Document ID: EPA-HQ-OAR-2008-0503-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-01-16T05:00Z

NOMINATION OF THE AEROSOL METERED-DOSE INHALER (MDI)

AS AN ESSENTIAL USE FOR 2009

Party/Country:			United States of America 

Contact Person:		Hodayah Finman 						

Title:				United States Department of State

	

Address:			2201 C Street, NW

	Washington, DC 20520

Telephone:		 	(202) 647-1123

Fax:				(202) 647-5947

Email:			 	FinmanHH@state.gov

Expert

Organization:			United States Environmental Protection Agency

Contact Person: 		Kirsten M. Cappel

Address:			Office of Air and Radiation (MC: 6205J)

1200 Pennsylvania Avenue, NW

				 Washington, DC 20460

Telephone:			(202) 343-9556

Fax:				(202) 343-2338

E-mail:				cappel.kirsten@epa.gov

			

I.	Summary of Nomination

Please identify and describe in detail the proposed uses.  Please
indicate for what disease or treatment the proposed use is intended. 
(Decision IV/25, pars. 2 and 3)

The proposed use is Metered Dose Inhalers (MDIs) where the active
ingredient is not solely salbutamol 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.  

Chlorofluorocarbons (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.  

In this nomination, the United States is not requesting CFCs for 2009
for use in MDIs where the sole active ingredient is salbutamol.  The
United States established a phaseout date of December 31, 2008 for these
products, after which time it will be illegal to market them.  

Please specify the active ingredient(s) used.  (Decision IV/25, pars. 2
and 3)

Cromolyn, 

Epinephrine, 

Ipratropium, 

Nedocromil, 

Pirbuterol, 

Salbutamol (in combination), and 

Triamcinolone.  

C.	Please identify the intended market(s) for sale or distribution for
each active ingredient.  (Decision XV/5, par. 2)

Information pursuant to Decision XV/5 will be submitted by the United
States under separate cover for confidentiality reasons.  Please note
that the U.S. is not 	nominating CFCs for MDIs to meet export demand. 

D. 	Please indicate below the quantity of CFCs requested for the
proposed use in each 

	year being nominated for each active ingredient and for each intended
market for 

	sale or distribution; if necessary, the quantities for intended markets
may be best 

	estimates from requesting companies.  If more specific data are not
available, data 

	aggregated by region and product group may be submitted for Article
5(1) intended 

markets for sale or distribution.  (Decision IV/25, pars. 2 and 3 and
Decision XV/5, 

par. 2)

Nominated quantities of CFCs (metric tonnes) for essential uses:

Ozone Depleting Substance	2009 Quantity (metric tonnes)

CFC-11, CFC-12, and CFC-114	282  metric tonnes

	

The United States is the intended market for the sale and/or
distribution of the MDIs.  As noted above, specific data on the amount
of CFCs by active ingredient requested in Decision XV/5 will be provided
under separate cover due to confidentiality concerns.

 

II.	Substantiation of Nomination

A.	Role in Society

1.	State whether the nomination is for the treatment of asthma and/or
chronic 

	obstructive pulmonary disease.  If not, explain why this use is
necessary for 

	health and/or safety or critical for the functioning of society? 
(Decision 

	IV/25, p 2 and 3)

Describe the nature of the disease(s) that 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).

This nomination requests CFCs solely for use in MDIs for the treatment
of asthma and/or COPD.  Asthma and COPDs, such as emphysema and chronic
bronchitis, reduce the capacity for breathing.  In asthma and often in
COPD, airways become inflamed and hyper-reactive, 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 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 care-givers 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.

COPD 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.

In its April 1999 report, the Technology and Economic Assessment Panel
stated that: “there is international consensus that primary treatment
of [asthma and COPD] should be by the inhaled route.  This permits
treatment to be delivered quickly and efficiently to the airways, which
minimizes risk of adverse reactions.  Therapy necessitates regular
treatment, often with more than one drug.  MDIs remain the dominant
inhaled delivery system in most countries and for all categories of
drugs.”  

The American Lung Association has issued a publication entitled “Lung
Disease Data: 2006" which contains statistics concerning the prevalence,
mortality, and treatment of asthma and COPD in the United States.  The
report states that:

“An estimated 29.8 million Americans have ever been diagnosed with
asthma by a health care professional (p. 13).  

Asthma ranks among the top 10 most prevalent conditions causing
limitations of activity (p. 13). 

Close to 20 million Americans currently have asthma, of which 11 million
had an asthma attack in 2003 (p. 13). 

Asthma is the leading serious chronic illness of children in the U.S. 
In 2003, an estimated 6.2 million children under age 18 (1.2 million
under the age of 5) had asthma, of which 4 million had an asthma attack
(p. 13). 

[In children, asthma] is the number one cause of school absences
attributed to chronic conditions, leading to an estimated 12.8 million
school days lost annually (p. 13). 

Asthma incurs an estimated annual economic cost of $16.1 billion to [the
U.S.].  This amount consists of $11.5 billion in direct healthcare costs
and $4.6 billion in indirect costs (e.g. lost productivity) (p. 16).  

In 2002, over 4,000 people died of asthma in the United States (p. 15). 

In addition to those with asthma, more than 10.7 million U.S. adults
(aged 18 and over) were estimated to have COPD in 2003 (p. 21).

COPD is the fourth-ranking cause of death, claiming the lives of 120,555
Americans in 2002 (p. 22).

According to estimates by the National Heart, Lung, and Blood Institute,
in 2004, the annual cost to the [U.S] for COPD was $37.2 billion.  This
included $20.9 billion in direct health care expenditures, $8.9 billion
in indirect morbidity costs and $7.4 billion indirect mortality costs
(p. 23).”

The problem is not limited to the United States:

The total incidence of asthma is estimated to be around 5-8% worldwide.

According to the World Health Organization (WHO), worldwide rates of
asthma are rising, on average, by 50% every decade. (WHO Fact Sheet No.
206)

COPD is estimated to affect up to 15% of the population and is the fifth
leading cause of death worldwide.

Asthma and COPD result in approximately 3 million deaths annually.
(World Health Report 1997, WHO)

There have been significant advancements in the development of
alternatives since the beginning of the essential use exemption program.
 For example, last year, for the first time since the inception of the
exemption program, the U.S. Government did not nominate CFC MDIs where
the sole active ingredient is salbutamol for an exemption for 2008.    

The need for an essential use exemption remains while suitable
alternatives are developed for certain uses and to complete the
transition to CFC-free alternatives in other products.  Exempted CFC
consumption for products to treat asthma and COPD in the United States
is necessary in 2009 for the health, safety and critical functioning of
society due to the prevalence and seriousness of these diseases.

2. 	Does this use include any MDI product approved after 31 December
2000 for

	the treatment of asthma and/or chronic obstructive pulmonary disease? 
(Decision

	II/2, par. 2)

No.

B. 	Description of Transition Status

	The following elements should be addressed or updated in each year's 
nomination: 

1. 	Has a transition strategy applicable to the intended market(s) for
sale or distribution and a plan of action been submitted to the UNEP
Ozone 	Secretariat under Decision XII/2, or IX/19, and XV/5?  (Decisions
IX/19, par. 5, XII/2, par. 5(c)), and XV/5, par. 4)

	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 United States Food
and Drug Administration (U.S. FDA).  These regulations describe the
criteria that U.S. FDA 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 U.S.
FDA website at http://www.accessdata.fda.gov/scripts/oc/ohrms/index.cfm
by searching for rules published on July 24, 2002.  The U.S. FDA issued
a final rule on April 4, 2005 (70 FR 17169) that sets the date to remove
the essential use designation for CFC MDIs whose active ingredient is
solely salbutamol, reflecting substantial progress towards phaseout of
essential uses in the United States.  Please see Section 5 of this
document for more information on the U.S. FDA rulemaking process.

2.	Explain, if known, how any such transition strategy applies to the
active ingredients(s) for each intended market for sale or distribution
as set forth above.  (Decision XV/5, par. 3) 

	Decision XV/5 requests the TEAP to provide recommendations to the
Parties with reference to a national transition strategy covering the
intended market.  The United States is nominating CFCs solely for
domestic use and therefore our transition strategy as a whole applies to
the entire intended market.

3. 	Describe progress in the transition to alternatives pursuant to the
national or regional transition strategy submitted to the Secretariat in
the domestic market.  (Decision XII/2, par. 5(c)) 

Significant 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, U.S. FDA 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 U.S. FDA.  Also, the United States
Government has overseen the consistent application of Decisions by the
Parties regarding the allocation of essential use allowances by ensuring
that the amount granted by the Parties is not allocated if it is not
needed nationally. 

In 2002, U.S. FDA 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 whether
a product using ODSs is no longer medically essential.  The U.S. FDA
finalized its first action to remove the essentiality of a medical
device in April 2005 with the ban on the sale and distribution of CFC
salbutamol MDIs effective December 31, 2008.  In addition, at the 18th
Meeting of the Parties to the Montreal Protocol (MOP), in accordance
with Decision XVII/5, the United States announced the intention to
publish two proposed rules to determine non-essentiality of the vast
majority of CFCs for MDIs in May and June of 2007.  The accelerating
shift by U.S. firms to CFC-free products, as well as the success of
these products in the U.S. market, is reflected in the continued
reduction of CFCs nominated by the United States for essential uses.  

There are several factors that affect the timetable for the introduction
of alternatives and substitutes including:

The length of time necessary for research and development of alternate
products;

The time required to seek U.S. FDA approval of new therapies;

The regulatory process to determine that a medical device is no longer
essential.

The process for determining the essentiality of a product is described
in a final rule developed by the U.S. FDA.  The final rule was published
in the Federal Register on July 24, 2002 (67 FR 48370) (the 2002 final
rule) (corrected in 67 FR 49396, July 30, 2002, and 67 FR 58678,
September 17, 2002).  The rule set standards that U.S. FDA would use for
determining whether the use of an ODS in a medical product is no longer
essential.  The final rule provided that to remove an essential use
designation, FDA must find that: 

At least one non-ODS product with the same active moiety is marketed
with the same route of administration, for the same indication, and with
approximately the same level of convenience of use as the ODS product
containing that active moiety; 

Supplies and production capacity for the non-ODS product(s) exist or
will exist at levels sufficient to meet patient need;

Adequate U.S. postmarketing use data is available for the non-ODS
product(s); and 

Patients who medically required the ODS product are adequately served by
the non-ODS product(s) containing that active moiety and other available
products. 

Furthermore, to remove the essential use designation of an active moiety
marketed in an ODS product represented by one NDA, there must be at
least one acceptable alternative, while for an active moiety marketed in
ODS products and represented by two or more NDAs, there must be at least
two acceptable alternatives (70 FR 17171).  

This is the standard that is being used in the current rulemakings
regarding the essential use status of MDIs where the sole active
ingredient is not salbutamol.

4.	Briefly describe the action plan adopted by the Party pursuant to
paragraphs 4 and 5 of decision XV/5 (providing for plans of action 
including a specific phase-out date for salbutamol CFC MDIs sold or
distributed in non-Article 5 Parties, specific measures and actions
sufficient to deliver the phase-out; and actions and measures needed to
ensure continuing access to or supply of CFC-containing MDIs by Article
5 Parties, where appropriate).  (Decision XV/5, pars. 4 and 5) 

As indicated previously in this document, the United States has
established a

 	phaseout date for the sale of CFC salbutomol products effective
December 31, 2008.  The United States has not traditionally exported CFC
salbutamol products to A5 countries.  However, as part of the U.S.
regulations on production for basic domestic needs, the U.S. does export
CFCs to Article 5 countries to meet their demand for manufacturing MDIs.
 

5.	Describe progress made towards determining and submitting a specific
date by which time the Party will cease making nominations for essential
use exemptions for CFCs for metered-dose inhalers where the active
ingredient(s) is not solely salbutamol and the metered-dose inhalers are
expected to be sold or distributed on the market of any Party not
operating under paragraph 1 of Article 5.  (Decision XV/5, par. 6) 

	The United States began rulemaking processes in 2006 to examine the
potential phaseout of CFC MDIs where the active ingredient is not solely
salbutamol.  U.S. FDA makes a determination on the essentiality of a
product through a public advisory process and accompanying
notice-and-comment rulemaking. This process may be a lengthy one taking
years to complete and is required by domestic law to ensure that an
essentiality determination is made with due consideration.  U.S. FDA has
already held two advisory council meetings, which are a preliminary step
for the agency to begin consideration of this issue.  At the 18th MOP,
in accordance with Decision XVII/5, the United States announced the
intention to publish two proposed rules to determine non-essentiality of
the vast majority of CFCs for MDIs in May and June of 2007.

 

6. 	Explain what substitutes and alternatives to the proposed use are
currently available in the domestic market and, to the extent known, in
each intended market for sale or distribution.  (Decision IV/25, pars.
1(a)(ii), 1(b)(i), 2 and 3(d)) 

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

Product		Drug Delivery System		Active Moiety		Product Approval Date 

Proventil HFA	HFA MDI		Salbutamol			15/08/96

Ventolin HFA                    HFA MDI	Salbutamol			19/04/01

Proais HFA                        HFA MDI	Salbutamol			29/10/04

Xepenex HFA                    HFA MDI                         
Levalbuterol                                     11/03/05	

Q-Var 			HFA MDI		Beclomethasone			15/09/00

Advair Diskus		DPI			Fluticasone/salmeterol		24/08/01

Flovent Diskus		DPI			Fluticasone			29/09/00

Flovent HFA                      HFA MDI		Fluticasone			14/05/04

Pulmicort Turbuhaler        DPI                                    
Budesonide	24/06/97

Serevent Diskus                 DPI                                    
Salmeterol	19/09/97

Asmanex Twisthaler          DPI                                    
Mometasone                                     30/03/05

Atrovent HFA                    HFA MDI                         
Ipratropium                                       27/11/05

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
elsewhere in the nomination, 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).

7. 	Explain steps being taken to implement these substitutes and
alternatives in the domestic market.  (Decision IV/25, pars. 1(a)(ii),
1(b)(i), 2 and 3(d)) 

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

Regulatory Actions to Facilitate Transition

The U.S. has made substantial progress 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, U.S. FDA has approved several new treatments for asthma and
COPD that do not rely on CFCs (see the table under question 6).
Additional alternatives are under review by U.S. FDA. In 2002, U.S. FDA
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.  Lastly, the U.S. Government has
overseen the consistent application of Decisions by the Parties
regarding the allocation of essential use allowances by ensuring that
the amount granted by the Parties is not allocated if it is not needed. 
Over the last several years, the US has continued to allocate essential
use allowances for a reduced amount of CFCs for the manufacture of
essential use MDIs.  

Removing Information Barriers: Government and Industry Activities

To encourage doctor and patient acceptance and use of CFC-free MDIs, MDI
companies in the U.S. are undertaking 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 are taken in accordance
with relevant regulations of U.S. FDA.

The International Pharmaceutical Aerosol Consortium (IPAC), to which
many U.S. MDI manufacturers belong, has also undertaken education
efforts, some with the assistance of the U.S. Environmental Protection
Agency (U.S. EPA).  Government and industry education efforts include
the following:

World Wide Web Sites

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

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 – U.S. EPA, U.S. FDA, 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.

Outreach

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).  U.S. EPA and U.S. FDA participate in meetings of the US
Stakeholders Group on the MDI Transition, which meets under the auspices
of the American Lung Association.

In addition to the activities conducted by IPAC, individual companies in
the pharmaceutical industry promote 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. 

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.

Addressing Economic Barriers

To facilitate the transition away from CFC-based salbutamol MDIs, a
number of U.S. pharmaceutical companies have programs to distribute free
or low-cost HFA based alternatives to underserved populations.  GSK has
established a “Bridges to Access” program which provides GSK drugs
at very low cost to lower-income individuals and families.  A second
major pharmaceutical company, Schering-Plough, established the
“SP-Cares” program, which provides free SP drugs to qualified
low-income uninsured patients.  These patient assistance programs have
the potential to alleviate difficulties that lower-income patients may
have in obtaining the higher-priced salbutamol HFA MDIs.  

These activities were factored into the U.S. FDA determination that
salbutamol CFC MDIs will no loner be “essential” as of the end of
2008 and represent significant progress in the transition away from CFCs
for essential uses in the United States.  U.S. EPA expects these
activities to increase in the next year as patients continue to
transition to salbutamol HFA MDIs.  

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 there are several MDIs with an alternative (non-CFC) propellant
available in the U.S., these products represent only a fraction of the
many drugs currently available in an MDI format.  U.S. FDA regulations
published in 2002 describe the criteria that FDA uses to determine when
it is appropriate to remove the essential use designation from products
that use ozone-depleting substances.  One element of these criteria is
the availability of at least two alternatives for a given use.  In some
instances, such as the essential use designation for salbutamol MDIs,
there are at least two alternatives available to patients and,
therefore, the FDA established a date for a ban on the sale of CFC
salbutamol MDIs.  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 near future.  

The 1993/94 UNEP Technical Options Report lists 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)

Dry Powder Inhalers (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.”	

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, manufacturers include leaflets 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 United States carry a U.S.
notification that the contents of the MDI include CFCs.	

To encourage doctor and patient acceptance and use of CFC-free MDIs, MDI
companies in the United States 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 U.S. FDA.

	

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 U.S. FDA 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 U.S. FDA 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 MDI essential use exemptions participate in regulatory proceedings
with a view toward legitimate environmental, health and safety concerns.

U.S. 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 U.S. FDA]
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 U.S. FDA 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

Knowingly and willingly making a materially false statement or
representation at a hearing that is part of a U.S. FDA rulemaking
process is a felony under U.S. criminal law [18 U.S.C. 1001(a)].

8. 	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 with all due diligence
and/or collaborate with other companies in such efforts. (Decision
VIII/10,   par. 1) 

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

9. 	Describe the steps to minimise emissions of CFCs during the
manufacture of the essential use products.  (Decision IV/25, pars.
1(b)(i), 2 and 3(b); Decision VI/9, 

par. 4; and Decision VIII/10, pars. 6 and 7) 

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.

10. 	Describe the steps being taken to provide a continuity of supply of
asthma 

	and chronic obstructive pulmonary disease treatments to importing 

	non-Article 5(l) countries, Article 5(l) countries and CEIT.  Also
describe the 

	steps being taken by companies to assist their MDI manufacturing
facilities 

	in Parties operating under Article 5(l) and CEIT in upgrading the
technology 

	and capital equipment needed for manufacturing non-CFC asthma and 

	chronic obstructive pulmonary disease treatments.  (Decision VIII/10,
pars. 9 

	and 10) 

	

	Many US pharmaceutical companies have a multinational presence, and
have introduced 

	CFC-free alternatives in 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 CFCs used
in years prior to the first year for which an exemption is requested.

		CFCs Used for MDIs Prior to Nomination (metric tonnes)

Ozone Depleting Substance	1993	1994	1995

CFC-l1, 12, 113, 114 (aggregate)	

2,981.55	

3,044.61	

3,300.2

	Data for years 1995-2006 are provided in the U.S. Reporting Accounting
Framework for

Essential Uses which is provided to the Secretariat on an annual basis.

2.	For the nominated quantities 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 non-essential by an importing
Party has been consulted, and that none of the volumes requested shall
be used for items posted on that list. 

No nominated quantities will be used for a product determined to be
non-essential by an importing Party.

3.	Provide details of the management of the stockpile and any surplus. 
(Decision IV/25, par. 1(b)(ii)) 

The U.S. FDA examines data on holdings of CFCs and recommends
adjustments to the amounts nominated and subsequently allocated through
U.S. EPA regulation to reflect the need for a cushion of a one year
operational supply.  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.”  Any amounts nominated
by the Party reflect the level of essential need in accordance with
Decision XVI/12 taking into account the availability of recycled and
stockpiled ODS.  The calculation of a one year’s operational supply
includes both pre-1996 CFCs and essential use CFCs.

4.	Provide details of the existing stock of pharmaceutical-grade CFCs
(pre- and post-1996) held by the Party requesting an essential use
exemption, describing the quantity (metric tonnes), the quality and 	the
availability for the year prior to the nomination.  Describe how this
stockpile will be utilised in coming years (Decision IV/25, par.
1(b)(ii) and Decision XVI/12, par. 3) 

	Data on aggregate stocks of CFCs held by MDI companies will be provided
with the 2006 accounting framework under separate cover.  EPA will
submit this information in February 2007.  

5.	Confirm that the nominating Party has given due consideration to the
following.  That: 

	a.	Each company's existing stock of pharmaceutical-grade CFCs
(including CFCs the company possesses or has title to, pre- and post-
1996) aims not to exceed one year's operational supply (the amount used
by the company to produce CFC MDIs in the preceding year); 

	b.	The Party's aggregate stocks of pharmaceutical-grade CFCs (pre- and
post-1996) aim not to exceed one year's operational supply for that
Party;  

	c.	The Party’s nomination has been reduced, if necessary, with the
objective of the Party’s aggregate stocks of available pre- and
post-1996 pharmaceutical-grade CFCs not exceeding one year’s
operational supply; and

	d.	All available pre-1996 stockpiles have been, or will be, depleted by
companies before drawing on essential use quantities and thereby assure
that pre-1996 stockpiles are taken into account in making essential use
requests.  (Decision IV/25, par. 1(b)(ii) and Decision XVI/12, par. 3) 

A description of the how the United States treats stocks is provided
above.  The United States aims to ensure no more than a one year
operational supply of stocks (aggregate pre and post 1996) available to
MDI companies and makes reductions to the amount of CFCs nominated and
allocated to reflect this calculation in accordance with the language in
Decision IX/6 and related decisions.

IV. 	Reporting Accounting Framework for Essential Uses Other than
Laboratory and 

	Analytical Applications

The U.S. Accounting Framework will be forwarded to the Ozone Secretariat
under separate cover after January 31, 2006. 

 	The Parties decided in Decision X/6 to approve CFCs in the aggregate
rather than by individual compound.  Therefore, Parties need only
provide the total requested quantity of CFC-11, CFC-12, CFC-113, and/or
CFC-114 in the aggregate.

 	"Use of Ozone-Depleting Substances; Essential-Use Determinations.  67
Federal Register 48370.

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