title: Clinically relevant test methods to establish in vitro equivalence for spacers and valved holding chambers used with pressurized metered dose inhalers (pMDIs).
abstract: 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.
authors.affiliation: Trudell Medical International, London, ON, Canada.
authors.forename: Jolyon
authors.initials: J
authors.lastname: Mitchell
authors.forename: Myrna B
authors.initials: MB
authors.lastname: Dolovich
mesh_terms: D000280:Administration, Inhalation; D002170:Canada; D004867:Equipment Design / Q000592:standards; D006801:Humans; D066298:In Vitro Techniques; D008422:Materials Testing / Q000379:methods*; D036501:Metered Dose Inhalers / Q000592:standards*; D010316:Particle Size; D004364:Pharmaceutical Preparations / Q000008:administration & dosage; D011786:Quality Control
chemical_list: D004364:Pharmaceutical Preparations