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In Vivo Fine Particle Dose (% Nominal)

Figure 2 Relationship between deposition of a radiolabeled DPI aerosol and the measured fine particle dose of the labeled powder inhaled for each subject. Both variables are expressed as the percent of nominal dose. The correlation is higher for the lower flow rate used to inhale the powder, possibly due to the more consistent amount of drug deposited in the oropharynx. (From Ref. 88.)

For deposition studies to be an accurate representation of the behavior of the drug inhaled, the aerosol produced from the tracer powder must be similar to the unlabeled aerosol, and validation of its performance characteristics must be demonstrated prior to use. This involves the same sizing and dosing measurements described earlier.

Validation of a Radiolabeled Aerosol Formulation: Particle Size and Unit Dose

Deposition is a function of the particle size characteristics of the aerosol and the in vivo response is influenced by the dose of drug inhaled per actuation from the inhaler. Thus, prior to using a labeled aerosol product to measure lung deposition and response, confirmation that the aerosol characteristics have not been altered by the labeling procedure must be obtained, as well as demonstrating that the dose of active substance in the aerosol formulation is dispensed consistently, similar to the original nonlabeled formulation, and that the drug is viable. The latter is particularly important when using imaging and simultaneous pharmacokinetic measurements to assess the response to the radiolabeled drug postinhalation [90].

Particle Size Measurements for Validation. The validity of the radiolabeling process is confirmed by a three-way comparison of drug particle size distributions before and after labeling and to the size distribution of radioactivity in the drug product after labeling [61,63]. The characterization of the aerosols is typically performed using cascade impaction, counting the radioactivity deposited on the impactor stages (Fig. 3) and then assaying the drug chemically. The unit spray content and consistency (drug, radioactivity) of the emitted doses from the aerosol inhaler, that is, a pMDI, DPI, or nebulizer, are assessed by comparing the amount and variability of drug (micrograms) and radioactivity (microcuries) emitted per actuation pre- and postlabeling as well as the coefficient of variation for the unit doses in terms of drug and radioactivity. Limits for acceptability are specified in the U.S. FDA Guidance for Industry— Metered-Dose Inhalers (MDI) and Dry Powder Inhaler (DPI) Drug Products— Chemistry, Manufacturing and Controls Documentation, issued in 1998 [85]. For synthesis of drugs with positron emitters, the structure and purity of the radiotracer must be verified, using HPLC, in comparison to an authentic standard prior to administration to human subjects.

When validating whether a radiolabeled aerosol has the same properties as the original aerosol, one needs to use a sizing system that gives both the measurement of the drug substance and the radioactivity. While there are a number of instruments used for sampling and classifying aerosols, multistage cascade impactors are used for validation work because radioactivity can be

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