[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]]
_______________________________________________________________________
Part III
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
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