Issue link: https://www.e-digitaleditions.com/i/1463386
A large gap exists between the relatively straightforward robust methods in the pharmacopeias, developed primarily for product release, and the more elaborate approaches to assist in understanding how inhalers are likely to perform in the hands of the patient or caregiver. We propose that there is a middle way forward and believe it is possible to retain robustness in methodologies, while achieving significant gains in clinical realism. 22 April 2022 Inhalation Jolyon P. Mitchell, PhD, a and Mark W. Nagel, HBSc b a Jolyon Mitchell Inhaler Consulting Services, Inc. b Trudell Medical International Merging pharmacopeial and clinically relevant oral inhaler testing streams: All or nothing or is there a middle way? How we might progress the current debate Introduction Inhalers are tested in the laboratory for several pur- poses, including product development, quality con- trol and support to the clinical programs [1, 2]. A large gap exists between the relatively straightforward robust methods in the pharmacopeias, which have been developed primarily for product release, and the more elaborate approaches that have been researched over the years to assist in understanding how inhalers are likely to perform in the hands of the patient or caregiver [3]. As a result, in vivo/in vitro correlations and relationships (IVIVCs/IVIVRs), in which mark- ers of lung deposition are compared with measures of fine particle mass fraction derived by pharmacopeial methods, have consistently been shown to systemat- ically overestimate whole lung deposition for a wide variety of orally inhaled products (OIPs) [4, 5]. In the example illustrating this type of bias, fine particle fraction was related to particles less than 3.0 μm aero- dynamic diameter [4]. In 2013, Olsson, et al. [6] showed that unbiased IVIVCs based on comparisons of whole lung deposi- tion compared with fine particle mass fraction exiting adult anatomic oropharyngeal models are achievable for three different inhaler classes (pressurized metered dose inhaler (pMDI), dry powder inhaler (DPI) and nebulizer) delivering the same active pharmaceutical ingredient ((API) budesonide). In their study, they replaced the standardized United States/European Pharmacopoeia (USP/Ph. Eur.) inlet with a model adult anatomically correct oropharynx and simulated patient inhalation at the inhaler. Based on their suc- cess, in 2014, we explored the feasibility of "bridg- ing-the-gap" between laboratory methods for the performance evaluation of orally inhaled products for product quality control (QC) and those for devel- opment and clinical support [7]. However, much of the equipment available to enable such studies was still at the research stage. More recently, the rapidly improving availability from commercial suppliers of key components that contribute to clinically perti- nent sampling systems has made practical the routine use of such methodologies in the laboratory. Options for improving clinical realism in testing have continued since 2014. ere is increasing inter- est in mimicking living lung airway tissue [8], as well as standardizing the testing associated with the dis- solution of the API at the site of deposition [9, 10] in order to improve understanding of the in-depth action of the API(s) concerned with the appropriate receptors in the lungs [11, 12]. Despite these promising developments, there remains a reluctance to adopt even simple adaptations to the existing compendial apparatuses for product per- formance testing, especially in the context of regu- latory submissions and in subsequent QC testing. Part of this hesitancy is likely the valid concern about reduced method robustness associated with increased apparatus complexity, especially by going too far in the direction of clinical realism. We propose that there is a middle way forward, in which a few sim- ple-to-implement changes are made to the measure-