Issue link: https://www.e-digitaleditions.com/i/1073928
12 February 2019 Inhalation determined; the guidance also provides advice for population bioequivalence on an evaluation of the single actuation content. 10 While for those with some knowledge of the art, this reverse engineering match- ing of delivered doses may appear to be not insur- mountable, a thorough understanding of the deliv- ered dose practicalities is required for the assessment of the delivered dose during the shelf-life of any test and reference products. is is especially true when considering the EM A guidelines for the in vitro equivalence of impactor stage groupings between reference and test products, which states that a differ- ence of ± 15%, for example, may be justifiable. It should be noted that this often-stated limit of ± 15% is only an example, perhaps recognizing potential variability with different inhaled products. It is presumed that any comparison would be valid through the shelf-life of the test product. While the delivered dose would be fixed at ± 15% of the (target) label claim of the reference product, it would also be linked to the APSD by the previously mentioned mass balance evaluation. It could be argued that sta- bility/shelf-life data is generally not publically avail- able, and any stability studies performed for the test (and reference) products would be subject to para- meters such as the age of the reference product. Consequently, confirmation of any such compari- son limits for delivered dose and stage groupings could only be confirmed during long-term stability studies. It may also be that wider APSD (and deliv- ered dose) limits than ± 15% may be justifiable, as for some commercial products this limit may be accepted as being not practicable. For exa mple, t he commercia l product Seebri ® Breez haler ® (glycopyrronium bromide, Novartis) is controlled to ± 25% of its mean FPM (20-33 µg) (< 5 µm), based on the label claim of 50 µg of the pre- metered dose of the API moiety, glycopyrronium. 11 Moreover, such wide ranges in any APSD metric, such as the previously mentioned FPM, may impact the UDD, especially if the ± 15% limits are adhered to, posing obvious development challenges. How- ever, any publically available information on deliv- ered dose and any APSD metrics would certainly support the development of generic products and their consideration by health authorities. Conclusions e delivered dose is an important quality charac- teristic for the development and quality control of innovator and generic DPIs. However, in contrast to the more clinically relevant APSD test, the UDD test alone provides no indication of any APSD char- acteristic of a DPI. Importantly, the delivered dose and APSD tests are inextricably linked by the mass balance assessment. Therefore, even though the number of actuations for the two tests may be differ- ent, the value of such a UDD test for DPIs could be would be required if ChP and JP was used as the source regulatory testing document. It can be envisaged that, for Ph. Eur. and USP, the number of actuations (and devices) would be signifi- cantly multiplied should level 2 testing be required, suggesting that for multi-dose devices which con- tain more than 100 doses, several thousand actua- tions of the devices may be required to comply with any requirements for UDD. Moreover, only the ChP, JP and 2018 FDA draft guidance provide an indication of the limits to be used for the evaluation of the individual values generated during inter- device testing and any level 2 testing (an additional 20 devices). Importantly, only the JP and 2018 FDA draft guidance have any limits for the mean deliv- ered dose, in that the mea n va lues determined during inter-device delivered dose testing must be within ± 15% of the label claim for delivered dose. Other aspects of the delivered dose ere is one important aspect of the delivered dose and its relationship to the APSD, the so-called mass balance. is evaluation requires that the mass of API emitted during the cascade impactor determi- nation of APSD is assessed against either the deliv- ered dose from the UDD test, with limits of ± 25% of the mean delivered dose applying in Ph. Eur., and JP, or ± 15% of the target delivered dose in USP and the 2018 FDA draft guidance. is is an important point because this evaluation essentially inextrica- bly links the emitted dose from the APSD test to the delivered dose in the UDD test. It could be argued that the determination of the emitted dose during the APSD testing is also a measure of the delivered dose, albeit, an indirect one. In terms of its relevance to the efficacious dose, the UDD can be presently considered as essentia lly a qua lit y control test, which through the mass balance evaluation pro- vides a system suitability test for the APSD test. e delivered dose is also an important parameter used in additional development pharmaceutics/char- acterization studies (for example, the effect of flow rate, product robustness, etc.) as well as for the devel- opment of generic DPIs. In Europe, the EMA guide- lines on the requirement for clinical documentation of orally inhaled products states that the target deliv- ered dose of the generic product should be similar to the reference product (within ± 15%). 9 is is in gen- eral agreement with the Ph. Eur. and EMA guide- lines for the delivered dose, which require that the mean delivered dose determined during the UDD test must be within 15% of the label claim. In contrast, the 2018 FDA guidance for generic products based on, for example, fluticasone propio- nate and salmeterol xinafoate, do not provide any limits for the evaluation criteria for the delivered dose of the test and reference products, but simply state that the single actuation content should be