Site Project Staff are responsible for
day-to-day management and planning of research activities, sample collection, laboratory
experiments, data analysis, and report preparation.
2.2. Project Organization and Distribution List
The project participants, contact information, and QAPP distribution list is provided in Table 2.1.
A project organization chart is provided in Figure 2.1.
Table 2.1 Project Contacts and Distribution List
Name
Mr. Michael Moeykens
Dr. Thabet Tolaymat
Ms. Kristin Fitzgerald
Mr. Jim Voit
Dr. Karen Koran
Dr. Raghuraman Venkatapathy
Mr. Steven Jones
Dr. Amro El Badawy
Dr. Mahendranath Arambewela
Phone/email
(513)569-7196
Moevkens.Michael(a),e] a.aov
(513)487-2860
Tolavmat.Thabet(S>epa.gov
(703) 308-0522
Fitzgerald.Kristin@epa.gov
(513)487-2867
Voit.Jim(a),epa.aov
(513)569-7304
^oran .Karen(S>epa. gov
(513)569-7077
Venkatapathv.Raahuraman(S!epa.aov
(513)782-4655
Steve. S.Jones(fl),cbifederalservices. com
(513)569-7688
El-Badawv.Amro(S>epamail.gov
513)569-7688
Arambewela.Mahendranath(S!epa.eov
Role
EPA Project Officer
EPA Principal Investigator
EPA OSWER End Data User
EPA LRPCD QA Manager
Pegasus Project Manager
Pegasus On-Site Technical
Manager
Pegasus Contract QA
Manager
Pegasus On-Site WA Leader
Pegasus On-Site Project staff
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The project schedule and milestones for main project activities are shown in Figure 2.2.
Table 2.2 Project Schedule
QAPP Preparation
Sampling/
Data Collection
Data
Verification/Validation
Monthly Reports
Report Writing
Report Submission
Aug
2012
Oct
2012
Dec
2012
Feb
2013
Apr
2013
Jun
2013
Aug
2013
Oct
2013
Dec
2013
Feb
2014
Apr
2014
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2. SCIENTIFIC APPROACH
2.3. Sample Collection
An application will be filed with the Ohio Board of Pharmacy in order to obtain a license for
purchasing the selected medications from a wholesaler. The board will issue a terminal
distributor of dangerous drugs license to purchase and utilize dangerous drugs for scientific
purposes within 30 days after receipt of the application. The license will be effective for
twelve months from the first day of January of each year. The license will be renewed
annually, if needed. Once the license is obtained, the various P-listed pharmaceutical
containers/packaging (bottles, pouches, blister packs, etc.) containing unexpired nicotine,
Coumadin and physostigmine will be purchased from a wholesaler. A variety of drug doses
and types (pills, patches, gums, lozenges, etc.) as well as a variety of container types will be
investigated.
The following records are required by the Ohio Board of Pharmacy for any laboratory that
is given a license to utilize dangerous drugs for scientific purposes:
1. The name of each drug;
2. The form of the medication (e.g., powder, granulation, tablet, or solution);
3. The total number of form types received for each medication (e.g., number of tablets
or volume of liquid) including the date and quantity of each receipt or manufacture,
and the name, address, and registration number, if any, of the person from whom
received;
4. The total quantity of each medication;
5. The quantity utilized in any manner by the laboratory including the date and manner
of utilization, and the name, address, and registration number, if any, of each person
to whom provided for utilization.
The above mentioned records will be recorded in the project logbook CH 276 which will be
signed by the WA Leader and witnessed by the EPA PI. The issued Ohio Board of Pharmacy
License number is LR. 022271550. The purchased pharmaceuticals under this license will be
stored in laboratory 131A located at the Center Hill Research Facility. The access to Lab
131A is limited as there is an access code that is given to a few number of known
individuals.
2.4. Methodology
As previously stated, this study aimed mainly at evaluating the necessity of triple rinsing
pharmaceutical containers (specifically nicotine, coumadin and physostigmine containers)
after removing the drugs in order for the container to be considered "RCRA empty". If triple
rinsing is not required, then simply emptying the drugs from a container makes it RCRA
empty. This section presents the experimental approach to conduct this evaluation.
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In the current study, three drugs will be evaluated, 1) warfarin sodium, 2) nicotine, and 3)
physostigmine salicylate. Various drug packaging /drug concentrations of each drug type
will be purchased from TirHealth outpatient pharmacy located in Cincinnati, OH. Examples
of drug packaging types include blister packs, plastic bottles, glass vials and glass ampoules.
A total of 19 different types of drug packaging/drug concentration will be investigated in this
study (7 for warfarin sodium, 11 for nicotine and 1 for physostigmine salicylate
3.2.1 Experimental Approach
• The medication (tablets, pills, lozenges, etc...) will be removed from the container
in a way to simulate use. The removed medication will be discarded and treated as
hazardous waste.
• The empty containers will be exposed to one of three conditions:
• No rinse
• Triple rinse with deionized water (DI)
• Cleaned container (negative controls). Preparation of the negative controls is
further discussed in Section 3.2.2.
Triplicate containers will be evaluated under each one of the above 3 conditions.
• The amount of residuals in each rinsed container will be determined as follows:
• Using a sensitive balance (Mettler Toledo AB104-S, readability of 0.1 mg),
determine the weight of the empty container (1) before and (2) after treatment.
The difference in weight (1 and 2) represents the amount of residuals.
• To check if the residuals in the empty container contain the active pharmaceutical
ingredient:
• The residuals in the empty container will be collected using a cotton tip
applicator (Figure 3.1). The cotton tip will be used to swab the empty
container's walls to collect any residuals.
Figure 3.1 Picture of the cotton tip applicator
The cotton piece (-10 mg) will be detached, with gloved-hand , from the
wooden stick and loaded into the TGA sample pan (Figure 3.2) (pan capacity is
Igm). Figure 3.3 presents a schematic for the steps performed to collect the
residuals from the containers on the cotton tip and loading it to the Thermal
Gravimetric Analysis (TGA) (TA Instruments, 2950 TGA) sample pan.
&
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Figure 3.2 Picture of the TGA sample pan
Figure 3.3 Schematic of sample preparation for TGA analysis
The TGA (Figure 3.4) measures the weight loss of the cotton piece loaded with
residual (if any) as a function of temperature. The TGA will be programmed to heat
the sample at a rate of 20°C/min to 600°C. The TGA balance readability is 0.1 ug.
[Pan
Furnace
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Figure 3.4 TGA components
The TGA is a technique in which the loss of mass of a substance is monitored as a
function of temperature or time as the sample specimen is subjected to a controlled
temperature program in a controlled atmosphere. The TGA instrument consists of a
sample pan that is supported by a precision balance and a furnace. The sample pan
containing the sample is heated to a specified temperature. The loss of the sample
weight is monitored as a function of temperature. TGA relies on a high degree of
precision in three measurements: weight, temperature, and temperature change. As
a result of heating the sample to high enough temperature, some residuals
decompose into gas, which dissociates into the air. The TGA analysis will generate
a plot of % weight loss (Y-axis) and temperature (X-axis). The temperature at
which the peak in weight loss occurs for the collected residual from the empty drug
container will be compared to that of the pure active pharmaceutical compound. If
the temperature at which the peak weight loss of both the residual and the pure
compounds is similar, then the residuals contain the active ingredient and if not then
the residuals is composed of something else. It should be noted that the TGA data is
qualitative which means the TGA results will not be used to quantify the amount of
active pharmaceutical ingredient in the residuals; it will rather be used to verify the
presence of absence of the active ingredient in the residuals.
• The following controls will be analyzed on the TGA along with the samples:
• Clean cotton piece without residuals
• Negative control: clean empty containers and clean cotton piece
• Positive control: pure active compounds of warfarin sodium, nicotine
or physostigmine salicylate loaded on a cotton piece.
3.2.2 Example of TGA Results
The TGA analysis of the clean cotton piece is presented in Figure 3.5. The 1st derivative of
the weight loss as a function of temperature (red line in Figure 3.5) shows the temperature at
which the peak in weight loss occur as a result of heating the cotton piece in the TGA furnace
to 600 °C. Based on Figure 3.5, the maximum weight loss of the cotton piece occurred at
425°C. When loading pure nicotine on the cotton piece, an additional peak of weight loss
occurred at 215 °C as presented in Figure 3.6. Thus, if the residuals in the empty nicotine-
based drug container showed a peak in weight loss at 215 °C, then the residuals contain the
active ingredient and if not, the residuals may still have nicotine but below the detection of
the TGA balance which is 0.1 ug. Figure 3.7 presents the TGA results of the residuals
collected from nicotine lozenges after loading the residual on a clean cotton piece. The
results showed that the residuals have a peak in weight loss at 305 °C which is different than
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that of the pure nicotine (215 °C). This means that the residuals may have nicotine below the
TGA balance detection but the majority of the residuals are something else.
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I
120
100
6C -
4C
2C -
100
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42$
a
CC-D
Pure Nicotine on Cotton Piece
Cotton Piece Only
0.0
600
300
Temperature (°C)
Figure 3.6 TGA analysis of pure nicotine loaded on cotton piece
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Nicorette Mini Lozenges 2mg-Plastic Container
T 1.4
0
100
200
500
300 400
Temperature (°C)
Figure 3.7 TGA analysis of residuals of nicotine lozenges as compared to
pure nicotine
3.2.3 Temperature of Maximum Weight Loss of Pure Pharmaceutical Compounds
The temperature at which the maximum weight loss occurs will be used to verify the
presence of the active pharmaceutical compounds in the residuals. This will be achieved
through comparing the temperature at which the maximum weight loss occurs for the pure
pharmaceutical compounds (presented in Table 3.1) to that of the residuals.
Table 3.1 Temperature for Maximum Weight Loss*
Pure
Compound
Warfarin Sodium
Physostigmine
Salicylate
Nicotine
Clean Cotton
Piece
CAS#
129-06-6
57-64-7
54-11-5
NA
Temperature for maximum weight loss
on TGA (°C)*
313
236
217
427
Acceptance
Criteria (°C)6
±5
±5
±5
±5
* These values are determined using the TGA in our laboratory utilizing the same method of
analysis used to analyze the residual samples
3.2.4 Preparation of the Clean Containers (Negative Control)
1. Empty the container containing the drug.
2. Rinse the container 3 times with methanol
3. Dry the container in a dessicator and weigh out the dry container.
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4. Repeat steps 2-3 until the weight of the dry container becomes constant.
5. Store the clean container in double Ziploc bags until further use.
6. In order to verify that the chosen solvent does not affect the bottle material, the following
preliminary experiments will be conducted:
1. Repeat steps 2-4 with at least one other type of solvent (e.g. acetone).
2. It will be confirmed that the methanol rinse does not affect the bottle material
if the dry weight measured in step 4 using the other rinsing solutions is similar
to the dry weight obtained from the methanol rinse.
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3. SAMPLING PROCEDURES
4.1. Sampling Strategy
Table 4.1 Sampling Schedule
Parameter
Weight of
residuals
Presence of
active
pharmaceutical
ingredient in
residuals
Type of
Measurement
Non-Critical
Critical
Type of
medication
3
3
Total Number
of packages
19
19
Number of samples
per package
12*
12*
Number
of
positive
control
NA*
9**
*3 not rinsed containers, 3 triple rinsed with water, 3 cleaned with methanol and 3 cleaned with other organic
solvent. The cleaned containers will serve as negative controls. NA: not applicable. **triplicate of each drug type
(warfarin sodium, nicotine and physostigmine)
As previously presented in Section 3.2.1., a total number of 19 drug packages will be
investigated in the current study. For each one of the 19 packages, 12 containers will be tested:
1) triplicate containers with no rinse, 2) triplicate containers will be rinsed with water, 3)
triplicate containers will be cleaned from residuals using methanol and one other organic solvent
(e.g. acetone) and will serve as negative controls. For each drug type (i.e. warfarin sodium,
nicotine, and physostigmine salicylate) triplicate samples of the pure active pharmaceutical
ingredient will be analyzed on TGA and will be used as positive control.
4.2. Sample Handling and Storage
Table 4.2 Sample Container, Preservation and Holding Times
Parameter
Weight of residuals
Presence of active
pharmaceutical ingredient in
residuals
Quantity of
Sample
Variable
Variable
Sample
Collection
NA*
Swab residuals on
Cotton Tip
Preservation
No
Preservation
No
Preservation
Max.
Holding
Time
Analyze
Directly
Analyze
Directly
* NA: Not Applicable. The empty container will be weighted out before and after rinsing. The difference in weight
will be the amount of residual.
4.3. Sample Labeling
The container under investigation will be labeled to include the following information: container
type, drug type, drug concentration, container condition (e.g., rinsed, non-rinsed, negative
control), date and time of sampling, the test that will be performed on this sample and the initials
of the personnel who processed the sample.
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3. MESUREMENT PROCEDURES
The analyses methods are summarized in Table 5.1. Standard Operating Procedures (SOP)
referenced in the Table are provided in Appendix A of this QAPP.
Table 5.1 Outline of Analysis Methods
Parameter
Weight of residuals
Presence of active
pharmaceutical
ingredient in residuals
Measurement
Non-Critical*
Critical
Instrument
AB104-S Balance (Mettler Toledo)
Hi Res TGA 2950, TA Instruments
Analytical
Method/SOP
SOP#1
SOP #2
# The data for the wieght of residuals generated under this QAPP should not be used for rule-
making as the purpose of this measurement is only to provide an approximate range of residuals
present in the containers. Sample package weights may differ greatly, which means that the
detection limits on a weight/weight basis (w/w) will vary significantly and the precision of the
balance used in the study will be impacted. Thus, the balance may not be sufficient to generate
accurate residual data
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4. QUALITY METRICS (QA/QC CHECKS)
Instruments/equipment will be maintained in accordance with the EPA ORD Policies and
Procedures Manual, Section 13.4, Minimum Quality Assurance (QA)/Quality Control (QC)
Practices for ORD Laboratories Conducting Research, and in accordance with the Standard
Operating Procedures (SOPs) and analytical methods shown in Table 5.1. All analytical data
will be collected in accordance with the QA/QC procedures specified in this QAPP. Table 6.1
summarizes the QA/QC checks, acceptance criteria, and corrective actions for each analysis.
The data quality indicators for the analyses are defined below.
Accuracy (bias): is broadly defined as how close the analyses will come to the true concentration
in the sample. The accuracy of measurements, incorporating a standard reference material or a
second source standard, will be calculated as percent recovery as follows.
Ca
Where: Cm = measured value of the check standard.
Ca = certified value of the check standard.
Precision: Precision is broadly defined as the scatter within any set of repeated measurements.
Laboratory replicates will be used to ensure precision. For samples that are measured in triplicate
or higher, the precision will be measured as the relative standard deviation (RSD).
The relative standard deviation between replicates will be calculated as follows:
%RSD = (—)xlOO
y'
Where: S = Standard deviation
y' = Mean of the replicates
Representativeness: is the extent to which measurements actually depict the true condition or
population being evaluated. The measurement of the residuals in the pharmaceutical containers
will be conducted using the container as a whole and not on portions of it. This will ensure a high
representativeness of the measurement. With regards to the TGA analysis on the residuals, a
cotton piece will be used to swab all the internal walls of the containers in order to ensure the
representativeness of the measurement for the actual residuals in the containers.
Completeness: is number of data points meeting all DQO / total number data points. A 90 %
completeness is required for this project. The completeness (C) will be calculated as follows:
%C = ^ x 100
Where: v = the number of actual measurements
T= the number of planned measurements
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Comparability: is the extent to which data from one study can be compared to past data from the
current project or data from another study. Data comparability will be maintained through the
use of defined and consistent sampling and analytical procedures. The SOPs defined in this
QAPP will be systematically followed each time a sample is being processed.
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Table 6.1 Summary of QA/QC Checks
Parameter
Weight of residuals
Presence of active
pharmaceutical
ingredient in
residuals
Measurement
Weight
Temperature
Weight
QC Check
Accuracy
Temperature
calibration
Calibration
Check
Accuracy
Method
Measure a
standard weight
1 point
calibration
2 point
calibration
Measure a
standard weight
Frequency
Once per day
before
conducting the
measurements
Initially (once at
start of the
project data
collection) and
as needed**
Initially (once at
start of the
project data
collection) and
as needed
Once per day
before and after
conducting the
measurements
Acceptance
Criteria
±0.1mg of the actual
weight
± 5 of the curie
temperature of the
standard metal6
±0.1 mg of the actual
weight
± 0. 1 mg of the actual
weight
Corrective Action
1- Investigate problem
2- Use another calibrated balance
3- Sample analysis will not begin
until all calibration checks are
within the acceptance criteria
1- Investigate problem
2- Re -calibrate
3- Sample analysis will not begin
until all calibration checks are
within the acceptance criteria
1- Investigate problem
2- Re -calibrate
3- Sample analysis will not begin
until all calibration checks are
within the acceptance criteria
1- Investigate problem
2- Re -calibrate
3- Sample analysis will not begin
until all calibration checks are
within the acceptance criteria
** As needed: temperature calibration is needed when the temperature of the peak weight loss of the cotton piece is not in the range of
427 ± 5 °C.
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5. ASSESMENT AND OVERSIGHT
7.1 Assessments and Responses Actions
EPA will conduct Technical Systems Audits (TSAs) on laboratory activities which will focus on
the critical target analytes. Detailed checklists, based on the procedures and requirements
specified in this QAPP, related SOPs, and EPA Methods will be prepared and used during these
TSAs. These audits will be conducted by the EPA/NRMRL QA Management Team or by QA
support contractors with oversight by the QA Management Team. Report of this activity will be
generated and included in the project record, including response to any findings or observations.
Data Quality Audits (DQAs) will be conducted on a minimum of 25% of the datasets generated
for this project for the critical target analytes. These audits will be conducted by the
EPA/NRMRL HF QA Management Team or by QA support contractors with oversight by the
QA Management Team. See Section 8 for additional discussion on ADQs.
Assessors do not have stop work authority; however, they can advise the EPA PI if a stop work
order is needed in situations where data quality may be significantly impacted, or for safety
reasons. The PI makes the final determination as to whether or not to issue a stop work order.
For TSA and DQA reports that identify deficiencies requiring corrective actions, the audited
party must provide a written response to each Finding and Observation to the PI, which shall
include a plan for corrective action and a schedule. If the audited party is a contractor, then the
response shall be delivered to the EPA PI. The PI is responsible for ensuring that audit findings
are resolved. The QA Management Team will review the written responses to determine their
appropriateness. If the audited party is other than the PI, then the PI shall also review and concur
with the corrective actions. The QA Management Team will track implementation and
completion of corrective actions. After all corrective actions have been implemented and
confirmed to be completed; the QA Management Team shall send documentation to the PI that
the audit is closed. Audit reports and responses shall be maintained by the PI in the project file
and the QA Management Team in the QA files.
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6. DATA REVIEW, VERIFICATION, AND VALIDATION
6.1. Data Reporting
Table 8.1 summarizes the reporting units for the measured parameters. The analyst will reduce
the results to the appropriate reporting units. The analysis results will be recorded in a laboratory
notebook and each page will be dated and signed by the person who performs the analysis, then,
those data will be fed manually to Excel spreadsheets for statistical analysis. Calculations (if
any) will be checked initially for errors by the analyst and then sent to a second editor for review.
Table 8.1 Reporting Units
Parameter
Weight of residuals
Presence of active pharmaceutical ingredient in residuals
Unit
ug
NA*
*NA: Not Applicable. For this parameter, the temperature at which the weight loss peak of
residuals occur will be compared to the temperature of the weight loss peak for pure active
compound.
8.2. EPA Data Review, Verification, and Validation
Criteria that will be used to accept, reject, or qualify data will include specifications presented in
this QAPP. Data will not be released outside of NRMRL until all study data have been reviewed,
verified and validated as described in this QAPP. The PI is responsible for deciding when
project data can be shared with interested stakeholders upon approval by the NRMRL Lab
Director.
Data verification will evaluate data at the data set level for completeness, correctness, and
conformance with the method. Data verification will be done by those generating the data. This
will begin with the analysts in the laboratory, monitoring the results in real-time or near real-
time. The WA leader shall contact the PI upon detection of any data quality issues which
significantly affect sample data. They shall also report any issues identified in the data report,
corrective actions, and their determination of impact on data quality.
Data reports are reviewed by the PI and the WA leader for completeness, correctness, and
conformance with QAPP requirements. All sample results are verified by the PI to ensure they
meet project requirements as defined in the QAPP and any data not meeting these requirements
are appropriately qualified in the data summary prepared by the PI (or in the work assignment
deliverables prepared by contractors that will be used by the PI). See Section 8.4 for the Data
Qualifiers. The Contract Laboratory Program guidelines on organic (EPA, 2008) and inorganic
(EPA, 2010) methods data review are used as guidance in application of data qualifiers.
Data validation is an analyte- and sample-specific process that evaluates the data against the
project specifications as presented in the QAPP. Data validation (i.e., audit of data quality) will
be performed by a party independent of the data collection activity. Data summaries for the
critical analytes that have been prepared by the contractor as well as laboratory data reports and
raw data shall be provided to the Pegasus on-site Technical Manager, who will coordinate the
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data validation. NRMRL SOP #LSAS-QA-02-0, "Performing Audits of Data Quality" will be
used as a guide for conducting the data validation. The outputs from this process will include the
validated data and the data validation report (DAQ Report). The report will include a summary
of any identified deficiencies, and a discussion on each individual deficiency and any effect on
data quality and recommended corrective action.
8.3 Pegasus Data Review, Verification, and Validation
Data verification and validation is performed following the guidance provided in the EPA
guidance document entitled, Guidance on Environmental Data Verification and Validation., EPA
QA/G-8.
Initial data assessment is conducted by an analyst who is knowledgeable regarding the WA
Quality requirements. The analyst determines that samples have been analyzed, calibration and
QC data requirements have been met, and the data are ready for verification. This assessment is
documented on the data summary sheet.
A complete verification (100% of the data) is conducted by knowledgeable personnel other than
the analyst, as assigned by the Project Leader, QA Manager, or On-Site Technical Manager.
This verification is documented on the cover of the data summary. Data verification includes
review of the data for completeness, correctness, and technical compliance as summarized
below.
• Completeness
o The data package received contains the documentation listed in the data validation
section (below).
o Forms and other required information have been completed.
o All expected samples and analyses were reported.
o Relevant information for each analysis, including QC results and supporting
documentation, are included in the data package.
• Correctness
o Results have been transcribed correctly to the reporting sheets.
o Sample results are supported by valid QC.
o Missing results and QC outliers have been noted.
. Technical compliance
o Sample hold times were met.
o The correct analytical method was used for each analysis, as specified in the
QAPP.
o The samples were properly preserved in accordance with the requested method.
o Calculations, QC frequencies, and acceptance criteria applied to the data are the
same as those specified in this QAPP.
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Ten percent of the spreadsheet cell calculations will be manually verified. Also, 10% of
spreadsheet cell calculations will be reviewed using the Excel formula review functions to trace
precedents and dependent cells. Data validation will be conducted by qualified individuals (or
organizations) that are sufficiently independent of those who performed the work, but are
collectively equivalent in technical expertise. Data validation is conducted to ensure that
activities are technically adequate, competently performed, properly documented, and satisfy
established technical and quality requirements. The Pegasus Contract QA Manager is
responsible for ensuring that assigned data validators are sufficiently independent to perform the
validation.
Data validation tasks begin with a review of the QAPP requirements. The data to be verified
include standards data, initial calibration data, continuing calibration data, sample results, and
QC data.
Additional validation may be recommended if significant anomalies are detected during the 10
percent review. Significant anomalies may include calibration inconsistent with method and/or
WA requirements, replicate analysis outside RPD limits, or calculation errors.
8.4 Data Qualification
Data qualification is an integral component of data reporting, review and validation. During data
reporting and review, qualifiers are applied to ensure the laboratory has provided data of known
quality. During data validation, qualifiers are applied to alert the data end user to quality
problems that may impact the usability of the data. Data qualifiers may be assigned to particular
sample results based on available information, including: laboratory QC, unavoidable analytical
interference, laboratory data summary information, etc. The data qualifiers and other data
descriptors to be used in this project are below in Table 8.1 and 8.2.
Table 8.1 Data Descriptors
Descriptor
NA
NR
ND
NS
Definitions
Not Applicable (See QAPP)
Not Reported by Laboratory or Field Sampling
Team
Not Detected
Not Sampled
Table 8.2 Data Qualifiers
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Qualifier
U
J
J+
J-
B
H
*
R
Definitions
The analyte was analyzed for, but not detected
above the reported sample quantitation limit.
The analyte was positively identified; the associated
numerical value is the approximate concentration of
the analyte in the sample.
The result is an estimated quantity, but the result
may be biased high.
For both detected and non-detected results, the
result is estimated but may be biased low.
The analyte is found in a blank sample above the
quantitation limit, and the concentration in the
sample is less than 10 times the concentration found
in the blank.
The sample was prepared or analyzed beyond the
specified holding time. Sample results may be
biased low.
Relative percent difference of a field or lab
duplicate is outside acceptance criteria.
The sample results are rejected due to serious
deficiencies in the ability to analyze the sample and
meet QC criteria. The presence or absence of the
analyte cannot be confirmed.
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8.5 Reconciliation With User Requirements
The data will be evaluated to check if they conform to the QA objectives of the project. A
statistical assessment for accuracy, precision, and completeness will be performed. All analyses
will be required to meet data quality objectives before formulation of the final report. Where
failures are observed in the individual methods, data will be marked as suspect.
Sample data will be presented in tabular format or in figure. All parameters will be reported
along with the mean, standard deviation and range, when applicable. Tabular data summaries
will be included in the main discussion of the reports.
8.6 Data Summary, Analysis and Storage
The data to be managed in this project are the TGA instrument data files, spreadsheets for
manually imported data for the weight of residuals, printed hard copy of the TGA data, the
laboratory notebook and the data analysis files. The data analysis files will be prepared using
Microsoft Excel and Sigmaplot Software. Microsoft Excel will be used to summarize the data
and calculate mean and standard deviation of the weight of the residuals based on the triplicate
samples analyzed for each condition. The TGA data will be plotted using SigmaPlot Software
and the peaks of the residuals under will be identified on the plots. The logbook number for this
projectisCH276.
Laboratory paper records will be maintained in accordance with Section 13.2, Paper Laboratory
Records, of the EPA ORD Policies and Procedures Manual. The WA 3-17 WA Leaders will
submit internally the raw data, including calculations and QA/QC requirements, for QA and
Management review at the conclusion of each experimental run. The Pegasus QA or Technical
Manager will submit the data to the EPA PI. Monthly progress reports will be submitted by
Pegasus to EPA every month. Distribution of the monthly report to other agencies will be at the
discretion of the EPA PI. The expected product of this research will be one final report
describing the analytical results of the samples analyzed.
Records will be generated in both paper (hard copy) and electronic formats, and submitted in the
format requested by the EPA PI. The following original documents generated in support of WA
activities constitute records which will be managed by the Pegasus Team:
• Contract-required documents and deliverables;
• WA-specific planning documents (i.e., Work Plan and this QAPP);
• Documentation that supports fulfillment of WA-specific planning document
requirements, including QA assessment reports;
Controlled access facilities that provide a suitable environment to minimize deterioration,
tampering, damage, and loss will be used for the storage of records. The electronic records will
be maintained on the secure network server (L:\Priv\Cin\NRMRL\TT-Group) that is backed up
on a routine basis. Electronic records that are not maintained on a secure network server will be
periodically backed up to a secure second source storage media, transferred to an archive media
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(e.g., compact discs, optical discs, magnetic tape, or equivalent), or printed. Electronic records
that are to be transferred for retention will be transferred to an archive media or printed, as
directed by EPA. The EPA record schedule (501) and record retention time (permanent). The
project files (electronic and non-electronic) generated under this QAPP will be retained
permanently. Records will be stored at EPA Center Hill Research Facility, Lab 134 unless
otherwise directed by the EPA PI who will serve as the custodian of the project records.
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7. REPORTING
9.1. Periodic Reports
Monthly reports will be prepared by the Pegasus WA Leader and sent to the Pegasus On-Site
Technical Manager and Project Manager, and submitted to the EPA every month. Distribution of
the monthly report to other agencies will be at the discretion of the EPA PI.
9.2. Final Report
The final report will be prepared at the end of the project to summarize all the project aspects,
give the final results, the conclusions and the recommendations. The report will be submitted in
both hard and electronic copies. The report will be submitted to the EPA PI through the Pegasus
On-Site Technical Manager; and upon approval of EPA, published as a memorandum.
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8. REFERENCES
[1] http://www.epa.gov/aging/resources/presentations/2010_0112_rcra_psi_call.pdf. Accessed,
August 20th, 2012.
[2] http://www.ecy.wa.gov/programs/hwtr/pharmaceuticals/pages/pu_metals.html. Accessed,
August 20th, 2012.
[3] TGA 2950 Thermo gravimetric Analyzer, Operator's manual. TA Instruments, Issued July
2000, PN 925602.001 Rev.
[4] Thermal Advantage, User Reference Guide. TA Instruments, Issued July 2000, PN
9259002.002 Rev. B.
[5] http://hrc.nevada.edu/qa/ipr/ipr-035.pdf. Accessed, August 20th, 2012.
[6] ASTM (2010). Standard Practice for Calibration of Temperature Scale for
Thermogravimetry, Designation E1582-10.
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APPENDIX A
STANDARD OPERATING PROCEDURES
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SOP1
Weight of Residual Determination Using Sensitive Balance
1.0 Scope and Application
This procedure is designed to measure the weight of residuals in the drug containers after
removing the medication.
2.0 Applicability
This procedure is applicable to AB104-S Mettler Toledo Balance located in Lab 134,
CHL. The maximum weight the balance can measure is 110 grams and the minimum is
10 mg.
3.0 Sample Preservation, Containers, Handling, and Storage
The weight of the sample will be measure immediately after receiving the
necessary treatment.
All generated wastes will be handled according to the USEPA waste
management guidelines.
4.0 Equipment and Apparatus
Supplies and Equipment
Weighing paper
Weighing pans
Standard Weights
Instruments
• AB104-S Mettler Toledo Balance
6.0 Procedure
Place the weighing paper/weighing pans on the balance and tare the balance.
Place the sample on the balance and record the weight measurement in the
laboratory notebook.
7.0 Quality Assurance/Quality Control
A calibration check will be performed once before measuring the weight of the samples in a
specific day. The weight calibration check is performed by measuring the weight of a calibrated
mass set after taring the balance. The measured weight must fall within the tolerance of
analytical balances presented in the following Table.
Tolerances for Analytical Balances
Weight Allowed Difference Between Weight And
Reading
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lg
500 mg
300 mg
200 mg
lOOmg
50 mg
30 mg
20 mg
10 mg
5mg
3mg
2mg
1 mg
0.1 mg
0.1 mg
0.1 mg
0.1 mg
0.1 mg
0.1 mg
0.1 mg
0.1 mg
0.1 mg
0.1 mg
0.1 mg
0.1 mg
0.1 mg
If the data does not fall within the specified limits of allowance, reject the measurements.
Corrective actions will be taken to ensure the quality of the weight data. These actions will
include verification of balance calibration by the NRMRL metrology lab or take balance out of
service, and use an alternate balance with specifications equal to the project instrument.
SOP 2
Thermal Gravimetric Analysis (TGA)
1.0 Scope and Application
This procedure is designed to measure weight loss of samples as a function of
temperature change or as a function of time at a fixed temperature.
2.0 Applicability
This procedure is applicable to TGA 2950 instrument. The TGA 2950 operates in the
temperature range from ambient to 1000°C, and has an isothermal temperature accuracy
of ±1°C and isothermal temperature precision of ±0.1°C. It has a weighing capacity of
l.Og, a sensitivity of O.lug and a precision of ±0.01%.
3.0 Health and Safety
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Hazards:
There is an electrocution hazard associated with the use of this equipment. The main
hazards are those encountered in the use of any electrical equipment along with the
following:
5. Explosion and fire caused by electrical sparks or short circuits due to open or frayed wiring.
6. The furnace and the balance chamber of the instrument are to be continuously purged with
gases which require the use of pressurized gas cylinders. These gas cylinders are very heavy
and unstable and can jeopardize the safety of the operator. Serious physical injuries can be
result from a falling cylinder or by exposure to the full force of escaping gas. A broken
valve on the cylinder can turn it into a lethal projectile. Gas pressure regulators may allow
the escape of gas if not screwed tight onto the cylinders or if damaged.
Precautions:
The operator should ensure the following:
• That there is proper grounding of electrical plugs namely for the computer and the
TGA 2950, etc.
• That any of the wiring is not frayed and/or open so that it comes in contact with
the operator accidentally.
• That the compressed gas cylinders are appropriately stored in an upright position
by using a bench-clamp or harness or a restraining chain.
• That he/she is familiar with the risks associated with the use of compressed gas
cylinders.
4.0 Sample Preservation, Containers, Handling, and Storage
No sample preservation required. The samples will be analyzed immediately.
All generated wastes will be handled according to the USEPA waste
management guidelines.
5.0 Equipment and Apparatus
Supplies and Equipment
Brass Tweezers
Class C calibration weight kit (1 mg to 1000 mg)
Standard Reference Material [SRM] for temperature calibration from a
qualified supplier
Permanent bar magnet procured from a qualified supplier. (This is available as
a part of the Curie calibration kit. It is noted that the above mentioned SRM
are also available as part of this Curie kit)
Platinum pans
Conditioner Kit
High purity Nitrogen
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Instruments
TGA 2950
6.0 Procedure
6.1 Calibrating the TGA
The TGA 2950 is capable of providing several pieces of valuable information about thermal
events in materials. All of the information provided (e.g., weight change) is quantitative, if
proper calibration is done prior to running sample materials. To obtain accurate experimental
results, the TGA should be calibrated when used for the first time, and periodically thereafter.
Types of Calibration
You can access the calibration functions by choosing the desired type of calibration from the
TGA Calibrate menu. Three types of calibration is needed for the TGA 2950: temperature,
weight and sample platform calibration.
6.1.1 Taring the TGA
The Tare function ensures that the weight measured by the balance reflects the weight of the
TGA sample only. When a pan is tared, the instrument reads the weight of the empty sample pan
and then stores the weight as an offset, which is subtracted from subsequent weight
measurements.
For optimum accuracy, the weight reading must be stable before it is accepted as an offset. The
TGA determines when the weight reading is sufficiently stable. You should tare the sample pan
before each experiment, even if you use the same pan in consecutive experiments. Taring is done
for both TGA weight ranges. Tare procedure:
1. Place the empty sample pan(s) on the sample platform.
2. Select Tare either on the instrument keypad, by selecting Calibrate/Tare from the TGA
menu, or by clicking on the button on the tool bar. If you are using an autosampler (AutoTGA),
the Tare Utility window will be displayed. This allows you to specify whether you will be taring
the entire platform or specific pan number(s).
6.1.2 Weight Calibration for TGA
Weight calibration should be performed on the TGA at least once a month. Because the TGA has
two weight ranges, taring is done for both ranges. The tare weight is stored by the instrument for
the appropriate weight range. The weight calibration functions guide you through the calibration
procedure step-by step. You will need to obtain the following items for this procedure:
two (2) empty sample pans
calibration weights
Brass tweezers.
NOTE: Always handle the calibration weights with brass tweezers, not with your fingers. The
oils and salt from your skin can change the calibration weight.
The next several pages provide the steps needed to perform TGA weight calibration. The
Instructions can also be found on the windows displayed as you step through the procedure
using the Advantage™ program.
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Step 1 of 5: Manually Tare the Balance
When you choose
Calibrate/Weight from the TGA menu, the first window that is displayed is the Weight
Calibration - Step 1 of 5 window. Follow these steps:
1. Unscrew the tare tube in a clockwise direction, then remove it.
2. Hang an empty sample pan of the same type and size as your experimental sample pan on the
tare hook. This is your tare pan.
3. Place the sample pan that you plan to use in your experiment on the sample platform.
4. Press the LOAD key on the instrument keypad to load the pan onto the sample hook.
5. Press the FURNACE key on the instrument keypad to close the furnace. Closing the furnace
prevent air currents from affecting the weight reading.
Click Continue to proceed. The Tare Stabilization window is displayed. See "Using the Tare
Stabilization Window" below for instructions.
Step 2 of 5: Zero the 100 mg Range
The Weight Calibration - Step 2 of 5 window should now be displayed.
The instrument is now measuring the weight in the 100 mg range. The tare weight is stored by
the instrument for the 100 mg range.
1. Replace the tare tube, by turning it in a counterclockwise direction to screw it back into the
instrument. This will prevent air currents from affecting the weight measurement
2. Select Continue to go on with the calibration procedure. The Weight Stabilization window is
displayed. See "Using the Weight Stabilization Window" for instructions.
Step 3 of 5: Zero the 1000 mg Range
The instrument is measuring the weight in the 1000 mg range. The tare weight is stored by the
instrument for the 1000 mg range. Select Continue to go on with the calibration procedure. The
Weight Stabilization window is displayed. See "Using the Weight Stabilization Window" for
instructions.
Step 4 of 5: Calibrate the 100 mg Range
This step in the procedure calibrates the 100 mg weight range for the TGA instrument.
1. Obtain the 100 mg class M standard weight from the TGA Accessory Kit.
2. Place the 100 mg weight in the sample pan.
3. Select LOAD to load the pan onto the sample hook.
4. Press the FURNACE key to close the furnace. Closing the furnace prevent air currents from
affecting the weight reading.
Enter the exact mass of the standard as seen on the TGA display (default value =100.0 mg), then
select Continue. The system will begin measuring the combined weight of the standard and the
pan. The Weight Stabilization window is displayed.
Step 5 of 5: Calibrate the 1000 mg Range
This step in the procedure calibrates the 1000 mg weight range for the TGA instrument.
1. Obtain the 1000 mg class M standard weight from the TGA Accessory Kit.
2. Select UNLOAD to unload the sample pan and remove the 100 mg weight.
3. Place the 1000 mg weight in the sample pan.
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4. Select LOAD to load the pan onto the sample hook.
5. Enter the exact mass of the standard as seen on the TGA display (default value = 1000.0 mg),
then select Continue. The system will begin measuring the combined weight of the standard and
the pan. The Weight Stabilization window is displayed. Once the weight reading is close to
1000 mg (+ 50 mg), then press the FURNACE key to close the furnace and stabilize the weight.
See "Using the Weight Stabilization Window" on the previous page for instructions. After you
accept the weight, the calibration is complete.
6. Unload the sample pan.
6.1.3 Adjusting the TGA Sample Platform
The Sample Platform Adjust procedure is used if the sample hang-down wire fails to pick
up a sample pan during an automatic loading procedure. The sample platform must be adjusted
so that the instrument can properly load and unload the sample pans.
To avoid weight signal noise, the TGA must be level so that the sample pan and hangdown- wire
hang inside the furnace and thermocouple tube without touching them. The first step of the
sample platform calibration procedure adjusts and levels the instrument.
Select Calibrate/Platform from the TGA menu. The first window in a step-by-step series of
instructions is displayed. The next several pages provide the steps needed to perform TGA
sample platform calibration. The instructions can also be found on the windows displayed as you
step through the procedure using the Advantage™ program.
NOTE: The sample platform adjustment procedure is slightly different for the TGA
Autosampler, turn to page 2-70 for those instructions.
Step 1: Center the Sample Pan
In order to center the sample pan, the top and bottom of the sample hang-down wire must be
adjusted and the instrument leveled. When you choose Calibrate/Platform from the TGA menu,
the Platform Adjust
Step 1 window is displayed.
1. Load an empty sample pan on the instrument balance (it can be done automatically or
manually).
2. Check to see whether the top end of the sample hang-down wire is hanging freely and roughly
centered within the top of the thermocouple tube inside the balance chamber.
If the wire is not roughly centered, turn the balance adjustment screw until the wire is centered.
3. Raise the furnace just to the bottom of the sample pan.
4. Check the alignment of the sample pan within the furnace. It should hang freely, roughly
centered, and should not be touching the sides of the furnace or the hangdown-tube. If the pan is
not centered, adjust the feet on the bottom of the instrument until the pan hangs correctly. Turn
the feet clockwise to lengthen or counterclockwise to shorten the instrument leveling feet.
5. Select Continue to go on with the calibration procedure.
Step 2: Platform Arm Positioning
The Platform Adjust - Step 2 window should now be displayed. Once the sample pan has been
centered over the furnace, you will need to adjust the position of the platform arm so that the
pans can load and unload correctly.
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• You can enter the number of units that you want to move the platform in the box on the left
side of the window, or
• You can use the slide bar to change the platform position by: (a) clicking on the appropriate
load direction button to move the platform one unit at a time, (b) clicking in the slider shaft to
move the platform five units for each click, or (c) placing the cursor on the slider and holding the
mouse button down as you slide it in the desired direction.
Select the Test Position button to move the platform arm to the selected position, and then select
Continue to go on with the calibration procedure.
Step 3: Manual Platform Adjustment
The Platform Adjust - Step 3 window should now be displayed.
1. Use a screwdriver to loosen the set screw located under the sample platform.
2. Move the sample platform: (a) rotate it until the sample holder is directly under the pan, then
(b) adjust the height of the platform until the bottom of the pan is located approximately 1 mm
above the platform.
3. Use the screwdriver to tighten the setscrew again (do not overtighten as you may strip the
threads).
4. Rotate the sample pan holder until the groove in the pan hole aligns with the wire on the
bottom of the sample pan.
5. Select Done when these steps have been accomplished. The Sample Platform Adjustment has
been completed.
6.1.4 Adjusting theAutoTGA Sample Platform
The Sample Platform Adjust procedure is used if the sample hang-down wire fails to pick up a
sample pan during an automatic loading procedure. The Autosampler sample platform must be
adjusted so that the instrument can properly load and unload the sample pans.
To avoid weight signal noise, the TGA must be level so that the sample pan and hangdown wire
hang inside the furnace and thermocouple tube without touching them. The first step of the
sample platform calibration procedure adjusts and levels the instrument.
Select Calibrate/Platform from the AutoTGA menu. The first window in a step-by-step series
of instructions is displayed. The next several pages provide the steps needed to perform the
AutoTGA sample platform calibration. The instructions can also be found on the windows
displayed as you step through the procedure using the Advantage program.
Step 1: Center the Sample Pan
In order to center the sample pan, the top and bottom of the sample hang-down wire must be
adjusted and the instrument leveled. When you choose Calibrate/Platform from the TGA menu,
the Platform Adjust Step 1 window is displayed.
1. Load an empty sample pan on the instrument balance (it can be done automatically or
manually).
2. Check to see whether the top end of the sample hang-down wire is hanging freely and roughly
centered within the top of the thermocouple tube inside the balance chamber.
If the wire is not roughly centered, turn the balance adjustment screw until the wire is centered.
3. Raise the furnace just to the bottom of the sample pan.
4. Check the alignment of the sample pan within the furnace. It should hang freely, roughly
centered, and should not be touching the sides of the furnace or the hang down tube. If the pan is
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not centered, adjust the feet on the bottom of the instrument until the pan hangs correctly. Turn
the feet clockwise to lengthen or counterclockwise to shorten the instrument leveling feet.
5. Select Continue to go on with the calibration procedure.
Step 2: Manual Platform Height Adjustment
The Platform Adjust - Step 2 window should now be displayed.
After the sample pan has been centered in step 1, the height of the platform must be manually
adjusted as follows:
1. Use a screwdriver to loosen the setscrew located in the platform hub.
2. Move the sample platform: (a) rotate the hub and platform until the sample holder is directly
under the pan, then (b) adjust the height of the hub and platform until the bottom of the pan is
located approximately 1 mm above the platform.
3. Use the screwdriver to tighten the setscrew again (do not overtighten as you may strip the
threads).
4. Select Continue to go on with the calibration procedure.
Step 3: Manual Sample Arm Length Adjustment
The Platform Adjust - Step 3 window should now be displayed. The length of the autosampler
arm must now be adjusted to allow proper pickup of the samples.
1. Use a screwdriver to loosen the two setscrews located on the sample arm.
2. Move the sample arm to adjust the position of the groove: (a) move the sample arm OUT to
make the sample holder groove rotate clockwise, or (b) move the sample arm IN to make the
sample holder groove rotate counterclockwise. When the groove aligns with the wire bale on the
bottom of the pan, go on to the next step.
3. Use the screwdriver to tighten the two setscrews on the sample arm.
4. Select Continue to go on with the calibration procedure.
Step 4: Platform Arm Positioning
NOTE: There may be a slight delay while the instrument initializes to prepare for this step. The
window controls will be disabled until this operation has been completed.
The Platform Adjust -Step 4 window should now be displayed.
Once the sample pan has been centered over the furnace, you will need to adjust the position and
rotation of the platform arm so that the pans can load and unload correctly.
• You can enter the number of units that you want to move the platform, in the box on the left
side of the position or rotation slide bar. or
• You can use the slide bar to change the platform position and rotation by: (a) clicking on the
appropriate direction button to move the platform one unit at a time, (b) clicking in the slider
shaft to move the platform five units for each click, or (c) placing the cursor on the slider and
holding the mouse button down as you slide it in the desired direction.
Select the Test Position button to move the platform arm to the selected position and rotation,
then select Done when you are satisfied that the platform arm is in the correct position.
6.1.5 Temperature Calibration for the TGA
Temperature calibration is useful for experiments in which precise transition temperatures are
essential. To temperature calibrate the TGA, first you need to analyze a high-purity metal for its
curie temperature, and then enter the observed and correct values in the temperature calibration
table.
NOTE: The Temperature Calibration Table is not available when the instrument is in the
calibration mode.
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Before you can perform the temperature calibration procedure for the TGA, you must first reset
the Temperature Calibration Table as follows: 1 Select Calibrate/ Temperature from the
TGA menu. The Temperature Table is displayed.
2. Click the Reset button to reset all temperature calibration data before performing any new
calibration experiments.
3. Click OK.
4. Gather the calibration data by following the steps on the next page to determine the curie
temperature.
5. Perform the temperature calibration as directed on the next page
Determining Curie temperature
A general procedure for Curie temperature calibration is given below.
1. Choose standards that encompass your experimental range. Multiple standards may be needed
for this purpose. Choose standards whose curie temperature differs substantially; each pair of
curie temperatures must differ from all other pairs by at least 10°C.
2. Place the curie temperature sample in a tared TGA sample pan and position the pan on the
sample platform.
3. Select the Experiment View. Enter the requested sample information, including name on the
Summary Page. Select the Ramp test from the Test list.
4. Click on the Procedure Page. Enter the requested test parameters that will program the TGA
to: (a) equilibrate to 100°C below the onset of the literature curie temperature of your material,
and (b) heat the material, at the same heating rate that you will use in your experiments, to above
the literature curie temperature.
5. Click on the Notes Page. Enter/verify the requested information.
6. Click on the Apply button to save the experimental and sample parameters entered
for this run. If more than one run is in the sequence list, schedule this run (will appear next to the
run number in the Sequence Pane for the scheduled run)
7. Start the method and observe Signal A (weight loss %) on the Signal Display Pane.
8. Slowly raise the magnet under the furnace until a weight gain (< 2%) is detected.
Secure the magnet in this position for the duration of the experiment.
9. Determine the curie temperature by analyzing the extrapolated end point of the Sshaped curve
using the data analysis program.
10. Enter the Observed and Correct temperatures in the Temperature table when all the
experiments are complete as directed in the next section.
Enter the Temperature Calibration
1. Select Calibrate/Temperature from the TGA menu. The Temperature Table is displayed.
This window shows the temperature calibration table that the instrument applies to the collected
data. Use this window to enter from one to five temperature calibration points (pairs of observed
and correct temperature points). The observed and correct temperature corresponds to the
experimental and theoretical transition temperature (e.g., melting point) of the calibrant
respectively.
2. If these values are correct, select OK.
If new values are to be entered:
a. Enter the Observed and Correct temperature points in the table.
b. Select OK when all points have been entered to save the settings to the instrument.
6.2 Running TGA for Samples
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The following steps will be followed to analyze a sample on TGA:
Select the pan type and material
Load the pan
Tare the empty sample pan
Load the sample into the pan
Enter the experimental information through the TGA controller (sample and
instrument information)
Create and select the thermal method on the controller
Attach and set up accessories as required (e.g., purge gas)
Start the experimental run
7.0 Quality Assurance/Quality Control
A calibration check should be performed after the weight and temperature calibrations have been
completed. After the temperature calibration check is performed, the 'observed' curie transition
temperature must fall within ± 5°C of the limits for SRM standards. The weight calibration check
is performed by placing a known weight from the calibrated mass set into the sample pan. The
'observed' weight must fall within the tolerance of analytical balance presented in the following
Table.
Tolerances for Analytical Balances
Weight
lg
500 mg
300 mg
200 mg
lOOmg
50 mg
30 mg
20 mg
10 mg
Allowed Difference Between Weight And
Reading
0.1 mg
0.1 mg
0.1 mg
0.1 mg
0.1 mg
0.1 mg
0.1 mg
0.1 mg
0.1 mg
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5 mg 0.1 mg
3 mg 0.1 mg
2 mg 0.1 mg
1 mg 0.1 mg
If the data does not fall within the specified limits of allowance, reject the measurements.
Perform the weight and temperature calibration again before performing any experiments for
data collection. If the calibration is rejected, re-calibrate the instrument and perform the
calibration check until the instrument is accepted to be in calibration. If the instrument cannot be
calibrated, contact the manufacturer to get it adjusted. Perform an additional calibration for
verification.
8.0 References
TGA 2950 Thermo gravimetric Analyzer, Operator's manual. TA Instruments, Issued July 2000,
PN 925602.001 Rev.
Thermal Advantage, User Reference Guide. TA Instruments, Issued July 2000, PN 9259002.002
Rev. B.
ASTM (2010). Standard Practice for Calibration of Temperature Scale for Thermogravimetry,
Designation E1582-10.
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12 Appendix E
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Memorandum
Date: October 31, 2014
To: Thabet Tolaymat, EPA ORD
From: Keith Weitz
Subject: Peer Review Comments Summary - Evaluation of P-Listed Pharmaceutical
Residues in Empty Pharmaceutical Containers
Task 6 of WA 3-05, Material Management Research, called for an external peer review
of the EPA report Evaluation of P-Listed Pharmaceutical Residues in Empty Pharmaceutical
Containers. Under the Resource Conservation and Recovery Act (RCRA), some pharmaceuticals
are considered acute hazardous wastes because their sole active pharmaceutical ingredients are
"P-listed commercial chemical products". Hospitals and healthcare facilities have struggled with
RCRA's empty container requirements when it comes to disposing of visually empty warfarin
and nicotine containers, and this report was prepared to investigate the issue. EPA's Office of
Resource Conservation and Recovery asked EPA's Office of Research and Development to
conduct research to evaluate the differences in pharmaceutical residues between triple rinsed P-
listed pharmaceutical containers and those that were not treated.
Specifically, nicotine gums, patches and lozenges are considered to be hazardous wastes
because nicotine and its salts are listed as EPA Waste No. P075, and Coumadin (also known as
warfarin) is hazardous because warfarin and its salts are listed as EPA Waste No. P001 (when
warfarin is present at concentrations greater than 0.3%). Therefore, when unused nicotine-based
smoking cessation products (e.g., patches, gums and lozenges) and Coumadin are discarded, they
are regarded as acute hazardous wastes and must be managed in accordance with all applicable
RCRA regulations. Furthermore, due to additional management requirements for P-listed wastes,
any acute hazardous waste residues remaining in containers (and therefore the container itself)
must be managed as hazardous unless the container has been rendered "RCRA empty" either by
triple-rinsing with an appropriate solvent or by another method proven to achieve equivalent
removal.
In this memorandum, peer review comments received per the subject report are
summarized. Comments are summarized based on the pre-defined (by EPA) peer review charge
questions:
1. Barring direct analysis of the active pharmaceutical ingredient, is the methodology
followed in this report sufficient to answer the research question posed?
2. Overall, are the presented data accurate enough to answer the research question?
3. Do the data collected in this study support the conclusion of the report?
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Reviewer comments as received, and organized by peer review charge question are
included in Attachment A.
Peer Review Panel
Peer reviewers engaged for this assignment were selected based on RTI expertise and
recommendations obtained from the research community. They were evaluated by RTI to ensure
that they met qualifications according to the EPA Peer Review Handbook. Reviewers included
the following individuals:
• Shannon Bartelt-Hunt, University of Nebraska, College of Engineering—Ph.D. and
M.S. in Civil Engineering (Environmental), University of Virginia; B.S. in
Environmental Engineering, Northwestern University. Ms. Bartelt-Hunt has expertise in
numerical and experimental investigations of contaminant transport in natural and
engineered systems, fate and transport of emerging contaminants, design of remediation
systems for contaminated soil and groundwater, design of barrier systems for waste
disposal applications.
• Jon Powell, Innovative Waste Consulting Services—B.S. in Environmental Engineering
Sciences and a Master of Engineering in Environmental Engineering Sciences from the
University of Florida. Mr. Powell is a Professional Engineer with broad expertise in
waste and materials management, with work spanning waste facility operations, design,
applied research, and training.
• Jennifer Redmon, RTI International—Master of Science and Environmental Science in
Environmental Chemistry, Toxicology and Risk Assessment, Indiana University; Master
of Public Affairs in Environmental Policy and Natural Resource Management, Indiana
University; B.S. in Public Affairs in Environmental Management, Indiana University.
Ms. Redmon is an environmental scientist and risk assessor with dual graduate degrees
that provide her with a multi-faceted background in environmental chemistry, toxicology,
risk assessment, environmental policy and natural resource management. Ms. Redmon is
also a certified hazardous materials manager.
Is the Methodology Sufficient to Answer the Research Question Posed?
1) Reviewers understood the basic research question to be "Is there a difference between triple-
rinsed P-listed pharmaceutical containers and those that are not triple-rinsed?" Reviewers
commented that a clear statement of this research question in the executive summary would be
helpful and provide necessary context when results are discussed.
Response:
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The research question is clearly stated in the executive summary of the revised report as follows
"The primary objective of the current study was to answer the research question "Is there a
difference between empty P-listedpharmaceutical containers that are triple-rinsed and those
that are not triple-rinsed? " The study objective was accomplished via two tasks: 1) calculating
the "maximum possible weight of residual drug/total residual /container "for each compound
and packaging combination to infer an upper limit for the amount of active pharmaceutical
compound in the total residue remaining in the container and 2) evaluating, qualitatively, the
presence of active pharmaceutical ingredient in the residues. The experimental test program
included the use of a sensitive balance to determine the total amount of residues in the empty
pharmaceutical containers and a thermal gravimetric analysis to qualitatively evaluate the
presence of the active pharmaceutical compounds in the residues. The P-listedpharmaceuticals
evaluated in the study were nicotine, Coumadin, andphysostigmine. "
2) To investigate the research question posed, actual P-listed containers were obtained and
emptied in a way that simulated actual use. Then, the empty containers were either not treated
(not rinsed); single triple rinse with DI water, or a double triple rinse with methanol to serve as a
negative control. The amount of residue (specifically nicotine, Coumadin, and physostigmine) in
each container was determined using a sensitive balance. The difference in weight between the
untreated and treated containers was attributed to any remaining residual. After weighing, the
residual was swabbed with a cotton swab and subjected to thermal gravimetric analysis (TGA) to
qualitatively identify the active pharmaceutical ingredient.
Response:
The above mentioned statement, "The amount of residue (specifically nicotine, Coumadin, and
physostigmine) in each container was determined using a sensitive balance ", does not
accurately represent the role of the sensitive balance in the study. The balance was used for
determining the total amount of residues in the empty containers and not for determining the
fraction of nicotine, Coumadin, andphysostigmine (if any) in the residues. The total amount of
residues determined using the balance along with information from the drug manufacturers were
then used to infer an upper limit for the amount of active pharmaceutical compound in the total
residue in the containers. In summary, to accurately represent the work conducted in the study
"The total amount of residues including the active pharmaceutical ingredient was determined
using a sensitive balance " is more accurate representation than "The amount of residue
(specifically nicotine, Coumadin, andphysostigmine) in each container was determined using a
sensitive balance."
3) For tablet or other non-liquid medications, all reviewers did not think the methodology used
was sufficient to answer the research question, which was determining the amount of active
pharmaceutical residual in each container. Reviewers commented that the use of the balance is
sufficient to determine the amount of the residual, but there is likely an uneven distribution of the
active ingredient in the tablet formulation. The report indicates that the coating or outer layer of
the medication likely does not contain the active ingredient. Reviewers thought it likely that the
residual in these containers is predominantly from the coating or outer layer of the medication. It
is not clear if the residual remaining in these containers contains the active ingredient or not, as
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the TGA analysis was inconclusive. In addition, reviewers noted that no active ingredient was
detected in any of the TGA analyses.
Response:
As mentioned in section 3 of the report, the objective of the study was not to determine the actual
amount of active pharmaceuticals in the residues. Rather, the tasks were to: 1) determine the
total amount of residues (using sensitive balance); 2) infer upper limit for the amount of active
ingredient in the residues using the data collected from task 1; and 3) qualitatively evaluate the
presence of the active pharmaceutical ingredients in the residues (using TGA). We agree with
the reviewers that the data presented for solid medication in this report do not quantify the
amount of the active pharmaceutical compounds in the residues of each container. However, the
study objectives (stated in section 3) did not include quantitative determination of the amount of
active ingredients and further work is warranted using other analytical techniques in order to
quantitatively determine the amount of the active pharmaceutical ingredients. To clarify this
point, the follow ing was added to the executive summary and conclusion sections in the revised
report "For medication in solid form (i.e., tablet, gum, and lozenge) and patches, there was no
difference between triple-rinsed containers and those that are not triple-rinsed. However, this
conclusion is based on a qualitative analysis by TGA which is limited by the TGA sensitivity.
Other analytical techniques are needed to verify the TGA results for these medications and to
quantitatively determine the amount of the active pharmaceutical compounds present in the
residues (if any)."
Furthermore, the TGA results and balance results should be considered collectively rather than
individually when analyzing the data and drawing conclusions. Analyzing the results in this
context makes the TGA results more meaningful. Thanks to the reviewers' comment, this
important point was clarified through examples in the revised conclusion section of the report as
follows:
• The nicotine nasal spray 10 mg/ml was the only medication to have positive TGA results
(active pharmaceutical drug was detected in the residuals) as the residues had a Tmaxwt
hss at 217°C that is representative of nicotine. But the Tmaxwt loss for the negative control
(cotton piece) was shifted in this case (as mentioned in the report the shift is not because
of any issues with the calibration) which may be attributed to a reaction between the
residual liquid and the cotton piece that caused changes in the properties of the cotton
piece. Nonetheless, the fact that this medication is in liquid from and contains 67.8 jug of
nicotine based on the theoretical calculations suggests that the detected TGA peak at 217
°C represent nicotine.
• For the blister packs and nicotine patches, the calculated upper limit for the amount of
active pharmaceutical compound in the total residue was relatively low and ranged from
0 to 8 jug. These amounts are upper limit and the actual amounts of active compounds in
the residues are more than likely lower because the outer layer of the medication acts as
a coating to prevent the loss of the drug until the medication reaches the target location
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in the body and thus, this layer does not probably contain the drug. The balance and
upper limit results support the TGA results which were negative for these pharmaceutical
packages.
• For the plastic containers encompassing warfarin tablets (1, 5, and 10 mg), detectable
quantities of residues were found in the empty containers. The TGA results for the same
containers showed clear peaks for these residues, however, the peaks did not correspond
to the warfarin and thus, they most likely represent the coating materials. These data
support the aforementioned assumption that the residues in these cases are mainly
composed of coating materials. Nonetheless, having negative TGA results do not
eliminate the possibility of the presence of the active pharmaceutical compound in the
residues but if it is present it represent a relatively small fraction.
• The aforementioned conclusions highlight the importance of considering the balance
results and TGA results collectively rather than individually when analyzing the data.
4) For liquid medicines, all reviewers did think the methodology of weighing the residual was
sufficient to answer the research question for the case of liquid medicines. In this case, the
residual is known to contain the active ingredient, since the active ingredient is likely to be more
homogeneously distributed throughout the medication. A) One reviewer questioned whether this
is true for all liquid medicines, commenting that many require agitation (shaking) prior to use.
Reviewers noted that by using the manufacturer's information regarding the percentage of the
active ingredient, and the amount of residual measured, the amount of pharmaceutically-active
residual can be determined. B) Despite this, reviewers found the results somewhat troubling in
that the TGA analysis did not detect any of the active pharmaceutical ingredients in the liquid
medications. Reviewers felt this may be due to the sensitivity of balance used for the TGA
analysis, which was not directly discussed in the report.
Response:
A) This is true for all liquid medications tested because of two reasons: 1) the tested liquid
mediations were solutions (not suspensions) and 2) there was no mentioning on the drug
package of a requirement or recommendation to shake the medication before use. A note of that
is included in section 7 in the revised report.
B) The following information was included in the revised report (sections 5.4.10 and 7) in the
response to the comment: "All TGA results were negative (no active pharmaceutical drug was
detected in the residuals) except for the nicotine nasal spray 10 mg/ml which had a Tmaxwtioss at
217 °C that is representative of nicotine. It should be noted that Tmax wt loss for the negative
control (cotton piece) was shifted in this case which may be attributed to a reaction between the
residual liquid and the cotton piece which may have resulted in changes in the properties of the
cotton piece. Nonetheless, the fact that this medication is in liquid from and contains 67.8 jug of
nicotine based on the theoretical calculations suggests that the detected TGA peak at 217 °C
represent nicotine."
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5) One reviewer suggested that some type of statistical treatment on the quantitative results could
be warranted. A 'readability' of 0.1 mg is important in this study because the differences for
some of the drugs tested were very close to this value - this fact, coupled with a lack of statistical
treatment, makes it difficult to conclude that a residue was present. Another comment
questioned data accuracy relating to some of the reported masses and significant figures.
Specifically, many of the results were reported to several decimal places (e.g., 0.3000 mg on
page 25) and the reviewer felt that readers are left to wonder how data could be reported that way
of the readable limit of the scale was 0.1 mg.
Response:
I would appreciate if the reviewers clarify what is meant by "lack of statistical treatment".
We do apologize for reporting some of the results with zeroes to fill decimal places that should
not be there. Throughout the report, all the extra zeroes were deleted for the total amount of
residuals that were experimentally determined by the balance.
6) Another reviewer commented that it would be useful if additional detail was presented in the
Methodological Approach (Section 4.0) explaining differences in the package types and
justifying why the chosen analytical methods were deemed optimal for the given study, potential
limitations, and comparison to other considered approaches. The study results suggest that the
sensitive balance was not sensitive enough to detect mass balance changes in all packages before
and after drug removal, and therefore the drug residue and active pharmaceutical amounts could
not be accurately quantified for all drugs, even when active pharmaceutical drug may have been
detected in the TGA results for the same sample. Additionally, Experimental Steps (Section 4.2)
notes that foil wrap packaging was not tested for plastic wrap peel offs, but does not provide
justification for this decision. The study results later suggest that samples with plastic wrap peel
contain no residual (within the range of the error of the balance), but the data appear suspect
because a portion of the packaging was not tested to confirm that it did not contain drug residual.
Response:
We added a table (Table 1 in the revised report) to the methodology section that includes
additional details regarding the investigated medications, doses, and types of packages.
Table 31. List of medications and package types
Medication
Warfarin
Nicotine
Form and Dose
Warfarin sodium tablets, 1 mg
Warfarin sodium tablets, 5 mg
Warfarin sodium tablets, 10 mg
Warfarin sodium tablets, 2 mg
Jantoven tablets, 1 mg
Jantoven tablets, 10 mg
Nicorette gum, 2 mg
Nicorette gum, 4 mg
Nicotine polacrilex gum, 2 mg
Package Type
Plastic container
Plastic container
Plastic container
Blister pack
Blister pack
Blister pack
Blister pack
Blister pack
Blister pack
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Medication
Physostigmine Salicylate
Form and Dose
Nicotine polacrilex gum, 4 mg
Nicorette mini lozenge, 2 mg
Nicorette lozenge, 4 mg
Nicotine transdermal patch, 7 mg
Nicotine transdermal patch, 14 mg
Nicotine transdermal patch, 21 mg
Nicotrol nasal spray, 10 mg/ml
Nicotine inhaler, 10 mg/cartridge
Physostig-mine salicylate, 1 mg/ml
Package Type
Blister pack
Plastic container
Plastic container
Plastic wrap (peel off)
enclosed In foil wrap
Plastic wrap (peel off)
enclosed In foil wrap
Plastic wrap (peel off)
enclosed in foil wrap
Glass vial
Plastic container
Glass ampule
The revised conclusion section in the report presented the limitations of the analysis and
interpretation of the results in light of the limitations (please refer to section 7 in the revised
report). As indicated in section 7, the medications packaged in blister packs and plastic wraps
contained minimal residuals, in the range of the error of the balance used in the study, after
removing the drugs. Although the sensitivity of the balance did not allow for determining the
actual amount of total residues in these package types, the results infer an upper limit for the
total amount of residues in these packages.
For the nicotine patches, the picture presented below shows that the nicotine patch faces a
plastic wrap and both are enclosed in an external foil type package. The active side of the
nicotine patch is only in contact with the plastic wrap that is facing it and securing it from
releasing the drug to other surfaces. The drug can only release when the internal plastic wrap is
peeled off. Therefore, the external foil package will not contain residues as it is not in contact
with the patch and that is the reason for not conducting any experimental testing on it. The
following information is added to the revised report (section 4.2) to clarify this point "The
external foil wrap packaging was not tested because the active side of the nicotine patch is only
in contact with the plastic wrap that is facing it and securing it from releasing the drug to other
surfaces. The drug can only release when the internal plastic wrap is peeled off. Therefore, the
external foil package will not contain residues as it is not in contact with the patch and therefore
it was not experimentally tested. "
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Nicotine Transdemal System
PATCH
14mq Hi!*:
Nicotine
Transdermal
System
External foil
package
Plastic wrap and
nicotine patch
facing each other
Are Data Accurate Enough to Answer the Research Question?
8) In general, all reviewers agreed that the study methods proposed were sound and allowed for
the collection and analysis of data regarding the question of whether there is residual contained
in the discarded packaging via sensitive balance. Reviewers believed the weight data on residual
are accurate enough to determine the amount of residual in the container. The mass results show
a downward trend for most of the different containers (non-blister packs) as more rinsing was
done, which is expected if there is residue present. So this observation appears to be effective in
terms of accuracy to help answer the research question.
Response:
Thank you.
8) However, the reviewers did not think that the data are accurate enough to determine whether
the residual contained the active pharmaceutical ingredient. One reviewer commented that the
report doesn't include the minimum level of detection of the active ingredients by TGA. Because
no active ingredients were detected using TGA, the reviewer noted that it is not clear whether no
active ingredients were present, or if the TGA was not sensitive enough to detect the small
amount of active ingredient in the sample. Another reviewer noted that drugs showing a mass
difference in residuals at the 1 or 10-mg level are clear and scale readability may not matter in
those cases.
Response:
As pointed out in response to comment 3, the TGA results and balance results should be
considered collectively rather than individually when analyzing the data and draw ing
conclusions. Analyzing the results in this context makes the TGA results more meaningful despite
the limitation of sensitivity of TGA in some of the investigated cases. For example, for the blister
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packs and nicotine patches, the calculated upper limit for the amount of active pharmaceutical
compound in the total residue was relatively low and ranged from 0 to 8 jug. These amounts are
upper limit and the actual amounts of active compounds in the residues are more than likely
lower because the outer layer of the medication acts as a coating to prevent the loss of the drug
until the medication reaches the target location in the body. Thus, residues my not contain the
drug. The balance and upper limit results support the TGA results which were negative for these
pharmaceutical packages. Another example of using TGA and balance data collectively was the
case of nicotine nasal spray 10 mg/ml which was the only medication to have positive TGA
results (active pharmaceutical drug was detected in the residuals). For this medication, the
residues had a Tmaxwtioss at 217°C that is representative of nicotine. But the Tmaxwt loss for the
negative control (cotton piece) was shifted in this case (as mentioned in the report the shift is not
because of any issues with the calibration) which may be attributed to a reaction between the
residual liquid and the cotton piece that caused changes in the properties of the cotton piece.
Nonetheless, the fact that this medication is in liquid from and contains 67.8 jug of nicotine based
on the theoretical calculations suggests that the detected TGA peak at 217 °C represent nicotine.
The following information was included in the revised conclusion section (section 7 in the
revised report) along with a table (Table 6) that summarizes the results and highlights the
limitation of analysis on a case by cases basis. This information clearly states the cases that had
conclusive results from the cases that had constraints because of sensitivity of equipment used in
the study.
• "For the medications in liquid form (Nicotrol nasal spray 10 mg/ml and Physostigmine
salicylate 1 mg/ml), there is a difference between triple-rinsed containers and those that
are not triple-rinsed. The residues in the not triple-rinsed containers contain the active
pharmaceutical ingredient.
• For Nicotine inhaler 10 mg/cartridge, there is a difference between triple-rinsed
containers and those that are not triple-rinsed. The residues in the not triple-rinsed
containers contain the active pharmaceutical ingredient.
• For medication in solid form (i.e., tablet, gum, and lozenge) and patches, the TGA results
showed no difference between triple-rinsed containers and those that are not triple-
rinsed. However, this conclusion is based on a qualitative analysis by TGA that is limited
by the TGA sensitivity. Other analytical techniques (e.g., gas chromatography or liquid
chromatography equipped with mass spectrometer) are needed to verify the TGA results
for these medications and to quantitatively determine the amount of the active
pharmaceutical compounds present in the residues (if any). "
With regards to the comment on determining the TGA sensitivity: it was practically difficult to
accurately determine the TGA sensitivity for the tested pure compounds. The major reason for
this difficulty was that the pure compounds were treated as samples (the pure compounds had to
be loaded on a cotton piece) and there was no control over how much sample was exactly loaded
on the cotton piece especially that these samples were tested in fume hood (for safety reasons)
and a fraction of the sample may be lost during loading because of the air current in the hood.
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9) One reviewer commented that the QA/QC data appear to suggest that tolerance limits of
different instruments were met. However, the reviewer noted instances where neither of these
methods are sufficient for data evaluation either due to method constraints (e.g. sensitive
balance), a need for additional QC (e.g. TGA data), or other uncertainties and study limitations
that are not thoroughly discussed in the report at this time. The reviewer detailed the key
concerns associated with the sensitive balance and TGA data as follows:
• A) Sensitive Balance Data - The sensitive balance was not sensitive enough to detect
mass balance changes in all packages before and after drug removal, and therefore the
drug residue and active pharmaceutical amounts could not be accurately quantified for
those drugs, even when active pharmaceutical drug may have been detected in the TGA
results for the same sample. Additionally, samples with plastic wrap peel were deemed to
contain no residual (within the range of the error of the balance), but a portion of the
packaging was not tested to confirm that it did not contain drug residual, and these peel
offs are lower in mass, and thereby more likely to be constrained by study method
limitations given that the smallest readable balance measurement was 0.1 mg. Therefore,
certain packaging types may not be suitable for testing with the balance used during the
testing. Perhaps a more sensitive balance could at least be secondarily used in cases
where either 1) TGA results reveal active pharmaceutical ingredients while the balance
does not indicate that there is residuals, or 2) the packaging is constructed of lower
weight material (e.g. peel offs).
Response:
• As previously mentioned in response to comment 6, the revised conclusion section in the
report presented the limitations of the analysis and interpretation of the results in light of
the limitations (please refer to section 7 in the revised report). Section 7 in the revised
report include the following "the medications packaged in blister packs and plastic
wraps contained minimal residuals, in the range of the error of the balance used in the
study, after removing the drugs. Although the sensitivity of the balance did not allow for
determining the actual amount of total residues in these package types, the results infer
an upper limit for the total amount of residues in these packages. " For the nicotine
patches, the picture presented in response to comment 6 showed that the nicotine patch
faces a plastic wrap and both are enclosed in an external foil type package. The active
side of the nicotine patch is only in contact with the plastic wrap that is facing it and
securing it from releasing the drug to other surfaces. The drug can only release when the
internal plastic wrap is peeled off. Therefore, the external foil package will not contain
residues as it is not in contact with the patch and that is the reason for not conducting
experimental testing on it. With regards to the use of more sensitive balance for the cases
where the residues were in the range of the error of the balance: we agree that it is a
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good measure to use a more sensitive balance in these cases, however, we did not have
access to such balance. Nonetheless, as stated above, although the sensitivity of the
balance did not allow for determining the actual amount of total residues in these
package types, the results infer an upper limit for the total amount of residues in these
packages.
• B) TGA Data - A full product listing in the main body of the report and an additional QC
of the final number of medications and a summary of TGA failures is needed. In Section
6.3, the authors should note which 4 drug products failed the TGA test to allow for
optimal transparency. The reader has to sift through the whole report to find which
products fail in the current version of the report. Furthermore, this section notes that 17
medications were tested, but the QAPP and Section 7 Conclusions notes that a different
number were tested (18 in conclusions, and 19 in the QAPP).
Response:
• A full product listing was included in Table 1 in the main body of the revised report;
please refer to section 4.1 in the report. The tests that did not meet the DOQfor TGA
were specified below Table 5 in the revised report. The total number of medications
included in the study was 18. One medication (nicotine inhaler) out of the 18 was not
tested experimentally because the actual amount of active pharmaceutical compound in
the residue was determined through information provided by the manufacturer (please
review section 5.4.11 in the report). Therefore 17 medications were experimentally tested
in the study. To clarify this point, the word "experimentally" was included in the phrase
in section 6.3 as follows "17 medications experimentally tested".
Do Data Collected Support the Conclusions of the Research?
Reviewers generally agreed that the data collected in the study do support the conclusion of the
report that all plastic containers used for medications and evaluated in this study contained
residuals, but that the amount of active pharmaceutical ingredients in the residual could not be
determined. Reviewers also generally agreed with the conclusions regarding the liquid drugs, as
the active ingredient should be homogeneously distributed throughout the medication.
However, reviewers also felt that the results do not sufficiently answer the overall research
question, which was to determine the difference in the amount of pharmaceutically-active
ingredient in the rinsed and non-rinsed containers. Reviewers felt that this question could not be
answered because the amount of pharmaceutically-active ingredient (or even the presence of the
active ingredient) could not be determined using the methods employed.
Reviewers also noted that the report contained inconsistent characterizations of the results. For
example, the executive summary of the report highlights that the qualitative TGA results show
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that there is "no observable difference [in the presence of active ingredients] between containers
that were triple rinsed and containers that were not" except for nicotine nasal spray. However,
the conclusions (Section 7) states that all medications in plastic containers contain measurable
residual levels, but it was not possible to determine the amount of active pharmaceutical
ingredients using TGA. Furthermore, the conclusions section does not discuss the nasal spray
results at all.
One reviewer recommended that a step-wise summary of the report findings is necessary to come
to a final conclusion on whether or not there is a difference between triple rinsing for some
pharmaceutical-package combinations. Specifically, the individual package type or drug results
are not summarized in a consistent and thorough manner. Adding a summary table would be a
very useful way to review the drug, dose, product, and package types evaluated along with at
least qualitative information on whether the TGA results were positive (indicating active drug
residual was present in discarded packaging), along with the measured residual weight (binned
into weight ranges, or with the average value), and the theoretical active pharmaceutical
ingredient weight (binned into volume ranges [e.g. within range of error, low, etc.] or with the
calculated value).
Another issue that one reviewer felt was not adequately discussed or described further (in the
results or conclusion section) was the discrepancy in the TGA results. For example, according to
Appendix C, one of the nicotine samples detected in residuals was found at a different
temperature than the positive nicotine control, 3 of the 3 warfarin residuals detected were all
found at temperatures different than the positive control, and the one physostigmine sample
detected via TGA was different than the pure compound. The reviewers commented that readers
are left to figure out what this all means. The warfarin data, for example, are noted by the
reviewer to show that as the concentration goes up (from 1 mg to 10 mg), the temperature that
the residue peak shows up goes down - this might suggest that purity is inversely related with
the mass loss peak. The reviewer noted that this trend seems to be reversed, however, when we
consider the pure compound had a much higher Tmax. The reviewer felt that having the authors'
comments on the TGA results in the cases where the Tmax was not equal would be helpful, as
well as somehow tying that into whether or not the authors think this would change or diminish
the observations seen in the mass measurement.
One reviewer commented that the conclusions should also elaborate on the sensitivity of the
balance used to measure the drug residual, along with other key study concerns and uncertainties.
To identify which results contain potential measurement limitations or concerns, it is necessary
to read through the entire report at this point. The summary table proposed above could form the
basis of a separate discussion regarding results uncertainty that is currently lacking. An
additional column noting any method sensitivity issues or other concerns with the specific result
would be prudent. Pulling these individual concerns out will help highlight study limitations and
increase transparency in the overall results, thereby leading to better confidence in the overall
study results. Results with noted concerns by the authors include Section 5.4.5.2 (method
sensitivity issue, limited medication quantity from vendor), Section 5.4.6.2 (method sensitivity
issue), Section 5.4.10.1 (inconclusive TGA results), and Section 5.4.10.2 (high standard
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deviation). Additionally, only one physostigmine product was obtained for analysis as well -
additional discussion in the conclusions or elsewhere should focus on why more of these drug
products could not be purchased and how this could affect the overall robustness of the data for
one of the three study drugs.
Another reviewer commented that the mass data and TGA data for the blister pack appear to
provide a conclusion that there is not an issue with residues in these types of containers. The
reviewer felt this to be a really important result that should be elucidated a bit more in the
executive summary and conclusions. The nicotine patch data also seem to suggest that residuals
are not an issue. However, a reviewer noted the confounding results with the liquid appear to
suggest that it would be difficult to make the case that residuals are minor.
10) In summary, reviewers felt the conclusions section of the report could be enhanced greatly
by:
1) providing a synthesized review of the study findings that includes a summary table of key
findings for all drug-product combinations,
2) highlighting study uncertainties and limitations,
3) noting ways to reduce study uncertainty or limitations if future resources become
available, and
4) making a final determination based on the final results in light of study uncertainties and
limitations.
Response:
a) The conclusion section was significantly revised (almost re-written) and improved to address
all of the above comments and provided a step by step synthesized review of the study findings
and a final determination based on these results to answer the research question of the study.
The revised conclusion section also presented the limitations of the analysis as well as methods
that can be used in future research for the cases where the results of the current techniques were
inconclusive. As recommended by the reviewers, Table 6 was created and added to the
conclusion section to summarize the study results and the uncertainty and limitations of the
analysis. Below id the revised conclusion section in the report:
"The current study aimed at evaluating if removing the P-listed drugs of warfarin sodium,
nicotine, and physostigmine salicylate from their containers is equivalent to triple rinsing the
containers. The study was conducted using thermal gravimetric analysis and weight
measurements using sensitive balance. The TGA was used to qualitatively evaluate the presence
of active pharmaceutical ingredient in the residuals after removing the drug from the rinsed
pharmaceutical containers by comparing the Tmaxwtioss of the residuals to that of the pure active
pharmaceutical compound. The total amount of residuals in pharmaceutical containers
containing warfarin, physostigmine salicylate and nicotine medications after removing the drugs
were measured using a sensitive balance. The theoretical "maximum possible weight of residual
drug/total residual /container" was calculated for each compound and packaging combination.
This calculated result may be used to infer an upper limit for the amount of pharmaceutical
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compound in the total residue remaining in the container. A total of 18 drug/packaging
combinations were evaluated in the study. The results obtained in the study are summarized in
Table 6 and indicate the following:
• For the medications in liquid form (Nicotrol nasal spray 10 mg/ml and Physostigmine
salicylate 1 mg/ml), there is a difference between triple-rinsed containers and those that
are not triple-rinsed. The residues in the not triple-rinsed containers contain the active
pharmaceutical ingredient. It should be noted that the tested liquid mediations were
solutions (not suspensions) and there was no mentioning on the drug package of a
requirement or recommendation to shake the medication before use.
• For Nicotine inhaler 10 mg/'cartridge, there is a difference between triple-rinsed
containers and those that are not triple-rinsed. The residues in the not triple-rinsed
containers contain the active pharmaceutical ingredient. The amount of nicotine in the
residue was not calculated based on experimental results; rather it was calculated based
on information provided by the manufacturer. On the package, it was stated that every
cartridge contain 10 mg nicotine and only 4 mg out of the 10 mgwill be delivered and
thus, 6 mg nicotine will be retained in each used cartridge.
• For the medications in solid form (i.e., tablet, gum, and lozenge) and patches, the TGA
results showed no difference between triple-rinsed containers and those that are not
triple-rinsed. However, this conclusion is based on a qualitative analysis by TGA that is
limited by the TGA sensitivity. Other analytical techniques (e.g., gas chromatography or
liquid chromatography equipped with mass spectrometer) are needed to verify the TGA
results for these medications and to quantitatively determine the amount of the active
pharmaceutical compounds present in the residues (if any).
The above conclusions present the straight answer to the main research question of the study
which was "Is there a difference between triple-rinsed P-listedpharmaceutical containers and
those that are not triple-rinsed? " Additional conclusions are presented below and highlight
other findings obtained herein as well as limitations of the analysis:
1. The medications packaged in blister packs and plastic wraps contained minimal
residuals, in the range of the error of the balance used in the study, after removing the
drugs. Although the sensitivity of the balance did not allow for determining the actual
amount of total residues in these package types, the results infer an upper limit for the
total amount of residues in these packages.
2. All medications packaged in plastic containers contained measurable amount of
residuals (using balance data) after removing the drugs. An exception happened for two
medications, Nicorette lozenges 2 mg andNicorette lozenges 4 mg. Although residues
were visually present in the empty containers of these two medications and were detected
by TGA, the amount of residues detected by the balance was within the range of the
balance error. The balance results in this case were inconclusive.
3. The theoretical "maximum possible weight of residual active compound/total residual
/container" was calculated for each compound and packaging combination (Table 5).
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The calculated amounts may be used to infer an upper limit for the amount of active
pharmaceutical compound in the total residue remaining in the container.
4. Any medication in liquid form must contain the active pharmaceutical ingredient in the
residuals. This is because the active pharmaceutical ingredient is homogenously
distributed in the liquid. Therefore, for any liquid medication, the actual amount of drug
in the residuals can be calculated by knowing 1) the weight of residuals, and 2) the
concentration of the active pharmaceutical ingredient in the medication as stated by the
manufacturer. Despite this fact, the TGA results for physostigmine medication did not
show the presence of the physostigmine compound in the residuals although the
calculated amount of physostigmine in the residue in each ampule was 73 jug. The reason
for the negative TGA results in this case could be explained by the limited capacity of the
cotton piece to absorb all the amount of liquid residue in the empty ampule. This means
that only a fraction of the total residue was loaded on the cotton piece and thus, only a
fraction of the 73 jug of physostigmine was available to be detected by the TGA. It should
be noted that the majority of residue absorbed by the cotton piece was the liquid water
solvent as indicated by the Tmaxwtioss at 103 °C.
5. The nicotine nasal spray 10 mg/ml was the only medication to have positive TGA results
(active pharmaceutical drug was detected in the residuals) as the residues had a Tmaxwt
loss at 217 °C that is representative of nicotine. But the Tmaxwt loss for the negative control
(cotton piece) was shifted in this case which may be attributed to a reaction between the
residual liquid and the cotton piece that caused changes in the properties of the cotton
piece. Nonetheless, the fact that this medication is in liquid from and contains 67.8 fj,g of
nicotine based on the theoretical calculations suggests that the detected TGA peak at 217
°C represent nicotine.
6. For the blister packs and nicotine patches, the calculated upper limit for the amount of
active pharmaceutical compound in the total residue was relatively low and ranged from
0 to 8 jug. These amounts are upper limit and the actual amounts of active compounds in
the residues are more than likely lower because the outer layer of the medication acts as
a coating to prevent the loss of the drug until the medication reaches the target location
in the body and thus, this layer does not probably contain the drug. The balance and
upper limit results support the TGA results which were negative for these pharmaceutical
packages.
7. For the plastic containers encompassing warfarin tablets (1, 5, and 10 mg), detectable
quantities of residues were found in the empty containers. The TGA results for the same
containers showed clear peaks for these residues, however, the peaks did not correspond
to the warfarin and thus, they most likely represent the coating materials. These data
support the aforementioned assumption that the residues in these cases are mainly
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composed of coating materials. Nonetheless, having negative TGA results do not
eliminate the possibility of the presence of the active pharmaceutical compound in the
residues but if it is present it represent a relatively small fraction.
Conclusions 5, 6, and 7 highlight the importance of considering the balance results and
TGA results collectively rather than individually when analyzing the data. "
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Table 32. Summary of the results and limitations of analysis
Medication]
Warfarin
Nicotine
Dose
Warfarin
sodium
tablets. 1 mg
Warfarin
sodium
tablets. 5 mg
Warfarin
sodium
tablets. 10 mg
Warfarin
sodium
tablets. 2 mg
Jantoven
tablets. 1 mg
Jantoven,
tablets. 10 mg
Nicorette
gum. 2 mg
Nicorette
gum. 4 mg
Nicotine
pqlacrilex
gum. 2 nig
Nicotine
E.olacrilex
gum. 4 mg
Package
Type
Plastic
container
Plastic
container
Plastic
container
Blister
pack
Blister
pack
Blister
pack
Blister
pack
Blister
pack
Blister
pack
Blister
pack
TGA Results
TfflsSSJloss
for
Residues
245 °C
239 °C
231 JC
None
None
None
None
None
None
None
.ImsssJioss
for Pure
Compound
313 °C
313°C
313 SQ
313'C
313 ?C
313°C
217JC
217 «£
217JC
217 °C
Results
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Limitation
of Analysis
Qualitative
Qualitative
Qualitative
Qualitative
Qualitative
Qualitative
Qualitative
Qualitative
Qualitative
Qualitative
Total weight of residues
Weight
(mg)
19.8
17.5
19.8
0.3
0.3
0.2
0.3
0.3
0.1
0.1
Limitation of
Analysis
NA
NA
NA
Within range
of error
Within range
of error
Within range
of error
Within range
of error
Within range
of error
Within range
of error
Within range
of error
Calculated Upper
Limit for Amount
of Active
Pharmaceutical
Ingredient (ug)
90
390
890
3
i
8
0.5
0.8
0.2
0,3
Table 6. Summary of the results and limitations of analysis (Cont'
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Medication
Nicotine
PJiyscistig-
mine
salicvlate
Dose
Nicorette
mini lozenge.
2 mg
Nicorette
lozenge. 4
nig
Nicotine
transdermal
patch. 7 mg
Nicotine
transdermal
patch. 14 mg
Nicotine
transdermal
patch. 21 mg
NijDotrol nasal
spray. 10
mg/ml
Nicotine
inhaler. 10
mg'cartridge
Physostig-
mirie
salicvlate.
1 mg ml
Package
Type
Plastic
container
Plastic
container
Plastic
wrap (peel
off)
Plastic
wrap (peel
off)
Plastic
wrap (peel
off)
Glass vial
Plastic
container
Glass
ampule
TGA Results
lass ss loss
for
Residues
306 =C
324 1C
None
None
None
217 1C
NA
103 1C
T-JBSSSJlo'S
for Pure
Compound
217 1C
217 »C
217 °C
217JC
217 °C
217 1C
NA
236 1C
Results
Negative
Negative
Negative
Negative
Negative
Positive
NA
Negative
Limitation
of Analysis
Qualitative
Qualitative
Qualitative
Qualitative
Qualitative
Uncertainty
with the
negative
control
Qualitative
Qualitative
Total weight of residues
Weight
(rag)
0.2
0.0
0.1
0.0
0.0
67.8
NA
73
Limitation of
Analysis
Uncertainty of
measurement a
Uncertainty of
measurement '
Within range
of error
W'ithin range
of error
Within range
of error
NA
NA
NA
Calculated Upper
Limit for Amount
of Active
Pharmaceutical
Ingredient (ug)
NA
NA
1.0
0.0
0.0
67.8
6000 b
73
"Although residues were visually present in the empty container and were detected by TGA, the amount of residues detected by the balance was
within the range of the balance error. The balance results in this case were inconclusive. b This value was not calculated based on experimental
results, rather it was calculated based on information provided by the manufacturer. On the package, it was stated that every cartridge contain 10
mg nicotine and only 4 mg out of the 10 mg will be delivered when used.
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b) The executive summary was also revised significantly to reflect the updated conclusions and
to solve the discrepancies highlighted by the reviewers. Also, information on the study objectives
and the experimental test program were included in the revised executive summary because this
information was missing in the original version. The new additions and the changes to the
executive summary are:
"The primary objective of the current study was to answer the research question "Is there a
difference between empty P-listedpharmaceutical containers that are triple-rinsed and those
that are not triple-rinsed? " The study objective was accomplished via two tasks: 1) calculating
the "maximum possible weight of residual drug/total residual /container "for each compound
and packaging combination to infer an upper limit for the amount of active pharmaceutical
compound in the total residue remaining in the container and 2) evaluating, qualitatively, the
presence of active pharmaceutical ingredient in the residues. The experimental test program
included the use of a sensitive balance to determine the total amount of residues in the empty
pharmaceutical containers and a thermal gravimetric analysis to qualitatively evaluate the
presence of the active pharmaceutical compounds in the residues. The P-listedpharmaceuticals
evaluated in the study were nicotine, Coumadin, andphysostigmine.
The results of the study indicated the following: 1) all the medications in liquid form (Nicotrol
nasal spray 10 mg/ml and Physostigmine salicylate 1 mg/ml) as well as the Nicotine inhaler
(lOmg/ cartridge) showed a difference between triple-rinsed containers and those that are not
triple-rinsed because the residues in the not triple-rinsed ones contained the active
pharmaceutical ingredient; 2) the TGA results for the medications in solid form (i.e., tablet, gum,
and lozenge) and patches showed no difference between triple-rinsed containers and those that
are not triple-rinsed. However, this conclusion is based on a qualitative analysis by TGA that is
limited by the TGA sensitivity. Other analytical techniques (e.g., gas chromatography or liquid
chromatography equipped with mass spectrometer) are needed to verify the TGA results for
these medications and to quantitatively determine the amount of the active pharmaceutical
compounds present in the residues (if any); 3) the medications packaged in blister packs and
plastic wraps contained minimal residuals, in the range of the error of the balance used in the
study, after removing the drugs; 4) medications packaged in plastic containers contained
measurable amount of residuals (using balance data) after removing the drugs (except for
Nicorette lozenges 2 mg andNicorette lozenges 4 mgfor which the balance data were
inconclusive); and 5) a theoretical "maximum possible weight of residual active compound/total
residual /container" was calculated and presented for each compound and packaging
combination. "
c) The reviewers also recommended commenting on the TGA results in the cases where the Tmax
for residues was not equal to that of the positive control. Therefore, the following statement was
added for the five cases where the TGA showed peaks for the residues that were different than
those of the positive control (sections 5.2.1.1, 5.2.2.1, 5.2.3.1, 5.4.5.1, and 5.4.6.1): "This
indicates that the majority of the residues (if not all) represents other chemical compounds that
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are used as a capping layer to encapsulate the dose of active pharmaceutical compound within
the tablet until the time of use. "
d) The reviewers had a comment on why only one physostigmine product was obtained for
analysis in the current study. We only testedphsostigmine salicylate injection (Img/ml) because
this is the only form and dose of physostigmine salicylate available in the market.
It should be noted that before we conducted the study, we asked the vendor to generate a list of
the forms, doses, and package types for each one of the target medications (nicotine, warfarin
and physostigmine). Our request from the vendor was to have a comprehensive list that includes
what is available in the market. Once we obtained the list from the vendor, we sent it to the
Office of Solid Waste and Emergency Response (OSWER) to seek their feedback on this list and
to get their advice on whether more medications need to be added to the list or not. The OSWER
consulted with their experts and their response to us was to proceed with the list as is. In
summary, the list of medication tested herein was approved by the OSWER as a comprehensive
list for the target medications.
Additional Comments
There were some spelling typos (e.g., weigh vs. weight, platic or platsic vs. plastic, Figure 12
when it should be Figure 10, Figure 12 text box is stuck on x-axis) that should be fixed but do
not change the accuracy of the results. However, there were some typographical errors that
mixed up the drug names for a given section. The drugs listed in Section 5.1.3 and 5.1.4 titles do
not match with the drugs listed in the paragraph text. Additionally, Section 5.2.1 notes 1 mg
tablets for warfarin in the title, but the medication line states the drug dose is 10 mg. These errors
make it more difficult to assume that there is a high level of data quality control regarding the
study design and results.
Response:
We do apologize for the mistakes. All the above mentioned mistakes were corrected (please refer
to the revised report). Additionally, a revision of the full report was conducted to check and
correct other mistakes.
Attachment A: Reviewer Comments as Submitted
Is the Methodology Sufficient to Answer the Research Question Posed?
Shannon Bartelt-Hunt:
• The research question posed by ORD is whether there are differences in pharmaceutical
residues between triple rinsed P-listed pharmaceutical containers and untreated
containers. To investigate this question, actual P-listed containers were obtained and
emptied in a way that simulated actual use. Then, the empty containers were either not
treated (not rinsed); single triple rinse with DI water, or a double triple rinse with
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methanol to serve as a negative control. The amount of residue in each container was
determined using a sensitive balance. The difference in weight between the untreated and
treated containers was attributed to any remaining residual. After weighing, the residual
was swabbed with a cotton swab and subjected to TGA to qualitatively identify the active
pharmaceutical ingredient.
For tablet or other non-liquid medications, I don't feel that the methodology used was
sufficient to answer the research question, which was determining the amount of active
pharmaceutical residual in each container. Use of the balance is sufficient to determine
the amount of the residual, but there is likely an uneven distribution of the active
ingredient in the tablet formulation. The report indicates that the coating or outer layer of
the medication likely does not contain the active ingredient. It seems likely that the
residual in these containers is predominantly from the coating or outer layer of the
medication. It is not clear if the residual remaining in these containers contains the active
ingredient or not, as the TGA analysis was inconclusive. No active ingredient was
detected in any of the TGA analyses.
I do think that the methodology of weighing the residual should be sufficient to answer
the research question for the case of liquid medicines. In this case, the residual is known
to contain the active ingredient, since the active ingredient is homogeneously distributed
throughout the medication. Using the manufacturer's information regarding the
percentage of the active ingredient, and the amount of residual measured, the amount of
pharmaceutically-active residual can be determined. Despite this, it is still troubling that
the TGA analysis did not detect any of the active pharmaceutical ingredient in the liquid
medications. This may be due to the sensitivity of the TGA analysis, which was not
directly discussed.
Jon Powell:
My understanding is that the research question is "Is there a difference between triple-
rinsed P-listed pharmaceutical containers and those that are not triple-rinsed?" A
statement of this research question in the executive summary would be helpful and
provide necessary context when results are discussed.
The methodology used was logical: 1. Is there a residue present? 2. Can we qualitatively
say what the residue is based on doing TGA on the pure active ingredient then the
residue?
It seems that some type of statistical treatment on the quantitative results could be
warranted. I have some slight concerns with the sensitivity of the balance used. A
'readability' of 0.1 mg is important in this study because the differences for some of the
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drugs tested were very close to this value - this fact, coupled with a lack of statistical
treatment, makes it difficult to conclude that a residue was present.
Another question of data accuracy relates to some of the reported masses and significant
figures - many of the results were reported to several decimal places (e.g., 0.3000 mg on
page 25), we are left to wonder how data could be reported that way of the readable limit
of the scale was 0.1 mg..
Jennifer Redmond:
The project objective section of the report states that the primary purpose of the study is
to "evaluate if simply removing the drug (specifically nicotine, Coumadin, and
physostigmine) from its container is equivalent to triple rinsing the container. It would be
useful if the report would state why only these three drugs were chosen for study
evaluation (e.g. based on volume usage) and how these drugs relate to other drug types or
classes subject to P-listed waste regulations.
It would be useful if additional detail was presented in the methodological Approach
(4.0) section of the report explaining differences in the package types and justifying why
the chosen analytical methods were deemed optimal for the given study, potential
limitations, and comparison to other considered approaches. The study results suggest
that the sensitive balance was not sensitive enough to detect mass balance changes in all
packages before and after drug removal, and therefore the drug residue and active
pharmaceutical amounts could not be accurately quantified for all drugs, even when
active pharmaceutical drug may have been detected in the thermal gravimetric analysis
(TGA) results for the same sample.
Additionally, 4.2 Experimental Steps notes that foil wrap packaging was not tested for
plastic wrap peel offs, but does not provide justification for this decision. The study
results later suggest that samples with plastic wrap peel contain no residual (within the
range of the error of the balance), but the data appear suspect because a portion of the
packaging was not tested to confirm that it did not contain drug residual.
There were some spelling typos (e.g. weigh vs. weight, platic or platsic vs. plastic, Figure
12 when it should be Figure 10, Figure 12 text box is stuck on x-axis) that should be
fixed but do not change the accuracy of the results. However, there were some
typographical errors that mixed up the drug names for a given section. The drugs listed in
Section 5.1.3 and 5.1.4 titles do not match with the drugs listed in the paragraph text.
Additionally, Section 5.2.1 notes 1 mg tablets for warfarin in the title, but the medication
line states the drug dose is 10 mg. These errors make it more difficult to assume that there
is a high level of data quality control regarding the study design and results.
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Are Data Accurate Enough to Answer the Research Question?
Shannon Bartelt-Hunt:
• I believe that the weight data on residual are accurate enough to determine the amount of
residual in the container. I do not think that the data are accurate enough to determine the
amount of pharmaceutically-active residual. The report doesn't include the minimum
level of detection of the active ingredients by TGA. Because no active ingredients were
detected using TGA, it is not clear whether no active ingredients were present, or if the
TGA was not sensitive enough to detect the small amount of active ingredient in the
sample.
Jon Powell:
• The mass results show a downward trend for most of the different containers (non-blister
packs) as more rinsing was done, which is expected if there is residue present. So this
observation appears to be effective in terms of accuracy to help answer the research
question. Please seem my previous comments, though, regarding the reported masses
from the Mettler-Toledo scale. Those drugs that showed a mass difference in residuals
typically saw differences at the 1 or 10-mg level, so my point about the scale readability
may not matter in those cases since the data are pretty clear.
• The QA/QC data appear to suggest that tolerance limits of different instruments were
met. Please see my comments below regarding the TGA results.
Jennifer Redmond:
• Overall, the study methods proposed were sound and allowed for the collection and
analysis of data regarding:
1) Whether there is residual contained in the discarded packaging via sensitive
balance, and
2) Whether the residual may contain the active pharmaceutical ingredient via TGA
analysis.
• However, there are instances where neither of these methods are sufficient for data
evaluation either due to method constraints (e.g. sensitive balance), a need for additional
QC (e.g. TGA data), or other uncertainties and study limitations that are not thoroughly
discussed in the report at this time. The key concerns associated with the sensitive
balance and TGA data are further detailed below.
• Sensitive Balance Data - The sensitive balance was not sensitive enough to detect mass
balance changes in all packages before and after drug removal, and therefore the drug
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residue and active pharmaceutical amounts could not be accurately quantified for those
drugs, even when active pharmaceutical drug may have been detected in the TGA results
for the same sample. Additionally, samples with plastic wrap peel were deemed to
contain no residual (within the range of the error of the balance), but a portion of the
packaging was not tested to confirm that it did not contain drug residual, and these peel
offs are lower in mass, and thereby more likely to be constrained by study method
limitations given that the smallest readable balance measurement was 0.1 mg. Therefore,
certain packaging types may not be suitable for testing with the balance used during the
testing. Perhaps a more sensitive balance could at least be secondarily used in cases
where either 1) TGA results reveal active pharmaceutical ingredients while the balance
does not indicate that there is residuals, or 2) the packaging is constructed of lower
weight material (e.g. peel offs).
• TGA Data - A full product listing in the main body of the report and an additional QC of
the final number of medications and a summary of TGA failures is needed. In Section
6.3, the authors should not which 4 drug products failed the TGA test to allow for optimal
transparency. The reader has to sift through the whole report to find which products fail
in the current version of the report. Furthermore, this section notes that 17 medications
were tested, but the QAPP and Section 7 Conclusions notes that a different number were
tested (18 in conclusions, and 19 in the QAPP).
Do Data Collected Support the Conclusions of the Research?
Shannon Bartelt-Hunt:
• Yes, the data collected in the study do support the conclusion of the report. The report
concludes that all medications in plastic containers contained residuals, but that the
amount of active pharmaceutical ingredients in the residual could not be determined. I
agree with the reports conclusions regarding the liquid drugs, as the active ingredient
should be homogeneously distributed throughout the medication.
• Despite this, the results do not sufficiently answer the research question, which was to
determine the difference in the amount of pharmaceutically-active ingredient in the rinsed
and non-rinsed containers. This could not be answered, because the amount of
pharmaceutically-active ingredient (or even the presence of the active ingredient) could
not be determined using the methods employed.
Jon Powell:
• As stated in my comment above, and in my comments in the conclusion section of the
PDF, the paper would benefit from having some more direct discussion about the results
and observations and what the data means.
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• One issue that was not discussed or described further (in the results or conclusion section)
was the discrepancy in the TGA results - by my count (Appendix C), one of the nicotine
samples that was detected in residuals was found at a different temperature than the
positive nicotine control, 3 of the 3 warfarin residuals detected were all found at
temperatures different than the positive control, and the one physostigmine sample
detected via TGA was different than the pure compound. As a reader, we are left to
figure out what this all means. Looking at the warfarin data, it appears that as the
concentration goes up (from 1 mg to 10 mg), the temperature that the residue peak shows
up goes down - this might suggest that purity is inversely related with the mass loss peak.
This trend seems to be reversed, however, when we consider the pure compound had a
much higher Tmax. In any case, commenting on the TGA results in the cases where the
Tmax was not equal would be helpful and somehow tying that into whether or not the
authors think this changes or diminishes the observations seen in the mass measurement
would be a good addition to the conclusion.
• The mass data and TGA data for the blister pack appear to provide a conclusion that we
do not have the issue with residues in these types of containers, which is a really
important result that should be elucidated a bit more in the executive summary and
conclusion.
• The nicotine patch data also seem to suggest that residuals are not an issue.
• The confounding results with the liquid appear to suggest that it would be difficult to
make the case that residuals are minor.
Jennifer Redmond:
• The executive summary of the report notes that the qualitative TGA results show that
there is "no observable difference [in the presence of active ingredients] between
containers that were triple rinsed and containers that were not" except for nicotine nasal
spray. However, the conclusions (Section 7) note that all medications in plastic containers
contain measurable residual levels, but it was not possible to determine the amount of
active pharmaceutical ingredients using TGA. Furthermore, the conclusions section does
not discuss the nasal spray results at all. A step-wise summary of the report findings is
necessary to come to a final conclusion on whether or not there is a difference between
triple rinsing for some pharmaceutical-package combinations.
• The individual package type or drug results are not summarized in a consistent and
thorough manner. Adding a summary table would be a very useful way to review the
drug, dose, product, and package types evaluated along with at least qualitative
information on whether the TGA results were positive (indicating active drug residual
was present in discarded packaging), along with the measured residual weight (binned
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into weight ranges, or with the average value), and the theoretical active pharmaceutical
ingredient weight (binned into volume ranges [e.g. within range of error, low, etc.] or
with the calculated value).
The conclusions should also elaborate on the sensitivity of the balance used to measure
the drug residual, along with other key study concerns and uncertainties. To identify
which results contain potential measurement limitations or concerns, it is necessary to
read through the entire report at this point. The summary table proposed above could
form the basis of a separate discussion regarding results uncertainty that is currently
lacking. An additional column noting if there are method sensitivity issues or other
concerns with the specific result would be prudent. Pulling these individual concerns out
will help highlight study limitations and increase transparency in the overall results,
thereby leading to better confidence in the overall study results. Results with noted
concerns by the authors include Section 5.4.5.2 (method sensitivity issue, limited
medication quantity from vendor), Section 5.4.6.2 (method sensitivity issue), Section
5.4.10.1 (inconclusive TGA results), and Section 5.4.10.2 (high standard deviation).
Additionally, only one physostigmine product was obtained for analysis as well -
additional discussion in the conclusions or elsewhere should focus on why more of these
drug products could not be purchased and how this could affect the overall robustness of
the data for one of the three study drugs.
In summary, the conclusions section of the report could be enhanced greatly by 1)
providing a synthesized review of the study findings that includes a summary table of key
findings for all drug-product combinations, 2) highlighting study uncertainties and
limitations, 3) noting ways to reduce study uncertainty or limitations if future resources
become available, and 4) making a final determination based on the final results in light
of study uncertainties and limitations.
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