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

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.

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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,

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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