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Obscuring the message: A critical examination of laboratory test methods for orally inhaled products that could lead the user astray: Part 2—Total Emitted Mass (TEM) and related metrics This is the second in a two-part educational series discussing potential pitfalls in testing OIPs and ways to avoid them. The first article focused on aerodynamic particle size distribution (APSD) determination and this article discusses total emitted mass. Jolyon P. Mitchell, PhD, FRSC(UK), CChem, CSci Jolyon Mitchell Inhaler Consulting Services, Inc. Mark W. Nagel, HBSc Trudell Medical International Jason A. Suggett, BPharm, PhD, MBA Trudell Medical International Dominic P. Coppolo, MBA, RRT, FAARC, AE-C Monaghan Medical Corporation obscure the findings, and therefore the interpretation of data, that are derived from such measurements. Like its predecessor, this article provides guidance for the selec- tion of the most suitable methods, identifying their limitations and associated potential pitfalls. Confusion between total dose and total mass per actuation/inhalation At the outset, it is important to clarify a commonly encountered misnomer, namely that TEM equates with the total clinically prescribed dose. In the context of OIP testing, the term "dose" should always be under- stood in terms of its use by the clinical professional, since more than one use (e.g., per actuation of pMDI or SMI, or per inhalation for a DPI), may be required to give the prescribed dose (total dose). On the other hand, the registered label claim "dose" is the mass(es) of API(s) that the manufacturer of the product intends the inhaler to deliver per single actuation/inhalation. e registered label claim "dose" most closely relates to TEM, as measured using a compendial method. In this article, the descriptor "emitted" has been intentionally added to emphasize the difference between the label claim value and the total mass of API that reaches the sampling/measurement apparatus. e relationships between these terms are summarized in Figure 1. e situation just described is complicated by the fact that, in the US, the FDA requires the registered label- claim "dose" (TEM US ) to be expressed ex-mouthpiece, whereas in the rest of the world, this quantity (TEM ROW ) relates to the total mass of medication emitted from the inhaler, including that which deposits on the mouth- piece. For the purpose of this article, TEM from here on refers to the rest of world definition. ese differences in definitions were captured by the European Pharmaceu- tical Aerosol Group (EPAG) in a publication presented a few years ago, in which they attempted to identify and standardize the numerous terms and definitions that currently exist in connection with OIPs. 5 In their arti- cle, they also referred to emitted dose. However, the Introduction is article is the second in a two-part series in which laboratory test procedures for the assessment of OIP performance are appraised. is first article focused on determination of aerodynamic particle size distribution (APSD). Attention is now turned towards the determi- nation of the total emitted mass (TEM) of active phar- maceutical ingredient (API), which is the other major in vitro performance metric that is identified in the pharmacopeial literature. 1-4 Total mass is often expressed per actuation for pressurized metered dose inhalers (pMDIs) and their associated add-on devices, such as spacers or valved holding chambers (VHCs), as well as for the new soft mist inhalers (SMIs). In the case of dry powder inhalers (DPIs), this metric is expressed per inhalation since the device cannot be operated properly without creating an inspiratory maneuver. In the case of nebulizing systems, however, the situation is more com- plicated because they are intended to deliver medica- tion either continuously or during inhalation only, in connection with therapy which typically lasts for several minutes. Nevertheless, for the purpose of this article, TEM for nebulizing systems is conveniently considered to be the total mass of API delivered within the treat- ment time, t treatment, and its adjunct measure of medica- tion delivery rate is simply TEM/t treatment, often expressed in units of µg API/min. As in Part 1, the focus of the article is to identify poten- tial pitfalls in set-up, execution and analysis that could 8 August 2017 Inhalation