Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products for Over-The-Counter Human Use; Proposed Amendment of Monograph for OTC Bronchodilator Drug Products

[[Page 13014]]

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.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend

the final monograph for over-the-counter (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 metered-dose 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 [[Page 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-CFC-

containing 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 double-blind, 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 self-pressurized 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 (m) 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 [[Page 13016]] particles of Teflon (3.2 m 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 [[Page 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). Puff-to-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 m 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

[[Page 13018]] 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 non-CFC-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 CFC-containing 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-CFC-containing 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-to-puff 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). [[Page 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 non-CFC 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 [[Page 13020]] 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 Sec. 341.76(d)(2) of

the final monograph for OTC bronchodilator drug products to remove

Sec. 341.76(d)(2)(i)(a) and (d)(2)(i)(b). The agency proposes amending

Sec. 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 Sec. 341.76(e) from the final monograph because that information

now appears in Sec. 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:

Sec. 310.545 Drug products containing certain active ingredients

offered over-the-counter (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).

Sec. 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:

Sec. 341.76 Labeling of bronchodilator drug products.

* * * * *

(d)* * *

(2) For products containing epinephrine, epinephrine bitartrate,

and racepinephrine hydrochloride identified in Sec. 341.16(d), (e), and

(g) for use in a hand-held rubber bulb nebulizer. * * *

* * * * *

[[Page 13021]] Dated: February 6, 1995.

William K. Hubbard,

Interim Deputy Commissioner for Policy.

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

BILLING CODE 4160-01-F