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Dry powder inhalers (DPIs) are used to deliver locally acting drugs (e.g., bronchodilators and corticosteroids) for treatment of lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). Demonstrating bioequivalence (BE) for DPI products is challenging, primarily due to an incomplete understanding of the relevance of drug concentrations in blood or plasma to equivalence in drug delivery to the local site(s) of action. Thus, BE of these drug/device combination products is established based on an aggregate weight of evidence, which utilizes in vitro studies to demonstrate equivalence of in vitro performance, pharmacokinetic or pharmacodynamic studies to demonstrate equivalence of systemic exposure, and pharmacodynamic and clinical endpoint studies to demonstrate equivalence in local action. This review discusses key aspects of in vitro studies in supporting the establishment of BE for generic locally acting DPI products. These aspects include comparability in device resistance and equivalence in in vitro testing for single inhalation (actuation) content and aerodynamic particle size distribution.
Bioequivalence (BE)1 refers to the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in a pharmaceutical equivalent2 or pharmaceutical alternative3 becomes available at the site of drug action when administered at the same molar dose under similar conditions. For the majority of orally administered drugs that reach their site(s) of action through the systemic circulation, BE is demonstrated based on drug concentration in a relevant biologic fluid (e.g., plasma or blood). However, this approach is not considered sufficient to establish BE of orally inhaled drug products for local action, such as dry powder inhalers (DPIs) that are used for treatment of lung diseases (e.g., asthma and chronic obstructive pulmonary disease (COPD)). Their drug delivery and intended action do not rely on the systemic circulation. Therefore, demonstration of BE for these locally acting drug products is more challenging.
The current thinking for establishing BE of DPIs is based on the aggregate weight of evidence (Fig. 1). This approach utilizes appropriate in vitro studies to determine comparative in vitro performance of test and reference DPI products, pharmacokinetic (or pharmacodynamic) studies to establish equivalence of systemic exposure, and pharmacodynamic (or clinical endpoint) studies to demonstrate equivalence in local action. Formulation and device similarities are also taken into account in ensuring equivalence of these orally inhaled drug products. This review is intended to discuss in vitro aspects of BE assessment of generic DPI products for local action. Specifically, our discussion focuses on passive (breath-actuated) DPIs because all the currently approved DPI products in the United States, with the exception of an active device delivering human insulin, are passive. We first provide background information relevant to orally inhaled drug delivery, including physiology of the airways, target area(s) for drug deposition in the lungs, and the impact of aerodynamic particle size on regional lung deposition. We then discuss product- and patient-related factors that affect local drug delivery to the respiratory tract, with the aim of providing a basic understanding of the roles that these factors may play in determining BE. We also discuss the important roles of formulation and device similarity in the development of a DPI product that has increased likelihood of establishing equivalence. Finally, we describe the in vitro considerations for supporting the establishment of BE for DPIs.
The airways provide a pathway for air to flow into and out of the peripheral region of the lungs where gas exchange takes place. Various levels of airways in the lungs can generally be categorized into two parts: the conducting zone and the respiratory zone, as illustrated by Weibel’s lung model (Fig. 2) (1).
The conducting zone consists of the first 16 generations of airways. This zone begins with trachea (generation 0), which divides into the two main bronchi. These two main bronchi further subdivide into smaller bronchi that enter into two left and three right lobes. Inside each lobe, the bronchi continue to undergo further division to form new generations of smaller caliber airways, the bronchioles. The conducting zone ends with terminal bronchioles (generation 16), the smallest airways devoid of alveoli. The airways in the conducting zone do not participate in gas exchange. Their main function is to allow the bulk flow of air to move into and out of the lungs during each breath. The conducting airways are the principal site of airway obstruction in respiratory diseases such as asthma and COPD.
The respiratory zone is the region where gas exchange occurs. It starts at the respiratory bronchioles (generation 17). These bronchioles further divide into additional respiratory bronchioles. This branching process continues through alveolar ducts and terminates in the alveolar sacs (generation 23).
From the trachea to the alveolar sacs, two pronounced physical changes occur in the airways. First, the airway caliber decreases as the airways branch. For example, the trachea diameter (1.8 cm) is considerably larger than alveolar diameter (0.04 cm). This narrowing of airways allows adequate penetration of the air into the lower airways for a given expansion of the lungs. Second, the cross-sectional area of the airways increases during each division due to an increase in the number of the airways. The total surface area increases moderately over the levels of airways between the trachea and the terminal bronchiole (from 2.5 to 180 cm2). However, from the terminal bronchiole to the alveolar sac, the cross-sectional area increases dramatically (from 180 to 10,000 cm2) (2), resulting in a significant decrease in the air flow velocity and promoting extensive and efficient diffusional gas exchange between the alveolar space and blood in the pulmonary capillaries. These changes in the air flow velocity and surface area have a significant effect on drug deposition in the lungs and systemic absorption of the inhaled drug, as explained below.
The therapeutic effect of inhalation therapy for treatment of local diseases, such as asthma and chronic obstructive pulmonary disease (COPD), is dependent upon the amount of aerosolized drug deposited and its distribution within the lungs. For instance, if the inhaled drug is delivered at an inadequate amount or to the region(s) of the lungs devoid of the target receptors, the effectiveness of the inhaled drug in treating respiratory diseases may be compromised.
An autoradiographic study (3) in the human lungs indicated that the concentration of receptors for β2-agonists such as albuterol varied throughout the lungs. β2-receptors are found in the smooth muscle from the large to small airways, with a greater population in bronchioles than in bronchi. A high density of β2-receptors is also observed in airway epithelial cells and bronchial submucosal glands, from the large bronchi to the terminal bronchioles. β2-receptors also appear to be populated in the alveolar wall, where smooth muscle cells are lacking. The physiological significance of these receptors in the alveolar region is not clear. The distribution of β2-receptors and smooth muscle in the lungs suggests that β2-agonist deposition in the conducting airways will result in optimal bronchodilatation (4).
Another autoradiographic study (5) showed that the receptors for muscarinic-3 (M3) antagonists such as ipratropium bromide (an anticholinergic) were also not uniformly distributed throughout the lungs. A high density of M3 receptors is found in submucosal glands and airway ganglia, and a moderate density is observed in smooth muscles throughout the airways, in nerves on intrapulmonary bronchi and in the alveolar wall. The distribution of these receptors in the lungs suggests that anticholinergics should be most effective when delivered to the conducting airways.
In comparison to bronchodilators, inhaled corticosteroids such as budesonide are believed to be most effective in treating inflammation in asthma when the drug is distributed throughout the lungs. This is based on the finding which indicated that inflammatory cells (e.g., eosinophils, lymphocytes, macrophages, and dendritic cells) were present throughout the airways and the alveolar tissues in asthma (6,7).
Aerodynamic particle size has a significant impact on the regional lung deposition. Its influence on the aerosol distribution along the airways can be understood by considering both the deposition mechanisms and airway geometry. Aerosols can be deposited by inertial impaction, gravitational sedimentation or diffusion depending on the inhalation flow rate and aerodynamic size (Fig. 3). Air velocity decreases exponentially with each airway generation (8). In the oropharynx and large airways including the trachea and bronchi, the air velocity is relatively high. The primarily deposition mechanism is inertial impaction. As a result, most large particles (>6 μm) are deposited in the oropharyngeal and large airways because of their inability to follow the change in flow direction of the inspired air stream, particularly in the oropharynx and at airway bifurcations. Smaller particles (2–6 μm) are likely to pass through the upper regions of the lungs and are deposited in the bronchioles, where the air velocity is low and deposition by gravitational sedimentation predominates. In the terminal bronchioles and alveolar region where air velocity is negligible, deposition of small particles (<2 μm) is mainly by diffusion. The study of Usmani et al. (4) showed such a particle size dependence of regional lung deposition using radiolabeled monodisperse albuterol aerosols. It indicated that smaller particles achieved more peripheral lung deposition (25%, 17%, and 10% for 1.5, 3, and 6 μm, respectively).
Because of its impact on the regional lung deposition, the aerodynamic particle size can also influence the efficacy and safety of a locally acting orally inhaled drug (4,9). In the same study of Usmani et al. (4), larger particles (3 and 6 μm) were shown to have a significantly greater bronchodilatation effect than smaller particles (1.5 μm) in patients with stable, mild-moderate asthma (FEV1, 76.8±11.4% predicted) (Fig. 4). The result of this study suggests that regional targeting of inhaled β2-agonist to the proximal airways is more effective than alveolar deposition with respect to bronchodilatation. It is also well known that deposition of aerosols in the deeper part of the lungs (i.e., the alveolar region) results in an increased proportion of the drug reaching the systemic circulation (10–12). This can be attributed to the absence of clearance by the mucociliary escalator, the pronounced increase in the total surface area as a result of progressive branching of airways, and the enhanced permeability of the thin alveolar membranes in comparison to that of the airway surface. Such an increase in the systemic exposure is generally undesirable due to potential systemic side effects of locally acting drugs. For instance, absorption of β2-agonists into the systematic circulation can cause a number of systemic effects (e.g., an increase in heart rate, transient hypoxemia, and hypokalemia) directly relating to the stimulation of β2-adrenoceptors (13).
DPIs contain micronized drug particles attached to larger carrier particles or micronized drug particles agglomerated into soft pellets. In general, drug delivery from DPIs to the site(s) of action in the lungs involves (1) bringing a static powder bed into a state of motion, (2) entraining the powder into an inhalation airstream, (3) separating drug particles from larger carriers or soft pellets into appropriately sized inhalable units, (4) transportation to various lung regions largely under the control of aerodynamic particle size, and (5) deposition and dissolution of the active substance for transport to and interaction with pulmonary receptors. Figure 5 shows a schematic representation of the operating principles of passive DPIs, which employ the patient’s inspiratory effort to provide energy for drug delivery. The key components of such a DPI include the dry powder formulation (i.e., drug substance and often drug carrier) and the inhaler device. These components, as well as patient factors (e.g., the mode of inhalation), are shown to have a significant impact on the powder fluidization and particle deagglomeration. Thus, these product- and patient-related factors have a subsequent influence on the aerodynamic size of particles from the DPI and drug deposition in the lungs.
The aerodynamic size of drug-containing particulates entrained in the inhalation airstream is the most important design variable for a DPI. It is defined as the diameter of a unit density sphere (Deq) with the same terminal velocity in still air as the particle under study. For particles larger than 1 μm, Dae can be related to particle density (ρp) and shape (χ) in the following expression:
where ρ0 is unit density. Several studies (9,14–16) which investigated the particle size effect on the clinical response for β2-agonist and anticholinergic aerosols suggested that the optimal aerodynamic size was approximately within the range of 1−5 μm. The fraction and the total mass of particles with aerodynamic diameters in this range are often referred to as fine particle fraction (FPF) and fine particle mass (FPM), respectively (17).
The particle shape and density influence drug deposition in the airways primarily due to their effects on the aerodynamic behavior of aerosols, as indicated in Eq. (1). Elongated particles have been demonstrated to enhance drug deposition in the lungs (18). However, such an improvement in the local drug delivery in the lungs is negated by the adverse impact of the elongated shape on the powder flow and its subsequent effect on reproducibility of dosing (19). For porous particles that are characterized by low density, their aerodynamic diameter can be several times smaller than their corresponding geometric diameter (20), thus improving drug deposition in the peripheral regions.
Surface properties (e.g., particle surface area and morphology) play an important role in determining particle interactions, stability, ease of dispersion, and deagglomeration. Small particles have a large total surface area. Therefore, these particles tend to minimize their surface free energy by increasing their size and decreasing the total surface area through agglomeration. This may lead to a decrease in the FPM. A large surface area increases the potential for water uptake and electrostatic charging, thus altering particle interactions and affecting particle deagglomeration. Surface morphology also has an impact on particle interactions. For instance, particles with a rough surface have more surface area than particles with a smooth surface. Moreover, surface irregularities can promote mechanical interlocking, a prominent mechanism that limits particle dispersion (21).
Polymorphism may result in differences in the physicochemical properties of drug substance, such as density, surface properties, and solubility (19). Although a change in solubility may not significantly impact lung deposition of aerosols, it may affect the availability of the drug to the site(s) of action in the lungs because of its influence on local dissolution on the surface of airways. Polymorphs may also exhibit different hygroscopicity, which could affect the physical and chemical stability of the drug. Excessive moisture uptake can lead to irreversible aggregation by inducing local dissolution and recrystallization (19). It can also alter the adhesive and cohesive properties of particles, promote hygroscopic growth, and thus increase particle size. These effects can adversely impact the FPM.
Due to the intrinsic cohesiveness and poor flow characteristics of small drug particles, an inert, coarse, soluble carrier (typically lactose) is added to the powder formulation to facilitate dispersion, improve the powder flow and fluidization, and overcome problems related to dose metering and dose uniformity. In this binary system, the fine drug particles adhere to the surface of carriers (Fig. 5). The adhesive characteristics acting between the drug and carrier are important in determining the aerodynamic size distribution of aerosols and hence availability of the drug to the lungs. Specifically, the adhesive forces between the drug and carrier must be small enough to allow drug particle detachment during inhalation, but must be sufficient to avoid demixing and thus allow good fluidization of the powder formulation. These adhesive forces can be influenced by several factors, including the physicochemical properties of both the drug and carrier, the drug-to-carrier ratio, the presence of other components, and process conditions (22). It has been shown that increasing the drug-to-carrier ratio increases the respirable fraction of drug particles (23). Like drug substance, the size, shape, density, polymorphism, hygroscopicity, surface properties, and morphology of the carriers have a pronounced influence on fluidization and deagglomeration of the powder formulation. For instance, a dry powder formulation using lactose with low surface roughness yields a higher FPM than that using lactose with high surface roughness (24). The addition of a third component (e.g., magnesium stearate or fine lactose) may help to improve detachment of drug particles from the carrier by saturating the high-energy, active sites on the carrier’s surface or through competitive and multilayer adhesion (25,26). This results in an increase in the FPM.
An alternative to the carrier-based powder formulation is the carrier-free powder formulation. With this type of formulation, micronized drug particles agglomerate into soft pellets to provide good flow properties and disintegrate into fine particles during inhalation. The use of a carrier-free powder formulation eliminates any potential allergenic reaction to the carrier and its contaminants.
The internal geometry (e.g., the dimension and shape of the channels) of an inhaler plays a critical role in determining the rate of air flow through the inhaler. This flow rate is an important determinant of drug delivery from DPIs (4,27), based on its effect on the fluidization and deagglomeration of particles and their deposition mechanisms. The flow rate through the device may be different among DPI devices, since DPIs with a different internal geometry may offer different levels of resistance to air flow generated at a given level of the patient’s inspiratory effort. The internal geometry of a DPI device also impacts the mechanism of powder fluidization and deagglomeration (e.g., relative motion, turbulence, shear force, capillary force, and collision). This is reflected in Table I, which provides examples showing that the primary mechanisms of powder fluidization and deagglomeration vary with the DPI device.
In addition, like the physicochemical properties of a dry powder formulation, the materials used to construct DPIs can affect accumulation of electrostatic charge (28). Some inhaler materials may accumulate and retain electrostatic charge more strongly than others, resulting in a reduced efficiency of drug release from a DPI device and a greater variation in characteristics of delivered aerosols.
The patient’s inspiratory effort is another critical factor in determining the degree of fluidization and deagglomeration of the powder formulation in DPIs. This inspiratory effort varies across the patient population and depends on the age, gender, disease, and breathing cycle of the patient. Therefore, DPI devices generally operate over a range of inspiratory flow rates (29), which may result in different particle size distributions and emitted doses, and differences in deposition profiles in the lungs.
Formulations of the currently approved DPIs are made up of either the active drug alone or the active drug associated with a carrier such as coarse lactose. Additional excipient(s) (e.g., fine lactose or magnesium stearate) are sometimes added to the drug–lactose mixture to improve particle deagglomeration. As explained above, the inactive ingredient used in DPIs influences fluidization and deagglomeration and hence the particle size distribution. Therefore, it is generally suggested that the formulation of the test product be Q1 and Q2 the same as the reference product. Q1 (qualitative sameness) means that the test product uses the same inactive ingredient(s) as the reference product. Q2 (quantitative sameness) means that concentrations of the inactive ingredient(s) used in the test product are within ±5% of those used in the reference product. This formulation equivalence recommendation is generally expected to increase the likelihood of establishing bioequivalence of the test and reference DPI products, particularly when the same or similar DPI devices are used. However, this recommendation alone is not sufficient to ensure bioequivalence. As mentioned above, in addition to the concentrations of drug and excipient(s), other formulation factors, such as size, shape, surface properties, and morphology of drug and carrier particles, can also influence drug deposition in the lungs, based upon their effect on powder fluidization and particle deagglomeration.
Under certain circumstances, the test product may use a formulation that is quantitatively different from the reference product. For example, the internal design of the test DPI device (e.g., the dimension and shape of channels) may differ from that of the reference product because the reference DPI device may be proprietary to its sponsor or protected by a patent. Since the in vitro DPI performance is influenced concomitantly by formulation and device characteristics, a drug-to-excipient ratio in the test formulation may be one of the formulation design variables needed to be adjusted in order to achieve equivalence to the reference product. If a Q2 different formulation is used for the test product, it is important to show through the in vitro studies described below that the necessary deviation in the drug-to-excipient ratio does not affect drug delivery from the test product. To explain why such a change in the drug-to-excipient ratio is appropriate, it would be helpful to conduct in vitro studies to evaluate the extent to which changes in the drug-to-excipient ratio affect drug delivery from the product. These studies may involve testing of multiple drug-to-excipient ratios that encompass combinations below and above the ratios used in the test and reference DPIs.
DPIs can differ greatly with respect to the design of the delivery device and operating principles. For example, there are currently three types of dosing systems used in DPIs: pre-metered single dose units, drug reservoir (device-metered), and pre-metered multiple dose units (Table II) (30). These DPIs may require different operational techniques to achieve proper dosing. Thus, a switch from one DPI to another (e.g., from a pre-metered multiple dose unit device to a drug reservoir device, for which these devices differ considerably in their operating principles, such as drug loading) may cause confusion to the patient, resulting in incorrect use of the DPI device and ineffective disease treatment. An observational study in 3,811 patients compared correct use of four DPIs (Aerolizer, Autohaler, Diskus, and Turbuhaler), and indicated that there were clear differences between these DPI devices in the percentage of patients who made at least one mistake during use (31). This finding suggests that interactions between the patient and device may play an important role in determining the effective use of DPI products.
For the reasons stated above, patient-related factors (e.g., patient’s perceptions of device, willingness to use, and ability to use correctly) are likely to have a considerable impact on the effective use of DPIs (29). Thus, the assurance of interchangeability of DPIs should take into consideration patient compliance. Similarity of the device shape and equivalence in the design and operating principles are expected to be important for ease of patient use. For instance, the use of the same dose format (e.g., pre-metered single dose units, pre-metered multiple dose units, or drug reservoir) helps to ensure the effective use of the test DPI product when a switch is made from the reference product, by minimizing confusion among patients and helping to ensure comparability with respect to the ease of patient use for chronic and/or emergency treatments. However, any necessary deviation in the internal device design that significantly increases the complexity of product use for the patient and/or requires significant patient retraining for its effective use can compromise the interchangeability of test and reference DPI products in the patient’s hands.
In vitro studies are used, in conjunction with in vivo studies (i.e., pharmacodynamic or clinical studies for local action, and pharmacokinetic or pharmacodynamic studies for systemic exposure), to demonstrate BE of orally inhaled drug products for local action. In general, although in vitro results are not always well correlated with in vivo performance, in vitro methods are usually less variable and more sensitive in detecting differences in product performance. BE assessment of DPIs warrants, in addition to in vivo studies, deliberations regarding device resistance and the influence of inspiratory flow rate on in vitro dose delivery and particle size distribution of the aerosolized drug. The comparative in vitro testing of DPIs is summarized below.
Passive DPIs utilize the patient’s inspiratory effort to generate energy for drug fluidization, deagglomeration, and delivery from the device. At a given level of the patient’s inspiratory effort, the flow rate through the DPI depends on the resistance to air flow provided by the device. The specific resistance of a DPI device is dependent on its internal geometry and dimensions. A wide range of specific resistance values for DPIs has been reported. Specific resistances for selected DPIs are summarized in Table III. Since the specific resistance of a DPI influences the achievable flow rates through the device, it has an impact on the emitted dose and FPM. For instance, the study of Hindle et al. (32) compared dose emissions from selected low-, medium-, and high-resistance DPIs. Their results suggested that the flow rate could have a significant impact on the dose emission depending on the specific resistance of the device. Therefore, specific resistance (R) is one of the important features to consider in in vitro assessment of the DPI performance. It is related to the pressure drop (ΔP) across the device and the volumetric flow rate (Q), as described below.
This equation indicates that the pressure drop across the device varies with the flow rate.
The specific resistance of the test and reference products may be different if the internal design of a generic DPI device differs from that of the reference product. It is important to ensure that such a difference in the specific resistance does not compromise the efficacy and safety of a test DPI. This can be done by showing that the in vitro performance of the test DPI (i.e., the single inhalation (actuation) content and particle size distribution) is equivalent to that of the reference product at each of three or more flow rates (see below). For the effective use of a test DPI, it is also important to ensure that the targeted patients are still able to operate the test device effectively and receive proper medication without any significant change in their inspiratory effort. Thus, although equivalence in specific resistance may not be necessary, the specific resistances of the test and reference DPIs should be comparable.
As mentioned above, DPIs are generally used over a range of inspiratory flow rates due to variations in the inspiratory effort across the patient population, and characteristics of emitted aerosols may vary with the inspiratory flow rate. These observations suggest that in vitro studies for DPIs should be performed over a range that consists of at least three different inspiratory flow rates to show the dependence of in vitro performance (e.g., the drug amount in an emitted dose and aerodynamic particle size) on flow rate. The innovator labeling provides a basis for the selection of flow rates for in vitro testing. For a reference product label that cites a delivered dose (or emitted dose) at only one flow rate, this labeled flow rate may be selected as the basis of the in vitro testing flow rate with the remaining two inspiratory flow rates equal to ±50% of the basis. These three flow rates in general constitute a range which reasonably covers inspiratory flow rates that are expected to be generated by the targeted patients described in the labeling.
One important aspect of DPI performance with respect to drug delivery is the amount of drug emitted per actuation (single inhalation content). It can be determined by using the USP <601> apparatus B in conjunction with a validated stability-indicating, drug-specific assay or a non-stability-indicating method if its use can be justified. A test DPI device may use materials different from those used to make a reference DPI device. A test formulation may also be different from a reference formulation with respect to the physicochemical properties of excipients (e.g., particle size) and drug-to-excipient ratio. As mentioned earlier, these differences in device material and formulation may have a subsequent effect on the in vitro performance of DPIs, in part due to their influence on the accumulation of electrostatic charge. Thus, it is important to demonstrate equivalence in the amount of aerosolized drug delivered per inhalation at multiple stages of product life. Such a demonstration can ensure that the dose delivered to the patient is the same for both test and reference products throughout the product life. For DPIs using a multi-dose system (i.e., drug reservoir or pre-metered multiple dose units), the life stage selection can be based on the labeled number of inhalations. For example, the beginning stage represents the first labeled inhalation(s), and the end stage represents inhalation(s) at the end of the product life based on labeling. For DPIs using pre-metered single dose units, the life stage selection can be based on the number of individual unit doses provided with the product. Furthermore, if a certain number of refills is allowed for a DPI device, testing may reflect the recommended number of refills for the life stage selection.
The study of De Boer et al. (27) investigated the effect of the flow rate on the dose discharge of Turbuhaler, Diskhaler, and Spinhaler. Their result indicates that the emitted dose increases with higher flow rates but the degree to which the emitted dose increased with the flow rate varied among DPI devices. Therefore, it is important to demonstrate the comparability of the test product to the reference product with respect to the impact of inspiratory flow rate on the emitted dose. This can be done by conducting the comparative in vitro tests on the single inhalation content at multiple inspiratory flow rates stated above. If a DPI has an actuation mechanism in which a threshold flow rate needs to be reached to initiate drug release from the device, and such a threshold is reflected in the labeling of the reference product, it is equally important for the test product to demonstrate the same threshold flow rate for drug release.
The aerodynamic diameter of aerosols is a key attribute for DPIs due to its relationship with the drug deposition pattern in the lungs, as explained above. The aerodynamic particle size distribution from DPIs can be determined by multiple-stage cascade impactors (e.g., Andersen Impactor or Next Generation Impactor) (33). The particle separation in these methods is based on the ability of particles to follow changes in the flow direction of their supporting gas (usually air), which depends largely on particle size, shape, and density.
The flow rate influences the aerodynamic particle size distribution. As a consequence, the FPF of the Turbuhaler was shown to decrease to approximately one third of the original value in vitro as the air flow rate of the test was reduced from 60 to 30 l/min (34). Hence, it is critical for a test DPI product to demonstrate comparability of the aerodynamic particle size distribution to the reference product at multiple inspiratory flow rates described above. Comparative in vitro tests on the aerodynamic particle size distribution at multiple stages of product life can be useful to ensure that the aerodynamic particle sizes of aerosols released from test and reference products are equivalent throughout the product life.
In practice, the aerodynamic particle size distribution of pharmaceutical aerosols is polydisperse in nature (i.e., a range of sizes around the mode(s)). Thus, equivalence in the FPM or FPF does not necessarily imply equivalence in the particle size distribution. Two pharmaceutical aerosols, which have the same FPF, may differ in particle size distribution. In principle, the differences in the particle size distribution may lead to differences in regional lung deposition. Moreover, the study of monodisperse β2-agonist aerosols in patients with stable, mild-moderate asthma indicated that particle size influenced the regional deposition within the lungs and hence impacted the efficacy of inhaled β2-agonist aerosols (4). For the above reasons, cascade impaction data that contain the whole deposition profile may be useful in assessing BE of DPIs.
Although the aerodynamic particle size distribution is known to impact lung deposition (35), its relationships with regional lung deposition and clinical efficacy are not fully understood. Additional research is warranted to improve our knowledge of the relationships between in vitro and in vivo data (i.e., the aerodynamic particle size distribution and clinical response such as FEV1 for β2-agonists) for orally inhaled drug products such as DPIs, and to determine whether or not reasonable in vitro/in vivo correlations (IVIVCs) may exist. A better understanding of such relationships and establishment of such IVIVCs may assist in setting aerodynamic particle size distribution specifications with clinical relevance.
This review provides in vitro considerations for BE of DPIs for local action. BE assessment should take into account device resistance and the effects of operating conditions described in the labeling (i.e., inspiratory flow rate) on in vitro drug product performance (e.g., single inhalation (actuation) content and particle size distribution). The considerations described in this review provide in vitro evidence to support and complement the results of in vivo BE studies of local delivery and systemic exposure, and therefore help to ensure equivalence between test and reference DPIs.
1[21 CFR 320.1(e)].
2Pharmaceutical equivalents means drug products in identical dosage forms that contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety, or, in the case of modified release dosage forms that require a reservoir or overage or such forms as prefilled syringes where residual volume may vary, that deliver identical amounts of the active drug ingredient over the identical dosing period; do not necessarily contain the same inactive ingredients; and meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times, and/or dissolution rates [21 CFR 320.1(c)].
3Pharmaceutical alternatives means drug products that contain the identical therapeutic moiety, or its precursor, but not necessarily in the same amount or dosage form or as the same salt or ester. Each such drug product individually meets either the identical or its own respective compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times and or dissolution rates [21 CFR 320.1(d)].
The opinions expressed in this review by the authors do not necessarily reflect the views or policies of the Food and Drug Administration (FDA).
An erratum to this article is available at http://dx.doi.org/10.1208/s12248-010-9243-8.