[Federal Register Volume 60, Number 46 (Thursday, March 9, 1995)]
[Proposed Rules]
[Pages 13014-13021]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-5825]




[[Page 13013]]

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Part III





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



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21 CFR Parts 310 and 341



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

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