[Federal Register Volume 61, Number 69 (Tuesday, April 9, 1996)]
[Rules and Regulations]
[Pages 15699-15700]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-8826]



=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 2

[Docket No. 92P-0403]


Chlorofluorocarbon Propellants in Self-Pressurized Containers; 
Addition to List of Essential Uses

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) has granted the 
petition of Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI), to add 
metered-dose albuterol sulfate and ipratropium bromide in combination 
for oral inhalation to the list of products containing a 
chlorofluorocarbon (CFC) propellant for an essential use. Essential use 
products are exempt from FDA's ban on the use of CFC propellants in 
FDA-regulated products and the Environmental Protection Agency's 
(EPA's) ban on the use of CFC's in pressurized dispensers. This 
document amends FDA's regulations governing use of CFC's to include 
metered-dose albuterol sulfate and ipratropium bromide in combination 
for oral inhalation as an essential use.

EFFECTIVE DATE: April 9, 1996.

FOR FURTHER INFORMATION CONTACT: Wayne H. Mitchell, Center for Drug 
Evaluation and Research (HFD-097), Food and Drug Administration, 7500 
Standish Pl., Rockville, MD 20855, 301-594-1049.

SUPPLEMENTARY INFORMATION:

I. Background

    In response to a citizen petition submitted by BIPI, in the Federal 
Register of October 17, 1995 (60 FR 53725), FDA published a proposed 
rule to amend 1A2.125 (21 CFR 2.125) to add metered-dose albuterol 
sulfate and ipratropium bromide in combination for oral inhalation to 
the list of productscontaining a CFC propellant for an essential use.
    Under 1A2.125, any food, drug, device, or cosmetic in a self-
pressurized container that contains a CFC propellant for a nonessential 
use is adulterated or misbranded, or both, under the Federal Food, 
Drug, and Cosmetic Act. This prohibition is based on scientific 
research indicating that CFC's may reduce the amount of ozone in the 
stratosphere and thereby increase the amount of ultraviolet radiation 
reaching the earth. An increase in ultraviolet radiation may increase 
the incidence of skin cancer, change the climate, and produce other 
adverse effects of unknown magnitude on humans, animals, and plants. 
Section 2.125(d) exempts from the adulteration and misbranding 
provisions of 1A2.125(c) certain products containing CFC propellants 
thatFDA determines provide unique health benefits that would not be 
available without the use of a CFC. These products are referred to in 
the regulation as essential uses of CFC's and are listed in 1A2.125(e).
    Under 1A2.125(f), any person may petition the agency to request 
additions to the list of uses considered essential. To demonstrate that 
the use of a CFC is essential, the petition must be supported by an 
adequate showing that: (1) There are no technically feasible 
alternatives to the use of a CFC in the product; (2) the product 
provides a substantial health, environmental, or other public benefit 
unobtainable without the use of the CFC; and (3) the use does not 
involve a significant release of CFC's into the atmosphere or, if it 
does, the release is warranted by the consequence if the use were not 
permitted.
     EPA regulations implementing provisions of the Clean Air Act 
contain a general ban on the use of CFC's in pressurized dispensers, 
such as metered-dose inhalers (MDI's) (40 CFR 82.64(c) and 82.66(d)). 
These regulations exempt from the general ban ``medical devices'' that 
FDA considers essential and that are listed in 1A2.125(e). Section 
601(8) of the Clean Air Act (42 U.S.C. 7671(8)) defines ``medical 
device'' as any device (as defined in the Federal Food, Drug, and 
Cosmetic Act), diagnostic product, drug (as defined in the Federal 
Food, Drug, and Cosmetic Act), and drug delivery system, if such 
device, product, drug, or drug delivery system uses a class I or class 
II ozone-depleting substance for which no safe and effective 
alternative has been developed (and where necessary, approved by the 
Commissioner of Food and Drugs (the Commissioner)); and if such device, 
product, drug, or drug delivery system has, after notice and 
opportunity for public comment, been approved and determined to be 
essential by the Commissioner in consultation with the Administrator of 
EPA (the Administrator). Class I substances include CFC's, halons, 
carbon tetrachloride, methyl chloroform, methyl bromide, and other 
chemicals not relevant to this document (see 40 CFR part 82, appendix A 
to subpart A). Class II substances include hydrochlorofluorocarbons 
(HCFC's)(see 40 CFR part 82, appendix B to subpart A).

II. Petition Received by FDA

    BIPI submitted a petition under 1A2.125(f) and 21 CFR part 10 
requesting an addition to the list of CFC uses considered essential. 
The petition is on file under the docket number found in brackets in 
the heading of this document and may be seen in the Dockets Management 
Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 
10923, Rockville, MD 20857. The petition requested that metered-dose 
albuterol sulfate and ipratropium bromide in combination for oral 
inhalation be included in 1A2.125(e) as an essential use of CFC's. The 
petition contained a discussion supporting the position that there are 
no technically feasible alternatives to the use of CFC's in the 
product. It included information showing that no alternative delivery 
systems (e.g., the dry powder inhaler) or other substitute propellants 
(e.g., compressed gases) can dispense the drug for effective inhalation 
therapy as safely and uniformly, in all situations, as CFC propellants. 
Also, the petition stated that the product provides a substantial 
health benefit that would not be obtainable without the use of CFC's. 
In this regard, the petition contained information to support the use 
of this product as a combination bronchodilator. The petition asserted 
that metered-dose albuterol sulfate andipratropium bromide in 
combination potentially reduces the amount of CFC's released into the 
atmosphere attributable to patients using one MDI for the combination 
product, rather than two MDI's, one for each of the two active 
ingredients.
    The agency has determined that, for some chronic obstructive 
pulmonary disease patients, the use of metered-dose albuterol sulfate 
and ipratropium bromide in combination provides a special benefit that 
would be unavailable without the use of CFC's,

[[Page 15700]]
and that the use of the drugs in combination has the potential to 
reduce the amount of CFC's released into the atmosphere. In this 
regard, FDA notes that albuterol sulfate and ipratropium bromide are 
currently listed separately (i.e., not in combination) in 1A2.125(e) as 
essential uses of CFC's. Based on the evidence currently before it, FDA 
also agrees that the use of a metered-dose delivery system for this 
product does not involve asignificant release of CFC's into the 
atmosphere. Therefore, FDA is amending 1A2.125(e) to include metered-
dose albuterol sulfate and ipratropium bromide in combination for oral 
inhalation in the list of essential uses of CFC propellants.
    A copy of the proposed rule was provided to the Administrator.

III. Comments on the Proposed Rule

    Interested persons were given 30 days to comment on the proposed 
rule. FDA received one comment regarding the proposed rule. The comment 
pointed out that CFC-free MDI's for albuterol sulfate and other drugs 
are generally expected to be developed and marketed in the near future, 
and that the availability of alternative propellants will undercut the 
factual basis for FDA's determination that the use of CFC's in MDI's is 
medically necessary. The comment suggested that FDA's determination be 
made conditionally, and that FDA reexamine the ``medical essentiality'' 
of the MDI if and when a CFC-free albuterol sulfate MDI is approved. 
The comment also suggested that future rulemaking may be necessary to 
provide for the transition between MDI's containing CFC's and CFC-free 
MDI's.
    FDA is aware of the development of CFC-free MDI's and shares the 
comment's concerns that proper provision should be made for the 
transition between MDI's containing CFC's and CFC-free MDI's. FDA, 
working with EPA, is developing a policy on this matter at this time, 
and anticipates that a rulemaking procedure may be necessary to 
implement that policy. Section 2.125 does not provide for a 
``conditional'' listing as an essential use and to provide for such a 
``conditional'' listing in this rule would be beyond the scope of the 
proposal. Any phase-out or reformulation requirement for MDI's 
containing albuterol sulfate and ipratropium bromide in combination 
undertaken because of the availability of alternative propellants will 
be undertaken as part of a properly implemented general policy on the 
elimination of CFC's from MDI's and other similar products.

IV. Analysis of Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354). 
Executive Order 12866 directs agencies to assess all costs and benefits 
of available regulatory alternatives and, when regulation is necessary, 
to select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this final rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. In addition, the final 
rule is not a significant regulatory action as defined by the Executive 
Order and so is not subject to review under the Executive Order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because the agency is not aware of any adverse 
impact this final rule will have on any small entities, the agency 
certifies that the final rule will not have a significant economic 
impact on a substantial number of small entities. Therefore, under the 
Regulatory Flexibility Act, no further analysis is required.

List of Subjects in 21 CFR Part 2

    Administrative practice and procedure, Cosmetics, Devices, Drugs, 
Foods.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
2 is amended as follows:

PART 2--GENERAL ADMINISTRATIVE RULINGS AND DECISIONS

    1. The authority citation for 21 CFR part 2 continues to read as 
follows:

    Authority: Secs. 201, 301, 305, 402, 408, 409, 501, 502, 505, 
507, 512, 601, 701, 702, 704 of the Federal Food, Drug, and Cosmetic 
Act (21 U.S.C. 321, 331, 335, 342, 346a, 348, 351, 352, 355, 357, 
360b, 361, 371, 372, 374); 15 U.S.C. 402, 409.

    2. Section 2.125 is amended by adding new paragraph (e)(14) to read 
as follows:


 Sec. 2.125  Use of chlorofluorocarbon propellants in self-pressurized 
containers.

 * * * * *
    (e) * * *
    (14) Metered-dose ipratropium bromide and albuterol sulfate, in 
combination, administered by oral inhalation for human use.
 * * * * *

    Dated: March 29, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-8826 Filed 4-8-96; 8:45 am]
BILLING CODE 4160-01-F