Issue link: https://www.e-digitaleditions.com/i/1532011
Inhalation February 2025 15 macopeia (Ph.Eur.) allows for adequately validated laser diffraction testing in leu of cascade impaction [12, 13]. is validation should include a thorough cross-validation against cascade impaction results, so that a robust cross-correlation between the results obtained from both methodologies can be estab- lished. Furthermore, the International Organization for Standardization's ISO 13320:2020 – Particle size analysis – Laser diffraction methods [9], provides guidance on the qualification, application and vali- dation for the determination of the PSD. Delivered dose (DD) Analytical perspective Respimat's metering volume of 15 mcl makes it is particularly suitable for delivery of highly potent drugs. is typically results in comparatively low delivered doses ex-device that might pose analytical challenges with respect to recovery. e delivered dose ex- device and its uniformity, in terms of vari- ation, should be based on single actuations using dose uniformity sampling apparatus (DUSA) tubes. Great care should be taken to assure reliable recov- ery of low amounts of drug emitted from the device. A common practice is to extend the linearity of the assay method, typically a high performance liquid chromatography (HPLC) method, to approximately 50% of the expected concentration of the drug in the work-up solution during delivered dose testing. With respect to the applied flow rate, it is advisable to maintain a constant flow rate of either 28.3 L/min or 30 L/min. ese flow rates are akin to those pre- scribed in the USP and Ph.Eur. for testing of pMDIs, which exhibit similar low resistances. (It is notewor- thy that Respimat was designed to have an air flow resistance similar to that of pMDIs.) e applied flow rate should match the flow rate used for cas- cade impactor testing. When testing delivered dose according to USP <601>, 2 liters of air should be applied. For manually actuated SMIs, synchroniza- tion between device actuation and application of the test flow rate is required, as with pMDIs. Regulatory perspective e determination of the delivered dose of inhala- tion products using the DUSA is well described in the USP and Ph.Eur. monographs [12, 13]. A key difference between them is in the inhalation volume requirements: 2 liters for the USP vs. no volume requirement for non-pressurized metered dose inhal- ers in Ph.Eur. Using a test flow rate of 30 L/min, 2 liters are applied within 4 seconds. Since the spray duration of Respimat is approximately 1.5 seconds, this provides ample time for adequate manual syn- chronization between actuation of the device and application of the test flow. However, automated syn- chronization like that for pMDIs can be applied to further mitigate any operator-based bias. a sheath flow, facilitated by an external gas supply, can be adjusted to optimize the aerosol concentra- tion in the laser beam. An inhalation module coupled to a Malvern Spray- tec (Malvern Panalytical, Westborough, Massachu- setts, US) is shown in Figure 4 (left). Additional parameters can be investigated and optimized using this setup. For example, it can be equipped with an induction port (IP) used for cascade impaction test- ing. However, the IP might act as a classification stage for larger particles and therefore, the results reflect only the PSD of the aerosol fraction that fol- lows the airflow without impaction in the IP. One should therefore evaluate both with and without an IP to assess the totality of the PSD including a poten- tial larger fraction. While it is the IP specified in the United States Pharmacopeia (USP) that is typically used in practice, anatomically idealized IPs like the Alberta Idealized roat (AIT) can be equipped to better estimate the aerosol PSD change caused by the induction port. Also, the inhalation module allows for application of a sheath flow that protects the opti- cal path from fouling as particles deposited on either the laser or detector window can bias the results. However, when the first Respimat products were developed, no such instrument was readily avail- able. erefore, Boehringer Ingelheim internally developed a dedicated setup relying on a Sympatec HELOS system (Sympatec, Clausthal-Zellerfeld, Germany) and a modified IP that allowed assessment of the geometric aerosol PSD pre-IP and simultane- ous assessment of the aerodynamic PSD by cascade impaction [10, 11], see Figure 4 (right). Regulatory perspective Contrary to the inhalation monograph <601> of the USP which does not specify laser diffraction PSD testing for oral inhalation, the European Phar- Figure 4 Malvern Spraytec with inhalation module and USP Throat (left); Boehringer Ingelheim laser diffraction test setup for Respimat (right)