Abstract
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Since there are many influences on clinical response, we believe that the approach advocated by these members of the Small Airways Study Group of the Respiratory Effectiveness Group is not helpful at all to the practicing clinician. In addition, by overinflating the importance of the size metric derived from in vitro cascade impactor data to the clinical context, their terminology could be misleading for regulators by erroneously causing a perception of a clear in vitro/in vivo correlation.
Their approach is unwarranted because it introduces the potential for error by implying that size boundaries of 2.1 and 5 μm aerodynamic diameter by themselves provide useful qualitative information to medical practitioners concerning regional deposition of particles in the human respiratory tract. The authors clearly intend to influence medical thinking about therapeutic aerosols (“the medical literature lacks standard nomenclature”). However, the therapeutic effect of inhaled drug products is simply not amenable to categorization by aerodynamic particle size alone, no matter how much one might wish that a simple parameter would suffice as an adequate categorization. For this reason, we maintain that recommending a “standard nomenclature” for medical practitioners for particle size based only on aerodynamic diameter, determined in vitro, has the potential for doing more harm than good.
The emphasis on in vitro-determined particle size as the major determinant of lung deposition and response has proven to be misplaced; the main reason that in vitro-determined particle size is so inadequate as a clinical tool is that the in vitro environment and deposition processes are markedly different from the in vivo environment and deposition mechanisms.(2) For example, factors influencing the in vitro-determined size of clinical aerosols include impactor operating flow rate, inlet design and dimensions, ambient humidity and temperature, evaporation through the impactor, stage efficiencies, and internal wall losses.
However, factors that determine where a therapeutic aerosol deposits within the respiratory tract, thereby affecting in vivo outcomes, include the inspiratory flow rate profile, the temperature and humidity within the respiratory tract (which influence particle growth), and more complex aspects associated with the differing types and degrees of lung disease (airway obstruction, changes to airway morphology, parenchymal destruction, etc.). All of these influences significantly affect the physical mechanisms governing the in vivo deposition of the drug dose inhaled, the subsequent distribution of the dose within the lung, and ultimately, the clinical response to the inhaled dose.(3)
Importantly, measurement of aerodynamic diameter by impactor (in vitro) has been developed primarily as a quality control test for the drug product and not as a means to identify unambiguously its ultimate deposition sites in the respiratory tract. Cascade impactor-derived particle size distributions, therefore, cannot by themselves be indicative of the likely clinical efficacy in response to the inhaled treatment.(4) This situation is true, even though there is some evidence that particles as small as ∼1 μm deposit more distally in the lung and may be more clinically effective at a lower dose than larger particles of the same active pharmaceutical ingredient.(5) We, therefore, wish to call to the reader's attention the following aspects that we believe necessarily and appropriately distinguish in vitro laboratory measurements of aerosol aerodynamic particle size distribution (APSD) from the in vivo clinical outcomes.
Differing size-separation modalities: Multistage cascade impactors are designed to separate particles by inertial impaction at a constant volumetric flow rate.(6) Their sigmoidal-shaped stage collection efficiency curves are intentionally intended by the designer of the apparatus to be as steep as possible to optimize size selectivity, an essential requirement for accurate measurement of the aerosol APSD.(7–9)
In contrast, particles passing through the human respiratory tract are size separated and deposited by the combined processes of turbulent deposition, inertial impaction, gravitational sedimentation, and Brownian diffusion within an envelope of a continuously varying flow rate during each inhalation.(10) As a result, the corresponding collection efficiency curves associated with predictions of regional deposition (extrathoracic, bronchial, bronchiolar, and alveolar deposition)(11) are each much less correlated to size than are the particles captured on a stage of a cascade impactor.(12)
Therefore, any nomenclature intended to advise clinicians but based on the performance of the component stages of a cascade impactor misinterprets aerosol physical behavior in both the lung and in the cascade impactor. Cascade impactors are not lung simulators, despite marketing drawings to that effect created historically by some manufacturers of the Andersen impactor.
Respiratory tract development with age: Defining rigid, laboratory-determined aerodynamic size-related limits associated with regional deposition in the human respiratory tract ignores the fact that the respiratory tract undergoes significant development with age, especially in the first few years of life.(13) Setting rigid limits for the different sized fractions of an inhaled aerosol, therefore, takes no account of differences in particle regional deposition behavior associated with age-related airway development and also ignores the changes resulting from disease in these neonatal and pediatric patients.(14)
Effect of airways disease on aerosol transport: Obstructive airway diseases will modify particle transport behavior,(15) ranging from minor effects if the affected airways remain patent to major effects in cases wherein the obstruction plugs the airways entirely. Although bronchial hygiene during inhalation with mucolytics(16) may be effective at removing mucus plugs from the airways of patients with severe asthma, chronic obstructive pulmonary disease, or cystic fibrosis before aerosol therapy, the process is not often complete, resulting in airway narrowing, changes in regional ventilation, and, in consequence, lung distribution of therapeutic aerosols.(17)
In contrast, airway remodeling associated with emphysema in patients with severe asthma and/or COPD(18) is likely to alter regional deposition significantly.(17) The lung morphology in these cases is the controlling factor in the behavior of the aerosol, not whether the particles are “coarse, fine, or extrafine.”
Coarse/fine/extrafine: We believe the terminology distinguishing “coarse” from “fine” particles has properly risen to the level of “jargon” in the inhalation community, because the upper airways are very efficient at protecting the human lung from particles; essentially, only “fine” particles can get into the lung at all, be they therapeutic or not. Nevertheless, following the arguments already presented, we do not believe that a specific quantitative value of aerodynamic size, determined in the laboratory, by itself is going to help a clinician. So why elevate these notions to a quantitative “nomenclature?” We recognize that such an approach can, of course, help a drug manufacturer simplify the quality control testing by providing boundary sizes as a means upon which to develop specifications.
However, even this approach can be seen to be valid if, and only if, clinical outcomes can be shown to have a quantitative relationship with particle size. Even in this limited context, we do not see any reason for one, and only one, quantitative definition of “fine.”
Nomenclature: The concept of nomenclature is reserved for describing distinct concepts, distinct species, distinct categories, and as part of a larger taxonomy. However, in the present context, we contend that there is nothing fundamentally distinct between the physical behavior in inhaled air of a 2.1 μm aerodynamic diameter particle (proposed as being “fine” by the nomenclature proposed by Hillyer et al.(1)) and that of a 2.0 μm aerodynamic diameter particle (proposed as being “extrafine”). Individual particles of 2.1 μm aerodynamic diameter are not always more or less penetrating, based on their actual penetration through the airways of the lungs, than those having an aerodynamic diameter of 2.0 μm.
Furthermore, some therapeutic aerosols are physically large and porous, leading to a small aerodynamic diameter, but increased deposition by interception at bends and bifurcations. So, examining all these aspects, can it be said that aerodynamic diameter is alone the key measure to link to therapeutic efficacy? If it was, it follows that the community of drug product developers and regulators could focus solely on in vitro size measurements by a cascade impactor, and stop doing and assessing the outcomes from clinical trials for new drug products, respectively, as well as ceasing bioequivalence testing for generic drug products.
New therapeutic targets: Grouping all particles <2.1 μm into one category called “extrafine” ignores potentially new therapeutic modalities that are targeted away from the “traditional” topical delivery to the airways. For instance, delivery of nanoaerosol particles with diameters < ca. 0.5 μm is currently a major area of development,(19,20) likely producing new systemic therapies that target preferentially the distal lung. These new therapies are properly called “nanoaerosols” and would simply be considered “extrafine” under the nomenclature proposed by Hillyer et al.,(1) in consequence, completely obscuring their physical behavior in the lung and their therapeutic potential.
In the same edition of Journal of Aerosol Medicine and Pulmonary Drug Delivery, Weers has outlined much of the well-understood dependence of lung deposition on flow rate(21); here the impaction parameter (the product of the square of the particle diameter times the flow rate) is proposed as a meaningful method of describing therapeutic aerosols. We believe the impaction parameter is very much a better descriptor for impaction in the lung than is aerodynamic diameter. In this context, Martin and Finlay(22) have presented a remarkable lung deposition correlation that includes the impaction parameter. Nevertheless, even such a correlation by no means elevates the impaction parameter by itself to be a decisive descriptor for clinical efficacy.
In conclusion, we assert that the particle size property of therapeutic aerosols is always a continuum with no convenient boundaries between subfractions extrafine, fine, and coarse particles. Instead, we contend that therapeutic efficacy depends on so many factors other than size, including particle velocity and the internal geometry of the respiratory tract leading up to the location at which deposition takes place that the postulate of a medically helpful size classification nomenclature is an error. Even the broadly discussed “5 μm aerodynamic diameter” boundary between coarse and fine particles advocated in the European Pharmacopeia(23) has still to be proven as being therapeutically relevant for each and every drug product lest improper assumptions about safety and efficacy are made without clinical substantiation.
Without such definitive evidence, we, therefore, propose that even this boundary and any such boundaries, based on an in vitro quality control test, remain only a useful talking point, and not a quantitative boundary deserving of a standardized nomenclature, as proposed by Hillyer et al.(1)
Footnotes
Author Disclosure Statement
The authors declare that no competing financial interests exist.