Why are more clinically relevant in vitro methods needed?
Delivered dose uniformity and APSD measurement are established methods for characterising inhaled products under standardised conditions. These methods are essential for generating repeatable and comparable data, but they do not reproduce every aspect of product use by a patient.
Differences in mouth-throat geometry, inhalation profile, device handling and the conditions encountered after deposition can all affect drug delivery and uptake. More clinically representative methods can help product developers investigate these factors, compare test and reference products under a wider range of conditions and generate data that better supports an understanding of in vivo performance.
Better IVIVCs do not replace compendial testing. They provide complementary information that can support product development, bioequivalence assessment and the interpretation of in vivo studies.
The evolving role of enhanced in vitro methods
FDA product-specific guidances (PSGs) for certain orally inhaled and nasal drug products increasingly reference enhanced in vitro approaches for bioequivalence assessment.
Depending on the individual guidance, these approaches may include realistic APSD measurement, inhaled dissolution testing and other product-characterisation studies. Together, they reflect a broader move towards generating more sensitive and clinically relevant in vitro evidence alongside established testing methods.
Requirements remain specific to the product and guidance concerned, so laboratories should always consult the current PSG when developing their testing strategy.
Explore the regulatory backgroundTwo complementary areas of testing
No single in vitro test describes the complete journey of an inhaled drug. Realistic APSD and inhaled dissolution provide complementary information about aerosol deposition and post-deposition behaviour. Used alongside established product-characterisation methods, they can help build a more complete understanding of product performance.
1. Realistic APSD (rAPSD)
Investigate product performance under more representative conditions
Realistic APSD measurement builds on established cascade impaction methods by introducing more clinically representative mouth-throat models and inhalation profiles.
A typical setup combines:
• An Alberta Idealised Throat
• A breathing simulator
• A mixing inlet
• A Next Generation Impactor (NGI)
• Appropriate flow control and vacuum equipment
Together, these components allow the performance of an inhaler to be assessed across different throat geometries and inhalation profiles while maintaining the constant flow required for calibrated impactor operation. This helps researchers explore how device, formulation and patient-related factors may influence dose delivery.
2. Inhaled dissolution
Investigate what happens after deposition
APSD measurement helps assess where particles of different aerodynamic sizes may deposit within the respiratory tract. Dissolution testing provides complementary information about how the deposited drug may dissolve in the limited fluid volumes available at the deposition site.
Unlike conventional dissolution testing for oral solid dosage forms, inhaled dissolution methods must account for the small quantity of drug collected and the low fluid volumes found at the deposition site. Appropriate dose collection, membrane selection, dissolution medium, apparatus configuration and test conditions are therefore important when developing a method that is both reproducible and sufficiently discriminatory.
Comparing dissolution behaviour can help researchers investigate formulation differences, understand potential effects on local and systemic exposure and support comparative or bioequivalence studies.
Other approaches for investigating clinically relevant product performance
Beyond realistic APSD and inhaled dissolution, additional methods can help investigate specific aspects of product use and performance.
Facemask testing
For patients who use an inhaler with a facemask, factors such as fit, seal and dead space can influence the dose available for inhalation. Facemask testing helps assess product performance under more representative conditions for paediatric and other patient groups who may not use a mouthpiece directly.
View more detailsParticle morphology
Particle size alone does not always explain how an inhaled product will perform. Assessing particle shape, surface characteristics and agglomeration can provide additional insight into aerosolisation, deposition behaviour and differences between test and reference products.
View more detailsCold Freon® effect
The rapid expansion and evaporation of propellant from an MDI can create a cooling sensation at the back of the throat, which may cause some patients to interrupt or alter their inhalation. Cold Freon® effect testing allows this aspect of product performance to be investigated and compared under controlled conditions.
View more detailsFrequently asked questions about more clinically relevant inhaler testing
An IVIVC describes a relationship between a result measured in vitro and an aspect of product behaviour observed in vivo. For inhaled products, establishing strong correlations is challenging because drug delivery can be influenced by patient physiology, inhalation technique, disease state, device characteristics and formulation behaviour.
No. Compendial APSD methods remain important for standardised product characterisation and routine quality testing. Realistic APSD methods provide complementary information under more clinically representative conditions.
Standard APSD testing typically uses a pharmacopoeial induction port and constant flow through the inhaler and cascade impactor. Realistic APSD introduces representative throat models and inhalation profiles, while using a mixing inlet to maintain constant impactor flow.
The Alberta Idealised Throat offers a more representative model of mouth-throat deposition than the standard pharmacopoeial induction port while remaining practical and reproducible for laboratory testing.
It decouples the changing flow through the inhaler from the constant flow needed through the impactor, allowing representative inhalation profiles to be used without affecting calibrated impactor operation.
APSD characterises the aerodynamic size distribution of the emitted aerosol. Dissolution testing investigates how the collected drug dissolves after deposition. Together, they provide information about different stages of the inhaled drug-delivery process.
They are included in some product-specific guidances as part of enhanced in vitro or alternative bioequivalence approaches. The exact requirements depend on the individual drug product and the current version of the relevant guidance.
Related Inhaler Testing Products
For further information about the other products in our inhaler testing range, please select one of the options below.
Delivered Dose Uniformity (DDU)
Our range of Delivered Dose Uniformity (DDU) sampling apparatus are designed to help accurately assess the total amount of emitted drug.
Delivered Dose Uniformity (DDU)
View MoreAncillaries
Optimise inhaler testing workflows with our broad range of supporting equipment required to make up fully-operating test systems for Delivered Dose Uniformity (DDU) and Aerodynamic Particle Size Distribution (APSD) of orally inhaled and nasal drug products (OINDPs).
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View MoreSpecial Applications
Copley Scientific offers a range of testing equipment for additional qualification and validation of orally inhaled and nasal drug products (OINDPs), including assessments of generic drug formulations, inhaled dissolution testing and improving IVIVCs.
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Take the labour out of inhaler testing with our semi-automated solutions.
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View MoreAerodynamic Particle Size Distribution (APSD)
Our range of precision engineered cascade impactors measure the size distribution (particle size) of inhaled drug products, providing critical information about where particles in aerosol clouds are likely to be deposited in the lungs following inhalation.
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