Issue link: https://www.e-digitaleditions.com/i/1532011
16 February 2025 Inhalation is based on the CEN (European Institute for Stan- dardization) standard, as this value is a good approxi- mation of the mid-inhalation flow rate achievable by healthy adults breathing at 500 mL tidal volume [15]. In contrast, the Respimat relies on a single breath for delivery. Coating of the stages is typically not required as the aqueous droplets splash rather than bounce off the impactor stages and therefore are less likely to be re-entrained into the air flow. Although not specified in the PSG, it might be beneficial to install a separate micro-orifice collector (MOC) filter to capture the extrafine sub-micron droplets, as in nebulizer testing. Regulatory perspective APSD cascade impactor testing for SMIs is well defined in the guidelines [12-14]. In the USP guide- line, an additional mass balance requirement of 85-115% of the target-delivered label claim is recom- mended, compared to the Ph.Eur guideline. is is not a performance test of the product but rather a sys- tem suitability test to assure the validity of the results. Cross-correlation between geometric and aerodynamic PSD While APSD testing by cascade impaction is well defined, it can be very time-consuming, particu- larly when every stage is separately assessed for drug deposition. In contrast, laser diffraction yields results within seconds after measurement. is difference in analytical throughput naturally poses the question whether one can replace APSD by cascade impaction with the faster laser diffraction methodology. Ziegler and Wachtel [10] found a good correlation between the two methods for Respimat, if well-defined con- ditions are met. In their study, a laser diffraction instrument was coupled with a cascade impactor that allowed for simultaneous determination of the geo- metric PSD by laser diffraction and the aerodynamic PSD by cascade impaction (Figure 4 (right)). A key finding in this study was that a good correlation can only be obtained when the air supply was humidi- fied to > 90% RH, which confirms the importance of controlling the droplet evaporation [10]. However, it should be reiterated that cascade impaction is the key methodology described in the USP and while the Ph.Eur. allows for laser diffraction, a thorough cross-validation is required to meet regulatory expec- tations in the EU. Summary and conclusions Due to its intrinsic design, Respimat requires special attention for plume testing ex-device. For example, a spray test has been established and is applied to every device leaving the Respimat assembly line. is 100% check is conducted by using a test cartridge filled with a control formulation and subsequent assessment of the plume geometry. Being designed for use with highly potent drugs targeting COPD Aerodynamic particle size distribution (APSD) Analytical perspective In the inhalation field, determination of the APSD of aerosols is important to estimate deposition in the lungs. e standard approach for sizing phar- maceutical aerosols is cascade impaction, though for wet aerosols, such as those generated by SMIs, addi- tional consideration must be given to hygroscopic size changes [12, 13]. Briefly, in cascade impaction, the aerosol is guided by an air flow through a cascade of different stages representing different size classes. ese stages are subsequently worked up for a quan- tification of the deposited mass of drug in different size categories. However, it is known that droplets partially evaporate during testing, biasing the APSD towards finer results [11, 14, 15]. is phenom- enon is recognized by the regulatory agencies and, as a result, APSD testing of nebulizers is conven- tionally conducted using a cooled impactor [16]. Another method to avoid evaporation during test- ing is to humidify the supplied air to to > 90% rela- tive humidity (RH). Wachtel, et al. showed virtually identical results obtained from both methods [17]. Figure 5 shows representative setups. Both methods have advantages and drawbacks. In summary, while cooling the impactor is a straightforward approach, it requires at least 90 minutes of cooling, which is partly affected by the environmental conditions, though dedicated coolers are available. In contrast, humidi- fying the air supply for APSD testing provides higher throughput and is independent of environmental conditions. For this approach however, an additional unit is required to constantly supply high volumes of air at > 90% RH. Notably, while an impactor setup can be cooled, cooling a laser diffraction setup poses a challenge. e guidelines specify a test flow rate of 28.3 L/min or 30 L/min compared to 15 L/min used for nebu- lizer testing. It is important to note that the 15 L/min Figure 5 NGI in a dedicated cooler (left) and the humidifier used by Boehringer Ingelheim to produce 100% relative humidity (right)