Document ID: EPA-HQ-OAR-2006-0159-0009
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-11-03T05:00Z

SEQ CHAPTER \h \r 1 ENCLOSURE

United States’ Nomination Of The Aerosol Metered Dose Inhaler (MDI)

 As An Essential Use

Country:		United States of America

Contact Person:	Scott Monroe

Title:			Essential Use Program Manager		

Address:  		U.S. Environmental Protection Agency

			Office of Air and Radiation (6205J)

1200 Pennsylvania Avenue, NW

Washington, DC  20460

Telephone:		1-202-343-9712

Fax:			1-202-343-2363

Email:			monroe.scott@epa.gov

I.	Summary of Nomination

A.	Please identify and describe in detail the proposed uses.  Please
indicate for what disease or treatment the proposed use is intended [(i)
pulmonary, e.g., asthma, or (ii) non-pulmonary conditions, e.g.,
cancer].

The proposed use is the Metered Dose Inhaler (MDI) for the treatment of
asthma and chronic obstructive pulmonary disease (COPD).  MDIs are
pocket-sized aerosol devices used to deliver (orally) precisely measured
doses of medicine directly to the lungs.  

CFCs are used as propellants and suspension agents in MDIs (CFC-11, 12
and 114).  They are also used in the manufacture of MDI valves and in
cleaning MDI manufacturing equipment.  

B.	Please indicate below each substance required for the proposed use
and the quantities requested of each substance in each year being
nominated.		

Nominated Quantities for 2007

Ozone Depleting Substance	2007 Quantity (metric tonnes)

CFC-11, CFC-12, and CFC-114	1,493 metric tonnes [see also p. 15]

	



II.	Substantiation of Nomination

							

A.	Role in Society

	State whether the nomination is for the treatment of asthma and/or
COPD.  If not, explain why this use is necessary for health and/or
safety or critical for the functioning of society.

	

This nomination requests CFCs solely for use in MDIs for the treatment
of asthma and/or COPD.

Describe the nature of the disease(s)which the proposed use is intended
to treat, e.g., the nature and prevalence of the disease and the role of
MDIs (versus other forms of therapy) in treating the disease(s).

Nature of the Diseases

Asthma and chronic obstructive pulmonary diseases (COPD), such as
emphysema and chronic bronchitis, reduce the capacity for respiration. 
In asthma and often in COPD, airways become inflamed and hyperreactive,
causing coughing and wheezing that disrupts breathing.  These diseases
can also cause swelling of the bronchi and produce mucus plugs that
further impede airflow.  In addition, nervous system stimulation can
contribute to further airway narrowing and worsening symptoms.  Finally,
in the case of emphysema and chronic bronchitis, this process gradually
destroys the surface area of the lung, reducing its capacity to exchange
oxygen and carbon dioxide.  Asthma and COPD greatly diminish the quality
of life for patients and their families, and in severe cases may cause
death.  

Asthma

Asthma is a chronic and debilitating respiratory disease with sudden,
unpredictable, and potentially life-threatening effects.  The treatment
of asthma requires constant vigilance and the active involvement of
patients, families, physicians and other caregivers in a comprehensive
program to monitor, anticipate, and promptly respond to the onset of
asthmatic attacks.

						

Patients with asthma may be restricted from normal physical activity,
may be limited in their choice of work, afflicted by the side effects of
some medications, and subject to unpredictable and sudden asthma attacks
which disrupt their daily activities and may even threaten their lives.

	Chronic Obstructive Pulmonary Disease (COPD)

Chronic obstructive pulmonary disease produces inflammation, swelling,
and mucus in the human airway, and gradually destroys the surface area
of the lung.  COPD is progressive and generally irreversible, and
severely restricts the capacity for respiration.

Prevalence of the Diseases

The American Lung Association has issued a publication entitled “Lung
Disease Data 2000" which contains statistics concerning the prevalence,
mortality, and treatment of asthma and COPD in the United States.  The
report states that:

There are approximately 17 million asthma sufferers in the U.S.  Asthma
is now the sixth-ranking chronic condition and the leading serious
chronic illness in children. (p. 5).

“Asthma is unquestionably, and unaccountably, on the rise.”  Between
1982 and 1995, the prevalence rate (the rate per thousand persons) of
asthma rose from 34.8 to 56.8, a 63% increase.  The prevalence of
pediatric asthma rose from 40.1 to 74.9, a 72.3% increase. (p. 5)  

There were 5,434 deaths from asthma recorded in 1997.  This represents
more than a two-fold increase since 1979. (p. 7)  

Asthma attacks bring an estimated 1.9 million Americans to emergency
rooms each year and account for one in six of all pediatric emergency
room visits in the U.S. (p. 5)

Asthma costs the U.S. an estimated $11.3 billion in 1998.  This amount
includes direct health care expenses ($7.5 billion) and indirect costs
such as lost productivity ($3.8 billion). (p. 5)

In addition to those with asthma, more than 16 million Americans are
estimated to suffer from COPD, and it is the fourth-ranking cause of
death in the United States. (p. 22)

COPD was responsible for the death of over 103,000 Americans in 1997. 
This is a new high in a steadily increasing toll (the 1980 figure was
just over 53,000). (p.22)

COPD costs the nation approximately $26.0 billion each year, which
includes both health care expenditures ($13.6 billion) and indirect
costs ($12.4 billion). (p. 22-23)

COPD is the third-ranking condition necessitating at-home care. ( p.23)

	Role of the MDI

There is international consensus that primary treatment of asthma and
COPD should be by the inhaled route.  This treatment is delivered
quickly and efficiently to the airways, which minimizes risk of adverse
reactions.  Therapy necessitates regular treatment, often with more than
one drug.  At this stage of the transition, MDIs remain the dominant
inhaled delivery system in most countries, for all categories of drugs.

2. 	Does the use include any MDI products approved after 31 December
2000 for the treatment of asthma and COPD?

	No.  

B.	Description of Transition Status

1.  	Has a transition strategy been submitted to the UNEP Ozone
Secretariat (and where can it be accessed)?	Consistent with the request
of the Parties in Decision VIII/12, the United States has submitted to
the UNEP Ozone Secretariat its transition strategy in the form of
regulations developed by the U.S. Food and Drug Administration (USFDA). 
These regulations describe the criteria that USFDA will use to determine
when it is appropriate to remove the essential use designation from
products that use ozone-depleting substances.  The final regulations
were published in the Federal Register on July 24, 2002.  The rule may
be accessed on the USFDA website at   HYPERLINK
http://www.accessdata.fda.gov/scripts/oc/ohrms/index.cfm 
http://www.accessdata.fda.gov/scripts/oc/ohrms/index.cfm  by searching
for rules published on July 24, 2002.  The USFDA issued a proposal in
June 2004 setting out the process and considerations to remove the
essential use designation of CFC albuterol at a date certain in the
future.  USFDA plans to issue a final decision in Spring 2005 on a date
certain by which albuterol CFC-MDIs would be considered non-essential in
the United States.  

2.	Describe progress in the transition to alternatives pursuant to the
national or regional transition strategy submitted to the Secretariat. 

Substantial progress has been made in recent years to facilitate an
orderly transition to safe and effective CFC-free alternatives. 
Following substantial investment in research and development by U.S.
firms, and completion of the required safety tests for new drug
products, USFDA has approved several new treatments for asthma and COPD
that do not rely on CFCs (see the table below).  Additional alternatives
are under review by USFDA.  Also, the U.S. Government has overseen the
consistent application of Decisions by the Parties regarding the
allocation of essential use allowances, by ensuring that amount granted
by the Parties are not used if they are not needed nationally.  In 2002
USFDA issued the final regulations that provide the framework for the
transition to CFC-free alternatives in the United States.  These
regulations describe the criteria for determining that a product using
ODSs is no longer medically essential.  The accelerating shift by U.S.
firms to CFC-free products, as well as the success of these products in
the U.S. market, are reflected in the 50% reduction in the 2007 U.S.
nomination as compared to the total approved by the Parties for 2004,
and the 20% reduction compared to the total approved for 2005. 

3.  	Explain what substitutes and alternatives to the proposed use are
currently available.

Describe any new or existing forms of treatment available if not
previously submitted during essential use assessment.	

Three CFC-free MDIs are now approved for marketing in the United States
(see next response), as are several dry powder inhalers (DPIs), and a
fourth CFC-free MDI has been approved for marketing.  Several additional
CFC-free products are either under review by USFDA or are under active
development by pharmaceutical companies.  Examples of areas of research
on new delivery systems are:

A soft mist inhaler that uses mechanical energy to direct two opposing
liquid jets to aerosolize on impaction.

A miniaturized, portable piezoelectric device that uses alternating
electric currents to generate a fine droplet mist from the surface of a
liquid.

An ultrasonic horn used to generate an aerosol cloud by capillary wave
action.

A device that aerosolizes a liquid by forcing it through a break-up
plate, mesh cap, or open-cell foam.

List the substitutes and alternatives to the proposed use that are
currently licensed and describe availability, including trends in the
availability and usage of alternative inhalation devices and the likely
impact of these trends on the need for CFCs for MDIs in the year for
which the nomination is made. 	

Below is a list of CFC-free products approved and available for the
treatment of asthma and COPD in the U.S:  

Product		Drug Delivery System		Active Moiety			Product Approval Date

Proventil HFA		HFA MDI		Albuterol			15/08/96

Ventolin HFA		HFA MDI		Albuterol			19/04/01

Undetermined (IVAX)	HFA MDI		Albuterol			10/29/04

Q-Var 			HFA MDI		Beclomethasone			15/09/00

Advair Diskus		DPI			Fluticasone/salmeterol		24/08/01

Flovent Rotadisk		DPI			Fluticasone			07/11/97

Pulmicort Turbuhaler	DPI			Budesonide			24/06/97

Serevent Diskus		DPI			Salmeterol			19/09/97

Ventolin Nebules		Nebulizer		Albuterol			23/04/92

Ventolin Syrup		Oral			Albuterol			10/06/87

Ventolin Solution 	Nebulizer		Albuterol			16/01/87

for Inhalation

Ventolin Tablets		Oral			Albuterol			10/07/86

In part because of the presence of two HFA albuterol products on the
market (Ventolin and Proventil;), USFDA issued a proposed rule in June
2004 setting out the process and considerations to set a date certain to
withdraw albuterol as an essential use moiety.  It should be noted that
withdrawal of any essential use product is an important, deliberative
process that is contingent upon many factors, including the potential
health and economic impacts of transitioning patients from generic to
brand-name medications. We anticipate that the USFDA rulemaking process
will conclude in Spring 2005, and at that time the United States will
give due consideration to the ramifications of the outcome of that
process to our Essential Use Exemption nominations.

The HFA MDI product Q-Var, a CFC-free beclomethasone MDI, has taken over
a small portion of the inhaled corticosteroid market.  The total U.S.
production for beclomethasone in 1998 was about 6 million units, which
required about 200 tonnes of CFCs for production.  In future years, the
overall market for CFC-containing beclomethasone products may continue
to shrink as the non-CFC alternative gains acceptance and as other
asthma therapies become more important.  

A dry-powder inhaler combination product of salmeterol and fluticasone
(tradename Advair) was approved by the FDA in 2000.  While Advair is not
a direct replacement product, it has achieved significant market
penetration since its approval and is expected to lead to reduced CFC
needs in future. 

We are hopeful that the availability and use of alternatives will
obviate the need to use the entire volume of CFCs that the U.S. is
nominating.  However, there are many factors involved, particularly
supply chain issues for U.S. manufacturers in obtaining licenses and
supplies of newly produced CFCs.  Because of the difficulty in
predicting with precision a sufficient supply of CFCs to ensure patient
safety during the transition, we consider the nominated volume to be
appropriate.

In addition to the MDI and the DPI, three other forms of therapy exist
for the treatment of asthma and COPD:

orally administered drugs

injectable drugs			

nebulizers

Orally administered and injectable drugs are prescribed for some
patients but rarely offer adequate relief by themselves.  As noted
above, there is “international consensus that primary treatment of
these diseases should be by the inhaled route.”  Nebulizers are
currently impractical replacements for MDIs due to issues of portability
and ease of use.  In its April 1999 report, the Technology and Economic
Assessment panel stated, “Novel oral compounds (leukotriene modifiers)
for the treatment of asthma have been introduced in some countries. 
These may be of value to a certain number of those with asthma, but it
is unlikely that these will be a full substitute for current effective
inhaled preventive therapy” (p. 191).

4.  	Explain steps being taken to implement these substitutes and
alternatives

List and describe in detail the education efforts being undertaken to
accomplish the transition.

The U.S. Government, pharmaceutical companies, and other U.S.
stakeholders have undertaken a number of education efforts, including:

World Wide Web Sites

USEPA and USFDA have websites with information on the transition to
CFC-free metered dose inhalers.  They are located at
www.fda.gov/cder/mdi/ and
http://www.epa.gov/ozone/title6/phaseout/mdi/index.html. 

The International Pharmaceutical Aerosol Consortium (IPAC), to which
several companies operating in the U.S. belong, also has a World Wide
Web site (  HYPERLINK www.ipacmdi.com. www.ipacmdi.com).   The purpose
of the web site is to provide patients and physicians with information
on the transition to CFC-free MDIs.  The web site showcases IPAC
brochures, newsletters, fact sheets, and publications that IPAC
distributes at medical conferences and symposia.

Brochure on the Transition

A group of parties – USEPA, USFDA, the US National Institutes of
Health, IPAC, the National Asthma Education and Prevention Program of
the National Heart, Lung, and Blood Institute – collaborated in the
publication of a brochure entitled “Your Metered-Dose Inhaler Will Be
Changing. . . Here are the Facts.”  This brochure explains the reasons
why the CFC MDI is being replaced, the effort being made to develop and
introduce the CFC-free MDI, the ways in which the CFC-free MDI may
differ from the CFC MDI, and a list of organizations from which patients
and physicians may receive further information.

Stakeholders

The U.S. Government maintains an ongoing dialogue on the MDI transition
with a range of stakeholder organizations (pharmaceutical companies,
public health organizations, and patient and provider advocacy
organizations).  USEPA and USFDA participate in meetings of the US
Stakeholders Group on the MDI Transition, which meets under the auspices
of the American Lung Association.

Educational Activities of Individual MDI Companies	

The pharmaceutical industry promotes respiratory education in many ways.
 MDI companies often play a supporting role in the development of
respiratory symposia.  MDI pharmaceutical companies assist medical
professionals through in-service education programs, and by providing
reprints of articles and reports, as well as copies of educational aids
for distribution to patients.  Finally, MDI companies support
respiratory patient organizations through financial grants and the
distribution of educational aids.

Advertisements and other promotional materials are placed in medical
journals and circulated to prescribing physicians by pharmaceutical
companies to heighten medical professionals awareness of new respiratory
care products on the market, including MDIs and DPIs. 

Role of Professional Associations

International professional associations such as the American Thoracic
Society (ATS), the American Academy of Allergy, Asthma, and Immunology
(AAAAI), and the European Respiratory Society (ERS) support medical
professionals active in the treatment of asthma and COPD.  These
associations publish medical journals, reports and newsletters and
organize medical congresses.  These activities are designed to inform
medical professionals about the management of asthma and COPD, and the
range of treatment options available for their patients.

Describe how MDI manufacturers or distributors differentiate the
packaging of non-CFC MDIs from CFC-driven MDIs and describe what
marketing strategies are being taken to assure that their non-CFC MDIs
are used, and describe the steps that companies applying for essential
use exemptions have taken to obtain approval for CFC-free alternatives
in their domestic and export markets.

MDI companies have and will continue to differentiate the packaging for
CFC-free MDIs from the packaging of CFC MDIs through the use of shapes,
sizes, colors, trademarks, logos, and other design features.  In
addition, leaflets have been and will be included in the packages
containing CFC-free MDIs which inform patients of the differences
between the CFC-free MDI and the CFC MDI.  These steps have been and
will continue to be taken in accordance with relevant regulations of the
U.S. FDA (for example, 21 Code of Federal Regulations (CFR) Part 201
(dealing with labeling requirements for drugs) and Part 314 (dealing
with approval of new drugs).  Also, all CFC MDIs sold in the U.S. carry
a USEPA notification that the contents of the MDI includes CFCs.	

To encourage doctor and patient acceptance and use of CFC-free MDIs, MDI
companies in the U.S. will undertake national promotional campaigns that
include, among other things, meetings with and letters to health care
professionals, information booths at medical conferences,
advertisements, and distribution of educational materials introducing
these products into the market.  These steps will be taken in accordance
with relevant regulations of USFDA.	

Numerous applications for approval of CFC-free asthma medications are
currently under review by USFDA.

Describe what steps have been taken to ensure that companies
manufacturing, distributing, or selling CFC MDIs and non-CFC
alternatives do not engage in false and misleading advertising targeted
at non-CFC alternatives or CFC MDIs.

The regulations of the USFDA prohibit advertisements which are false,
lacking in fair balance, or otherwise misleading (21 CFR 202(e)(5)).  An
advertisement shall be so deemed if, for example, it contains a
“representation or suggestion, not approved or permitted for use in
the labeling, that a drug is better, more effective, useful in a broader
range of conditions. . . than has been demonstrated by substantial
evidence or substantial clinical experience. . .” (21 CFR
202.1(e)(6)(i)).  The USFDA has a variety of means at its disposal to
enforce this requirement.  See generally sections 301, 502, and 505 of
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 351, 352, and 355)
and 21 CFR Parts 202 and 314.U.S. Federal regulations may be accessed at
http://www.access.gpo.gov/su_docs/index.html.

Describe what steps have been taken to ensure that companies applying
for essential use exemptions participate in regulatory proceedings with
a view toward legitimate environmental, health and safety concerns.

FDA regulations governing participation in regulatory proceedings
generally prohibit any company, including any MDI company, from
advancing environmental, health and safety concerns that are
illegitimate, or from otherwise engaging in conduct that misleads or
obfuscates.  These regulations require, among other things, that:

“All submissions to the Dockets Management Branch [of the USFDA] are
representations that, to the best of the knowledge, information, and
belief of the person making the submission, the statements made in the
submission are true and accurate.  All submissions are subject to the
False Reports to the Government Act (18 U.S.C. 1001) under which a
willfully false statement is a criminal offense” [21 CFR §10.20(i)];

Any company filing a “citizen petition” with the USFDA must certify
that the petition “includes representative data and information known
to the petitioner which are unfavorable to the petition” [21 CFR
§10.30(b)]; and

Participants in a hearing at the USFDA must observe “judicial
standards of practice and ethics.” [21 CFR §12.90]

Explain why alternatives and substitutes are not sufficient or
appropriate to eliminate the proposed use.

MDIs possess numerous characteristics that, taken together, set them
apart from other inhalation delivery systems.  MDI propellants provide
the energy needed for drug delivery independent of any external power
source or extra inspiratory effort on the part of the patient.  In MDIs,
the delivered dose depends significantly on the metering valve and
formulation, not entirely on patient inspiration.  A patient who must
take multiple medications can operate a variety of MDIs using the same
technique.  MDIs provide very good protection from atmospheric humidity
and patient exhalation.  MDIs can be used for the inhalation of all of
the most commonly used respiratory 	medications and are widely available
for use with these medications.  They can be adapted to meet the needs
of special patient populations, including young children and infants.

Although three MDIs with an alternative (non-CFC) propellant are
available in the U.S., these products represent only a fraction of the
many drugs currently available in an MDI format.  Further, the market
penetration of the albuterol HFA MDI has been relatively low
(approximately 10% of all albuterol MDIs sold) due to the significant
cost differential between the HFA MDIs and generic CFC MDIs.Market
penetration for the beclomethasone HFA product may not make a large
impact of CFC use, since the overall market for beclomethasone has
shrunk in recent years.  While other CFC-free MDIs may be introduced in
the next few years, it is clear that CFC MDIs will still be vital for
the treatment of asthma and COPD in the U.S. for the foreseeable future.

Reports of the Aerosols Technical Options Committee

The 1993/94 UNEP Technical Options Report listed the reasons why the MDI
is a vital therapy option.  These reasons remain pertinent today:

	Nebulizers (1993/94 UNEP Technical Options Report, p. 49)

Most nebulizers "require a source of electricity or compressed gas, and
are very bulky and complicated to set up and use."

Currently available hand-held nebulizers are "inefficient."

Dose reproducibility in nebulizers "is not reliable."

Electric nebulizers require "10-20 minutes to deliver a dose."

	Oral Medication (1993/94 UNEP Technical Options Report, p. 50)

Oral medication usually produces "more side effects than inhaled
medication."

Some drugs which are effective by inhalation "are not absorbed as oral
therapy."

Treatment guidelines "have favoured a move from oral to inhaled route
for the treatment of respiratory diseases."	

			

	Injectable Therapy (1993/94 Technical Options Report, p.50)

Injectable therapy “is not practical for general use in ambulatory
patients and is therefore reserved for the treatment of hospitalized
patients.”	

	Dry Powder Inhalers (1993/94 UNEP Technical Options Reports, pp. 48-49)

DPIs are “difficult for patients with low inspiratory flow rates,
“e.g. small children, COPD patients, and asthmatics suffering from an
acute asthma attack.

DPIs require “special packaging for use in humid climates.”

Patient acceptance of DPIs “is not uniform.”

5. 	Assure that each company requesting essential use allocations has
fully complied with Decision VIII/10.1 to demonstrate ongoing research
and development of alternatives to CFC MDIs will all due diligence
and/or collaborate with other companies on such efforts.

All companies requesting essential use exemptions submitted information
to the U.S. government demonstrating their ongoing research and
development of alternatives to CFC MDIs. 

6.  	Describe the steps to minimize emissions of CFCs during the
manufacture of essential use products.

	The waste minimization strategies employed in the manufacture of MDIs
include: 

Use of a vapor return hose

Vapor return hoses minimize emissions during the transfer of CFCs from
tank trucks to on-site storage tanks.  These hoses ensure that CFC vapor
from the top of the storage tank flows back into the delivery vehicle
rather than being vented to the atmosphere.

Trucks and canisters dedicated to a single material

Delivery trucks and canisters are dedicated to a single type of
material.  Refilling of a truck or canister results in reduced emissions
through emission-controlled sampling and testing of the refilled truck
or canister for quality and purity of the CFC.  The need to vent and
clean multiple-use trucks and canisters is eliminated, thereby
decreasing associated emissions.

Installation of permanent, hard piping

Temporary, flexible hosing for CFC transfer is replaced with permanent,
hard piping.  The piping reduces CFC vapor emission because it does not
need to be drained, disconnected, or vented between runs.

Detection and prevention of pump failure

Electronic sensors and automatic valves are installed in order to close
off and isolate a pump in the event of pump failure.  Listening devices
are also installed to detect imminent pump failure.

Detection and prevention of leaks

Inspection and maintenance programs are employed to minimize the risk
of, and promptly detect and remedy, leaks in transfer networks.

Minimization of mixing vessel waste material

The blending of CFCs and pharmaceutical active ingredient(s) results in
an extremely small amount of CFC-containing waste material.  A process
has been developed to minimize this waste product.

Destruction or reclamation of CFC-containing waste material	

CFC-containing waste material from blending and cleaning operations is
destroyed.  The possibility of reclaiming the CFCs in this waste
material is being explored.

Minimization of leaks during blending

Seals on blending vessels have been redesigned and improved to minimize
emissions during the formulation blending process.  Hermetically sealed
vessels are drained and cleaned without venting to the environment. 
Programs are in place to check for leaks during the blending process.

Replacement of rubber elastomers in MDIs

New elastomers have been employed to reduce the number of rejected lots
and the leak rate of MDIs.

In-line stainless steel filters	

CFC filters are used more efficiently and replaced less frequently,
thereby reducing the release of CFCs during each filter change.

Special gassing adapters

Gassing adapters specially designed for the MDI minimize the release of
propellant during the filling of each MDI canister.

Use of CFC-free solvents

CFC-free solvents are used for many elements of the cleaning process.

7. 	Provide details of the management of the stockpile and any surplus.

CFC stockpiles safeguard patient care by protecting against disruptions
and shortfalls in the production of new CFCs.  As an alternate source of
pharmaceutical propellants, these stockpiles ensure continuous
availability of essential MDIs in the event of off-specification
production, shipping and other logistical difficulties, catastrophic
loss, and unexpected delays in issuance of licenses for essential use
production.  CFC stockpiles also provide a margin of safety when the
need for essential CFC MDIs is greater than anticipated as a result of: 
(i) larger than expected increases in CFC MDI market demand; (ii)
unforeseen delays in the approval of CFC-free MDIs; (iii) lower than
anticipated acceptance of alternatives to the MDI; and/or (iv)
manufacturing rationalization. 

Due to the decrease in general demand for CFCs during the transition,
there is now only one facility, located in the Netherlands, still
supplying pharmaceutical grade CFC-11 and CFC-12 for the U.S. market. 
At present U.S. MDI companies are wholly dependent upon pharmaceutical
grade CFC produced at this Dutch facility, which is scheduled to close
in 2005.  During 2005, there should be one or more other facilities in
the U.S. or Europe that can produce CFCs for use in MDIs.  Stockpiled
CFCs provide a small margin of safety should there be unexpected delays
or difficulties in new production.

The Montreal Protocol's Technology and Economic Assessment Panel (TEAP)
has recommended a 12-month level of reserves as reasonable to guard
against unforeseen events.  Decision XVI/12, taken by the Parties at
their Sixteenth Meeting in November 2004, instructed nominating
countries to “give due consideration to existing stocks, whether owned
or agreed to be acquired from a metered-dose inhaler manufacturer, of
banked or recycled controlled substances as described in paragraph 1(b)
of decision IV/25, with the objective of maintaining no more than one
year’s operational supply.”

The USEPA monitors reserves through information provided by companies
that receive essential use allowances.  In putting forward our 2007
essential use exemption nomination, the United States carefully reviewed
the size of company reserves, bearing in mind that information on
reserves at the end of 2003 or 2004 is not a reliable indicator of the
amounts that will be held, and their distribution at the beginning of
2007.  Bearing in mind this uncertainty, the United States has given due
consideration to the existence of stocks in accordance with Decision
XVI/12.  The United States also reviews the requests we receive from
companies for exemptions to ensure that the amount requested is
consistent with our view of the actual patient need in the marketplace. 

USEPA regulations prohibit the sale of CFCs produced under the authority
of essential use allowances into any other market.  Companies that
produce or import CFCs with essential use allowances must either destroy
all stockpiled essential-use CFCs when the MDI transition ends using
approved technologies, or transfer the CFCs to other MDI companies as
provided by the Parties.

	Describe the steps being taken to provide a continuity of supply of
asthma and COPD treatment to importing non-Article 5(1) countries,
Article 5(1) countries and CEIT.  Also describe the steps being taken by
companies to assist their MDI manufacturing facilities in Parties
operating under Article 5(1) and CEIT in upgrading the technology and
capital equipment needed for manufacturing non-CFC asthma and COPD
treatments.

Although the U.S. exports only a small amount of CFC MDIs, many U.S.
pharmaceutical companies are multinational, and have introduced CFC-free
alternatives in many other countries.  As reformulation programs are
completed, and necessary regulatory approvals secured, CFC-free
alternatives will be introduced in both domestic and export markets. 

III.	Substantiation of Volumes

1.	Please indicate below the actual or estimated quantities of
controlled substances used in years prior to the first year for which an
exemption is requested.

Metric Tonnes Used For MDIs	

Ozone Depleting Substance	1993	1994	1995

CFC-11	646.25	351.42	742.85

CFC-12	1406.95	1606.94	1481.93

CFC-114	928.35	1086.25	1075.42

Total	2981.55	3044.61	3300.2

Data for years beyond 1995 are included the U.S. Reporting Accounting
Framework for Essential Uses.

The U.S. 2007 request of 1,493 metric tonnes includes a request for 932
metric tonnes for albuterol MDIs.  As noted above, there are currently
three HFA albuterol products approved for marketing in the United
States, although post-marketing data is only available for two of the
three.  USFDA issued a proposed rule in June 2004 setting out the
process and considerations to set a date certain to withdraw albuterol
as an essential use moiety.  It should be noted that withdrawal of any
essential use product is an important, deliberative domestic process
that is contingent upon many factors, including the potential health and
economic impacts of transitioning patients from generic to brand-name
medications. We anticipate that the USFDA rulemaking process will
conclude in Spring 2005, and at that time the United States will give
due consideration to the ramifications of the outcome of that process to
EUE nominations.

With regard to CFC MDIs other than albuterol MDIs, the United States
assumes that CFC-free alternatives will continue to increase their share
of the asthma/COPD market. However, the experience of all Parties has
demonstrated that the myriad of factors that play into a national
request, including unpredicted rationalization of production, makes it
very difficult to predict the precise level of CFCs needed over two
years in the future.  The USEPA has conferred with USFDA to ensure that
the U.S. nomination reflects a careful consideration of the various
factors that will affect volume requirements in the year 2006.  These
factors include:  (i) rate of increase in the diagnosis and treatment of
asthma and other respiratory diseases; (ii) the rate of increases in
prescriptions of CFC MDIs; (iii) the rate of approval, introduction, and
acceptance of CFC-free MDIs; and (iv) the rate of approval,
introduction, and acceptance of alternatives to the MDI.

The U.S. in the past has submitted essential use requests that were
conservative in order to ensure that the needs of patients in the U.S.
are met.  For example, the U.S. requested a total of 2,975 metric tonnes
of CFCs for the year 2004, but ultimately allocated only 2,078 metric
tonnes to companies due to reduced need reported by certain companies. 
Since 2000, the U.S. has reduced the total amount of its nominated
exemptions by almost fifty percent. A conservative approach to essential
use nominations provides a valuable safety valve in the case of
unanticipated patient need, without incurring negative consequences for
the ozone layer.  The U.S. believes that it is critical to request
enough CFCs to meet potential patient needs in the face of uncertainty,
since underestimating the need could have significant public health
consequences. 	

	Estimate the proportion of the nominated quantity intended for use in
MDIs for export.  Assure that the Secretariat’s list of CFC MDI active
ingredients and/or category of products determined to be nonessential by
an importing Party has been consulted, and that none of the volumes
requested shall be used for items posted on that list.

We estimate that less than one percent of the total volume requested for
2007 will be used for production of CFC MDIs for export to other
industrialized countries.  These exports
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