Inhalation

INH0420

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The first in a series of articles from the IPAC-RS Cascade Impaction Working Group concerning the limitations of metrics commonly used in the assessment of aerodynamic particle size distributions (APSDs) of orally inhaled products (OIPs). The current article discusses the surprisingly limited utility of the fine particle dose metric in quality control. 18 April 2020 Inhalation The liability of fine particle dose (FPD) Can we rely on the fine particle dose metric alone for quality control? Adrian P. Goodey, PhD a ; Jolyon P. Mitchell, PhD, FRSC(UK), CChem, CSci b ; William H. Doub, PhD c and J. David Christopher, MSc a a Merck & Co. b Jolyon Mitchell Inhaler Consulting Services, Inc. c OINDP In Vitro Analysis product quality. 3 Each document clearly presents FPD as the primary metric for characterizing the APSD of an OIP, acknowledging only via caveat that "additional cri- teria may be appropriate" if FPD alone is insufficient for APSD characterization. However, as discussed in the following article, FPD is generally quite poorly suited to the quality control of APSDs. is matter should be of concern to regulators, drug manufacturers and patients alike. Our aim is therefore to stimulate discussion regarding the purpose of APSD testing in QC and the importance of using appropriate metrics. The liability of fine particle dose (FPD) e liability of relying on FPD in the QC environment can be quickly illustrated with the following example. Imagine that you work in QC and that you are tasked with determining the suitability of a newly manufac- tured batch of an OIP for release to the European mar- ket. In this scenario, your job is to determine whether the performance of the current batch is sufficiently similar to that of the clinical batches previously used to demonstrate the safety and efficacy of the product, as defined by the approved specifications. In this case, the product in question is a solution pres- surized metered dose inhaler (pMDI). Figure 1 sum- marizes the typical performance of this pMDI as well as that of the newly manufactured batch. In panel A, the 200 mass-weighted APSDs shown in gray illustrate the typical performance of the product while the sole dis- tribution highlighted in red is the APSD of the current batch. e same APSDs are presented in cumulative form in Panel B. Individual FPD values determined e following is the first in a series of articles by the Cas- cade Impaction Working Group of the International Pharmaceutical Aerosol Consortium for Regulation and Science (IPAC-RS) concerning the limitations of metrics commonly used in the assessment of aero- dynamic particle size distributions (APSDs) of orally inhaled products (OIPs). e current article concerns the surprisingly limited utility of the fine particle dose metric in quality control. e next article in this series will continue the theme of scrutinizing metrics used to make batch disposition decisions, with a focus on the stage grouping metrics favored by the United States Food and Drug Administration (FDA). ese articles are written to educate: to dispel common misconcep- tions, to raise awareness of risks and to encourage scien- tists to scrutinize current practices. ese articles should not be mistaken for regulatory guidance documents. Introduction Fine particle dose (FPD), the active pharmaceutical ingredient (API) mass less than 5 µm aerodynamic diameter, is a commonly used metric in the assessment of aerodynamic particle size distributions (APSDs) of orally inhaled products (OIPs). In particular, for products marketed in Europe, both the European Pharmacopoeia 1 and the European Medicines Agency (EMA) 2 recommend use of FPD (referred to as "fine particle mass" by the EMA) for quality control (QC) of OIPs. Similarly, in their 2006 guidance on the quality of inhaled pharmaceutical products, Health Canada defaults to the use of fine particle mass less than 5 µm to characterize inhaler APSDs in the context of assessing

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