25142 Federal Register / Vol. 61, No. 98 / Monday, May 20, 1996 / Rules and Regulations

conditions existing or anticipated at the

affected airports.

The FAA has determined through

testing that current non-localizer type,

non-precision instrument approaches

developed using the TERPS criteria can

be flown by aircraft equipped with

Global Positioning System (GPS)

equipment. In consideration of the

above, the applicable Standard

Instrument Approach Procedures

(SIAPs) will be altered to include ‘‘or

GPS’’ in the title without otherwise

reviewing or modifying the procedure.

(Once a stand alone GPS procedure is

developed, the procedure title will be

altered to remove ‘‘or GPS’’ from these

non-localizer, non-precision instrument

approach procedure titles.) Because of

the close and immediate relationship

between these SIAPs and safety in air

commerce, I find that notice and public

procedure before adopting these SIAPs

are, impracticable and contrary to the

public interest and, where applicable,

that good cause exists for making some

SIAPs effective in less than 30 days.

The FAA has determined that this

regulation only involves an established

body of technical regulations for which

frequent and routine amendments are

necessary to keep them operationally

current. It, therefore—(1) is not a

‘‘significant regulatory action’’ under

Executive Order 12866; (2) is no a

‘‘significant rule’’ under DOT

Regulatory Policies and Procedures (44

FR 11034; February 26, 1979); and (3)

does not warrant preparation of a

regulatory evaluation as the anticipated

impact is so minimal. For the same

reason, the FAA certifies that this

amendment will not have a significant

economic impact on a substantial

number of small entities under the

criteria of the Regulatory Flexibility Act.

List of Subjects in 14 CFR Part 97

Air Traffic Control, Airports,

Navigation (Air).

Issued in Washington, DC on May 3, 1996.

Thomas C. Accardi,

Director, Flight Standards Service.

Adoption of the Amendment

Accordingly, pursuant to the

authority delegated to me, part 97 of the

Federal Aviation Regulations (14 CFR

part 97) is amended by establishing,

amending, suspending, or revoking

Standard Instrument Approach

Procedures, effective at 0901 UTC on

the dates specified, as follows:

PART 97—STANDARD INSTRUMENT

APPROACH PROCEDURES

1. The authority citation for part 97 is

revised to read as follows:

Authority: 49 U.S.C. 40103, 40113, 40120,

44701; 49 U.S.C. 106(g); and 14 CFR

11.49(b)(2).

2. Part 97 is amended to read as

follows:

§§ 97.23, 97.27, 97.33, 97.35 [Amended]

By amending: § 97.23 VOR, VOR/

DME, VOR or TACAN, and VOR/DME

or TACAN; § 97.27 NDB, NDB/DME;

§ 97.33 RNAV SIAPs; and § 97.35

COPTER SIAPs, identified as follows:

* * * Effective June 20, 1995

Mountain Home, AR, Baxter County

Regional, VOR/DME RNAV or GPS RWY 5,

Amdt IA CANCELLED

Mountain Home, AR, Baxter County

Regional, VOR/DME RNAV RWY 5, Amdt

IA Paragould, AR, Kirk Field, VOR or GPS

RWY 4, Amdt 3A CANCELLED

Paragould, AR, Kirk Field, VOR RWY 4,

Amdt 3A

Vacaville, CA, Nut Tree, RNAV or GPS RWY

20, Amdt 1 CANCELLED

Vacaville, CA, Nut Tree, RNAV RWY 20,

Amdt 1

Harrisburg, IL, Harrisburg-Raleigh, NDB or

GPS RWY 24, Amdt. 9 CANCELLED

Harrisburg, IL, Harrisburg-Raleigh, NDB RWY

24, Amdt. 9

Winfield/Arkansas City, KS, Strother Field,

NDB or GPS RWY 35, Amdt. 3A

CANCELLED

Winfield/Arkansas City, KS, Strother Field,

NDB, RWY 35, Amdt. 3A

Houma, LA, HounaTerrebonne, NDB or GPS

RWY 18, Amdt. 4A CANCELLED

Houma, LA, HounaTerrebonne, NDB RWY

18, Amdt. 4A

Corinth, MS, Roscoe Turner, NDB or GPS

RWY 17, Amdt. 8 CANCELLED

Corinth, MS, Roscoe Turner, NDB RWY 17,

Amdt. 8

Portales, NM, Portales Muni, NDB or GPS

RWY 1, Orig. CANCELLED

Portales, NM, Portales Muni, NDB RWY 1,

Orig.

Alice, TX, Alice Intl, VOR or GPS RWY 31,

Amdt. 11 CANCELLED

Alice, TX, Alice Intl, VOR RWY 31, Amdt.

11

Alpine, TX, Alpine-Casparis Municipal, NDB

or GPS RWY 19, Amdt. 5 CANCELLED

Alpine, TX, Alpine-Casparis Municipal, NDB

RWY 19, Amdt. 5

Ballinger, TX, Bruce Field, NDB or GPS RWY

35, Amdt. 1 CANCELLED

Ballinger, TX, Bruce Field, NDB RWY 35,

Amdt. 1

Houston, TX, Houston Gulf, VOR or GPS

RWY 31, Amdt 1A CANCELLED

Houston, TX, Houston Gulf, VOR RWY 31,

Amdt 1A

Monahans, TX, Roy Hurd Memorial, VOR/

DME or GPS RWY 12, Amdt. 1

CANCELLED

Monahans, TX, Roy Hurd Memorial, VOR/

DME RWY 12, Amdt. 1

Palestine, TX, Palestine Muni, NDB or GPS

RWY 35, Amdt. 7 CANCELLED

Palestine, TX, Palestine Muni, NDB RWY 35,

Amdt. 7

Fond Du Lac, WI, Fond Du Lac County, VOR/

DME or GPS RWY 36, Amdt. 6

CANCELLED

Fond Du Lac, WI, Fond Du Lac County, VOR/

DME RWY 36, Amdt. 6

Sparta, WI, Sparta/Fort Mc Coy, NDB or GPS

RWY 29, Amdt. 1 CANCELLED

Sparta, WI, Sparta/Fort Mc Coy, NDB RWY

29, Amdt. 1

Summersville, WV, Summersville, NDB or

GPS RWY 4, Amdt. 2 CANCELLED

Summersville, WV, Summersville, NDB RWY

4, Amdt. 2

[FR Doc. 96–12639 Filed 5–17–96; 8:45 am]

BILLING CODE 4910–13–M

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 310 and 341

[Docket No. 94N–0247]

RIN 0910–AA01

Cold, Cough, Allergy, Bronchodilator,

and Antiasthmatic Drug Products for

Over-the-Counter Human Use;

Amendment of Monograph for OTC

Bronchodilator Drug Products

AGENCY: Food and Drug Administration,

HHS.

ACTION: Final rule.

SUMMARY: The Food and Drug

Administration (FDA) is amending the

final monograph for over-the-counter

(OTC) bronchodilator drug products by

removing pressurized metered-dose

aerosol container dosage forms for the

ingredients epinephrine, epinephrine

bitartrate, and racepinephrine

hydrochloride. This action is being

taken because the OTC marketing of

such drug products will require an

approved application containing certain

information not required by the

monograph. The agency is also

amending the regulation that lists

nonmonograph active ingredients by

adding any ingredient(s) in a

pressurized metered-dose aerosol

container for OTC bronchodilator drug

products. This final rule is part of the

ongoing review of OTC drug products

conducted by FDA.

EFFECTIVE DATE:June 19, 1996.

FOR FURTHER INFORMATION CONTACT:

William E. Gilbertson, Center for Drug

Evaluation and Research (HFD–105),

Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857,

301–827–2304.

SUPPLEMENTARY INFORMATION:

I. Background

In the Federal Register of October 2,

1986 (51 FR 35326), FDA issued a final

monograph establishing conditions
Federal Register / Vol. 61, No. 98 / Monday, May 20, 1996 / Rules and Regulations 25143

under which OTC bronchodilator drug

products are generally recognized as

safe and effective and not misbranded.

Section 341.76(d)(2)(i) (21 CFR

341.76(d)(2)(i)) provides for products

containing epinephrine, epinephrine

bitartrate, and racepinephrine

hydrochloride for use in a pressurized

metered-dose aerosol container

(hereinafter referred to as an inhaler or

MDI). The agency stated in the final

monograph (51 FR 35326 at 35333 to

35334) that data and information

available at that time concerning the

technology to produce reliable MDI

dosage forms allowed the agency to

generally recognize OTC MDI drug

products as safe and effective. Further,

the agency had anticipated that MDI

drug products would continue to

contain a chlorofluorocarbon (CFC)

propellant and that marketing would

continue under approved applications,

as stated in § 2.125(d) (21 CFR 2.125(d)),

containing information on

manufacturing controls for the MDI.

In the Federal Register of March 9,

1995 (60 FR 13014), FDA issued a notice

of proposed rulemaking to amend the

final monograph for OTC bronchodilator

drug products to remove pressurized

MDI aerosol container dosage forms for

the ingredients epinephrine,

epinephrine bitartrate, and

racepinephrine hydrochloride. The

agency also proposed to amend the

regulation that lists nonmonograph

active ingredients to add any

ingredient(s) in a pressurized MDI

aerosol container for OTC

bronchodilator drug products.

In the proposal, the agency discussed

several developments that changed its

view about the inclusion of pressurized

MDI dosage forms in the final

monograph for OTC bronchodilator drug

products. The agency determined that

an assessment of the safety and

effectiveness of each MDI aerosol drug

product must be made based on a

reconsideration of the nature of MDI

aerosol drug products, potential future

reformulations to include new

propellants, and the recommendations

of various international workshops and

FDA advisory committee discussions.

The agency proposed that all MDI

aerosol dosage forms must have

premarket approval to ensure their

safety and effectiveness.

Interested persons were invited to file

by May 23, 1995, written comments or

objections on the proposed regulation.

Interested persons were invited to file

comments on the agency’s economic

impact determination by May 23, 1995.

In response to the proposal, one drug

manufacturer and an association of

pharmaceutical scientists submitted

comments. Copies of the comments are

on public display in the Dockets

Management Branch (HFA–305), Food

and Drug Administration, 12420

Parklawn Dr., rm. 1–23, Rockville, MD

20857. Final agency action on OTC MDI

aerosol drug products containing

epinephrine, epinephrine bitartrate, and

racepinephrine hydrochloride occurs

with the publication of this final rule

amending the final monograph for OTC

bronchodilator drug products.

As discussed in the proposal (60 FR

13014), the agency advised that the

conditions under which the drug

products that are subject to this

amendment to the final monograph will

no longer be generally recognized as

safe and effective and are misbranded

(nonmonograph conditions) will be

effective 30 days after the date of

publication in the Federal Register.

Therefore, on or after June 19, 1996, no

OTC drug product that is subject to the

monograph and that contains a

nonmonograph condition, i.e., a

condition that would cause the drug to

be not generally recognized as safe and

effective or to be misbranded, may be

initially introduced or initially

delivered for introduction into interstate

commerce unless it is the subject of an

approved application or abbreviated

application (hereinafter called

application). Manufacturers are

encouraged to comply voluntarily with

the final rule at the earliest possible

date.

All ‘‘OTC Volumes’’ cited throughout

this document refer to the submissions

made by interested persons pursuant to

the call-for-data notice published in the

Federal Register of August 9, 1972 (37

FR 16029), or to additional information

that has come to the agency’s attention

since publication of the advance notice

of proposed rulemaking. The volumes

are on public display in the Dockets

Management Branch.

II. The Agency’s Conclusions on the

Comments

One comment, from a pharmaceutical

scientists’ association, agreed with the

agency’s proposal to amend the final

monograph for OTC bronchodilator drug

products to remove MDI aerosol dosage

forms for the ingredients epinephrine,

epinephrine bitartrate, and

racepinephrine hydrochloride. The

comment also agreed that such products

should have premarket approval to

ensure their safety and effectiveness.

The comment explained that changes in

an MDI aerosol could have significant

effects on the distribution

characteristics of the drug in the

airways, produce a pharmacological

interaction, and/or enhance toxicity of

the drug product. With the phaseout of

CFC-containing propellants in MDI

aerosol drug products, the comment

mentioned that the safety and

effectiveness of the replacement

propellants in these products will need

to be established.

The comment stated that

appropriately focused and welldesigned clinical studies will be

necessary to establish the clinical safety

and effectiveness of new non-CFCcontaining MDI aerosol formulations.

New chemistry, manufacturing, and

controls evaluations will be needed to

document that the new formulation is

compatible with the bronchodilator

active ingredient and that drug delivery

from the new system is comparable to

the old system. The comment added

that much of the testing needed to

confirm the integrity and proper

functioning of MDI aerosol drug

products containing non-CFC

propellants can be determined by in

vitro testing. Such testing could

determine particle size, total canister

contents, and consistency and

reproducibility of dose delivery through

the life of the dosage form, as well as

assess drug related impurities and

leakage rate.

The comment expressed some

concern about epinephrine, epinephrine

bitartrate, and racepinephrine

hydrochloride used in a hand-held

rubber bulb nebulizer. The comment

stated that the agency’s concerns about

MDI aerosol dosage forms, particularly

changes in the distribution

characteristics of the drug in the

airways, are equally applicable to handheld rubber bulb nebulizers and

spraying devices currently available.

The comment also questioned the

emphasis placed on many of the

comments and conclusions drawn by

the authors of articles cited within the

proposed amendment because many of

those references did not provide details

of the composition of MDI aerosol drug

products discussed. The comment did

not specify which references failed to

provide sufficient details.

Another comment, from a drug

manufacturer, disagreed with the

agency’s proposal. The comment

claimed that the proposal does not

provide a reasonable basis to support

the revocation of the ‘‘generally

recognized as safe and effective’’ status

of these OTC MDI aerosol drug

products. The comment contended that

the proposal raises questions about the

safety and effectiveness of these drug

products in the absence of any data

showing that epinephrine-containing

MDI aerosol drug products are not safe

and effective when used according to
25144 Federal Register / Vol. 61, No. 98 / Monday, May 20, 1996 / Rules and Regulations

the labeling. The comment stated that

the safety information discussed in the

proposal relates to MDI aerosol products

containing albuterol, and it does not

raise any questions with respect to the

safety of epinephrine-containing MDI

aerosol drug products. The comment

argued that because all CFC-containing

MDI aerosol drug products must now be

the subject of an approved new drug

application (NDA), there is no public

health issue concerning these drug

products and, therefore, no need for this

proposed monograph amendment.

The comment added that in the final

monograph for OTC bronchodilator drug

products (51 FR 35326 at 35333), the

agency recognized that manufacturer

compliance with FDA’s current good

manufacturing practice (CGMP)

regulations would adequately address

the control of the quality of drug

product containers, components, and

the drug product itself, and that specific

requirements for MDI aerosol drug

delivery systems in the monograph were

unnecessary. The comment indicated

that while CGMP compliance is

important to assure the proper use of

MDI aerosol delivery systems, the

proposed amendment provides no

evidence that CGMP compliance is a

concern for currently-marketed

epinephrine MDI aerosols.

The comment agreed with the agency

that non-CFC propellants could render

an MDI aerosol product a ‘‘new drug’’

under § 310.3(h)(1) (21 CFR 310.3(h)(1)).

In that case, additional data would be

required to support safety and

effectiveness. However, the comment

argued that new propellant formulations

can be reviewed under an NDA without

revoking the OTC monograph status of

currently marketed CFC-containing MDI

aerosol formulations.

The comment mentioned that the

proposal to remove OTC MDI aerosol

drug products from the final monograph

for OTC bronchodilator drug products is

not based on the deliberations of any

advisory committee and is in conflict

with the determination of the Advisory

Review Panel on OTC Cold, Cough,

Allergy, Bronchodilator, and

Antiasthmatic Drug Products that

epinephrine-containing OTC MDI

aerosol drug products are ‘‘generally

recognized as safe and effective.’’ The

comment stated that the agency should

withdraw the proposal until such time

as an advisory committee has reviewed

the data and voted on a

recommendation.

The comment also expressed concern

that the agency’s action could

unnecessarily raise the data burden of

NDA’s for epinephrine-containing, CFCpropelled MDI’s by imposing, without

justification, new safety and

effectiveness data requirements that are

satisfied by the current monograph

status. The comment noted that in

§ 330.11 (21 CFR 330.11), if an OTC

drug product meets all the conditions of

an applicable monograph, only a review

of information pertaining to deviations

from those conditions is necessary. The

comment contended that § 330.11

encourages innovation and

improvement in the pharmaceutical

industry without unnecessary regulatory

delays and unjustified data burdens.

The comment added that, if new NDA’s

need to be submitted, the additional

data required could have the effect of

forcing from the market a product that

has been the subject of an approved

NDA and has had a safe marketing

history for many years. Therefore, for

these reasons, the comment requested

that the agency withdraw the proposed

amendment and take no further steps to

complete this rulemaking.

The agency has considered the

information presented by the comments

and determined that marketing of

pressurized MDI aerosol bronchodilator

drug products containing CFC

propellants requires an approved NDA

containing information beyond that

required by the final monograph for

OTC bronchodilator drug products.

Since publication of that final

monograph in 1986, the agency has

reconsidered the nature of MDI aerosol

drug products, potential future

reformulations to include new

propellants, and the recommendations

of various international organizations

and agency advisory committees

concerning the regulatory and data

requirements needed to assure the

clinical community and patients of the

safety and effectiveness of MDI aerosol

drug products.

In the proposed monograph

amendment (60 FR 13014 to 13020), the

agency discussed several specific

developments that have changed its

views about MDI aerosol dosage forms.

These included: (1) Recent publications

reporting chemistry, manufacturing, and

controls problems resulting from

changes to the container and closure

system of redesigned MDI aerosol

dosage forms; (2) the need for safety and

effectiveness data for the new drug

products as a result of those chemistry,

manufacturing, and controls changes;

(3) international workshops and FDA

advisory committee discussions

focusing on regulatory requirements for

modifications to an approved innovator

MDI and bioequivalence of generic MDI

aerosol drug products; (4) legislation

that requires a phaseout of ozonedepleting substances, including CFC

propellants in MDI aerosol drug

products; and (5) the need for safety

data on the alternative propellants that

will replace CFC’s in MDI aerosol

dosage forms, as well as evidence that

the new MDI’s deliver the drug

effectively.

The agency’s decision to remove

epinephrine ingredients in pressurized

MDI aerosol dosage forms from the final

monograph for OTC bronchodilator drug

products is not based on a specific

safety or effectiveness concern that has

been identified for any of the currently

marketed OTC MDI aerosol drug

products. All such products are

currently the subject of an approved

NDA based on agency regulations in

§ 2.125(d). The removal of these OTC

drug products from the monograph is

being done to ensure continued safety

and effectiveness of these products and

to provide a regulatory basis for

adequate regulation of the manufacture

of all future OTC MDI aerosol drug

products, including those with the new

propellants. This action is based on the

agency’s increased awareness that minor

modifications in the manufacturing

procedures of these products and the

proposed phaseout of CFC propellants

have the potential for substantial impact

on the safety and effectiveness of these

OTC drug products and are not

adequately addressed by CGMP

guidelines.

In response to the comment regarding

the ‘‘generally recognized as safe and

effective’’ status of currently marketed

OTC MDI aerosol drug products

containing epinephrine, epinephrine

bitartrate, and racepinephrine

hydrochloride, the agency maintains

that its preclearance of these products

under NDA’s alleviates concerns about

the safety and effectiveness of these

drug products. However, the agency

now considers preclearance of the

manufacturing processes of these

products an important part of assuring

their continued safe and effective use.

The agency points out that the safety

information discussed in the proposal

relates not only to MDI aerosol drug

products containing albuterol, but to all

such products in pressurized MDI

dosage form. Recent data presented to

the agency indicate that variability in

the performance of an MDI aerosol may

result from the physical characteristics

of the drug substance, formulation

differences, valve and actuator design,

and the adequacy of control parameters,

specifications, and test methods for each

component and the final drug product.

Design modification of any component

of the drug product may result in

significant alterations of the dose

delivered to the lung. In addition,
Federal Register / Vol. 61, No. 98 / Monday, May 20, 1996 / Rules and Regulations 25145

changes in the source or the

composition of the drug product may

introduce unknown contamination or

impurities (extractables) when the

propellant comes in contact with the

plastic or rubber components of the

canister (Ref. 1).

Because all currently marketed OTC

CFC-containing MDI aerosols containing

epinephrine are the subject of approved

applications, the agency does not agree

with one comment that this monograph

amendment will require additional data

or new applications to support the

safety and effectiveness of these

bronchodilator drug products. Based on

agency preclearance under existing

applications, the safety and

effectiveness of currently marketed OTC

MDI drug products are not in question.

However, the agency does consider it

necessary that OTC marketing of new or

reformulated MDI aerosol drug products

or products manufactured by a different

manufacturer or in a different facility

require preclearance via an approved

application containing information not

required by the monograph to assure the

continued safe and effective use of these

drug products.

An NDA deviation (§ 330.11) applies

to products whose ingredient(s) is

included in an OTC drug monograph.

OTC MDI aerosol drug products already

require an NDA for marketing because

of the CFC propellants (§ 2.125(d)). A

change in manufacturing procedures

may only require a supplement to an

NDA. If a change in manufacturing

facilities occurs or a product is

manufactured by a different company,

the affected manufacturer should

consult with the agency to ascertain

what will be required in the

supplemental application.

In the proposed amendment (60 FR

13014 at 13018), the agency cited

several international workshops and

agency advisory committee discussions

that identified the regulatory

requirements necessary to determine the

safety and effectiveness of reformulated

bronchodilator drug products. The

Commission of the European

Communities, the Drug Information

Association, and the agency’s Generic

Drugs Advisory Committee with

representatives from the PulmonaryAllergy Drugs Advisory Committee

(Refs. 2, 3, and 4, respectively) agreed

that any change in excipients (including

propellants) might result in changes in

drug deposition patterns within the lung

and might affect absorption and

systemic safety. Further, these

organizations and committees stated

that premarket approval is essential to

ensure the identity, strength, quality,

and purity of pressurized OTC and

prescription bronchodilator drug

products.

In response to some of the comment’s

concerns regarding the use of

ephinephrine, epinephrine bitartrate,

and racepinephrine hydrochloride in

hand-held rubber bulb nebulizers, the

agency agrees that some of these

concerns about MDI aerosol dosage

forms, particularly changes in the

distribution characteristics of the drug

in the airways, are equally applicable to

hand-held rubber bulb nebulizers and

spraying devices. The agency intends to

reexamine the use of these OTC

bronchodilator drugs in hand-held

rubber bulb nebulizers in a future issue

of the Federal Register.

The agency does not agree with one

comment that this amendment should

be withdrawn until an advisory

committee has provided its

recommendation. As stated earlier, the

agency is not questioning the safety and

effectiveness of currently marketed OTC

MDI aerosol drug products. However,

the agency considers it necessary to

review and evaluate the manufacturing

controls for these drug products to

assure their continued safe and effective

use. This monograph amendment deals

with process issues (the procedure by

which the product gets on the market or

how manufacturing changes occur), and

in this particular case the agency does

not consider it necessary to bring this

amendment to an advisory committee

for deliberation. However, in some

cases, it may be appropriate to bring

procedural issues to an advisory

committee.

In the proposed monograph

amendment (60 FR 13014 at 13020), the

agency indicated that there is a statutory

phaseout of CFC propellants used in

these MDI aerosol products, although an

exemption for MDI’s for the treatment of

asthma and chronic obstructive

pulmonary disease exists through 1997.

Based on the intended phaseout of CFCcontaining propellants in MDI aerosol

dosage forms, the agency is aware that

the pharmaceutical and other industries

are investigating alternative propellants

to replace CFC’s in MDI’s. Given the

complexity of MDI aerosol formulations

and the interdependence of each of the

MDI components, the agency is

concerned that the use of new

excipients, including non-CFCcontaining propellants, could change

the distribution characteristics of the

MDI bronchodilator drug in the airways,

produce a pharmacological interaction,

or enhance toxicity of the active drug

substance. Such changes in MDI aerosol

formulations might alter pulmonary

absorption, potentially resulting in

changes in the safety and/or therapeutic

effectiveness of the bronchodilator drug

product. Thus, the agency intends to

require manufacturers who reformulate

currently approved MDI aerosol drug

products with new propellants to

submit additional data or a new NDA to

demonstrate that inhalation and

ingestion of new formulations will not

result in local tissue irritation effects or

other undesirable consequences, such as

loss of effectiveness or local retention,

resulting from inappropriate drug

deposition characteristics. The

additional data must include an

assessment of the absorption,

distribution, and retention

characteristics of new propellant

systems in man following inhalation.

Drug deposition profiles including the

quantity of drug reaching the respiratory

airways and its depth of penetration

must also be characterized.

Based on the above discussion, the

agency considers it essential that any

reformulated MDI aerosol (including use

of a new propellant or component

design alterations) have premarket

approval under an approved NDA to

ensure the safety and effectiveness of

the bronchodilator drug product.

Therefore, the agency is removing the

ingredients epinephrine, epinephrine

bitartrate, and racepinephrine

hydrochloride in pressurized MDI

aerosol dosage forms from the final

monograph for OTC bronchodilator drug

products because such products will

continue to require an approved NDA

containing certain information not

required by the monograph. However,

the monograph status of these

ingredients when used in a hand-held

rubber bulb nebulizer is not changed.

Such products will remain in the final

monograph at this time.

III. References

The following references are on

display in the Dockets Management

Branch (address above) and may be seen

by interested persons between 9 a.m.

and 4 p.m., Monday through Friday.

(1) Adams, W. P. et al., ‘‘Regulatory

Aspects of Modifications to Innovator

Bronchodilator Metered Dose Inhalers and

Development of Generic Substitutes,’’ Journal

of Aerosol Medicine, 7:119–134, 1994.

(2) ‘‘Report of the Commission of the

European Communities’ Committee for

Proprietary Medicinal Products, Matters

Relating to the Replacement of CFCs in

Medicinal Products,’’ December 15, 1993, in

OTC Vol. 04BFMA3.

(3) Drug Information Association, MDI’s in

the Milennium: Workshop on Regulatory

Issues of Efficacy, Safety, and Quality with

Metered Dose Inhalers (MDI’s) Drug Dosage

Forms, October 18 and 19, 1993, in OTC Vol.

04BFMA3.

(4) Transcripts of the FDA Generic Drugs

Advisory Committee Meeting with
25146 Federal Register / Vol. 61, No. 98 / Monday, May 20, 1996 / Rules and Regulations

Pulmonary-Allergy Drugs Advisory

Committee Representation, September 14 and

15, 1993, identified as TS, Docket No. 94N–

0247, Dockets Management Branch.

IV. The Agency’s Final Conclusions

In this amendment, the agency is

removing the ingredients epinephrine,

epinephrine bitartrate, and

racepinephrine hydrochloride in

pressurized MDI aerosol dosage forms

from the final monograph for OTC

bronchodilator drug products.

Accordingly, the agency is amending

§ 341.76(d)(2) to remove

§ 341.76(d)(2)(i)(a) and (d)(2)(i)(b). The

agency is also amending

§ 310.545(a)(6)(iv) for bronchodilator

drug products by adding new paragraph

(a)(6)(iv)(C) and listing thereunder ‘‘any

ingredient(s) in a pressurized metereddose aerosol container.’’ In addition, the

agency is removing § 341.76(e) from the

final monograph because that

information now appears in § 330.1(i)

(21 CFR 330.1(i)) as part of the general

labeling policy for OTC drug products.

The agency points out that incorrect

dates were inadvertently inserted in

§ 310.545(a)(6)(iv)(C) and (d)(26) of the

proposed amendment (60 FR 13014 at

13020). Consequently, the agency is

revising the dates in these sections to

indicate that the conditions of this final

rule will be effective 30 days after the

date of publication in the Federal

Register. Further, proposed

§ 310.545(d)(26) is renumbered in this

final rule as § 310.545(d)(25).

V. Analysis of Impacts

The agency received one comment in

response to the agency’s request for

comments on any substantial or

significant economic impact that this

rulemaking would have on OTC

bronchodilator MDI aerosol drug

products that contain epinephrine,

epinephrine bitartrate, and

racepinephrine hydrochloride (60 FR

13014 at 13020). The comment

indicated that this rulemaking would

have a significant impact on the OTC

bronchodilator industry and itself if

additional data or new NDA’s were

requested for existing NDA-approved

MDI aerosol drug products. As

discussed above, this monograph

amendment should have minimal

impact on any existing MDI aerosol drug

product marketed under an approved

NDA. Any changes in manufacturing

procedures will require a standard

supplemental application that would

have been required before the

amendment was finalized.

FDA has examined the impacts of this

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. This monograph amendment

does not change the status of any

currently marketed MDI aerosol drug

products. All such products are

currently the subject of an approved

application. As is currently the case for

marketed MDI aerosol products, in the

interest of public health and safety, an

approved application will be required

for any product that is reformulated to

contain a non-CFC propellant. In

addition, there are a limited number of

MDI aerosol bronchodilator drug

product manufacturers. Accordingly,

the agency certifies that this 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.

VI. Environmental Impact

The agency has determined under 21

CFR 25.24(c)(6) that this action is of a

type that does not individually or

cumulatively have a significant effect on

the human environment. Therefore,

neither an environmental assessment

nor an environmental impact statement

is required.

List of Subjects

21 CFR Part 310

Administrative practice and

procedure, Drugs, Labeling, Medical

devices, Reporting and recordkeeping

requirements.

21 CFR Part 341

Labeling, Over-the-counter drugs.

Therefore, under the Federal Food,

Drug, and Cosmetic Act and under

authority delegated to the Commissioner

of Food and Drugs, 21 CFR parts 310

and 341 are amended as follows:

PART 310—NEW DRUGS

1. The authority citation for 21 CFR

part 310 continues to read as follows:

Authority: Secs. 201, 301, 501, 502, 503,

505, 506, 507, 512–516, 520, 601(a), 701, 704,

705, 721 of the Federal Food, Drug, and

Cosmetic Act (21 U.S.C. 321, 331, 351, 352,

353, 355, 356, 357, 360b–360f, 360j, 361(a),

371, 374, 375, 379e); secs. 215, 301, 302(a),

351, 354–360F of the Public Health Service

Act (42 U.S.C. 216, 241, 242(a), 262, 263b–

263n).

2. Section 310.545 is amended by

adding new paragraphs (a)(6)(iv)(C) and

(d)(25) and by revising paragraph (d)

introductory text to read as follows:

§ 310.545 Drug products containing

certain active ingredients offered over-thecounter (OTC) for certain uses.

(a) * * *

(6) * * *

(iv) Bronchodilator drug products.

* * *

(C) Approved as of June 19, 1996. Any

ingredient(s) in a pressurized metereddose inhaler container.

* * * * *

(d) Any OTC drug product that is not

in compliance with this section is

subject to regulatory action if initially

introduced or initially delivered for

introduction into interstate commerce

after the dates specified in paragraphs

(d)(1) through (d)(25) of this section.

* * * * *

(25) June 19, 1996, for products

subject to paragraph (a)(6)(iv)(C) of this

section.

PART 341—COLD, COUGH, ALLERGY,

BRONCHODILATOR, AND

ANTIASTHMATIC DRUG PRODUCTS

FOR OVER-THE-COUNTER HUMAN

USE

3. The authority citation for 21 CFR

part 341 continues to read as follows:

Authority: Secs. 201, 501, 502, 503, 505,

510, 701 of the Federal Food, Drug, and

Cosmetic Act (21 U.S.C. 321, 351, 352, 353,

355, 360, 371).

§ 341.76 [Amended]

4. Section 341.76 is amended by

removing paragraphs (d)(2)(i) and (e),

redesignating paragraph (d)(2)(ii) as

paragraph (d)(2), and revising the

heading of newly redesignated

paragraph (d)(2) to read as follows:

§ 341.76 Labeling of bronchodilator drug

products.

* * * * *

(d) * * *

(2) For products containing

epinephrine, epinephrine bitartrate, and

racepinephrine hydrochloride identified
Federal Register / Vol. 61, No. 98 / Monday, May 20, 1996 / Rules and Regulations 25147

in § 341.16(d), (e), and (g) for use in a

hand-held rubber bulb nebulizer.

* * *

Dated: April 11, 1996.

William K. Hubbard,

Associate Commissioner for Policy

Coordination.

[FR Doc. 96–12499 Filed 5–17–96; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF THE INTERIOR

30 CFR Part 250

RIN 1010–AB96

Flaring or Venting Gas and Burning

Liquid Hydrocarbons

AGENCY: Minerals Management Service

(MMS), Interior.

ACTION: Final rule.

SUMMARY: This rule amends regulations

governing restrictions on flaring or

venting gas to include restrictions on

burning liquid hydrocarbons. MMS

made this amendment to clarify that

burning liquid hydrocarbons is

allowable only under certain

circumstances as approved by the

Regional Supervisor.

EFFECTIVE DATE: This final rule is

effective on June 19, 1996.

FOR FURTHER INFORMATION CONTACT:

Sharon Buffington, Engineering and

Standards Branch, telephone (703) 787–

1600.

SUPPLEMENTARY INFORMATION: On

February 17, 1995, MMS published a

rule in the Federal Register (60 FR

9312) that proposed to amend the

requirements at 30 CFR 250.175, flaring

and venting of gas, to include burning

liquid hydrocarbons. This rule is

necessary because requests to burn

liquid hydrocarbons are increasing, and

we determined that we needed to

provide regulatory guidance on burning.

Response to Comments

During the 60-day comment period,

MMS received eight comments,

predominately from the oil and gas

industry. MMS appreciates the

suggestions and comments that we

received. We reviewed all of the

comments, and in some instances, we

revised the final language based on

these comments. MMS grouped the

comments by the following major

issues:

1. In § 250.175(c), MMS proposed that

the Regional Supervisor allow a lessee

to burn a ‘‘minimal’’ amount of liquid

hydrocarbons with prior approval.

Several comments suggested that MMS

determine the absolute value of

‘‘minimal.’’ One comment suggested

that we create a table of allowable burn

amounts by using distance from shore as

the determining factor. In general, the

comments said that the term ‘‘minimal’’

is not specific enough.

Response

MMS agrees that, if possible, using an

absolute value for the term ‘‘minimal’’

would be desirable. However, we feel

that it is impractical to determine an

solute value because it depends on

many economic, technical, safety, and

environmental factors. Therefore, an

amount that may be prudent to burn in

one area may not be acceptable to burn

in another correlative area. Conserving

natural resources is a major

consideration in burning liquid

hydrocarbons. However, our

determination of the allowable

‘‘minimal’’ amount that you can burn

will also depend on technical, safety,

and environmental factors.

2. Several comments suggested that

storing and transporting or re-injecting

liquid hydrocarbons poses a greater risk

than burning them.

Response

MMS agrees that in some cases the

alternatives to burning liquid

hydrocarbons may be risky to the

environment or personnel. That is the

reason MMS provided the option of

showing the Regional Supervisor that

the alternatives are infeasible or pose

significant risk. MMS will evaluate the

information that you supply concerning

the risks of the alternatives case by case.

Please be assured that the Regional

Supervisor will evaluate your requests

to burn hydrocarbons fairly and

promptly by using the information that

you supply in your requests.

3. Section 250.175(c)—One comment

suggested that MMS rewrite the first

sentence of paragraph (c) because the

phrase ‘‘lessees must not burn liquid

hydrocarbons’’ may portray a negative

bias against burning liquid

hydrocarbons.

Response

MMS did not intend to portray a

negative bias against burning liquid

hydrocarbons. Our intent was only to

set boundaries on burning liquid

hydrocarbons. However, to avoid any

confusion, MMS will restate the first

sentence of paragraph (c) to say that

‘‘Lessees may burn produced liquid

hydrocarbons only if the Regional

Supervisor approves.’’

4. Section 250.175(a)(3)—Several

comments opposed MMS’s changing the

limit on flaring, without prior approval,

during well evaluations and cleaning, to

48 cumulative hours (from 48

continuous hours). The individuals felt

that 48 cumulative hours are not always

sufficient (especially in deep water).

Similarly, one comment recommended

that MMS state that the Regional

Supervisor has the authority to increase

the flaring limit.

Response

MMS feels that, for environmental

and conservation reasons, it needs to

change the term ‘‘continuous’’ to

‘‘cumulative’’ for flaring during well

evaluations and cleaning operations

(without prior approval). Otherwise, the

term ‘‘continuous’’ would permit

multiple flarings of up to 48 hours each

simply by having a shut-in period

between flarings.

MMS realizes that 48 hours of flaring

will not always meet well testing needs.

For these occasions, the Regional

Supervisor has the authority to increase

the flaring limit. MMS will continue to

evaluate requests for more than 48

cumulative hours of flaring during well

evaluations or cleaning. However,

without prior approval, MMS will only

allow 48 cumulative hours per testing

operation on a single completion. This

limit of 48 hours should be adequate to

accommodate most operations.

MMS amended the final rule to clarify

that the Regional Supervisor has the

authority to specify a shorter or longer

flaring limit. In addition, the MMS

Regions are working on guidelines for

extended testing and flaring for deep

water.

5. Section 250.175(a)(2)—One

comment recommended that MMS

delete or define ‘‘temporary’’ which

modified ‘‘situations’’ because it is too

vague.

Response

MMS agrees that the term

‘‘temporary’’ can be vague, and we

deleted it from the final rule.

6. Section 250.175(c)—One comment

recommended that MMS define

‘‘significant risk’’ because it is vague.

Response

MMS has changed the phrase to

‘‘significant risk that may harm.’’

7. Several comments suggested that

MMS mandate the type of burner that it

will permit a lessee to use.

Response

MMS recognizes that many burners

exist with widely varying specifications.

However, since technology constantly

changes, MMS feels that it is impractical

and too restrictive to mandate an

allowable type of burner. However, the