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Guidance for Industry (PDF
version of this document)
U.S.
Department of Health and Human Services March 2003
Guidance for
Industry Additional copies are available from:
Office of Training and
Communications
(Internet)
http://www.fda.gov/cder/guidance/index.htm
U.S.
Department of Health and Human Services March 2003
Table of Contents I. INTRODUCTION II. BACKGROUND III. INTEGRATION OF DOSE-COUNTING MECHANISMS INTO MDI PRODUCTS UNDER DEVELOPMENT
Guidance
for Industry
[1] 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.
I. INTRODUCTIONThis 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. II. BACKGROUNDMetered-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.[2] 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.
III. INTEGRATION OF DOSE-COUNTING
MECHANISMS INTO MDI PRODUCTS UNDER DEVELOPMENT
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