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stage groupings are typically used introduces a differ- ent risk, wherein batches may be incorrectly rejected. As members of the IPAC-RS Cascade Impaction Working Group, we contend that neither FPD nor stage groupings are reliable metrics for making batch disposition decisions. Moreover, given the potential impact to patients and their medicines, we believe drug developers and the authorities who regulate them have a responsibility to address these shortcomings. Acknowledgements e authors acknowledge the IPAC-RS Board and the Cascade Impaction Working Group for their helpful review and discussion of the manuscript. References 1. European Directorate for Quality in Medicines (EDQM): European Pharmacopeia 10.0, mono- graph 2.9.18. Preparations for inhalations: Aerody- namic assessment of fine particles. Strasbourg, France EDQM. 2017. 2. European Medicines Agency: Guideline on the pharmaceutical quality of inhalation and nasal prod- ucts. EMEA/CHMP/QWP/49313/2005 Corr. 2006. http://www.ema.europa.eu/docs/en_GB/document_ library/Scientific_guideline/2009/09/WC500003568. pdf. Accessed August 2019. 3. Health Canada: Pharmaceutical quality of inhalation and nasal products. 2006. http://www.hc-sc.gc.ca/dhp- mps/prodpharma/applic-demande/guide-ld/chem/ inhalationnas_e.html. Accessed October 2019. 4. Tougas TP, Goodey AP, Hardwell G, Mitchell J and Lyapustina S. A Comparison of the Performance of Efficient Data Analysis versus Fine Particle Dose as Metrics for the Quality Control of Aerodynamic Particle Size Distributions of Orally Inhaled Pharma- ceuticals. AAPS PharmSciTech, 2017, Vol. 18, No. 2, 451-461. 5. FDA Draft Guidance: Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Products – Quality Considerations. April 2018. Adrian P. Goodey, PhD, (corresponding author) is Prin- cipal Scientist, Specialty Dosage Forms, Merck & Co., Rahway, New Jersey, US, adrian.goodey@merck.com. Jolyon P. Mitchell, PhD, FRSC(UK), CChem, CSci is Scientific Consultant, Jolyon Mitchell Inhaler Consulting Services, Inc., London, Canada, mitchelljolyon@gmail. com. William H. Doub, PhD, is Consultant, OINDP In Vitro Analysis, St. Louis, Missouri, US, oindp_iva1@ charter.net. J. David Christopher, MSc, is Executive Direc- tor, Research CMC Statistics, Merck & Co., West Point, Pennsylvania, US, j.david.christopher@merck.com. e APSD data from these additional OIPs confirm that the fundamental limitations of the FPD metric are, in fact, universal and are not unique to the unpalatable example highlighted in the previous figures. Summary In this article, the insensitivity of FPD to shifts in inhaler APSD is clearly illustrated. In addition to highlighting the liability of relying on FPD alone for control of an APSD, the underlying causes have been discussed. Moreover, data from eight different products are examined to demonstrate the broad relevance of this phenomenon. e conclusion is clear: due to the insensitivity of FPD to APSD size, FPD cannot be used alone as a metric for APSD quality control. FPD can be used to control the mass-dimension of the APSD, but it must be used in conjunction with an orthogonal metric that is sensitive to changes in the size-dimension (such as MMAD). Importantly, supplementing FPD with metrics such as ISM or material balance (total mass ex-inhaler), neither of which are sensitive to APSD size changes, is not sufficient. e implications of this obser- vation extend beyond the realm of QC testing. Indeed, any study relying solely on FPD to compare APSDs may equate aerosols that are, in fact, significantly different. In the next article of this short series, we intend to place impactor stage groupings (currently favored by the US FDA 5 as a quality control measure for OIP APSD) under similar scrutiny. Fine Particle Dose, as we have seen, essentially represents a single, very large grouping of stages, and the resulting weakness is that it fails to detect large differences between APSDs. In QC, this can result in misclassifications where batches are inap- propriately released. Conventional Stage Groupings, on the other hand, typically split the size-fractionated mass into three groups. As such, the grouping approach does not suffer the inherent limitations of FPD. How- ever, as the reader will see, the manner in which the 22 April 2020 Inhalation The IPAC-RS APSD Database e APSD data used in this manuscript originate from QC testing of actual OIPs. The blinded IPAC-RS database includes APSD data for 34 OIPs, which are either commercially marketed or in late development (Phase IIB or later), from seven manufacturers. To ensure blinding and confidentiality, APSD data were submitted to the IPAC-RS secretariat. For each product, the APSD data consist of API recoveries from individual impactor components (e.g., induction port, stages, filter, etc.) expressed as a percent of the product label claim. More information regarding the data- base can be found at: https://wayback.archive-it.org/7993/201704051 82408/https:/www.fda.gov/ohrms/dockets/ ac/00/techrepro/3609_rpt2.pdf