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12 February 2025 Inhalation tests required for inhalers, an SMI requires tests spe- cific to the unique feature of a slow-moving gentle mist of fine droplets and the device mechanisms required to achieve this. In particular, conventional spray pattern, plume geometry and plume velocity tests are not sufficient, as these tests were historically developed as quality control methods for evaluating pMDIs and nasal devices, which typically comprise injection-molded nozzles and corresponding poten- tial defects. In addition, these tests are conducted without application of an external flow rate, as the spray velocity of pMDIs is rather high compared to SMIs. erefore, applying different external flow rates to mimic patient inhalation is recommended. is article provides an overview of parameters that should be investigated during early development and routine testing of an SMI. For reliable results, the methods should be validated for the unique proper- ties of the aerosol generated by the SMI. Moreover, a thorough understanding of the device as well as the formulation characteristics is necessary to iden- tify the critical attributes contributing to the overall quality of the aerosol ex-device. e United States Food and Drug Administra- tion (FDA) defines an SMI as an inhalation spray, whereas the corresponding guideline from the Euro- pean Union defines it as a non-pressurized metered dose inhaler [6, 7]. e US view is further explained by the US FDA's product specific guidance (PSG) for Tiotropium Bromide, spray, metered, inhalation [8]. is PSG describes new testing requirements for spray duration and spray velocity in addition to con- ventional requirements for pMDIs (plume geometry/ many), the majority of methodologies and regulatory guidances described in the article are applicable to other SMIs [3]. Respimat relies on the Uniblock nozzle, which in turn utilizes lithographically manufactured micro- channels leading to impinging jets to generate a fine, slow-moving aerosol [4]. e device meters 15 mcl, which are subsequently forced by a spring-driven piston pump through the Uniblock nozzle (Fig- ure 1) at approximately 250 bar to yield a soft mist, exhibiting at a distance of 10 cm from the nozzle, a speed of approximately 0.8 m/s which is 3-10 times slower than the average plume speed of a pressurized metered dose inhaler (pMDI) [5]. Respimat and other SMIs can be characterized as low resistance devices, as shown in Figure 2. Con- trary to most DPIs, which are passive devices, they are active aerosol-generating devices. erefore, the SMI, rather than the patient, supplies the energy required to aerosolize the formulation. Conse- quently, no strong inspiratory effort is required to generate favorable aerosol and spray characteristics for delivery to the lungs. Background In general, an SMI is treated similarly to other prod- ucts containing solutions for oral inhalation with regard to physicochemical properties such as assay, related substances, pH, osmolality, etc. Testing differs mainly in the assessment of pharmaceutical perfor- mance, i.e., the quality of the aerosol plume emit- ted ex-device. In addition to general physicochemical Figure 2 Pressure drops for representative dry powder inhalers (DPIs), a representative pressurized metered dose inhaler (pMDI) and the Respimat soft mist inhaler, at various flow rates (in-house testing) 0 20 40 60 80 100 Flow Rate Achieved (L/min) 6 5 4 3 2 1 0 Pressure Drop (kPa) DPI A DPI B DPI C DPI D DPI E pMDI A Respimat SMI