'ICF
Market Characterization of the U.S.
Metered Dose Inhaler Industry
Prepared for:
Stratospheric Protection Division
Office of Air and Radiation
U.S. Environmental Protection Agency
Washington, D.C. 20460
Prepared by:
ICF
2550 S Clark St.
Suite 1200
Arlington, VA 22202
February 2021
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Table of Contents
1. Summary 1
2. Introduction 1
3. Market Characterization 2
3.1. Overview of MDI Products 2
3.2. Major Manufacturers 2
4. Subsector Background and HFC Use 3
4.1. Propellants in Medical Inhalers 3
4.2. Current and Projected Sales of HFC MDIs 6
4.3. Imports and Exports of MDI Products in the United States 9
5. References 11
Appendix A: Analysis of the DPI Market 14
DPI Product Sales Analysis 14
Medical Inhaler User Population 16
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1. Summary
Metered dose inhalers (MDIs) are handheld pressurized inhalation systems that deliver small,
precisely measured therapeutic doses of medication directly to the airways of a patient. The
pharmaceutical industry historically used chlorofluorocarbons (CFCs), specifically CFC-11,
CFC-12, and CFC-114, as a propellant. The pharmaceutical industry began introducing
hydrofluorocarbon (HFC) propellants for MDIs as replacements for CFCs in the mid-1990s,
specifically HFC-134a in 1996 followed by HFC-227ea in 2006 (also known as
hydrofluoroalkanes (HFA)).
By 2014, the CFC MDI market was replaced with HFC MDIs and not-in-kind (NIK) medical
inhalers. In 2020, approximately 458 metric tons (MT) of HFC-134a and 78 MT of HFC-227ea
propellant were contained in MDIs sold in the United States. The use of HFC MDIs in the United
States is expected to continue as they may be more appropriate for certain patients than NIK
medical inhalers, such as when the patient requires a reliever medication for exacerbations of
asthma, patient preference, or other requirements (e.g., inhalation strength) (GSK 2019,
MCTOC 2018, IPAC 1999). In 2040, approximately 514 MT of HFC-134a and 87 MT of HFC-
227ea propellant is estimated to be sold in MDIs.
2. Introduction
MDIs are handheld pressurized inhalation systems that deliver small, precisely measured
therapeutic doses of medication directly to the airways of a patient.1 MDIs provide reliable and
effective therapy for asthma and chronic obstructive pulmonary disease (COPD) (MCTOC
2018). According to the Centers for Disease Control and Prevention (CDC), in 2018 in the
United States, 19.2 million adults and 5.5 million children had asthma while 12.8 million adults
had some form of COPD (CDC 2018a, CDC 2018b).
The pharmaceutical industry historically used CFCs, specifically CFC-11, CFC-12, and CFC-
114, as a propellant in MDIs. The pharmaceutical industry began introducing HFC propellants
for MDIs as replacements for CFCs in the mid-1990s, specifically HFC-134a in 1996 followed by
HFC-227ea in 2006 (also known as HFA2). Medication for asthma and COPD also shifted in
part to not-in-kind (NIK) products in the form of dry powder inhalers (DPIs). The remainder of
this report characterizes HFC use by the pharmaceutical industry for MDIs in the United States,
including key market players and historical and current sales of HFC MDIs and other medical
inhalers.
1 MDIs can be used to administer medicine orally or nasally. Only MDIs designed for oral use are
considered in the scope of this market characterization.
2 In the pharmaceutical industry, HFC is also referred to as HFA and HFC-134a is occasionally referred to
as norflurane.
1
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3. Market Characterization
This section provides an overview of MDI products and applications as well as the current
market and key manufacturers.
3.1. Overview of MDI Products
MDI devices include a valve and actuator designed to facilitate a consistent delivery of a specific
dose of a drug to the patient in particles of a specific size distribution delivered via a propellant.
MDIs require gas propellants with vapor pressures that allow them to be liquefied at ambient
temperatures at pressures between 40 and 70 psi inside the canister. Propellants used in MDIs
for inhaled medications must be certified by the U.S. Food and Drug Administration (FDA) as
current Good Manufacturing Practice (cGMP) inhalation grade with high purity levels.
Propellants for MDIs must meet cGMP requirements for the methods, facilities, and controls
used in manufacturing, processing, and packaging to ensure the product is safe for use and that
it has the ingredients and strength it claims to have (FDA
2020a).
MDI Products Available in 2020
The first HFC MDI approved by the FDA was for albuterol sulfate
utilizing HFC-134a propellant in 1996. As of 2020, the number of
FDA-approved MDI products has expanded considerably (FDA
2020b). Current MDI products and their FDA approval dates are
shown in Table 1. As of 2018, salbutamol (also known as
albuterol) sulfate MDIs still represent approximately 60 percent
of the overall MDI market in the United States (ICF 2020).
Inhalation grade HFC-227ea and HFC-134a are both used in
MDIs as a propellant.
Albuterol Sulfate
Beclomethasone Dipropionate
Budesonide
Ciclesonide
Epinephrine
Fluticasone Propionate
Formoterol Fu ma rate
Formoterol Fumarate Dihydrate
Glycopyrrolate
Ipratropium Bromide
Levalbuterol Tartrate
Mometasone Furoate
Salmeterol Xinafoate
3.2. Major Manufacturers
The United States manufactures MDIs and imports a significant proportion of MDI products from
the European Union (EU) and Asia. Manufacturers of HFC MDIs available in the United States
are listed in Table 1 by product name, active ingredient, propellant type, and date of FDA
approval.3
Table 1. Manufacturers of Currently Available HFC MDIs for use in the United States
Manufacturer3
MDI Product
Name3
Active Ingredient3
FDA Approval
Dateb
HFC-227ea
AstraZeneca
Symbicort®
Budesonide; Formoterol Fumarate
Dihydrate
07/21/2006
Merck Sharp and
Dohme
Asmanex®HFA
Mometasone Furoate
04/25/2014
3 Several manufacturers of MDIs also produce DPIs under the same product line. See Appendix A for a
list of DPI manufacturers.
2
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Manufacturer3
MDI Product
Name3
Active Ingredient3
FDA Approval
Dateb
Merck Sharp and
Dohme
Dulera®
Mometasone Furoate; Formoterol
Fumarate Dihydrate
06/22/2010
HFC-134a
Sunovion
Pharmaceuticals Inc
Xopenex®
Levalbuterol Tartrate
03/11/2005
AstraZeneca
Bevespi
Aerosphere®
Formoterol Fumarate; Glycopyrrolate
04/25/2016
Breztri
Aerosphere®
Budesonide; Formoterol Fumarate;
Glycopyrrolate
07/23/2020
Boehringer Ingelheim
Atrovent®
Ipratropium Bromide
11/17/2004
Covis Pharma B.V.
Alvesco®
Ciclesonide
01/10/2008
GlaxoSmithKline
Advair®
Fluticasone Propionate; Salmeterol
Xinafoate
06/08/2006
Flovent®
Fluticasone Propionate
05/14/2004
Ventolin®
Albuterol Sulfate
04/19/2001
Kindeva Drug
Delivery LP
Proventil®
Albuterol Sulfate
08/15/1996
Teva
ProAir®
Albuterol Sulfate
10/29/2004
Norton Waterford
LTD
QVAR®
Redihaler™
Beclomethasone Dipropionate
08/03/2017
Armstrong
Pharmaceuticals Inc.
Primatene Mist
Epinephrine
11/07/2018
Cipla LTD
Generic Albuterol
Sulfate Inhaler
Albuterol Sulfate
04/08/2020
Lupin Inc
Generic Albuterol
Sulfate Inhaler
Albuterol Sulfate
08/24/2020
Perrigo
Pharmaceuticals Co
Generic Albuterol
Sulfate Inhaler
Albuterol Sulfate
02/24/2020
Note: The companies in this report may not represent an exhaustive list of all companies manufacturing within the
United States.
a FDA (2020c).
b FDA (2020b).
4. Subsector Background and HFC Use
4.1. Propellants in Medical Inhalers
Historically the pharmaceutical industry relied on CFC propellants, including CFC-11, CFC-12,
and CFC-114, which have significant ozone depletion potential (ODP) and have been phased
out under the Clean Air Act and Montreal Protocol on Substances that Deplete the Ozone
Layer. MDI manufacturers began transitioning to non-ozone-depleting HFC propellants in the
mid-1990s with the introduction of HFC-134a in 1996 followed by HFC-227ea in 2006 (ICF
International 2016, EPA 2020). HFCs were the preferred propellants as MDIs transitioned from
CFCs because HFC propellants allowed for the same continuation of MDI therapy without the
ozone depleting potential. By keeping the function of the therapy the same, there was no
change to the way a patient interacted with the MDI (IPAC 1999).
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Table 2 summarizes the environmental characteristics, including ODP and global warming
potential (GWP), for current MDI propellants.
Table 2. Environmental Characteristics of Propellants in MDIs
Propellant
ODPa
GWP
HFC-134a
0
1,430
HFC-227ea
0
3,220
Note: GWPs are aligned with the exchange values used in the AIM Act.
a Ozone Secretariat (1987).
HFC-227ea and HFC-134a have demonstrated similar properties to CFC propellants. HFC-
227ea has a lower vapor pressure, so it has primarily been used in HFC-134a formulations to
lower the pressure and provide improved drug substance solubility in certain formulations
(Mexichem Fluor 2015). Industry sources indicate that advances in valve technology have made
the use of HFC-227ea not technically necessary in HFC-134a formulations to reduce the
pressure (Noakes n.d.).
The pharmaceutical industry also made significant shifts toward NIK inhalers such as DPIs and,
more recently, soft mist inhalers (SMIs).4'5 These NIK inhalers have no ODP and no GWP as
they do not contain any propellant. DPIs deliver powdered medication that is propelled by the
inhalation of the patient (MCTOC 2018).
In 2020, approximately 64% of inhaler sales were HFC-134a MDIs and HFC-227ea MDIs
accounted for approximately 11%.6 Table 3, Figure 1, and Figure 2 show the historic unit sales
and HFC propellant sold in medical inhalers in the United States from 2015 through 2020.
Table 3. Historic HFC Propellant Sold in MDIs in the United States (2015-2020)
2015
2016
2017
2018
2019
2020
Amount of HFC Sold in MDIs i
(MT)
HFC-134a
669
597
524
450
452
458
HFC-227ea
119
105
91
76
77
78
Total
788
702
615
526
529
536
Amount of HFC Sold in MDIs i
(MMTCO2 Eq.]
I
HFC-134a
1.02
0.92
0.82
0.72
0.72
0.73
HFC-227ea
0.38
0.33
0.29
0.24
0.24
0.25
Total
1.40
1.25
1.11
0.96
0.96
0.98
Note: Totals may not sum due to independent rounding.
Source: EPA (2020).
4 The only manufacturer of FDA-approved SMIs is Boehringer Ingelheim (FDA 2020c).
5 The lengthy development and regulatory timescales, the rarity of new technical advancements, as well
as the higher costs for new SMIs compared to MDIs and DPIs make SMIs less relevant to the discussion
of the current and near future pharmaceutical market and will therefore not be discussed further in this
market characterization. (MCTOC 2018).
6 The market of NIK inhalers is assumed to be the share necessary to meet the estimated forecasted
medical inhaler demand and is calculated as the total inhaler market minus the HFC MDI market. A
separate analysis was conducted to further investigate the size of the NIK inhaler market (see Appendix
A).
4
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Figure 1. Historic Sales of Medical Inhalers in the United States (2015-2020) ('000 Units)
120,000
100,000
c
Z)
o
o
o
80,000
v 60,000
40.000
20.000
0
2015
2016 2017 2018 2019
¦ HFC-134a »HFC-227ea h Not-In-Kind
2020
Sources: EPA (2020), MCTOC (2018), Appendix A
Note: The 2015-2016 NIK estimates were derived from a DPI market share of 30%
(MCTOC 2018). NIK estimates for 2017-2019 were determined in the DPI sales analysis
detailed in Appendix A. The 2020 NIK estimate was determined by applying the growth
rate of MDIs between 2019 and 2020 in EPA (2020).
Figure 2. HFC Propellant for MDIs Sold in the United States (2015-2020) (Million Metric Tons CO2
Equivalent (MMT C02 Eq.))
Source: EPA (2020).
EPA is not aware of any available propellants on the market that are currently alternatives to
HFCs as propellants in MDIs, due to concerns with toxicity and flammability. The two most
5
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promising potential replacements for HFC-134a and HFC-227ea are HFO-1234ze(E) and HFC-
152a. Both have most of the requisite physical properties to function as a propellant in MDIs
with significantly lower GWPs than the current HFCs in use; however, neither propellant has
significant use in pharmaceuticals and will require extensive clinical research before they could
replace the current HFCs (Pritchard 2020).
HFO-1234ze(E) is mainly used in refrigeration, technical aerosols, and some novelty aerosols
(e.g., party string), and long-term human safety data would need to be collected before it could
be considered for use in MDIs (Pritchard 2020). HFC-152a was considered as a possible
replacement for CFCs in MDIs along with HFC-134a and HFC-227ea; however, its higher
density and flammability would require numerous changes to manufacturing processes and the
MDI design to ensure safe and effective use (Pritchard 2020).
Koura, formerly Mexichem Fluor,7 considers HFC-152a to be a likely replacement for other HFC
propellants, because manufacturing sites can be adapted for the safe-handling of flammable
materials (Koura 2021). Propellant-only clinical trials for HFC-152a have been approved by the
FDA and it is anticipated that program data from these trials will support the completion of a
Drug Master File (DMF) for the commercial use of medical-grade HFC-152a with the goal of
introducing commercially available HFC-152a MDIs (Corr 2020).
NIK inhalers are not expected to completely replace HFC MDIs, as NIK inhalers have a different
mechanism for the delivery of medication. MDI inhalers may be more appropriate for certain
patients, such as when the patient requires a reliever medication for exacerbations of asthma,
patient preference, or other requirements (e.g., patient inhalation strength) (GSK2019, MCTOC
2018, IPAC 1999).
4.2. Current and Projected Sales of HFC MDIs
EPA's Vintaging Model (EPA 2020) estimates that 56 million HFC MDIs (48 million HFC-134a
MDIs and 8 million HFC-227ea MDIs) were sold in the United States in 2020, which accounts
for both MDI products manufactured in the United States and MDIs imported from the EU and
Asia. HFC MDI estimates were based on ICF (2020), an MDI sales analysis conducted as an
update to EPA's Vintaging Model. The estimates in this analysis were derived from annual U.S.
MDI sales in dollars, the estimated average manufacturers price (AMP) of MDIs, and the charge
size of MDIs, differentiating between HFC-134a and HFC-227ea MDIs (ICF 2020).
7 Koura is the largest supplier of medical grade HFC propellants globally and in the United States. Koura's
global market share of HFC propellants for MDIs is 75%.
6
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Annual U.S. MDI sales were reported in annual reports from MDI manufacturing companies8
(see Table 1). If sales data were unavailable for an MDI product,9 Medicaid's State Drug
Utilization Data (SDUD) of MDI product (in grams) reimbursed per year were used as a proxy10
(ICF 2020). The AMP per unit was gathered from the National Average Drug Acquisition Costs
(NADAC) metric that is reported annually by Medicaid and converted to AMP, utilizing the data
from Levinson (2005) to account for difference between wholesale and retail cost as well as the
pricing of generic versus proprietary inhalers.
The average charge size (i.e., propellant quantity) per unit was assumed to be equal to the net-
fill weight of each cannister, because the active ingredients in MDI products typically make up
less than 0.01% by weight of the total product.11 The resulting average charge size for HFC-
134a inhalers is 10.5 grams and 9.6 grams for HFC-227ea inhalers based on the volume sold
per MDI unit (ICF 2020, EPA 2020). Using the year of peak MDI sales (i.e., 2011 and 2014 for
HFC-134a and HFC-227ea, respectively), the resulting amount of HFC propellant in MDIs sold
in 2020 is 536 metric tons (MT) (i.e., 458 MT of HFC-134a and 78 MT of HFC-227ea) (EPA
2020). HFCs in MDIs in the United States accounts for 0.5 percent of total estimated HFC use in
2020 (EPA 2020).
Between 2015 and 2018, estimated HFC MDI sales decreased by 31%, from 80 million units to
55 million units as shown in Figure 1.12 NIK inhalers are not expected to completely replace
HFC MDIs; therefore, EPA (2020) assumes that the HFC MDI market retains its size post-2018,
with a growth rate of approximately 1% per year through 2030 and 0.8% per year from 2030
through 2040 to align with expected population growth based on projections from the U.S.
Census (U.S. Census 2017, EPA 2020). In 2020, HFC propellant sold in MDIs is estimated to
grow to approximately 601 MT in 2040 (i.e., 514 MT of HFC-134a and 87 MT of HFC-227ea).
EPA (2020) does not currently model transitions from HFC-134a and HFC-227ea to HFC-152a
in MDIs; however, the replacement of current HFC propellants by HFC-152a prior to 2040 is
possible (Koura 2021). The projected amount of HFC propellant in MDIs sold from 2020 through
2040 can be found in Table 4, Figure 3, and Figure 4.
8 In instances where a manufacturer did not delineate between MDI and DPI sales in the same product
line, products were assumed to be MDIs.
9 Alvesco®, Aerospan® (not included in Table 1 as it was discontinued in 2018), and Atrovent® were the
only MDIs in the sales analysis for which Medicaid data was utilized.
10 Information on the proportion of the U.S. MDI market that is met with Medicaid reimbursement products
was not readily available, thus sales from this proxy data is likely underestimated. (ICF 2020)
11 This value was derived from a review of MDI product labels attained from the National Institutes of
Health U.S. National Library of Medicine DailyMed database (NIH 2021).
12 Although the ICF (2020) MDI sales analysis estimates a decrease in HFC MDI sales from 2015 to
2018, it is possible sales remained constant or increased during that period. Estimated HFC MDI sales
from 2015 to 2018 could be underestimated as a result of assumptions on the market penetration of
generics and AMP.
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Table 4. Projected HFC Propellant Sold in MDIs in the United States (2020-2040)
2020
2025
2030
2035
2040
Amount of HFC Sold in MDIs (MT)
HFC-134a
458
474
489
502
514
HFC-227ea
78
80
83
85
87
Total
536
554
572
587
601
Amount of HFC Sold in MDIs (MMT C02 Eq.)
HFC-134a
0.73
0.75
0.78
0.81
0.84
HFC-227ea
0.25
0.25
0.26
0.27
0.28
Total
0.98
1.0
1.04
1.08
1.12
Note: Totals may not sum due to independent rounding.
Figure 3. Projected HFC Propellant in MDIs Sold in the United States (2020-2040) (MT)
700
600
Q 500
2 400
O
if)
J 300
CD
CL
o
Ql 200
O
Li.
x 100
2020
2025 2030
¦ HFC-227ea «HFC-134a
2035
2040
Source: EPA (2020).
Figure 4. Projected HFC Propellant in MDIs Sold in the United States (2020-2040) (MMT CO2 Eq.)
Source: EPA (2020).
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For comparison, approximately 123 ± 12 million HFC MDIs (i.e., 97 million HFC-134a MDIs and
26 million HFC-227ea MDIs, corresponding to 1,018 MT ± 89 MT of HFC-134a and 250 MT ±
38 MT of HFC-227ea, respectively) were manufactured in and imported into the United States in
2019 as derived from Koura bulk gas and imported MDI estimates (Koura 2021).13 The values
estimated by Koura take into consideration several assumptions that may be overestimated
(e.g., amount of MDI product imported into the United States by manufacturers) (Koura 2021).
In addition, the annual estimates do not consider users and inhalers directly, but rather models
used for manufacturing, which may not necessarily reflect the consumer inhaler market that
year (e.g., does not account for inventory of MDI products) (Koura 2021). Given the various
assumptions and uncertainties associated with EPA (2020) and the Koura model, it is likely that
actual annual HFC MDI use in the United States is between 56 and 123 million MDIs.
4.3. Imports and Exports of MDI Products in the United States
As noted above in Section 3.2, the manufacture of MDIs does occur in the United States, but
the United States also imports HFC MDIs from the EU and other trading partners. It is estimated
that the amount of MDI products manufactured in the United States is approximately equal to
the amount of MDI products imported to the United States (Koura 2021).
Table 5 summarizes the countries exporting HFC MDIs into the United States. Exporting
countries were identified from available import/export information databases14 and cross-
referenced with the Drug Establishments Current Registration Site (DCERS)15 to determine if
the product was manufactured in the exporting country (SeAir 2021, Zauba 2021, FDA 2020d).
MDIs imported into the United States come from two regions, the EU (Belgium, France,
Germany, Spain, Sweden, and the Netherlands) and Asia (China, India, Japan, and Singapore)
(SeAir 2021, Zauba 2021). The imported MDIs were likely manufactured in China, France,
Germany, India, Singapore, and Sweden (FDA 2020d).
Table 5
>. Origin of HFC MDIs Imported into the United
States
Manufacturer3
MDI Product Name3
Exporting
Countries'5
Manufacturing Facility
Found on DECRS List?
HFC-227eac
AstraZeneca
Symbicort®
Belgium, Germany,
Sweden
Belgium: No
Germany: No
Sweden: Yes
Merck Sharp and Dohme
Asmanex®HFA
Singapore
Yes
13 Koura (2021) estimates are in metric tonnes and have been converted to MDIs assuming the same
charge as that for the MDI sales analysis. It was assumed that estimates from Koura for manufacturing
uses were equal to the MDI sales and use in that same year.
14 Exporting country represents the country of the final port before entry into the United States and does
not necessarily represent the country where the product was manufactured.
15 The Drug Establishments Current Registration Site (DCERS) is a database of current information
submitted by drug firms to register establishments (facilities) which "manufacture, prepare, propagate,
compound or process drugs that are commercially distributed in the U.S. or offered for import to the U.S."
FDA (2020d).
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Manufacturer3
MDI Product Name3
Exporting
Countries'5
Manufacturing Facility
Found on DECRS List?
Merck Sharp and Dohme
Dulera®
No Import Records Found
HFC-134a
Sunovion
Pharmaceuticals Inc.
Xopenex®
India
Yes
AstraZeneca
Bevespi Aerosphere®
Belgium
No
AstraZeneca
Breztri Aerosphere®
No Import Records Found
Boehringer Ingelheim
Atrovent®
The Netherlands
No
Covis Pharma B.V.
Alvesco®
No Import Records Found
GlaxoSmithKline
Advair®
China, Japan
China: Yes
Japan: No
GlaxoSmithKline
Flovent®
France
Yes
GlaxoSmithKline
Ventolin®
Japan, Spain
Japan: No
Spain: No
Kindeva Drug Delivery LP
Proventil®
No Import Records Found
Teva
ProAir®
Belgium, Germany
Belgium: No
Germany: Yes
Norton Waterford LTD
QVAR® Redihaler™
Records Found but not Viewable
Armstrong
Pharmaceuticals Inc.
Primatene Mist
No Import Records Found
Cipla LTD
Generic Albuterol
Sulfate Inhaler
India
Yes
Lupin Inc
Generic Albuterol
Sulfate Inhaler
No Import Records Found
Perrigo Pharmaceuticals
Co
Generic Albuterol
Sulfate Inhaler
No Import Records Found
Note: Due to limited availability of import/export information, the data provided may not be a total representation of
all importers of HFC MDIs into the United States.
a FDA (2020c).
b Based on U.S. import information found from Seair EXIM Solutions (Seair2021) and Zauba Technologies Pvt Ltd
(Zauba 2021)
c The vast majority of HFC-227ea MDIs are imported into the United States mostly from the EU and most recently
from India (Koura 2021)
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5. References
Centers for Disease Control and Prevention (CDC). 2014a. Use of long-term control medication
among persons with active asthma. Available online at:
https://www.cdc.gov/asthma/asthma stats/lonqterm medication.htm.
Centers for Disease Control and Prevention (CDC). 2014b. Frequent use of quick-relief
medication among persons with active asthma. Available online at:
https://www.cdc.gov/asthma/asthma stats/overuse.htm.
Centers for Disease Control and Prevention (CDC). 2018a. Summary Health Statistics Table for
U.S. Adults: National Health Interview Survey, 2018, tables A-2b, A-2c. Available online at:
https://ftp.cdc.gov/pub/Health Statistics/NCHS/NHIS/SHS/2018 SHS Table A-2.pdf
Centers for Disease Control and Prevention (CDC). 2018b. Summary Health Statistics Table for
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Centers for Disease Control and Prevention (CDC). 2020. Asthma Action Plans. Available
online: https://www.cdc.gov/asthma/actionplan.html.
Corr, Stuart. 2020 HFA-15a as a Sustainable pMDI Propellant. Koura. Available online at:
https://www.zephex.com/wp-content/uploads/2020/07/Corr-202Q-1.pdf.
De Marco et al. 2013 The coexistence of asthma and chronic obstructive pulmonary disease
9COPD): Prevalence and risk factors in young, middle-aged, and elderly people from the
general population. PLoS One. Available online at:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3651288/#!po=32.3529.
Department of Health & Human Services (DHHS) Centers for Medicare & Medicaid Services.
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Manufacturers. Available online at: https://www.medicaid.gov/medicaid-chip-program-
inform ation/by-topics/prescription-drugs/downloads/rx-releases/mfr-releases/mfr-rel-073.pdf.
Department of Health & Human Services (DHSS) Centers for Medicare & Medicaid Services.
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Manufacturers. Available online at: https://www.medicaid.gov/medicaid-chip-program-
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Giraud and Allaert. 2009. Improved asthma control with breath-actuated pressurized Metered
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https://www.researchgate.net/profile/Francois Allaert/publication/40448031 Improved asthma
control with breath-
actuated pressurized Metered Dose Inhaler pMDI The SYSTER survev/links/5ad58ee3a6fd
cc293580ad2c/lmproved-asthma-control-with-breath-actuated-pressurized-Metered-Dose-
lnhaler-pMDI-The-SYSTER-survev.pdf.
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GlaxoSmithKline. 2019, GSK Public policy positions: respiratory products and global warming.
Available online at: https://www.gsk.com/media/2962/respiratory-products-and-global-warming-
policv.pdf.
ICF International. 2016. Preliminary Assessment of Global HFC Consumption in Aerosols.
Prepared by ICF International for the U.S. Environmental Protection Agency (EPA). September
2016.
ICF. 2020. Observed Trends for HFC-227ea Emissions in the United States and HFC-227ea
and HFC-134a Emissions from the MDI Aerosols End-Use in EPA's Vintaging Model. Prepared
by ICF for the U.S. Environmental Protection Agency (EPA). June 24, 2020.
International Pharmaceutical Aerosol Consortium (IPAC). Ensuring Patient Care: The Role of
the HFC MDI 2nd edition. 1999. Available online at: https://f1856665-a297-420b-a480-
7c0957181470.filesusr.com/ugd/495d79 cecf8e047cd84c67999dec8cc7f03ef1.pdf.
Koura. 2021. Personal communication between Tim Noakes (Koura), Richard Greenhough
(Koura), Maureen Hardwick (International Pharmaceutical Aerosol Consortium (IPAC)), Mark
Wagner (ICF), and Paula Garcia-Holley (ICF). February 2, 2021.
Levinson, D.R. 2005. Medicaid Drug Price Comparisons: Average Manufacturer Price to
Published Prices. June 2005. Available online at: https://oig.hhs.gov/oei/reports/oei-05-05-
00240.pdf.
Levy et. al. 2013. Asthma patients inability to use a pressurized metered-dose inhaler (pMDI)
correctly correlates with poor asthma control as defined by the Global Initiative for Asthma
(GINA) strategy: a retrospective analysis. US National Library of Medicine. National Institutes of
Health. Available online at:
https://www.ncbi. nlm.nih.gov/pmc/articles/PMC6442852/#!po=6.25000.
Medicaid. 2020a. State Drug Utilization Data. Available online at:
https://www.medicaid.gov/medicaid/prescription-drugs/state-drug-utilization-data/index.html.
Medicaid 2020b.November 2019 medicaid & CHIP Enrollment Data Highlights. Available online
at: https://www.medicaid.gov/medicaid/program-information/medicaid-and-chip-enrollment-
data/report-highlights/index.html.
Medical and Chemicals Technical Options Committee (MCTOC). Report of the Medical and
Chemical Technical Options Committee 2018 Assessment Report. 2018. Nairobi, Kenya: United
Nations Environment Programme (UNEP). Available online at:
https://ozone.unep.org/sites/default/files/2019-04/MCTQC-Assessment-Report-2018.pdf.
Mexichem Fluor. 2015. Response to Charge Letter: Request for Data on HFC Consumption in
the Global Aerosols Sector sent on December 1, 2015. Correspondence with Tim Noakes.
December 11, 2015.
National Institutes of Health (NIH). 2021. U.S. National Library of Medicine DailyMed Database.
Available online at: https://dailymed.nlm.nih.gov/dailymed/index.cfm. Accessed January 7, 2021.
Noakes, Tim. n.d. HFA Propellants: Manufacture, storage, and use. Avoiding problems.
Mexichem Fluor. Available online at: http://www.unido.ru/upload/files/d/2dav mexichem.pdf.
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Ozone Secretariat. 1987. The Montreal Protocol on Substances that Deplete the Ozone Layer.
United National Environment Programme (UNEP). Available Online at:
https://ozone.unep.org/treaties/montreal-protocol.
Pritchard, John. 2020. The Climate is Changing for Metered-Dose Inhalers and Action is
Needed. US National Library of Medicine. National Institutes of Health. Available online at:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410333/.
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trade-data/usa-import-data.aspx. Accessed January 8, 2021.
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file_v5.1_10.08.20.
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(CGMP) Regulations. Available online at: https://www.fda.gov/drugs/pharmaceutical-guality-
resources/current-good-manufacturing-practice-cgmp-regulations.
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Available online at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm.
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Therapeutic Equivalence Evaluations. Available online at:
https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm.
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https://www.zauba.com/USA-imports-exports/lmports. Accessed January 8, 2021.
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Appendix A: Analysis of the DPI Market
An analysis of the DPI market was performed to inform the total medical inhaler market size and
market penetration of NIK inhalers. The analysis is based on sales data for DPI products from
annual manufacturer reports and the SDUD of Medicaid. The estimates derived using this
approach were then compared with the total potential inhaler market estimated for the U.S.
population with asthma and COPD.
DPI Product Sales Analysis
A total of 25 proprietary DPI products were identified in the United States (see Table 6). In 2019,
only 15 of the 25 proprietary DPI products were available in the market as the remainder were
discontinued or were not reported due to low sales volumes.
Table 6. Manufacturers of DPIs
Manufacturer3
DPI Product
Name3
Active Ingredient3
FDA Approval
Date3
AstraZeneca
Pulmicort®
Flexhaler®
Budesonide
7/12/2006
Tudorza
Pressair®
Aclidinium Bromide
7/23/2012
Duaklir Pressair®
Aclidinium Bromide; Formoterol
Fu ma rate
3/29/2019
Boehringer
Ingelheim
Spiriva®
Tiotropium Bromide
1/30/2004
GlaxoSmithKline
Breo Ellipta®
Fluticasone Furoate; Vilanterol
Trifenatate
5/10/2013b
4/30/2015C
Flovent Diskus®
Fluticasone Propionate
9/29/2000
Advair
Diskus®1
Fluticasone Propionate; Salmeterol
Xinafoate
8/24/2000
Incruse® Ellipta®
Umeclidinium Bromide
4/30/2014
Relenza®
Zanamivir
7/26/1999
Arnuity® Ellipta®
Fluticasone Furoate
8/20/2014d
5/17/2018e
Trelegy Ellipta
Fluticasone Furoate; Umeclidinium
Bromide; Vilanterol Trifenatate
9/18/201 r
9/9/20209
Anoro® Ellipta®
Umeclidinium Bromide; Vilanterol
Trifenatate
12/18/2013
Serevent®
Salmeterol Xinafoate
9/19/1997
Merck Sharp and
Dohme
Asmanex
Twisthaler
Mometasone Furoate
3/5/2005h
2/1/2008'
Mylan
Pharmaceuticals Inc
TOBI® Podhaler
Tobramycin
3/22/2013
Wixela Inhub
Fluticasone Propionate; Salmeterol
Xianfoate
1/30/2019
Sunovion
Pharmaceuticals
Inc.
Arcapta®
Neohaler
Indacaterol
7/1/2011J
Seebri Neohaler
Glycopyrrolate
10/29/201 &
Utibron
Neohaler®
Indacaterol/ Glycopyrrolate
10/29/201 &
Teva
Proair Digihaler
Albuterol Sulfate
12/21/2018
Proair
Respiclick®
Albuterol Sulfate
3/31/2015
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Manufacturer3
DPI Product
Name3
Active Ingredient3
FDA Approval
Date3
Armonair
Digihaler
Fluticasone Propionate
2/20/2020
Teva
ArmonAir®
RespiClick®
Fluticasone propionate
1/27/2017k
Airduo Digihaler®
Fluticasone Propionate; Salmeterol
Xinafoate
6/12/2019
Airduo
Respiclick®
Fluticasone Propionate; Salmeterol
Xinafoate
1/27/2017
Note: Bolded manufacturer entries represent manufactures that produce both DPIs and MDIs. Bolded DPI
products represent product lines that consist of both DPIs and MDIs.
a FDA (2020c).
b FDA approval of Breo Ellipta 0.1 mg/inhale; EQ 0.025 mg base/inhale on 5/10/2013.
c FDA approval of Breo Ellipta 0.2mg/inhale; EQ 0.025 mg base/inhale on 4/30/2015.
d FDA approval of Arnuity Ellipta 0.1 mg/inhale and 0.2 mg/inhale on 8/20/2014.
e FDA approval of Arnuity Ellipta .05 mg/inhale on 5/17/2018.
f FDA approval of Trelegy Ellipta 0.1 mg/inhale; EQ .0625 mg base/inhale; EQ .025 mg base/inhale on 9/18/2017.
g FDA approval of Trelegy Ellipta 0.2 mg/inhale; EQ .0625 mg base/inhale; EQ .025 mg base/inhale on 9/9/2020.
h FDA approval of Asmanex Twisthaler 0.22 mg/inhale on 3/30/2005.
' FDA approval of Asmanex Twisthaler 0.11 mg/inhale on 2/1/2008.
j Arcapta® Neohaler, Seebri Neohaler, and Utibron Neohaler® were discontinued 3/10/2020.
k Armonair® RespiClick® was discontinued in 2017.
Sales data, in dollars, for DPI products were obtained from annual reports of their respective
manufacturing companies. If sales data for certain products were not publicly available (i.e.,
Serevent®, Relenza®, TOBI® Podhaler, Asmanex® Twisthaler®, and Wixela™ Inhub™), data
from the SDUD of Medicaid were used as a proxy. The SDUD provides information on the
number of units of DPI product that Medicaid is reimbursing (e.g., 22,320,652 units of Anoro®
Ellipta® of Alvesco® reimbursed in 2019), the number or prescriptions, and the amount
reimbursed. When sales data from annual reports were lower than the reimbursement value
from the SDUD (i.e., Tudorza Pressair®), the larger value was applied.
Using this approach, approximately 18.9 million DPIs were assumed to be sold and used in the
United States in 2019. Considering that the estimated HFC MDI market size by EPA (2020) in
2019 is 55.3 million inhalers, the total market size for inhalers in the United States was 74.2
million (see Table 7). Therefore, the market share of DPIs is 25 percent while that of HFC MDIs
is 75 percent. This market share is close to that reported for the United States market in
MCTOC (2018), i.e., 30 percent DPIs.
Table 7. Estimated MDI and DPI Use in the United States (2019)
Number of Inhalers
Percent of Total
HFC MDIs
55,344,000a
75%
DPIs
18,903,907
25%
Total Inhalers
74,247,907
100%
a EPA (2020).
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Medical Inhaler User Population
In 2018, approximately 12.8 and 24.7 million people had COPD and asthma, respectively, in the
United States (CDC 2018a, CDC 2018b). Based on this data, potential annual inhaler use was
estimated under four different scenarios, as shown in Table 8. In the most conservative scenario
(Scenario 1), 100% of the population with COPD and/or asthma was assumed to use one
inhaler per month for 12 months (i.e., 12 inhalers per year).16 In the most realistic scenario
(Scenario 4), 50% of the population with COPD and/or asthma was assumed to use one inhaler
a month for three months of the year.17 This analysis results in a large range of annual inhaler
use, from 19.1 million to 450 million units annually (see Figure 5).
Some people can have both asthma and COPD18 and others do not use medication.19
Furthermore, some medications are administered differently from inhalers (e.g., use of
nebulizer). In addition, although it is estimated that DPIs last for a month20 and HFC MDI
inhalers for long-term control are also consumed within a month, when inhalers are used as a
rescue (i.e., quick-relief) medication, they may last longer.
A summary of the assumptions for the four scenarios and two analyses conducted to estimate
the size of the U.S. medical inhaler market are summarized in Table 8, and is followed by Figure
5, which compares the resulting estimates of each approach.
Table 8. Assumptions for Analyses on Estimated Annual Inhaler Use in the United States
Scenario/Analysis
Assumptions
Scenario 1
100% of population with COPD and/or asthma use one
inhaler per month for 12 months (2018)
Scenario 2
50% of population with COPD and/or asthma use one inhaler
a month for 12 months (2018)
Scenario 3
100% of population with COPD and/or asthma use one
inhaler per month for 3 months (2018)
Scenario 4
50% of population with COPD and/or asthma use one inhaler
a month for 3 months (2018)
16 Although some asthma and COPD patients may be prescribed multiple inhalers a month as part of their
asthma action plans, including a long-term control and a quick-relief inhaler, use of one inhaler a month is
assumed to be a reasonable scenario because some patients may not use prescribed inhalers (CDC
2020).
17 Over 60% of MDI patients in a study were unable to use their MDI device and there is evidence that
poor inhalation technique impacts both asthma control and patient adherence to treatment (Giraud and
Allaert 2009, Levy et al. 2014). Therefore, it is likely that although treatments may be prescribed for long-
term control, the actual use period is shorter and a 3-month treatment was assumed.
18 De Marco et al. (2013) indicate that for subjects with asthma the percentage of the asthma-COPD
overlap syndrome was 16%, 30%, and 61% for ages 20-44, 45-64, and 65-84, respectively. In addition,
De Marco et al. (2013) report that for subjects with COPD the percentage of the asthma-COPD overlap
syndrome was 33%, 27%, and 25% forages 20-44, 45-64, and 65-84, respectively.
19 Nearly 39.0% of all adults and 40.2% of all children with self-reported active asthma used at least one
kind of LTC medication in the past 3 months (CDC 2014a). Furthermore, nearly 24.3% of all adults and
18.7% of all children self-reported active asthma used quick-relief medications (QRMs) frequently in the
past 3 months and using more than 2 days per week is considered frequent use (CDC 2014b).
20 Multi-dose DPIs typically contain enough doses for at least one month's treatment (MCTOC 2018).
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Scenario/Analysis
Assumptions
MDI Sales + DPI Sales
Combined results from ICF (2020) MDI sales analysis (see
Section 4.2) and DPI sales analysis (see Appendix A)
U.S. Estimates Derived
from MCTOC (2018)
Derived Estimates for USA
Reflects assumptions reported in MCTOC (2018) for the
global and U.S. MDI and DPI markets (see Footnote Error!
Bookmark not defined.)
U.S. MDI Estimates
Derived from Koura (2021)
Reflects MDI estimates derived from Koura (2021) bulk gas
and MDI import estimates
Figure 5. Comparison of Analyses of U.S. Medical Inhaler Market Size (2018/2019)a
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MDIs and DPIs) is between 74 and 225 million inhalers annually with DPI use ranging from 19
to 68 million inhalers annually.
ICF recognizes several assumptions may warrant further review and refinement, including:
• Five of the 25 DPI products identified have generics available (i.e., Flovent Diskus®,
Advair Diskus®,22 Wixela™ Inhub™, AirDuo Digihaler®, and AirDuo RespiClick®). It
was assumed that sales from the generics were negligible, although it is possible that
they are sizable and calculated DPI volumes are underestimated.
• One "prescription" as reported in the SDUD corresponds to one inhaler and one "unit"
corresponds to one dose. The Unit Type Each as defined by Medicaid Manufacturer
Release No. 73 and Manufacturer Release No. 82 do not indicate if a unit is an inhaler
or a dose (DHHS 2006, DHHS 2010). Furthermore, Release No. 73 indicates that
labelers erroneously report drugs using the Unit Type Each (DHHS 2006). Should a
"unit" be equivalent to an inhaler rather than a dose, results of the analysis would be
underestimated.
• As of September 2020, only 21 % of the United States population was enrolled in the
Medicaid program and there is no readily available information on how much of the DPI
market is met with Medicaid reimbursed products (Medicaid 2020b). Thus, the DPI
sales, and therefore, use estimated from SDUD data for these products (i.e., Serevent®,
Relenza®, TOBI® Podhaler, Asmanex® Twisthaler®, and Wixela™ Inhub™) is likely
underestimated.
22 A generic version of Advair Diskus is available from Hikma Pharmaceuticals and was approved by the
FDA on 12/17/2020.
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