U.S.
Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Clinical Medical
March
2003
Guidance for
Industry
Integration of Dose-Counting Mechanisms into MDI Drug Products
Additional copies are
available from:
Office of Training and
Communications
Division of Communication Management
Drug Information Branch, HFD-210
5600 Fishers Lane
Rockville MD 20857
(Tel): 301-827-4573
(Internet)
http://www.fda.gov/cder/guidance/index.htm
U.S.
Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Clinical Medical
March
2003
Guidance
for Industry
Integration of Dose-Counting Mechanisms into
MDI Drug Products
This guidance represents the Food and Drug Administration's (FDA's)
current thinking on this topic. It does not create or confer any
rights for or on any person and does not operate to bind FDA or
the public. An alternative approach may be used if such approach
satisfies the requirements of the applicable statutes and
regulations. If you want to discuss an alternative
approach, contact the FDA staff responsible for implementing
this guidance. If you cannot identify the appropriate FDA
staff, call the appropriate number listed on the title page of
this guidance.
This
guidance is intended to assist manufacturers who are developing or
plan to develop drug products for oral inhalation using
metered-dose inhalers (MDIs). The guidance reflects the Agency's
current recommendations regarding the integration of dose-counting
mechanisms into MDI drug products for oral inhalation. Although
the contents of the guidance should be considered by any
manufacturer of any MDI drug product (including nasal MDI
products), this guidance is not specifically intended for
manufacturers of already marketed MDI drug products for oral
inhalation nor for manufacturers developing MDIs for other routes
of administration (e.g., nasal MDIs). It is also not intended for
manufacturers developing multidose dry powder inhalers (MDPIs),
which already incorporate dose counters as an integral part of the
delivery system. Manufacturers developing new MDPIs are
encouraged to continue including dose counters in their products
and may find the contents of this guidance useful in their
planning.
For the
purposes of this guidance, the term dose counter includes
both mechanisms that use a numeric count to indicated doses
remaining, as well as dose-indicating mechanisms that do not
enumerate the number of actuations, but rather indicate via color
coding or other means when a device is nearing the end of its
useful life. Also, the use of the term integrated in this
document is intended to define dose counters that are an integral
part of the MDI canister and/or actuator, and not simply an add-on
that can be removed and used multiple times with various products.
FDA's guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency's current thinking on a
topic and should be viewed only as recommendations, unless
specific regulatory or statutory requirements are cited. The use
of the word should in Agency guidances means that something
is suggested or recommended, but not required.
Metered-dose inhalers have been available for nearly 50 years and
have come to be regarded as the preferred method of delivery for
many important drugs intended to treat obstructive airway
diseases, such as asthma, emphysema, and chronic bronchitis.
MDIs represent a
reliable, convenient dosing device for delivery of medications to
the lungs. However, they have one major disadvantage over other
dosage forms. Currently available MDIs offer no practical way for
patients to track the remaining numbers of doses or amount of
medication. A complicating, but necessary design feature of MDIs
is that they contain more formulation than strictly required to
expel the labeled number of actuations. This additional amount of
formulation (propellant, drug substance, and any excipients) is
necessary to ensure the dosing consistency of each spray through
the labeled number. For instance, an MDI labeled to deliver 120
metered-actuations may expel 20 to 30 additional actuations
(depending on the specific fill target for that product).
However, the amount of drug per spray in those additional 20 to 30
actuations may in many cases be inconsistent and with continued
use beyond the label claim will become negligible. Since the
inactive components in the drug formulation may exceed 95 to 99
percent, an MDI used beyond the recommended dose may appear to be
delivering a therapeutic spray when it isn't. Other than
carefully and consistently tracking each actuation in writing and
subtracting this total from the labeled number of actuations,
there is no method by which a patient can determine how many
effective doses are left in an MDI. Various means of testing
the inhalers (e.g., shaking the canister) are unreliable and
some in addition may damage the MDI (e.g., the float-test,
placing the canister in water).
Currently, patients must guess how many doses are left in their
MDIs and have two practical options: (1) throw away an MDI that
may still contain acceptable metered-doses or (2) use a product
when it may be beyond the recommended number of doses and risk not
receiving the correct drug dose. The former is wasteful, and the
latter is potentially dangerous. The addition of an accurate dose
counter to an individual MDI unit would allow the patient to
reliably track the numbers of actuations used from that individual
inhaler (i.e., to identify when the label claim number of
actuations has been reached). This would prevent the patient from
discarding an inhaler unnecessarily or using the product beyond
the recommendations provided in the labeling for that product.
The
recommendations in this guidance address primarily MDI products
designed to deliver drugs to the lungs for any indication. This
is because the consequences of not receiving an acceptable metered
dose are more clinically important for oral inhalation drug
products than for the current medications available in nasal MDIs.
Medications delivered to the lungs often play a vital role in the
treatment of airway diseases and are potentially life-saving.
Nasally delivered drugs are more typically intended to treat
bothersome, but non-life-threatening, conditions. However, if a
nasal MDI were developed where the issue of dosing beyond the
recommended label claimed number of doses were associated with a
more serious consequence, this guidance would be applicable.
Finally,
this guidance is not intended to preclude other accurate means of
informing patients as to the remaining number of metered-doses
left in an MDI. If manufacturers develop other ways apart from
the use of a dose counter, the FDA is willing to consider those
innovations and, if satisfactory, to deem them reasonable
alternatives.
The
Agency recommends that manufacturers with metered-dose inhalers
under development for oral inhalation integrate a dose-counting
device into the development of their MDI drug product. Dose
counters should provide, either through a direct numeric count or
color coding, a clear indication of when an MDI is approaching the
end of its recommended number of actuations as well as when it has
reached or exceeded that number. An indication that an MDI is
approaching the end of its recommended number of actuations should
occur when a sufficient number of actuations are left to give
patients enough time to obtain a new MDI. If a numeric count is
chosen, we recommend that the counter be designed so that it
counts downward from the recommended number of actuations to zero,
rather than counting upwards, enabling patients to know when a
device is approaching the end of its life (i.e., the number of
actuations is approaching zero).
As
previously mentioned, this guidance specifically refers to orally
inhaled MDI drug products currently under development or which are
being planned for development. Although the integration of dose
counters into currently approved MDIs is also encouraged, it is
recognized that the economics of doing so may be burdensome,
particularly for MDIs using chlorofluorocarbons as propellants
(since these products will eventually be universally phased-out
under the provisions of the Montreal Protocol on Protection of the
Ozone Layer). Manufacturers with MDI drug products in the latter
stages of development are encouraged to integrate a dose counter
into their product as soon as feasible, although the integration
may not be possible prior to submission of a new drug
application. In such cases, manufacturers are encouraged to
commit to developing an integrated dose counter in the
postmarketing period.
Dose
counters should be engineered to reliably track actuations and
should be designed to be as close to 100 percent reliable as
possible. However, if some low frequency of error is unavoidable,
the device should be designed to specifically avoid undercounting
(i.e., the MDI sprays, but the counter does not advance).
Undercounting could result in patients assuming they have
medication left in their MDI when they do not, a circumstance that
is potentially dangerous. The reliability of dose counters should
be established during development under in-vitro testing
(simulating use and potential abuse), as well as in clinical use.
The documentation of dose counter functionality, reliability, and
accuracy would ideally be derived from assessments in clinical
trials including, where possible, phase-3 trials. However, for
dose counters added either late in a development program or
postapproval, in-use studies should be designed and conducted to
obtain this information. Note that in either case, these studies
do not need to establish the clinical benefit of incorporating a
dose counter, rather, they should address issues related to
ergonomics, ruggedness, and accuracy of the counters in clinical
settings. The range of patients in whom this information is
developed should include reasonable representation of special
populations likely to use the drug (e.g., pediatrics,
geriatrics). Finally, if the same dose counter design and
mechanism is incorporated into multiple different MDIs, it would
not ordinarily be necessary to repeat the in-use studies for each
additional MDI product in which a counter of the same design is
used, once the in-use data have been satisfactorily developed with
the device. However, since dosing characteristics vary between
MDIs, in-vitro testing would ordinarily be expected in all such
cases.
A
lock-out mechanism to prevent doses beyond the labeled number of
actuations would be an optional feature of dose counters.
However, a lock-out feature would not be recommended for
bronchodilator medications used to treat acute bronchospasm. For
these rescue bronchodilators, the ability of the MDI to
actuate beyond the labeled number of actuations and to provide
even a partially therapeutic dose of drug could be life saving.