# NOMINATION OF THE AEROSOL METERED-DOSE INHALER (MDI)

# AS AN ESSENTIAL USE FOR 2008

Country: United States

Contact Person: John Thompson

Title: Division Director

Address: U.S. Department of State

> Washington, DC 20520

Telephone: 202/647-9799

Fax: 202/647-5947

Email: ThompsonJE2@state.gov

Expert Contact Person\*: Hodayah Finman

Title: Team Leader

Address: U.S. Environmental Protection Agency

Office of Air and Radiation (6205J)

> 1200 Pennsylvania Avenue, NW
>
> Washington, DC 20460

Telephone: 202/343-9246

Fax: 202/343-2338

Email: finman.hodayah@epa.gov

*\* Expert(s) in the country who can be contacted for clarification.*

**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.
    (Decision IV/25, pars. 2 and 3)**

> The proposed use is Metered Dose Inhalers (MDI) 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.
>
> 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 U.S. is not requesting CFCs for 2008 for use
> in metered-dose inhalers where the sole active ingredient is
> salbutamol. The U.S. established a phaseout date of December 31, 2008
> for these products, after which time they will be illegal to sell.
>
> It is the intention of the U.S. government not to file a 2008
> essential use exemption request for CFCs for use in metered-dose
> inhalers where the sole active ingredient is salbutamol. However, the
> 2005 and 2006 allocation rules that make CFCs available for essential
> uses were significantly delayed and it is uncertain at this time what
> impact that may have on supplies of salbutamol products in the early
> part of 2008. Therefore, the U.S. reserves the right to submit a 2008
> nomination for use in products where the sole active ingredient is
> salbutamol next year in January 2007 should there be an essential need
> to do so.

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

    Flunisolide, Metaproterenol, Ipratropium and Salbutamol (in
    combination), Pirbuterol, Epinephrine, Triamcinolone, Cromolyn and,
    Nedocromil.

B.  **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, the U.S. is not nominating CFCs for MDIs to meet export
    demand.

C.  **Please indicate below the quantity of CFCs**[^1] **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           2008 Quantity (metric tonnes)

  CFC-11, CFC-12, and CFC-114         384.97 metric tones (see p.15 as
                                      well)
  ----------------------------------- -----------------------------------

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 chronic obstructive pulmonary diseases
(COPD), 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.

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.

> 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 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 cost 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)

The problem is not limited to the Unites 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. As a result, the U.S. government, for the first time since
> the inception of the exemption program, is not nominating CFC MDIs
> where the sole active ingredient is salbutamol for an exemption. The
> United States has begun rulemaking processes this year to examine the
> essentiality of MDIs where the sole active ingredient is not
> salbutamol that use CFCs as well.
>
> The need for an essential use exemption remains while we develop
> suitable alternatives for certain uses or 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
> 2008 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 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.[^2] The rule may be accessed on the USFDA website at
<http://www.accessdata.fda.gov/scripts/oc/ohrms/index.cfm> by searching
for rules published on July 24, 2002. The USFDA 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 salbutamol,
reflecting substantial progress towards phaseout of essential uses in
the U.S. Please see Section 5 of this document for more information on
the USFDA 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, 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
> the amount granted by the Parties is not allocated if it is 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
> if a product using ODSs is no longer medically essential. The USFDA
> finalized their first action to remove the essentiality of a medical
> device in 2004 with the ban on the sale and distribution of CFC
> salbutamol MDIs effective December 31, 2008. 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 more than 50%
> reduction in the 2008 U.S. nomination as compared to the total
> approved by the Parties for the U.S. for consumption in 2007 (the 2008
> amount is approximately one third of the U.S. 2007 nomination).
>
> 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;

```{=html}
<!-- -->
```
-   The time required to seek USFDA 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 USFDA. The final rule was published
> in the Federal Register of 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 FDA would use for
> determining whether the use of an ODS in a medical product is no
> longer essential.
>
> All CFC MDI's where the sole active ingredient is not salbutamol
> currently marketed in the United States do not have acceptable
> alternatives with the same active moieties. The standard to remove an
> essential-use designation for products where there are not adequate
> alternatives available with the same active moiety provide that FDA
> must find that:

-   Substantial technical barriers do not exist to formulating the
    product without ODS;

-   The product does not provide an unavailable important public health
    benefits; and

-   Use of the product releases cumulatively significant amounts of ODS
    into the atmosphere or the release is warranted in view of the
    unavailable important public health benefits.

> 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

phase-out date for the sale of CFC salbutomol products effective
December 31, 2008. The U.S. has not traditionally exported CFC
salbutamol products to A5 countries but the EPA is currently evaluating
the amount of CFCs needed to meet demand for MDIs in Article 5 Parties
as part of the U.S. regulations on production for basic domestic needs.

**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 has begun rulemaking processes this year to examine
the potential phaseout of CFC MDIs where the active ingredient is not
solely salbutamol. USFDA 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. The USFDA has already held
two advisory council meetings, which are a preliminary step for the
agency to begin consideration of this issue. As per Decision XVII/5, the
United States will inform the Ozone Secretariat as to the estimated
dates for publication of these proposed rules prior to the 18^th^ MOP if
the proposed rules have not published by that time or an essential use
is not the subject of one of the current rulemakings.

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]{.underline}

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]{.underline}

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 under question 6). Additional
alternatives are under review by USFDA. 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. 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. 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 more
than 50% reduction in the 2008 U.S. nomination as compared to the total
approved by the Parties for consumption in the U.S. in 2007. In fact,
depending on the outcome of the ongoing rulemaking process, the EPA
allocation of CFCs to manufacturers for 2008 may be substantially lower.

[Removing Information Barriers: Government and Industry
Activities]{.underline}

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.

U.S. pharmaceutical companies have undertaken a number of education
efforts. The International Pharmaceutical Aerosol Consortium (IPAC), to
which many U.S. MDI manufacturers belong, has undertaken the following
education efforts, some with the assistance of the U.S. Environmental
Protection Agency (U.S. EPA). Some of these education efforts include:

-   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 ([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.

-   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). 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.
>
> 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]{.underline}
>
> To facilitate the transition away from CFC based salbutamol MDIs, a
> number of U.S. pharmaceutical companies are creating 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. In addition, GSK's "Orange Card Program" and the "Together
> Rx" program offer eligible Medicare patients the ability to purchase
> drugs at significantly reduced prices. Lastly, GSK intends to annually
> distribute 2 million VENTOLIN HFA MDIs to physicians as samples. A
> second major pharmaceutical company, Schering Plough, established the
> "SP Cares" program, which is similar to GSK's Bridges to Access
> program to distribute free drugs, including PROVENTIL HFA, to
> 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 USFDA 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.
>
> ***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 seven 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. USFDA regulations
> published in 2002 describe the criteria that the Agency 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 patient and, therefore, the USFDA
> 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]{.underline} (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]{.underline} (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]{.underline} (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]{.underline} (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."

> ***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.
>
> ***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 MDI 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

-   Knowingly and willingly making a materially false statement or
    representation at a hearing that is part of a USFDA 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 U.S. 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)      2981.55    3044.61    3300.2
  ------------------------------------- ---------- ---------- ------------

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 USFDA examines data on holdings of CFCs and recommends adjustments
> to the amounts nominated and to the amounts subsequently allocated 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 2005 accounting framework under separate cover.

**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**

Accounting framework to be forwarded to the Ozone Secretariat under
separate cover after January 31, 2006.

[^1]: 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.

[^2]: \"Use of Ozone-Depleting Substances; Essential-Use
    Determinations.\" 67 Federal Register 48370.