Metered-dose inhaler components

Following delivery of 1,200 mg of HFC-134a by inhalation from metered-dose inhalers to four healthy adult male volunteers (16 actuations of 75 mg per inhalation each inhalation within 30 s of the previous inhalation), the only fluorinated urinary component was trifluoroacetic acid. Urinary trifluoroacetic acid accounted for less than 0.0005% of the administered dose, indicating minimal metabolism (Monte et al. 1994). 

Data adequacy The key study was well designed and conducted and documented a lack of effects on heart and lung parameters as well as clinical chemistry. Pharmacokinetic data were also collected. The compound was without adverse effects when tested as a component of metered-dose inhalers on patients with COPD. Animal studies covered acute, subchronic, and chronic exposure durations and addressed systemic toxicity as well as neurotoxicity, reproductive and developmental effects, cardiac sensitization, genotoxicity, and carcinogenicity. The values are supported by a study with rats in which no effects were observed during a 4-h exposure to 81,000 ppm. Adjustment of the 81,000 ppm concentration by an interspecies and intraspecies uncertainty factors of 3 each, for a total of 10, results in essentially the same value (8,100 ppm) as that from the human study. ... 

Pressurized metered dose inhalers are still the most frequently used systems and they have proven their value in therapy. However, their application in early phases of biopharmaceuti-cal research and further development of dosage forms seems less convenient, since they require special components including propellants, special containers, metering valves, and controlled filling conditions (pressure-filling or cold-filling). 

Metered-Dose Inhalers and Nasal Aerosols Content uniformity, aerodynamic particle size distribution, microscopic evaluation, water content, leak rate, microbial bioburden, valve delivery, extractables, leachables from plastic and elastomeric components. 

Inhalation drug products include inhalation aerosols (metered dose inhalers) inhalation solutions, suspensions, and sprays (administered via nebulizers) inhalation powders (dry powder inhalers) and nasal sprays. The CMC and preclinical considerations for inhalation drug products are unique in that these drug products are intended for respiratory tract-compromised patients. This is reflected in the level of concern given to the nature of the packaging components that may come in contact with the dosage form or the patient. 

A change in the primary packaging components for any product when the primary packaging components control the dose delivered to the patient (e.g., the valve or actuator of a metered-dose inhaler). 

Specific considerations for container/closure system components for specialized delivery systems such as metered dose inhalers, dry-powder inhalers, disposable pen injectors, transdermal patches, or other novel dosage forms... 

TABLE 3 Summary of Components and Materials Used In Metered Dose Inhaler Valves... 

Inhalation drug products, also referred to as orally inhaled and nasal drug products (OINDPs including inhalation aerosols and solutions, nasal aerosols and sprays), have a high likelihood of packaging component-dosage form interaction,and therefore have individual USFDA guidance documents. As an example, consider the metered dose inhaler (MDI), shown... 

Figure 4 Essential components of a metered-dose inhaler.

The pressurized metered dose inhalers in the use of environmentally friendly propellants means the choice of hydrofluoroalkanes, wherein the dosage form can be a suspension of the solution form. The problems of formulating suspensions, as discussed earlier, apply here as well, but particularly with respect to interactions with the formulation components specific to pressurized inhaler systems. 

Metered-dose inhalations and nasal aerosols should be evaluated for appearance (including content, container, and the valve and its components), color, taste, assay, degradation products, assay for cosolvent (if applicable), dose content uniformity, labeled number of medication actuations per container meeting dose content uniformity, aerodynamic particle size distribution, microscopic evaluation, water content, leak rate, microbial limits, valve delivery (shot weight), and extractables and leachables from plastic and elastomeric components. Samples should be stored in upright and inverted/on-the-side orientations. 

The active component of inhalation aerosol is beclomethasone dipropionate, an anti-inflammatory corticosteroid having the chemical name 9-chloro-ll(beta),17,21-trihy-droxy-16(beta)-methylpregna-l,4-diene-3,20-dione 17,21-dipropionate. It is a pressurized, metered-dose aerosol intended for oral inhalation only. Each unit contains a solution of beclomethasone dipropionate in propellant HFA-134a (1,1,1,2 tetrafluoroethane) and ethanol. The 40-mcg strength delivers 40 meg of beclomethasone dipropionate from the actuator and 50 meg from the valve. The... 

The metering valve is the key to measuring and presenting a consistent and accurate dose to the patient it is made up of a number of precision-made plastic or metal components. The valve is crimped onto a canister, which is ordinarily made of aluminum. Finally, there is the actuator, which holds the canister and through which the patient inhales the dose. 

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