13014 Federal Register / Vol. 60, No. 46 / Thursday, March 9, 1995 / Proposed Rules

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 310 and 341

[Docket No. 94N–0247]

RIN 0905–AA06

Cold, Cough, Allergy, Bronchodilator,

and Antiasthmatic Drug Products for

Over-The-Counter Human Use;

Proposed Amendment of Monograph

for OTC Bronchodilator Drug Products

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice of proposed rulemaking.

SUMMARY: The Food and Drug

Administration (FDA) is proposing to

amend the final monograph for over-thecounter (OTC) bronchodilator drug

products to remove 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 proposing to amend the

regulation that lists nonmonograph

active ingredients to add any

ingredient(s) in a pressurized metereddose aerosol container for OTC

bronchodilator drug products. This

proposal is part of the ongoing review

of OTC drug products conducted by

FDA.

DATES: Written comments or objections

by May 23, 1995; written comments on

the agency’s economic impact

determination by May 23, 1995. FDA is

proposing that any final rule that may

issue based on this proposal become

effective 30 days after its date of

publication in the Federal Register.

ADDRESSES: Submit written comments

or objections to the Dockets

Management Branch (HFA–305), Food

and Drug Administration, rm. 1–23,

12420 Parklawn Dr., Rockville, MD

20857.

FOR FURTHER INFORMATION CONTACT:

William E. Gilbertson, Center for Drug

Evaluation and Research (HFD–810),

Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857,

301–594–5000.

SUPPLEMENTARY INFORMATION:

I. Background

In the Federal Register of October 2,

1986 (51 FR 35326), FDA issued a final

monograph establishing conditions

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).

In the final monograph (51 FR 35326

at 35333, comment 10), the agency

responded to a comment that agreed

that bronchodilators in a MDI dosage

form should be available OTC, but

objected to allowing them to enter the

marketplace without preclearance by

FDA through approval of applications

(new drug (NDA) or abbreviated new

drug (ANDA)). The comment contended

that the complexities of pressurized

MDI aerosol dosage forms for inhalation

are such that agency preclearance is

necessary to assure the safety and

effectiveness of these drug products.

The comment stated that the proposed

rulemaking was deficient because it did

not discuss the complexities of the

design, control, manufacture, and

market use of MDI drug delivery

systems and the monograph did not set

forth manufacturing standards for MDI

delivery systems. The comment

suggested that a full application would

not be required, but that preclearance of

‘‘manufacturing controls information

and bioavailability data’’ by the agency

should be required.

Based on the data and other

information available when the final

monograph for OTC bronchodilator drug

products was published, the agency

disagreed with the comment, stating its

belief that the state of the technology for

MDI drug delivery systems was such

that bronchodilator drug products in

MDI dosage forms could be generally

recognized as safe and effective. The

agency indicated that it had reviewed

data available at that time from its Drug

Product Problem Reporting System

computerized data base for all

bronchodilator drug products in MDI

dosage forms. The agency noted that no

problems related to metered-dose

mechanisms had been reported for these

OTC drug products between 1980 and

1984. Therefore, the agency concluded

that the technology available to produce

reliable MDI mechanisms allowed the

agency to generally recognize MDI

dosage forms for OTC bronchodilator

drug products containing epinephrine

preparations as specified in the final

monograph.

The agency also pointed out in the

final rule (51 FR 35326 at 35334),

however, that agency regulations in 21

CFR 2.125(d) state that the use of a

chlorofluorocarbon (CFC) as a

propellant in a self-pressurized

container of a drug product will not

result in the drug product being

adulterated and/or misbranded

provided the drug has an NDA.

Therefore, all OTC bronchodilator drug

products in MDI’s that contain a CFC as

a propellant (which include all

marketed OTC MDI products containing

epinephrine) were marketed only under

an approved application. The agency

anticipated that MDI products would

continue to contain a CFC propellant

and that marketing would continue

under approved applications containing

information on manufacturing controls

for the MDI.

Since publication of the final

monograph for OTC bronchodilator drug

products, several developments have

changed the agency’s views about

pressurized MDI dosage forms. These

include: (1) Legislation that requires a

phaseout of ozone-depleting substances,

including CFC propellants in MDI drug

products; (2) the need for safety data on

the alternative propellants that will

replace CFC’s in MDI dosage forms, as

well as evidence that the new MDI’s

deliver the drug effectively; (3) recent

publications reporting chemistry,

manufacturing, and controls problems

resulting from changes to the container

and closure system of redesigned MDI

dosage forms; (4) the need for safety and

effectiveness data for the new drug

products as a result of these chemistry,

manufacturing, and controls changes;

and (5) international workshops and

FDA advisory committee discussions

focusing on regulatory requirements for

modifications to an approved innovator

MDI and bioequivalence of generic MDI

aerosol products. These issues have

caused the agency to reconsider the

inclusion of MDI dosage forms in the

final monograph for OTC bronchodilator

drug products. The agency has

determined that an assessment of the

safety and effectiveness of each product

must be made. The agency’s discussion

of these issues follows.

II. New Issues That Affect MDI Drug

Products

A. Proposed Replacement of CFC

Propellants

The Clean Air Act Amendments of

1990, Title VI (Pub. L. 101–549), signed

into law on November 15, 1990, requires

the phaseout of ozone-depleting

substances. The Environmental

Protection Agency (EPA) has

promulgated regulations implementing

the phaseout provisions contained in

section 604 of the Clean Air Act
Federal Register / Vol. 60, No. 46 / Thursday, March 9, 1995 / Proposed Rules 13015

Amendments of 1990 (58 FR 65018,

December 10, 1993). Ozone-depleting

substances covered by the Clean Air Act

Amendments of 1990 include CFC’s and

hydrochlorofluorocarbons. The

international community has agreed to

adjust the phaseout schedule for CFC’s

to reduced levels of production and

consumption (production plus imports

minus exports) of 25 percent of baseline

level in 1994 and 1995, with a complete

phaseout by 1996 (58 FR 65018 at

65020). Existing supplies of previously

manufactured products will continue to

be marketed until supplies are

exhausted. All pressurized MDI

antiasthma drugs (both the OTC

products containing epinephrine,

epinephrine bitartrate, and

racepinephrine hydrochloride and

numerous antiasthma drugs available by

prescription only) contain CFC’s as the

propellant. A procedure has been

established for obtaining essential-use

exemptions of ozone-depleting

substances used in medical products

from this production phaseout. Because

there are no currently approved

inhalation products that can fully

substitute for drugs in MDI’s used to

treat the symptoms of asthma and

chronic obstructive pulmonary disease

(COPD) (Ref. 1), FDA and EPA have

supported essential use exemptions

(Refs. 2 and 3).

In the Federal Register of October 18,

1994 (59 FR 52544 at 52546), EPA

announced that the Montreal Protocol

Technology and Economic Assessment

Panel had recommended that essential

use exemptions for 1996 and 1997 be

granted for CFC’s used in MDI’s. At an

October 1994 meeting, the Parties to the

Montreal Protocol on Substitutes that

Deplete the Ozone Layer reviewed these

recommendations and granted essential

use exemptions for 1996 and 1997 for

MDI’s for the treatment of asthama and

COPD (Ref. 4).

Beginning in the late 1980’s, the

pharmaceutical and other industries

began searching for appropriate CFC

alternatives. Currently two compounds,

HFC–134a and HFC–227ea, are being

investigated as alternative propellants to

replace CFC’s in MDI’s. Reformulation

of currently approved MDI drug

products with these new propellants

will require toxicological and clinical

studies to establish the safety and

efficacy of the new drug products. The

agency intends to require sponsors to

submit NDA’s for these new drug

products. These NDA’s must be

approved before the new products can

be marketed.

References

(1) Letter from M. R. Taylor, FDA, to M. H.

Shapiro, EPA, December 21, 1993, in OTC

Vol. 04BFMA3.

(2) Petition from Sterling Winthrop, Inc., to

EPA, August 20, 1993, in OTC Vol.

04BFMA3.

(3) ‘‘Metered Dose Inhalers: A Special

Case,’’ International Pharmaceutical Aerosol

Consortium, July 19, 1993, page 31 and

Appendix A, page 1, in OTC Vol. 04BFMA3.

(4) Report of the 6th Meeting of the Parties

to the Montreal Protocol on Substances that

Deplete the Ozone Layer, October 6–7, 1994,

in OTC Vol. 04BFMA3.

B. Safety and Effectiveness Data for

Alternative Propellants

MDI’s offer a convenient way to

administer aerosolized bronchodilator

drugs for the treatment of asthma and

COPD. Response to drugs administered

by inhalation is prompt, often very

specific with minimal side effects, and

faster in onset than responses to drugs

given orally (Ref. 1). With most drugs,

MDI response approaches the rapidity of

intravenous therapy. Drugs that

normally are decomposed in the

gastrointestinal tract can be

administered safely by inhalation. The

MDI dosage form makes inhalation

therapy simple, convenient, and more

acceptable than atomizers and

nebulizers, which are bulky and require

cleaning.

Bronchodilator drugs in pressurized

MDI aerosols are widely available. Many

formulations contain a drug either

suspended or dissolved in CFC

propellants at high pressure in a small

canister. In addition to supplying the

necessary force to expel the product, the

propellant blend also acts as a vehicle

and diluent. Thus, the propellant has

much to do with determining the

characteristics of the product as it leaves

the container. Desirable vapor pressures,

stability, and reactivity of CFC

propellants are of prime importance in

the formulation and manufacture of MDI

aerosols. From a solubility standpoint,

CFC’s are miscible with most nonpolar

solvents over a wide range of

temperature and are capable of

dissolving many substances (Ref. 1). The

CFC propellants used in MDI’s are not

miscible with water. A cosolvent,

typically ethanol, must be included in

present formulations to increase the

solubility of polar drug molecules.

As noted above, manufacturers may

need to reformulate their MDI aerosols

to replace the CFC propellants with

suitable alternatives. The agency is

concerned that the use of new

excipients, including non-CFCcontaining propellants, could change

the distribution characteristics of the

drug in the airways, produce a

pharmacologic interaction, or enhance

toxicity of the active drug substances.

Reformulation of pressurized MDI

aerosols containing non-CFC-containing

propellants might also result in changes

in drug deposition patterns within the

lung. These changes might alter

pulmonary absorption, potentially

resulting in changes in safety and/or

therapeutic effectiveness of the

bronchodilator.

Propellants can affect the therapeutic

effectiveness of bronchodilators. A 1983

study (Ref. 2) measured the effects of

two different albuterol (salbutamol) MDI

products containing the same amount of

drug per inhalation. In this doubleblind, crossover study, 46 subjects with

stable asthma were challenged with

methacholine to produce a moderate

bronchial obstruction. Following the

methacholine challenge, the subjects

were randomized into two groups. Each

group received two inhalations from one

of two different brands of albuterol MDI

aerosol preparations. The peak

expiratory flow (PEF) was measured

three times in 10 minutes after the

inhalation of the drug product. The test

was repeated after 3 days to 1 month by

giving the subjects the test aerosol that

they had not received in the first test.

PEF values were determined in the same

manner as described for the initial

inhalation test product. The data

indicated that one preparation relieved

bronchial obstruction more effectively

than the other preparation. The author

suggested that, because both MDI

aerosols contained the same drug, the

significant difference of the relaxing

effect on the bronchial obstruction with

these aerosols in the same subject may

be due to the properties of the vehicle

(propellant).

Currently, MDI aerosols are selfpressurized with CFC propellants that

provide a fixed volume of propellant

and drug each time the canister valve is

pressed. A fixed amount of drug is

aerosolized by the pressure of the

propellant into small droplets that

evaporate to produce smaller respirable

particles. These droplets should be

between 2 to 5 microns (μm) for

maximum delivery of drug to the

respiratory tract and to minimize

deposition in the oropharynx (Ref. 3).

Propellant vapor pressure, which

affects both the droplet size and the

velocity at which the particle leaves the

MDI device, is important in determining

drug deposition in the lung (Ref. 4).

Newman et al. (Ref. 5) measured the

effects of changes in metered volume

and propellant vapor pressure on

deposition in the lungs of a pressurized

MDI aerosol in 10 subjects with

obstructive airway disease. Radiolabeled
13016 Federal Register / Vol. 60, No. 46 / Thursday, March 9, 1995 / Proposed Rules

particles of Teflon (3.2 μm mass median

aerodynamic diameter) were

incorporated into canisters formulated

with two different metered volume sizes

(25 and 50 microliters) and with two

different propellant vapor pressures.

The study indicated that the majority of

the dose from a pressurized MDI aerosol

is deposited in the oropharynx and that

only a small amount reaches the lungs.

Increasing the metered volume had no

effect on the quantity of aerosol

deposited in the lungs, but produced a

significantly more central pattern of

deposition within the bronchial tree. An

increase in vapor pressure, however,

resulted in a significant increase in

whole lung deposition and a significant

reduction in extrathoracic deposition.

The authors concluded that changes in

formulation alter the deposition pattern

of MDI aerosols and, consequently,

might bring about changes in clinical

effectiveness.

In addition to vapor pressure and

velocity characteristics of the

propellant, the surfactant and cosolvent

in a solution product are other

important formulation considerations.

Surfactants lubricate the MDI canister

valve and prevent aggregation of the

individual drug particles. Surfactants

also influence droplet evaporation,

particle size, and overall hydrophobicity

(degree of insolubility in water) of the

particles reaching the respiratory

passageways and pulmonary fluids (Ref.

1). Variations in the rate of evaporation

of propellants and the cosolvent, if

present, may lead to a particle size

distribution containing a higher or

lower proportion of fine particles (Ref.

6), which could have a significant

impact on the safety and effectiveness of

the new drug product.

A considerable and variable amount

of drug is deposited in the oral cavity

and thus is swallowed and subject to

absorption from the gastrointestinal

tract (Ref. 7). The agency is concerned

with the possibility that new non-CFC

propellants in an MDI product may

interact with a cosolvent or other

components (e.g., surfactants, valve

components, or antioxidants) to produce

an irritant or potentially hazardous

formulation, or a less effective

formulation, when applied to the

respiratory system. The agency

concludes that additional data will be

necessary 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. These

additional data will include information

on the absorption, distribution, and

retention characteristics of new

propellant systems in man following

inhalation. This information needs to

include an assessment of the likely

systemic burden of the propellant.

Therefore, the agency considers

premarket approval to be essential for

any MDI aerosol drug products that

combine a known active ingredient with

a new propellant system or new valve.

References

(1) Sciarra, J. J., and A. J. Cutie, ‘‘Aerosols,’’

in Remington’s Pharmaceutical Sciences,

18th ed., edited by A. R. Gennaro, Mack

Publishing Co., Easton, PA, pp. 1694–1721,

1990.

(2) Parkkali, L., ‘‘Comparison of Two

Different Salbutamol Inhalation Aerosols in

Release of Bronchial Obstruction,’’ Current

Therapeutic Research, 33:539–542, 1983.

(3) Rees, P. J., and T. J. H. Clark, ‘‘The

Importance of Particle Size in Response to

Inhaled Bronchodilators,’’ European Journal

of Respiratory Diseases, Suppl. 119, 63:73–

78, 1982.

(4) Transcripts of the FDA Generic Drugs

Advisory Committee Meeting with

Pulmonary-Allergy Drugs Advisory

Committee Representation, September 14–15,

1993, identified as TS, Docket No. 94N–0247,

Dockets Management Branch.

(5) Newman, S. P. et al., ‘‘The Effect of

Changes in Metered Volume and Propellant

Vapour Pressure on the Deposition of

Pressurized Inhalation Aerosols,’’

International Journal of Pharmaceutics,

11:337–344, 1982.

(6) Dalby, R. N., and P. R. Byron,

‘‘Comparison of Output Particle Size

Distribution from Pressurized Aerosols

Formulated as Solutions or Suspensions,’’

Pharmaceutical Research, 5(1):36–39, 1988.

(7) Wong, B. J. O., and F. E. Hargreave,

‘‘Bioequivalence of Metered-dose Inhaled

Medications,’’ Journal of Allergy and Clinical

Immunology, 92(3):373–379, 1993.

(8) The 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.

C. Chemistry, Manufacturing, and

Controls Concerns

The agency believes that careful

consideration must be given to the

interactions that can occur between the

drug substance, the container and

closure system, and the excipients of a

MDI aerosol product. Unlike dosage

forms composed only of excipients and

drug, a MDI consists of the container,

the valve, the actuator (mouthpiece),

and the formulation. These components

collectively constitute the drug product

that delivers the drug substance in the

desired form to the biological target.

Variability in the performance of a MDI

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 drug product. Design modifications

of the MDI may result in significant

alterations of the dose delivered to the

lung. Changes in the source or the

composition of any component of the

MDI drug product may introduce

unknown contaminants (Ref. 1).

Impurities (extractables) may occur

when the propellant comes in contact

with the plastic or rubber components

of the MDI canister.

The agency is concerned about the

possible association of impurities and

extractables with paradoxical

bronchospasm as well as with more

general toxicity. In one study (Ref. 2), a

24-year-old asthmatic patient who had

reported acute wheezing immediately

after using an aerosol of beclomethasone

dipropionate was challenged with

several aerosols. The subject

experienced immediate

bronchoconstriction after two puffs of

an aerosol containing beclomethasone

dipropionate and also after inhalation of

the vehicle (all the components of the

aerosol less the beclomethasone). When

the patient was challenged with a

different brand of beclomethasone

aerosol, however, no bronchospasm

occurred. Because the contents of the

two beclomethasone aerosols were

similar, the authors concluded that

rubber or plastic derivative(s) present in

the metering valve may have been

responsible for the bronchospasm. The

authors noted that the manufacturers of

the beclomethasone aerosols had

confirmed that their internal metering

valves were different. The authors also

pointed out that the conclusion drawn

in a similar study (Ref. 3) suggested that

the substance(s) responsible for the

reaction might be derived either from

the metering valve or the aluminum can.

Most MDI aerosol canisters are made

of aluminum. Aluminum is essentially

inert, but will react with certain

solvents and other chemicals (Ref. 4).

Although aluminum can be used

without an internal organic coating for

certain aerosol formulations (especially

those which contain only active

ingredient and propellant), many MDI

aluminum canisters are internally

coated with epon- or epoxy-type resin

for added resistance to formulation

interaction. The agency is concerned

about what interactions might occur

between the aluminum canister and the

epon- or epoxy-type resin coating and

new non-CFC propellants that may

eventually be used in these products.

The formulation, actuator, and valve

determine the performance of a

pressurized MDI aerosol (Ref. 4). The
Federal Register / Vol. 60, No. 46 / Thursday, March 9, 1995 / Proposed Rules 13017

metering valve must accurately deliver

a measured amount of product and

should be reproducible not only for

each dose delivered from the same

package but from package to package.

An integral part of the MDI valve is the

metering chamber that is responsible for

the delivery of the desired amount of

drug. MDI valves function by filling the

metering chamber with product, sealing

off this chamber from the remaining

formulation in the canister when the

valve stem is partially depressed, and

then releasing the contents of the

chamber through the valve stem upon

further depression (actuation) (Ref. 5).

The valves should retain their prime

charge over fairly long periods of time

(Ref. 4). However, it is possible for

material in the chamber to return slowly

to the main body of product. The degree

to which this can occur varies with the

construction of the valve and the length

of time between uses (actuations). Puffto-puff dosage variability due to

inadequate valve priming may lead to

therapeutic failure and a subsequent

asthma attack requiring emergency room

and hospital treatment.

One study (Ref. 6) compared the

relative bronchodilator effectiveness of

two puffs from two different albuterol

MDI aerosols containing the same

concentration of active ingredient. The

study was a randomized, single-blind,

crossover clinical trial involving 17

adults with intermittent or mild chronic

asthma. Initially, each subject received

two puffs of the generic albuterol MDI

and two puffs of the brand name

albuterol MDI drug product on two

occasions at least 3 days apart. The test

dose was the first two puffs out of each

canister; neither inhaler was primed.

Pulmonary function was measured

before each test dose and at frequent

intervals over an 8–hour period after

drug inhalation. Results of this portion

of the study indicated that the

bronchodilator response was greater

with the generic MDI than with the

brand name MDI product.

The study was repeated with both

MDI products primed prior to the test

dose (i.e., two puffs were first

discharged into a wastebasket) in 11

subjects willing to return for further

testing. Retest data indicated that there

was no significant difference in

bronchodilation between the two

primed inhalers. The results suggested

that failure to prime the MDI canister

could alter the therapeutic response.

The authors explained that variations in

valve and actuator design or factory

quality control procedures could

account for the difference in therapeutic

effectiveness of the two products. They

added that modifications in valve

design or storage position may account

for the loss of valve prime and, thus, be

responsible for puff-to-puff dosage

variability. On the basis of this study,

the authors stated that MDI

manufacturers must conduct in vitro

studies to determine the frequency of

valve priming required for their

product, the effect storage position has

on valve priming, and the uniformity of

drug content of each of several puffs

after priming.

Accurate assessment of drug

deposition profiles, both the quantity of

drug reaching the respiratory airways

and its depth of penetration, is critically

important in evaluating the

bioavailability of MDI aerosol products

(Ref. 4). The aim of the MDI drug

product is to deliver the maximum

amount of drug to the respiratory tract

and minimize deposition in the

oropharynx (Ref. 7). The portion of the

drug product that is ultimately

deposited at the desired biological target

consists of a mixture of micronized or

solubilized active drug substance in a

residue matrix of oily excipient material

and/or low volatile propellant and/or

solvent (Ref. 1). A particle size range

less than 5 μm is generally considered

more effective than larger particles in

producing bronchodilatation (Ref. 8).

MDI formulations currently available

consist of drugs suspended in CFC

propellants or drugs dissolved in

propellants containing a significant

proportion of less volatile solvents.

Particle size distribution from MDI’s

containing drugs dissolved or

suspended in propellant/cosolvent

mixtures is governed by the physical

characteristics of the valve and the

actuator, the concentration of

nonvolatile components in the mixture,

the initial droplet size (which depends

on such factors as actuator design, spray

characteristics, and physicochemical

characteristics of the solution being

sprayed), and the volatile propellant

evaporation rate (Ref. 7). The agency is

concerned how new non-CFC

propellants will affect particle size and

particle size distribution.

The effectiveness of two albuterol

MDI aerosol products (brands A and B)

was compared in a double-blind study

involving 31 asthmatics (Ref. 9). Each

subject received sequential treatment

(0.2 mg albuterol/dose) on two

successive days (day 1, inhalation

sequence A then B; day 2, inhalation

sequence B then A). Results of this

study indicated that all subjects had a

significantly greater bronchodilation

response to the B MDI product than to

the A MDI product. Further, in the

sequence A-B, the B MDI always

produced further bronchodilation while

in the sequence B-A sequence, there was

no further bronchodilation response to

the A MDI. The study indicated that 0.2

mg of B was as effective as 0.4 mg of A.

The study showed that two different

albuterol inhalers containing the same

active ingredients in the same dose can

differ significantly in therapeutic

effectiveness. The author suggested that

the bioavailability of albuterol MDI’s

may differ from brand to brand because

of differences in aerosol particle size or

distribution, concentration, and/or the

physicochemical characteristics of the

propellant.

Factors influencing the ultimate

deposition of stable small inhalation

particles include the formulation of the

products, design of components

(specifically the valves or actuators),

administrative skills and techniques of

the product user, and the anatomical

and physiological status of the

respiratory system (Ref. 4). Besides the

previously mentioned effects of

propellant vapor pressure and the

metered volume of propellants on drug

deposition in the lungs, the selection of

the appropriate surfactant (required in

pressurized suspension MDI aerosols)

and its concentration are important

considerations in MDI aerosol drug

formulations. As discussed above,

surfactants influence droplet

evaporation, particle size, and overall

hydrophobicity of the particles reaching

the respiratory passageways and

pulmonary fluids (Ref. 4).

Particle size distribution is also

influenced by the MDI component

design. Changes in component design,

including the actuator and adapter, have

been shown to alter the particle size

distribution and consequently the

penetration and deposition of the active

ingredient in the lung. The agency is

aware that a variation of particle size

distribution up to 40 percent could

result from altering the actuation type,

valve dimensions, distance from

actuator, and other device component

variables (Ref. 4). Because the valve and

actuator of an approved MDI product

may be proprietary to the innovator

firm, and therefore unavailable to other

drug manufacturers, use of a different

valve or actuator for products

containing active ingredients currently

included in the monograph for OTC

bronchodilator drug products may

require data to support safety and

effectiveness.

Given the complexity of the MDI

formulations and the interdependence

of each of the MDI components, the

agency believes that pressurized MDI

aerosol drug products must be carefully

evaluated for safety and therapeutic

effectiveness. Based on agency
13018 Federal Register / Vol. 60, No. 46 / Thursday, March 9, 1995 / Proposed Rules

preclearance under existing NDA’s,

currently marketed OTC MDI drug

products are not in question. However,

the agency would have great concerns

about the safety and effectiveness of

new OTC drug products entering the

marketplace without agency

preclearance, for the reasons discussed

in this document. The agency would

have still greater concerns if new nonCFC-containing propellants were to be

used in new products without agency

evaluation of the reformulated products.

The agency noted in the final

monograph for OTC bronchodilator drug

products (51 FR 35326 at 35334) that the

use of a CFC-containing self-pressurized

container of a drug product will not

result in the drug product being

adulterated and/or misbranded

provided the drug has an approved

NDA. OTC MDI bronchodilator drug

products that contain a CFC-containing

propellant may therefore be marketed

only under an approved NDA.

Similarly, based on the intended

phaseout of CFC-containing propellants

in MDI aerosol dosage forms, the agency

now concludes that it is essential that

any MDI aerosol reformulation

(including use of a new propellant) or

component design alterations require

premarket approval under an approved

NDA to ensure the safety and

effectiveness of the bronchodilator drug

product.

References

(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) Godin, J., and J. L. Malo, ‘‘Acute

Bronchoconstriction Caused by Beclovent

and Not Vanceril,’’ Clinical Allergy, 9:585–

589, 1979.

(3) Bryant, D. H., and J. Pepys, ‘‘Bronchial

Reactions to Aerosol Inhalant Vehicle,’’

British Medical Journal, 1:1319, 1976.

(4) Sciarra, J. J., and A. J. Cutie, ‘‘Aerosols,’’

in Remington’s Pharmaceutical Sciences,

18th ed., edited by A. R. Gennaro, Mack

Publishing Co., Easton, PA, pp. 1694–1721,

1990.

(5) Fiese, E. F. et al., ‘‘Test Method for

Evaluation of Loss of Prime in Metered-Dose

Aerosols,’’ Journal of Pharmaceutical

Sciences, 77(1):90–93, 1988.

(6) Blake, K. V. et al., ‘‘Evaluation of a

Generic Albuterol Metered-Dose Inhaler:

Importance of Priming the MDI,’’ Annals of

Allergy, 68:169–174, 1992.

(7) Dalby, R. N., and P. R. Byron,

‘‘Comparison of Output Particle Size

Distribution from Pressurized Aerosols

Formulated as Solutions or Suspensions,’’

Pharmaceutical Research, 5(1):36–39, 1988.

(8) Rees, P. J., and T. J. H. Clark, ‘‘The

Importance of Particle Size in Response to

Inhaled Bronchodilators,’’ European Journal

of Respiratory Diseases, Suppl. 119, 63:73–

78, 1982.

(9) Chhabra, S. K., ‘‘Differing

Bioavailability of Salbutamol Metered-Dose

Inhalers,’’ Journal of Asthma, 24:215–218,

1987.

D. International Workshops and FDA

Advisory Committee Discussions

Both the agency and the international

community recognize the need to

significantly reduce the production and

consumption of substances which

deplete the ozone layer. One class of

substances currently under discussion

are CFC’s, which are highly resistant to

biotic and abiotic decomposition and,

therefore, pass undecomposed from the

atmosphere to the stratosphere. Because

of the deleterious effect of CFC’s on the

ozone layer, international consensus is

that products containing CFC

propellants, including MDI’s, must be

phased out or reformulated with a

suitable non-CFC-containing propellant.

Several international workshops and

agency advisory committee discussions

have taken place to identify the

regulatory requirements necessary to

determine the safety and effectiveness of

reformulated MDI bronchodilator drug

products. On December 15, 1993, the

Commission of the European

Communities (CEC) issued a guideline

report (Ref. 1) that identifies quality,

safety, and effectiveness considerations

to be addressed by companies in

submissions in support of replacements

for CFC propellants in an already

authorized medicinal product. The

report specifies the following major

clinical requirements: (1) Ensure safety

and effectiveness of the reformulated

product, and (2) demonstrate that the

change in formulation due to a change

in excipients has no adverse effect on

the benefit/risk ratio to users in

comparison with the existing CFCcontaining product.

The report stated that clinically

validated studies, including

pharmacodynamic, pharmacokinetic,

and in vivo and/or in vitro deposition

studies, can be used to determine the

effectiveness of the reformulated MDI

product. Data on the absorption,

distribution, and retention of the new

propellant(s) in adults and children

under 12 years of age following

inhalation are needed to assess the

likely systemic burden of the

propellant(s) (e.g., heart rate, serum

potassium, and assessment of

paradoxical bronchospasm). The report

cautioned 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. The

guideline emphasizes that monitoring

the introduction of new non-CFCcontaining products is necessary in

order to identify rare or unexpected

adverse effects.

The Drug Information Association

held a workshop on October 18 and 19,

1993 (Ref. 2) to discuss the regulatory

and data requirements needed to

reassure the clinical community and

patients that reformulated MDI aerosol

products are safe and effective. The

workshop summarized the chemistry

and manufacturing concerns of the CEC

and other regulatory health

organizations regarding the safety and

effectiveness of reformulated MDI

aerosol products. Participants discussed

how small changes in MDI aerosol

product formulation or component

design can significantly affect the safety

and effectiveness of a bronchodilator

aerosol drug product. Careful

consideration was given to

bioequivalence issues involving puff-topuff variability, unit spray content,

storage conditions, new propellants,

particle size, and extractables and

impurities profiles. The workshop’s

conclusions agreed with the

international approach to premarket

approval of pressurized MDI

bronchodilator drug products. These

conclusions would apply to both

prescription and OTC drug products.

On September 14 and 15, 1993, the

agency’s Generic Drugs Advisory

Committee with representation from the

Pulmonary-Allergy Drugs Advisory

Committee (hereinafter referred to as the

Committee) met to discuss the agency’s

current policy concerning the

documentation of bioequivalence for

suspension and solution MDI aerosol

products (Ref. 3). The Committee stated

that premarket approval is essential to

ensure the identity, strength, quality,

and purity of generic MDI aerosol

products. In addition to the in vitro data

required for a new or reformulated

existing MDI aerosol under an approved

NDA, the Committee recommended in

vivo bioequivalence documentation for

generic suspension MDI aerosol

products for oral inhalation. The

Committee also recommended the

following bioequivalence testing

guidelines for MDI oral inhalation

solution products: (1) If excipients are

essentially the same, in vitro studies

only would be acceptable with the same

device, and (2) whether the excipients

are or are not essentially the same, in

vivo and in vitro studies are required

with different devices. Furthermore, the

Committee concluded that products

with excipients that are not essentially

the same may need additional studies

(e.g., for safety) (Ref. 3).
Federal Register / Vol. 60, No. 46 / Thursday, March 9, 1995 / Proposed Rules 13019

Adams et al. (Ref. 4) indicated that,

unlike most dosage forms, inactive

ingredients in MDI aerosol formulations

and the container and closure system

are important contributors to the safety

and effectiveness and, thus, to the

therapeutic equivalence of these

products. The agency is aware that

different pharmacodynamic effects in

aerosolized drugs have been

hypothesized to occur due to

differential deposition of drugs in

various segments of the respiratory tract,

resulting in different absorption

characteristics. Such differences

between test and reference products

could arise from differences in

characteristics of the suspension

formulation or in the performance

characteristics of the delivery devices

(valve and actuator) used in the

products.

FDA’s Division of Bioequivalence (the

Division), in the Office of Generic

Drugs, has developed interim guidance

that recommends methods to generic

applicants to document in vivo

bioequivalence of albuterol MDI

aerosols and recommends a safety

evaluation study as part of the

documentation of in vivo

bioequivalence (Ref. 5). The Division

advises that the methods presented

therein are not rigid and are not

considered by the Division to be the sole

methods of documenting

bioequivalence. However, because

limited experience exists in the

application of these methods to the

determination of bioequivalence of

different albuterol MDI aerosol drug

products, the report encouraged

sponsors to assess the general

applicability and reliability of the

methods recommended.

In response to this interim guidance,

one comment (Ref. 6) requested that the

agency withdraw the guidance because

it would permit a generic version of

albuterol MDI aerosol to be released for

marketing without long-term safety

studies. The comment referred to data

presented by another MDI aerosol

manufacturer during the September 14

and 15, 1993, Committee meeting (Ref.

3). The comment explained that clinical

comparison of two nearly identical MDI

aerosol products produced similar

pharmacodynamic responses, but

exhibited significant differences in

safety profiles (changes in serum

potassium and glucose, finger tremor,

and heart rate). Because of safety

concerns, the MDI aerosol manufacturer

withdrew its request for agency

approval of its product. The comment

pointed out that the manufacturer’s data

presented at the meeting demonstrate

that even minor changes in drug

delivery may affect patient safety. The

comment added that different valves

and new suppliers of drug substances

and excipients used in MDI aerosol

products may lead to patients being

exposed to new valve extractives and to

new impurities. The comment

emphasized that although some minor

changes may be evident in single-dose

studies, longer-term clinical trials are

needed to assess the full side effect

liability of changed products (i.e., new

excipients or component design

alterations) for regular or intermittent

administration.

Wong and Hargreave (Ref. 7) discuss

the need for premarket approval and

subsequent bioequivalence

requirements for reformulated and

generic MDI aerosol products. The

authors state that there is a need to

demonstrate clinical bioequivalence and

relative potency of MDI aerosols before

marketing generic versions, new types

of delivery devices, and new products of

the same class of drug. The authors

explain that certain characteristics of

the inhaled aerosols are known to

influence effectiveness, e.g., particle

size, coalescence of droplets and

evaporation of propellants, rate of

delivery, concentration of the drug

during nebulization, plume geometry,

and the constituents (i.e., drug,

propellants, and surfactants). Other

factors, such as the valve assembly,

rubber seals, and actuator mouthpiece

in a pressurized MDI, can also influence

drug availability and, therefore, need

consideration and regulation to ensure

adequate drug deposition in the lungs.

The authors point out that although

several in vitro tests and in vivo

radioaerosol studies can be used to

predict or measure the deposition of

inhaled particles in the airway, none of

these studies can yet be relied on to

ensure clinical bioequivalence. The

authors conclude that both in vitro and

in vivo testing of clinical effect should

be required to establish the

bioequivalence of generic MDI aerosols.

As part of the required premarket

approval process, the agency is

continuing to review methodology for in

vitro and in vivo bioequivalence testing

for reformulated and generic MDI

aerosol products. The agency has also

sponsored pharmacodynamic studies to

help develop that methodology. The

agency agrees with the conclusion in the

CEC’s report that changes in propellants

should be considered major changes in

pressurized MDI aerosol products and

that extensive premarket testing is

required prior to market approval of

MDI aerosols reformulated with nonCFC propellants. The agency also agrees

with the Committee’s recommendation

that in vivo bioequivalence

documentation should be provided for

generic suspension MDI aerosol

products for oral inhalation.

References

(1) 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.

(2) Drug Information Association, ‘‘MDI’s

in the New Millennium: 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.

(3) Transcripts of the FDA Generic Drugs

Advisory Committee Meeting with

Pulmonary-Allergy Drugs Advisory

Committee Representation, September 14–15,

1993, identified as TS, Docket No. 94N–0247,

Dockets Management Branch.

(4) 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.

(5) FDA Division of Bioequivalence, Office

of Generic Drugs, ‘‘Interim Guidance for

Documentation of In Vivo Bioequivalence of

Albuterol Inhalation Aerosols (Metered Dose

Inhalers),’’ January 27, 1994, in OTC Vol.

04BFMA3.

(6) Petition from Glaxo Inc., to FDA, April

6, 1994, in OTC Vol. 04BFMA3.

(7) Wong, B. J. O., and F. E. Hargreave,

‘‘Bioequivalence of Metered-Dose Inhaled

Medications,’’ Journal of Allergy and Clinical

Immunology, 92(3):373-379, 1993.

III. Summary of Agency’s Proposed

Changes

The agency is proposing that all MDI

aerosol dosage forms must have

premarket approval to ensure their

safety and effectiveness. This proposal

is based on a reconsideration of the

nature of these products, potential

future reformulations to include new

propellants, and the recommendations

of the agency’s Committee (discussed

above).

This proposed amendment removes

the ingredients epinephrine,

epinephrine bitartrate, and

racepinephrine hydrochloride in

pressurized MDI aerosol dosage forms

from the final monograph for OTC

bronchodilator drug products. It does

not affect the monograph status of these

ingredients when used in a hand-held

rubber bulb nebulizer. Such products

will remain in the final monograph for

OTC bronchodilator drug products.

All currently marketed OTC

pressurized MDI aerosol drug products

are the subject of approved applications.

The agency has explained in this

document why it concludes that agency

approval remains essential for these
13020 Federal Register / Vol. 60, No. 46 / Thursday, March 9, 1995 / Proposed Rules

products. A statutory phaseout of CFC

propellants used in these MDI aerosol

products exists, although an exemption

for MDI’s for the treatment of asthma

and COPD exists through 1997. Based

on this phaseout, manufacturers may

eventually decide or need to reformulate

their existing MDI aerosol products with

non-CFC-containing propellant systems.

The agency considers it essential that

any such reformulated products be

evaluated and approved by the agency

before they are marketed.

Consequently, the agency is proposing

to amend § 341.76(d)(2) of the final

monograph for OTC bronchodilator drug

products to remove § 341.76(d)(2)(i)(a)

and (d)(2)(i)(b). The agency proposes

amending § 310.545(a)(6) for

bronchodilator drug products by adding

new paragraph (C) and listing

thereunder ‘‘any ingredient(s) in a

pressurized metered-dose aerosol

container.’’ The proposal would also

remove § 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.

FDA has examined the impacts of the

proposed 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 proposed rule is

consistent with the regulatory

philosophy and principles identified in

the Executive Order. In addition, the

proposed rule is not a significant

regulatory action as defined by the

Executive Order and, thus, 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. All currently marketed MDI

aerosol drug products are currently the

subject of an approved application. This

proposed amendment of the monograph

will not affect the status of any currently

marketed product. As is currently the

case for marketed MDI aerosol products,

an approved application will be

required for any product that is

reformulated to contain a non-CFC

propellant. Accordingly, the agency

certifies that the proposed 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.

The agency invites public comment

regarding 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.

Comments regarding the impact of this

rulemaking on these drug products

should be accompanied by appropriate

documentation. A period of 75 days

from the date of publication of this

proposed rulemaking in the Federal

Register will be provided for comments

on this subject to be developed and

submitted. The agency will evaluate any

comments and supporting data that are

received and will reassess the economic

impact of this rulemaking in the

preamble to the final rule.

The agency has determined that 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.

Interested persons may, on or before

May 23, 1995, submit written comments

or objections to the Dockets

Management Branch (address above).

Written comments on the agency’s

economic impact determination may be

submitted on or before May 23, 1995.

Three copies of all comments or

objections are to be submitted, except

that individuals may submit one copy.

Comments and objections are to be

identified with the docket number

found in brackets in the heading of this

document and may be accompanied by

supporting memorandum or brief.

Comments and objections may be seen

in the office above between 9 a.m. and

4 p.m., Monday through Friday.

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, it is proposed that

21 CFR parts 310 and 341 be 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, 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) and

(d)(26) 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.

(A)—(B) [Reserved]

(C) Approved as of April 10, 1995.

Any ingredient(s) in a pressurized

metered-dose 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)(26) of this section.

* * * * *

(26) April 10, 1995, 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); by

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

(d)(2), and revising the paragraph

heading to read as follows:

§ 341.76 Labeling of bronchodilator drug

products.

* * * * *

(d)* * *

(2) For products containing

epinephrine, epinephrine bitartrate, and

racepinephrine hydrochloride identified

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

hand-held rubber bulb nebulizer. * * *

* * * * *
Federal Register / Vol. 60, No. 46 / Thursday, March 9, 1995 / Proposed Rules 13021

Dated: February 6, 1995.

William K. Hubbard,

Interim Deputy Commissioner for Policy.

[FR Doc. 95–5825 Filed 3–8–95; 8:45 am]

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