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A common drawback of many inhalation products is significant throat deposition, often approximately 50% of the total dose ex-device. High throat deposition not only can result in the loss of active material but may cause safety concerns. It is believed that deposition in the throat follows a ballistic (momentum-based) trajectory. As such, throat deposition is a direct consequence of particle/droplet size (which correlates with mass) and speed. Inhalation February 2025 11 Analytical challenges and regulatory perspectives in the development of soft mist inhalers (SMIs) Parameters that should be investigated during early development and routine testing of an SMI David Stadermann, Dipl. Ing (FH) a , Sitaram Velaga, PhD a and Herbert Wachtel, PhD b a Kenox Pharmaceuticals Inc. b Boehringer Ingelheim CAUTION: is article is being published only for pur- poses of education, not as a definitive guide for product development. Regulations within the US and around the world vary and are continually evolving. erefore, we strongly caution you to work closely with representa- tives of the regulatory agencies, as well as in-house reg- ulatory personnel and/or independent consultants, to determine requirements for your particular product and the best approach in seeking regulatory approval. Introduction A common drawback of many inhalation products is significant throat deposition, often approximately 50% of the total dose ex-device. High throat depo- sition not only can result in the loss of active mate- rial but may cause safety concerns. It is believed that deposition in the throat follows a ballistic (momentum- based) trajectory. As such, throat depo- sition is a direct consequence of particle/droplet size (which correlates with mass) and speed. erefore, a reduction in particle/droplet mass/size and speed should result in lower throat deposition. is think- ing has led to the development of soft mist inhalers (SMIs), which have a key differentiating property: a slowly moving (gentle) mist composed of fine (low mass) droplets. SMIs are considered non-pressurized, propellant- free, metered dose inhalers that deliver a single breath inhalable aerosol of a drug solution [1]. However, device designs addressing certain deliv- ery challenges can come with tradeoffs. While dry powder inhalers (DPIs) do not require synchroniz- ing actuation and inspiration, they rely on a mini- mum inspiratory flow rate to deliver an effective dose [2]. Although SMIs have low throat deposition, they are limited to use with solution formulations, deliver relatively low doses and require sophisticated device engineering. e limitation regarding solu- tions stems from the spray nozzle design, which typ- ically comprises micropores or microfluidic channels in the micron range that can be clogged by suspen- sion particles. For delivery of biologics using SMIs, no general recommendations can be made because this class of drugs differs widely in terms of sensitivity to shear stresses and dosing requirements. erefore, it is advisable to evaluate SMI use with biologics on a case-by-case basis. While this article discusses the Respimat ® Soft Mist™ Inhaler (Boehringer Ingelheim, Ingelheim, Ger- Figure 1 The Uniblock spray nozzle of the Respimat Soft Mist Inhaler (SMI) Nozzles Glasss (front) Silicone (back) Filter structure