Issue link: https://www.e-digitaleditions.com/i/1208415
A clinically more relevant approach for comparing the aerodynamic particle size distribution (APSD) of a generic dry powder inhaler (DPI) to that of an originator has been proposed, which could potentially replace an EU standard. This article describes the results of a study that follows these principles for APSD in vitro bioequivalence (IVBE) assessment of three tiotropium DPIs. 18 February 2020 Inhalation A clinically relevant approach to assess in vitro bioequivalence for regulatory approval of DPIs: A case study A comparison of three tiotropium DPIs using a mouth/throat model and a range of realistic inhalation profiles Dennis Sandell, PhD;a Peter Elfman, MSc b and Mårten Svensson, PhD b aS5 Consulting b Emmace Consulting AB pared based on a mix of data obtained under different realistic conditions. is approach therefore follows the general philosophy for comparing treatments used in standard clinical testing. A further advantage with the DOE approach 1 is that the potential effects by PIFR, T PIFR and T can be individually estimated, thus allowing deeper understanding of device and formula- tion characteristics for both products studied. is article describes the results of a study that follows these principles for APSD IVBE assessment of three tiotropium DPIs: the Spiriva ® Handihaler ® (innovator product, Boehringer Ingelheim), the Tiova ® Rotacaps ® Caution: is article is being published for purposes of education and discussion. e approach for IVBE com- parability assessment applied here challenges the current standards in several ways and should not be used as a reg- ulatory tool unless agreed upon with the regulator. Introduction In 2016, a clinically more relevant approach for com- paring the aerodynamic particle size distribution (APSD) of a generic dry powder inhaler (DPI) to that of an originator was proposed by Sandell. 1 Brief ly, products are compared using anatomically correct mouth/throat (MT) models and a range of realistic patient- and product-specific inhalation profiles (IPs), and parameters described by Delvadia, et al 2 with characteristics defined by peak inspiratory flow rate (PIFR), acceleration (time to PIFR, T PIFR ) and inhala- tion time (T), varied according to a reduced factorial designed experiment (DOE) to cover the full range of profiles found in the relevant patient population. Moreover, it was shown 1 how the PIFR percentiles could be determined based on device resistance and published data for different relevant patient popula- tions, 3 thereby avoiding the need to determine these experimentally in patients for every new DPI. It was argued 1 that using the proposed approach is a clinically more relevant means to assess APSD in vitro bioequivalence (IVBE) between a generic and an originator DPI that potentially can replace the EU standard to separately compare at three constant flows, corresponding to 10%, 50% and 90% PIFRs of the relevant patient population. The proposed approach should be more relevant, not only since it uses a test method better mimicking the way a patient uses the product, but also because products are com- Table 1 A reduced 3 3-1 factorial design: Percentiles (%) for PIFR, T PIFR and T for defining inhalation profiles for comparison of products IP No. PIFR T PIFR T 1 10 10 10 2 10 50 90 3 10 90 50 4 50 10 90 5 50 50 50 6 50 90 10 7 90 10 50 8 90 50 10 9 90 90 90 IP No. = inhalation profile number PIFR = peak inspiratory flow rate T PIFR = acceleration (time to PIFR) T = inhalation time