Everything you need to know about core test methods for soft mist inhalers (SMIs) including practical guidance on minimising the data-compromising impact of droplet evaporation and how to refine methods to improve clinical relevance.
Welcome to the third blog in our device-focused series. The first covered MDIs, the second explored DPIs, and today we’re turning to a newer class of orally inhaled product (OIP) device: soft mist inhalers (SMIs). This post provides a clear, practical primer on SMI testing, focusing on compendial methods for Delivered Dose Uniformity (DDU) and Aerodynamic Particle Size Distribution (APSD).
First commercialised in 2004, SMIs address two inherent challenges shared by MDIs and DPIs: low lung deposition and patient-related dose variability. Designed as portable devices that deliver a metered dose within a single inhalation, they combine ease of use with efficient drug delivery to the deep lung. SMIs are attracting growing commercial interest as developers look to capitalise on these defining advantages. Depending on formulation characteristics and shear sensitivity, SMIs may also be of interest for certain higher value or biologic-based therapies.
Whether you’re at the forefront of SMI development or already working on generic products, DDU testing and APSD measurement are key requirements. Together, they confirm consistent delivery of a defined respirable dose: the cornerstone of reliable therapeutic effect.
In this blog, we cover:
- How SMIs work and how this impacts testing
- Compendial methods for DDU and APSD
- The issue of droplet evaporation and how to safeguard data quality
- Regulatory requirements for demonstrating bioequivalence (BE)
Reading time: 10 minutes
Understanding how SMIs work
SMIs mechanically aerosolise a metered dose of liquid formulation without relying on a propellant. The specific aerosolisation mechanism varies between platforms. The Respimat® SMI platform, currently the best-established commercial example, uses energy stored in an internal spring to force the formulation through a precision-engineered nozzle to generate an aerosol. Emerging platforms combine alternative aerosolisation technologies with established prefilled syringe technology.
The cloud of aerosolised particles that SMIs produce:
- contains a high fraction of fine, respirable particles
- is slow moving
- is long lasting, typically persisting for over a second
As a result, SMI characteristics differ substantially from those of MDIs and DPIs.
How SMIs differ from MDIs and DPIs
A closer examination of SMIs, relative to MDIs and DPIs, is useful in highlighting their key differences.
The fine, slow-moving, long-lasting mist produced by SMIs:
- Is mechanically generated, giving SMIs a lower carbon footprint than propellant-driven MDIs
- Reduces particle momentum and, by extension, throat deposition relative to both MDIs and DPIs
- Correspondingly enhances lung deposition, including to the peripheral airways where deposition can be clinically advantageous
- Reduces dependence on closely coordinated actuation and inhalation, as required for MDIs, and on the strong inspiratory manoeuvre required for DPIs.
These features align with efforts to lower the environmental footprint of respiratory therapies and support efficient, targeted inhaled drug delivery across patient populations.
Set against these relative attractions are certain limitations which include:
- Unsuitability for suspensions, due to the microscopic geometry of the nozzle
- Dose and payload limitations
- Higher cost
- Complexity of preparation and priming.
Taken together, these benefits and limitations help explain why SMIs are attracting interest for specific applications, while also highlighting why robust, device-specific testing remains important.
How SMI design impacts testing
Because SMIs are actively actuated, metered-dose devices, many core tests resemble those used for MDIs. However, the way the device is prepared, actuated and aerosolised also introduces SMI-specific considerations, particularly around priming, spray duration, spray velocity and droplet evaporation.
The slow-moving, persistent mist produced by SMIs is central to how these devices perform. Parameters such as spray duration, spray velocity, plume geometry and spray pattern may therefore be relevant in product development and regulatory submissions. However, the core laboratory methods for confirming delivered dose and respirable aerosol performance remain DDU testing and APSD measurement.
Device preparation, priming and actuation
For many commercially available SMIs, the product consists of the device and a prefilled cartridge or syringe containing formulation. Depending on the device format, routine product use may involve:
- Loading the prefilled cartridge or syringe into the device, with formats ranging from single-dose devices to reservoirs containing around 60 doses.
- Twisting the base of the device to ready it for use; this extracts a dose for delivery and/or may also initiate mechanisms such as spring compression.
- Pressing the dose-release button, initially for priming and then for drug delivery.
- Priming or re-priming cycles, depending on the device instructions.
These steps must be followed rigorously in all testing to ensure repeatable dose delivery.
The basics: Compendial methods for SMIs
Compendial methods provide an assessment of core SMI performance metrics under well-controlled conditions. Collectively they verify that:
- Each actuation delivers a consistent mass of drug: DDU
- Aerosolised particles are within the target size range for lung deposition: APSD
For multidose devices, testing may also need to consider dose consistency across the entire product life, including beginning, middle and end-of-life stages.
These core compendial methods characterise critical quality attributes and establish a robust reference point for evaluating more complex testing.
SMI Delivered Dose Uniformity (DDU) Testing
SMI DDU test set-up showing the vacuum pump (left) and flow controller (centre) used to establish and verify test-flow conditions, alongside the dose-collection device.
Because the device generates the aerosol mechanically, rather than relying on the patient’s inspiratory effort to disperse the dose, testing is typically performed using defined constant flow conditions. DDU testing for SMIs is performed at 28.3 L/min or 30 L/min, as for MDIs, using an identical test set-up. Further details of DDU testing requirements can be found in our brochure.
DDU testing assesses whether a product delivers doses consistently across the required number of inhalers and at different stages of container life, supporting confidence in product performance and batch quality. Put simply, DDU data confirm that products consistently deliver a defined dose to the patient.
SMI Aerodynamic Particle Size Distribution (APSD) Measurement
Items for APSD measurement set-up for SMIs, showing the vacuum pump (right) and flow controller (centre) used to establish test conditions, a Next Generation Impactor (NGI) for size fractionation of the dose, and an NGI Cooler™ to minimise droplet evaporation.
Cascade impaction provides APSD data for the sub-10 micron fraction of the delivered aerosol, with measurement focused on the fraction below 5 microns in aerodynamic diameter. Based on aerodynamic size, this fraction is most likely to deposit in the lungs. DDU and APSD are therefore complementary: the first reveals how much drug is delivered; the second indicates how much of that delivered dose is likely to reach its target, the lungs.
As with DDU testing, APSD measurement for SMIs is carried out under constant flow-rate conditions, reflecting the active nature of drug delivery. Depending on the cascade impactor used, the specified flow rate is either 28.3 L/min or 30 L/min.
However, there is one crucial difference between routine MDI and SMI APSD measurement set-ups: the need for impactor cooling, as evidenced by the inclusion of a cooler, such as the NGI Cooler shown above.
Droplet evaporation: Understanding the risk, Addressing the issue
In APSD measurements for SMIs, solvent loss from droplets within the impactor can compromise data quality. As droplets evaporate, their size can reduce, potentially causing deposition on the wrong impactor stage. The net result is a skewing of reported APSD values towards finer particle sizes.
Current FDA PSGs for SMI products recommend minimising evaporation during APSD measurement. Cooling the impactor to 5°C, as specified for nebuliser APSD measurement, is the easiest way to prevent this problem and we offer the NGI Cooler™ for this purpose. By lowering the temperature of the impactor, evaporation is minimised, helping safeguard data integrity.
Regulatory requirements for the demonstration of BE
At the time of writing, there are four FDA PSGs for SMIs (spray, metered, inhalation), all relating to products commercialised with the Respimat® platform. These are:
- Tiotropium bromide
- Olodaterol hydrochloride
- Olodaterol hydrochloride/tiotropium bromide
- Albuterol sulfate/ipratropium bromide
Across these PSGs, the recommended evidence package includes seven in vitro test methods alongside a single in vivo PK study for the demonstration of BE. The listed in vitro methods are:
- Single Actuation Content (delivered dose)
- APSD
- Spray pattern
- Plume geometry
- Priming and repriming
- Spray duration
- Spray velocity
To date, these PSGs do not specify realistic APSD, which may reflect the relatively patient-independent performance of SMIs and the regulatory focus on spray characteristics such as duration and velocity. These additional spray and plume measurements reflect the specific way SMIs generate and deliver the aerosol. Alongside these, DDU and APSD remain central to confirming dose delivery and the aerodynamic size profile of the emitted droplets.
However, given the wider regulatory interest in alternative BE approaches and more clinically representative in vitro evidence for OIPs, it is reasonable to expect SMI testing requirements to continue evolving as the evidence base develops.
SMI testing: A summary
Core compendial methods for SMIs – DDU testing and APSD measurement – are closely aligned with those used for MDIs. These similarities reflect the active, metered dose delivery mechanism shared by both device types.
However, SMI testing also brings distinct considerations. As SMIs generate a solution-based aerosol, droplet evaporation can affect APSD measurements, making impactor cooling an important part of safeguarding date quality.
Beyond compendial testing, current BE expectations for SMIs may also include product-specific assessments such as spray duration, spray velocity, spray pattern and plume geometry. These tests reflect the importance of the generated mist to SMI performance, while DDU and APSD remain central to understanding delivered dose consistency and respirable aerosol characteristics.
As SMI development continues, particularly for applications where efficient lung delivery is a priority, testing approaches are likely to become more refined. The tests outlined here provide a practical foundation for assessing this important class of inhalers and supporting confident product development.
This blog provides a practical overview of SMI testing fundamentals, but many of the topics discussed here can be explored in greater depth.
If you are setting up SMI testing or refining an existing method, explore our related guidance on:
Next in the series: We’ll explore testing for nebulisers, where tidal breathing and facemask use introduce a different set of practical considerations.
