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Figure 1 Relationships between the various terms used to describe the total mass of medication delivered from OIPs label-claim mass (rest of world) TEM ROW Single Actuation/ Inhalation pMDI/DPI/SMI N Clinical Dose label-claim mass (US) TEM US mouthpiece retention Number of actuations prefix "total" has been added in the present article in order to distinguish more clearly these measures from the sub-fractions of the emitted mass that may be related to regional deposition in the respiratory tract. TEM is deemed a critical quality attribute, in addition to APSD, by the regulatory agencies in North America, Europe 6-8 and, indeed, globally. e methods by which both metrics are obtained are well-defined for pMDI, DPI and SMI products in both the US (USP) and European (PhEur) Pharmacopeias. 1, 2 Likewise, similar information is provided for nebulizing systems in both pharmacopeias; in addition, guidance is provided for the determination of TEM/t treatment . 3, 4 Although they are not "single actuation/inhalation" in use, nebulizing sys- tems are included with pMDI and DPI products in the considerations that follow, because they deliver a mea- surable mass of API in a given time interval that can be equated with TEM, when determined from onset of operation to the end of delivery. Be wary of confusing TEM obtained by the dosage unit sampling apparatus (TM DUSA ) with total mass sampled by the cascade impactor system (TM CI ) in con- nection with APSD determination At first sight, TEM obtained by dosage unit sampling apparatus (TM DUSA ) associated with determination of content uniformity, and total mass sampled by the cas- cade impactor system (TM CI ), linked with determina- tion of APSD, should be equivalent, since both metrics essentially describe the total amount of medication emitted from the inhaler-on-test (pMDI or DPI). However, TM DUSA is typically determined after the min- imum number of actuations/inhalations usually equiv- alent to the label-claim dose have been delivered to the sampling apparatus. 1, 2 is may be as few as a single actuation/inhalation, depending upon the product involved. In contrast, the number of actuations/inhala- tions required for a typical APSD determination may be as many as five or ten, depending upon the detect- ability of the compound and potency of the API. Highly potent substances, such as formoterol fumarate, will require more actuations/inhalations to achieve ade- quate analytical sensitivity, compared with a relatively low potent API, such as albuterol. e current General Chapter <601> of the US Pharmacopeia specifies that the number of minimum recommended doses (actua- tions/inhalations) discharged must be sufficient to ensure an accurate and precise determination of APSD, but adds the rider that the minimum number be not greater than ten. 1 e increased number of actuations/ inhalations is necessary because the aerosol bolus is frac- tionated into as many as ten or more components, depending on the measurement apparatus configura- tion. After recovery, the assay for the pertinent API may therefore result in values close to the limit of detection for some stages. The determination of APSD is also associated with bias from wall deposition within the cascade impactor that can be as much as 5% of TM CI . 1, 2 Further reductions in TM CI may also be caused by losses associated with imperfect recovery from the non-sizing components, such as the induction port and pre-separa- tor (if present), as well as the stages and back-up filter (micro-orifice collector in the Next Generation Impac- tor) (Figure 2). Returning to the determination of TM DUSA , recovery of API from the much simpler appa- ratus only necessitates assay of one sample per determi- nation, excluding API mass that might be recovered from the mouthpiece of the inhaler itself. It follows that TM DUSA is inherently more sensitive than TM CI to minor variations in API mass from one actuation/inha- lation to the next. An important advantage of TM DUSA -based data is that these measurements are likely to be more sensitive to fluctuations in API output through the life of the inhaler, either in use or in stor- age-based stability trials. Given these differences in methodologies, the normal expectation is that TM CI will be slightly less than TM DUSA . Inhalation August 2017 9