Clinically Relevant Test Methods to Establish In Vitro Equivalence for Spacers and Valved Holding Chambers Used with Pressurized Metered Dose Inhalers (pMDIs)
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Regulatory guidance in Canada and Europe recommends that the manufacturer of an inhaled drug product delivered by pressurized metered-dose inhaler (pMDI) identify a spacer (S) or valved holding chamber (VHC) to be used with their designated product. It therefore becomes necessary to include the S/VHC in the process of establishing bioequivalence (BE) to the reference pMDI product for both new-entry generic and subsequent market entry products (SMEPs). S/VHCs substantially modify the aerodynamic particle size distribution (APSD) of the inhaled medication, and potentially the spatial distribution of the mass of active pharmaceutical ingredient(s) [API(s)] depositing in the respiratory tract. The processes whereby S/VHCs can influence BE outcomes are examined, and the inadequacy of compendial in vitro methods to provide pertinent information to assess BE for the pMDI+VHC combination is highlighted. A three-part strategy is proposed whereby in vitro testing for BE can simulate more clinically-relevant conditions than in the current compendial procedures: 1. The inclusion of a short delay between inhaler actuation and sampling onset is appropriate when determining APSD at flow rate(s) suitable for the intended patient population; 2. Assessment of total emitted mass ex S/VHC by simulating tidal breathing pattern(s) appropriate for intended use; 3. Incorporation of appropriate face model(s), representative of the intended patient age range(s), into test procedures for S/VHCs with facemask, enabling clinically-appropriate dead space and fit-to-face to be simulated. Although the compendial authorities have been slow to recognize the need for such in vitro testing, a Canadian standard provides direction for implementing most proposals, which should result in better performance predictions and more appropriate clinical outcomes, highlighting similarities and differences between reference and test products.
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