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Considering flow conditions in the DPI test system has led us to understand more about why experts have improved the pharmacopeial protocol over time. Still, there are aspects of the fundamentals that are not yet clarified but worth understanding and accommodating in the protocols. We believe these include specifications for the solenoid valve, the effect of the pre-separator, control of the flow rate and measurement of the flow rate. 10 April 2022 Inhalation Testing dry powder inhalers (DPIs): Pulling back the curtain on the pharmacopeial DPI flow system and thinking critically about it Improving best practice and being ready when it does not work Daryl L. Roberts, PhD Applied Particle Principles, LLC Control and reproducibility of the testing of dry powder inhalers (DPIs) has been on the minds of serious industry participants for years [1, 2], and new participants enter the field regularly, seeking to learn proper methods [3, 4]. Hasn't enough been said already about testing dry powder inhalers? After all, the equipment, setup, and methods are fairly well described in the current industrial handbooks, such as the United States Pharmacopeia (USP) Chapter <601> [5] and European Pharmacopoeia (Pharm. Eur.) Section 2.9.18 [6]. So all testing needs to be done that way, and everything will be okay, won't it? Yes, true, but… the USP no longer lists some of the example flow system components. Oh really, why not? How do I know if the performance of the components changes with time? Good questions. Each reader who has gotten this far in this article likely has his or her own question! So another article on dry powder testing? Yes! Here, we seek to take the curious user inside the flow system to aid in creating understanding, not of "how to" but "why," and not "what went wrong" but "because." We also aim to create enough understanding to take on hard ques- tions such as "What if I have a carrier-free product and do not use a pre-separator; what happens then?" A better understanding of methods for testing DPIs is important also because regulatory officials, such as the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA), understand that particle size affects the fate of inhaled particles in the lung. So data on the size of particles that contain the active pharmaceutical ingredient (API) are essential to a proper assessment of the safety and efficacy of an inhaled drug product. Cascade impactors make it possible to obtain such data. But this tool does not, and never will, represent a lung. Consequently, there is an ongoing discussion of how realistic cascade test methods should be or even can be; and there is a natural tension between realism and practical equipment that can lead to compromises on both ends of that spectrum. Inhaler testers ide- ally then will understand their methods well enough to explain the limitations of their well-designed, but necessarily in vitro, methods. In this article, we will think critically about the motion of air from the moment the solenoid valve gets its signal to open until the solenoid valve closes and the air motion comes to a halt (Closing does halt the air motion, doesn't it?). And we will think about the fact that there are particles in the system, not just air. After all, the testing is all about the particles, isn't it? Or is it? Our hope is that each reader who has a question can better think through any issue after reading this article. Along the way, we describe ongo- ing investigations of remaining uncertainties in the testing equipment and methods. Testing basics e standard for testing the aerodynamic particle size distribution (APSD) of powders emitted by DPIs involves drawing air through the DPI for a specified

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