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Inhalation April 2022 23 when attempting to discover how a given inhaler will perform in clinical trials with trained patients/ volunteers. Further, it should be remembered that pharmacopeial testing, even with modifications to be described, can provide only limited insight about how the inhaler might perform in the hands of patients with varying airways disease [23], who may often have less than ideal compliance with the instructions for use [24]. Looking at the situation more closely, firstly, it is self-evident that the right-angle bend USP/Ph. Eur. induction port that precedes the aerosol sampling train and therefore "conditions" the aerosol before size characterization is a poor realization of the com- plexity of the human oropharynx. Further, it can- not be adjusted in size to reflect infant or small child inhaler use. At least one study has demonstrated that APSDs emitted from a pMDI measured with this inlet are shifted to coarser particle sizes compared to measurements made under identical conditions with an inlet having idealized adult oropharyngeal geom- etry [25]. is bias results in an underprediction of oropharyngeal deposition when the compendial inlet is used compared with the situation when an adult patient uses the inhaler [26]. In consequence, there is an overprediction of the mass fraction likely to reach the lungs. Although a similar bias has been demonstrated comparing pMDI- and DPI-gener- ated APSDs obtained with a USP/Ph. Eur. induction port with those determined using an idealized child inlet [27], the corresponding discrepancies compared with oropharyngeal deposition for small children and infants are largely unknown. Secondly, for most inhaler classes other than OIPs, sampling the aerosol at constant flow rate does not recreate the continuously varying flow rate regime that is associated with normal respiration. Pharma- copeial methods for evaluating pMDIs also do not provide for a breath-hold after inhalation, a maneu- ver that has been shown to be important for improv- ing lung deposition from this class of inhaler [28]. Apart from the informative chapter in the United States Pharmacopeia that addresses the testing of spacers and valved holding chambers used as add-on devices with pMDIs [18], these procedures also do not mimic delayed inhalation or exhalation instead of inhalation, both of which can occur with patients who cannot coordinate the inhalation maneuver. is issue is especially significant with pMDI [29] and with soft mist inhaler (SMI) actuation, where some degree of hand/breath synchronization is required [30]. In the case of DPI testing, mimicking a highly standardized inhalation maneuver is unlikely to cap- ture the range of performance that the inhaler might expect to encounter in use [31], especially the effect of airway disease [32]. ment technique. We believe it is possible to retain robustness in methodologies, while achieving signifi- cant gains in clinical realism. What the pharmacopeial methods can and cannot do e USP and Ph. Eur. compendial methods of rel- evance are those that provide delivered dose unifor- mity (DDU)/dose content uniformity (DCU) and inhaler aerosol aerodynamic particle size distribution (APSD), as these measures define the burden of med- ication and the likely deposition profile in the respi- ratory tract [13-15]. Additional chapters relate to similar testing for products/preparations for nebuli- zation [16, 17] and spacers and valved holding cham- bers (VHCs) used with pMDIs [18]. If undertaken by trained operators in accordance with the instruc- tions given in the relevant chapter/monograph, these procedures are generally recognized by regulatory agencies as having the required capability to sup- port product authorization requests and subsequent product quality assessments [19, 20], because they can provide the highest degree of measurement pre- cision and accuracy. e high degree of standardiza- tion associated with these methods is also important to the pharmaceutical industry so that they can be readily transferred and validated from one laboratory to another [21]. e dose uniformity sampling apparatus (DUSA) described for DDU captures the entire mass of med- ication ex inhaler directly into a cylindrical cartridge containing a filter and sampling takes place at a con- stant flow rate. is equipment is also used to deter- mine product content uniformity throughout the lifetime of the inhaler from initial use to exhaustion. Inhaler aerosol APSD is determined by a multi-stage cascade impactor with or without its pre-separator, depending on the need to avoid carry-over of larger carrier particles into the impactor in the case of the many dry powder inhalers that utilize this technology to disperse the API(s) upon inhalation by the patient. A standardized right-angle bend induction port is used as the inlet, thereby providing a greatly simpli- fied model of the adult oropharynx. e aerosol ex inhaler is sampled at constant flow rate (an import- ant requirement for stable size-fractionating stage cut-point sizes) except for DPI testing, when a sim- plified inhalation maneuver is simulated with control over the flow rate/rise time profile with a fixed 4 kPa pressure drop maintained across the inhaler [13-15]. e limitations of these methods are significant when compared with the reality of the patient inhalation experience, arising mainly because of their intrin- sic simplicity compared with the complexity of the physiological and biochemical processes associated with the function of the human respiratory tract during the respiratory cycle [22]. eir straightfor- wardness therefore creates an unavoidable deficiency