Laboratory Performance Testing of Aqueous Nasal Inhalation Products for Droplet/Particle Size Distribution: an Assessment from the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS).

Although nasal inhalation products are becoming more and more important for the delivery of medicines, characterization of these products for quality control and assessment of bioequivalence is complicated. Most of the problems encountered are associated with the assessment of aerodynamic droplet/particle size distribution (APSD). The droplets produced by the various nasal devices are large, and for suspension products, individual droplets may contain multiple drug particles or none at all. Assessment of suspension products is further complicated by the presence of solid excipient particles. These complications make it imperative that the limitations of the instruments used for characterization as well as the underlying assumptions that govern the interpretation of data produced by these instruments are understood. In this paper, we describe various methodologies used to assess APSD for nasal inhalation products and discuss proper use, limitations, and new methodologies on the horizon.

Addressing the Need for Controls on Particle Bounce and Re-entrainment in the Cascade Impactor and for the Mitigation of Electrostatic Charge for Aerodynamic Particle Size Assessment of Orally Inhaled Products: an Assessment by the International Consortium on Regulation and Science (IPAC-RS).

Multi-stage cascade impactors (CI) are accepted for the determination of metrics of the drug mass aerodynamic particle size distributions (APSD) of aerosols emitted from orally inhaled products (OIPs). This is particularly important for products where the drug to excipient ratio or particle density may not be the same in each aerodynamic size fraction; examples of such products are carrier-containing dry powder inhalers (DPIs) and suspension pressurized metered-dose inhalers (pMDIs). CI measurements have been used as the "gold standard" for acceptance of alternative methods of APSD assessment, such as laser diffraction for nebulized solutions. Although these apparatus are labor-intensive, they are accepted in regulatory submissions and quality control assessments because the mass of active pharmaceutical ingredient(s) in the aerosol can be quantified by chemical assay and measured particle size is based on the aerodynamic diameter scale that is predictive of deposition in the respiratory tract. Two of the most important factors that modify the ideal operation of an impactor are "particle bounce," that is often accompanied by re-entrainment in the air flow passing the stage of interest, and electrostatic charge acquired by the particles during the preparation and aerosolization of the formulation when the inhaler is actuated. This article reviews how both factors can lead to biased APSD measurements, focusing on measurements involving pMDIs and DPIs, where these sources of error are most likely to be encountered. Recommendations are provided for the mitigation of both factors to assist the practitioner of these measurements.

Determination of Passive Dry Powder Inhaler Aerodynamic Particle Size Distribution by Multi-Stage Cascade Impactor: International Pharmaceutical Aerosol Consortium on Regulation & Science (IPAC-RS) Recommendations to Support Both Product Quality Control and Clinical Programs.

The multi-stage cascade impactor (CI) is the mainstay method for the determination of the aerodynamic particle size distribution (APSD) of aerosols emitted from orally inhaled products (OIPs). CIs are designed to operate at a constant flow rate throughout the measurement process. However, it is necessary to mimic an inhalation maneuver to disperse the powder into an aerosol when testing passive dry powder inhalers (DPIs), which constitute a significant portion of available products in this inhaler class. Methods in the pharmacopeial compendia intended for product quality assurance initiate sampling by applying a vacuum to the measurement apparatus using a timer-operated solenoid valve located downstream of the CI, resulting in a period when the flow rate through the impactor rapidly increases from zero towards the target flow rate. This article provides recommendations for achieving consistent APSD measurements, including selection of the CI, pre-separator, and flow control equipment, as well as reviewing considerations that relate to the shape of the flow rate-sampling time profile. Evidence from comparisons of different DPIs delivering the same active pharmaceutical ingredients (APIs) is indicative that the compendial method for APSD measurement is insensitive as a predictor of pharmacokinetic outcomes. Although inappropriate for product quality testing, guidance is therefore provided towards adopting a more clinically realistic methodology, including the use of an anatomically appropriate inlet and mimicking patient inhalation at the DPI while operating the CI at constant flow rate. Many of these recommendations are applicable to the testing of other OIP classes.

Valved Holding Chambers and In Vitro Metered Dose Inhaler Performance: Effects of Flow Rate and Inhalation Delay.

BACKGROUND: Multiple factors may influence the performance of a metered dose inhaler (MDI) when used with a valved holding chamber (VHC or "spacer"). METHODS: Andersen Cascade Impactor measurements were conducted for three MDI products and two different VHCs using a specially designed system that accommodated variable delay times between MDI actuation and introduction of the aerosol into the impactor, and allowed reduced flow through the VHC while the impactor was operated at 28.3 L/min. Deposited drug mass and aerodynamic particle size distribution were determined using validated high-performance liquid chromatography (HPLC) methods. A two-level, three-factor full-factorial design of experiments (DOE) design was applied to assess the influences of VHC type, flow rate, and inhalation delay on a total of seven performance characteristics for each MDI product. An experiment without a VHC was added to assess the influence of VHC presence. RESULTS: DOE study shows the presence and type of VHC are the major influences on emitted dose and respirable fraction. Following the VHC effect, the inhalation delay has the most significant influence on most MDI performance metrics-emitted dose, respirable particle dose and fraction (aerosols between 1.1 and 4.7 µm), and fine particle dose and fraction (aerosols under 4.7 µm). CONCLUSION: This study illustrates the use of DOE analysis to effectively assess the effects of patient handling parameters (flow rate and inhalation delay) on the performance of MDI drugs when used with a VHC. The results of this study will inform Food and Drug Administration reviewers, the pharmaceutical industry, and healthcare practitioners as to safe and effective use of MDI products when used in conjunction with spacer devices.

Evaluation of Abbreviated Impactor Measurements (AIM) and Efficient Data Analysis (EDA) for Dry Powder Inhalers (DPIs) Against the Full-Resolution Next Generation Impactor (NGI).

The full-resolution next generation impactor (NGI) and three abbreviated impactor systems were used to obtain the apparent aerodynamic particle size distribution (APSD) and other quality measures for marketed dry powder inhalers (DPIs) using the compendial method and efficient data analysis (EDA). APSD for the active pharmaceutical ingredient (API) in Spiriva® Handihaler®, Foradil® Aerolizer®, and Relenza® Diskhaler® was obtained using a full-resolution NGI at 39, 60, and 90 L/min, respectively. Two reduced NGI (rNGI) configurations, the filter-only configuration (rNGI-f) and the modified-cup configuration (rNGI-mc), and the fast-screening impactor (FSI) with appropriate inserts to provide a 5-µm cut size were evaluated. The fine particle dose (FPD) obtained using the FSI for Spiriva was statistically similar to that obtained using the full NGI. However, the FPD for both Foradil and Relenza obtained using the FSI was significantly different from that obtained using the full NGI. Despite this, no significant differences were observed for the fine particle fraction (FPF) obtained using the FSI relative to that obtained from the full NGI for any of the DPIs. The use of abbreviated impactor systems appears promising with good agreement observed with the full-resolution NGI, except for small differences observed for the rNGI-mc configuration. These small differences may be product- and/or flow rate-specific, and further evaluation will be required to resolve these differences.

Developing an in vitro understanding of patient experience with hydrofluoroalkane-metered dose inhalers.

As a result of the Montreal Protocol on Substances that Deplete the Ozone Layer, manufacturers of metered dose inhalers began reformulating their products to use hydrofluoroalkanes (HFAs) as propellants in place of chlorofluorocarbons (CFCs). Although the new products are considered safe and efficacious by the US Food and Drug Administration (FDA), a large number of complaints have been registered via the FDA's Adverse Events Reporting System (FAERS)-more than 7000 as of May 2013. To develop a better understanding of the measurable parameters that may, in part, determine in vitro performance and thus patient compliance, we compared several CFC- and HFA-based products with respect to their aerodynamic performance in response to changes in actuator cleaning interval and interactuation delay interval. Comparison metrics examined in this study were: total drug delivered ex-actuator, fine particle dose (<5 µm), mass median aerodynamic diameter, plume width, plume temperature, plume impaction force, and actuator orifice diameter. Overall, no single metric or test condition distinguishes HFA products from CFC products, but, for individual products tested, there were a combination of metrics that differentiated one from another.

Evaluation of an abbreviated impactor for fine particle fraction (FPF) determination of metered dose inhalers (MDI).

Abbreviated impactors have been developed recently to allow more rapid evaluation of inhalation products as alternates to the eight-stage Andersen Cascade Impactor (ACI) which has been widely used in the pharmaceutical industry for assessing aerodynamic particle size distribution. In this paper, a two-stage abbreviated impactor, Westech Fine Particle Dose Impactor (WFPD), was used to characterize the aerodynamic particle size of metered dose inhaler (MDI) products, and the results were compared with those obtained using the standard eight-stage ACI. Seven commercial MDI products, with different propellants (chlorofluorocarbon/hydrofluoroalkane) and formulation types (suspension/solution, dry/normal/wet), were tested in this study by both WFPD and ACI. Substantially equivalent measures of fine particle fraction were obtained for most of the tested MDI products, but larger coarse particle fraction and extra-fine particle fraction values were measured from WFPD relative to those measured using the ACI. Use of the WFPD also produced more wall loss than the ACI. Therefore, it is recommended that the system suitability be evaluated on a product-by-product basis to establish substantial equivalency before implementing an abbreviated impactor measurement methodology for routine use in inhaler product characterization.

Measurement of drug in small particles from aqueous nasal sprays by Andersen Cascade Impactor.

PURPOSE: To determine if cascade impactor (CI) measurement of drug in small particles from aqueous nasal sprays, described in FDA's 2003 draft Nasal Bioavailability/Bioequivalence Guidance, can be optimized to reduce measurement variability. To examine the influence of flow rate configurations and number of impactor stages on CI deposition and explore the importance of inlet volume. METHODS: A total of eight assemblies and manual vs. automatic actuation were tested for deposition on the sum of all stages of the CI, and for Group 2 total drug mass per the Guidance. Mean deposition and variance about the mean were determined for each assembly. RESULTS: The path length for a spherical 1 l inlet was too short to allow adequate aerosol formation. Data variance was reduced by a factor of two or more by using an automatic actuator relative to manual actuation. Impactor assembly modification did not improve variance over the standard assembly. CONCLUSIONS: Use of a spherical inlet (≥ 2 l volume) and automatic actuation are recommended for comparative measurements of drug in small particles arising from aqueous nasal sprays. The standard (8-stage) 28.3 lpm CI flow rate configuration is recommended when using the Andersen Cascade Impactor (ACI), as no other assembly showed a distinct advantage.

Effects of device and formulation on in vitro performance of dry powder inhalers.

The study examined the sensitivity of DPI in vitro performance to formulation and device changes. Rotahaler/Rotacaps was selected as the reference DPI drug product, and Aerolizer was selected as the test device. Since the test device was recognized to have much greater efficiency of dispersion, simple modifications to both formulation and device were made in an effort to provide a closer match to the in vitro performance of the reference product. The modifications included varying the drug and lactose particle sizes and/or lactose fine particle content in the test formulations, as well as lowering the specific resistance of the test device. These modifications were intended to address variables important for drug product performance for a defined experimental design and were not intended to mimic the extensive formulation and device design strategies that are employed in an industrial setting. Formulation and device modifications resulted in a modified test product that approached the reference product in the in vitro performance.

Equivalence considerations for orally inhaled products for local action-ISAM/IPAC-RS European Workshop report.

The purpose of this article is to document the discussions at the 2010 European Workshop on Equivalence Determinations for Orally Inhaled Drugs for Local Action, cohosted by the International Society for Aerosols in Medicine (ISAM) and the International Pharmaceutical Consortium on Regulation and Science (IPAC-RS). The article summarizes current regulatory approaches in Europe, the United States, and Canada, and presents points of consensus as well as ongoing debate in the four major areas: in vitro testing, pharmacokinetic and pharmacodynamic studies, and device similarity. Specific issues in need of further research and discussion are also identified.

Evaluation of metered dose inhaler spray velocities using phase Doppler anemometry (PDA).

Droplet velocity is an important parameter which can significantly influence inhalation drug delivery performance. Together with the droplet size, this parameter determines the efficiency of the deposition of MDI products at different sites within the lungs. In this study, phase Doppler anemometry (PDA) was used to investigate the instantaneous droplet velocity emitted from MDIs as well as the corresponding droplet size distribution. The nine commercial MDI products surveyed showed significantly different droplet velocities, indicating that droplet velocity could be used as a discriminating parameter for in vitro testing of MDI products. The droplet velocity for all tested MDI products decreased when the testing distance was increased from 3 cm to 6 cm from the front of mouthpiece, with CFC formulations showing a larger decrease than HFA formulations. The mean droplet diameters of the nine MDIs were also significantly different from one-another. Droplet size measurements made using PDA (a number-based technique) could not be directly compared to results obtained using laser light scattering measurements (a volume-based technique). This work demonstrates that PDA can provide unique information useful for characterizing MDI aerosol plumes and evaluating MDI drug delivery efficiency. PDA could also aid the evaluation of in vitro equivalence in support of formulation or manufacturing changes and in evaluation of abbreviated new drug applications (ANDAs) for MDIs.

Evaluating elevated release liner adhesion of a transdermal drug delivery system (TDDS): a study of Daytrana™ methylphenidate transdermal system.

BACKGROUND: Complaints from healthcare providers that the adhesive on the Daytrana™ methylphenidate transdermal drug delivery system (TDDS) adhered to the release liner to such an extent that the release liner could not be removed prompted this study. Daytrana™ has a packaging system consisting of a moisture-permeable pouch contained within a sealed tray containing a desiccant; the tray is impermeable to ambient moisture. The objective of this project was to determine if the Daytrana™ packaging system influenced the difficulty in removing the release liner. METHOD: Both a sealed tray and an open tray containing sealed pouches were placed into an environmental chamber at 25°C and 60% relative humidity for 30 days; afterwards, release liner removal testing using a peel angle of 90° and a peel speed of 300 mm/min was performed. RESULTS: TDDS from open chamber trays required less force to remove the release liner than did TDDS from closed chamber trays. For the 10 mg/9 h TDDS and the 15 mg/9 h TDDS (the dosages examined), there were substantial differences in release liner removal force between an old lot and a new lot for closed chamber trays but not for open chamber trays. CONCLUSION: The results demonstrate that for this particular TDDS, storage conditions such as humidity influence release liner adhesion. This project also demonstrates that, to ensure adequate product quality, adhesion needs to become an important design parameter, and the design of a TDDS should consider the ability to remove the release liner under anticipated storage conditions.

Assessment of the influence factors on nasal spray droplet velocity using phase-Doppler anemometry (PDA).

Droplet velocity is an important parameter that can be used to characterize nasal spray products. In this study, a phase-Doppler anemometry (PDA) system was used to measure the droplet velocities of nasal sprays. A survey of seven commercial nasal spray products showed a range of droplet velocities from 6.7 to 19.2 m/s, all significantly different from each other. A three-level, four-factor Box-Behnken design of experiments (DOE) methodology were applied to investigate the influences of actuation parameters and formulation properties on nasal spray droplet velocity using a set of placebo formulations. The DOE study shows that all four input factors (stroke length, actuation velocity, concentration of the gelling agent, and concentration of the surfactant) have significant influence on droplet velocity. An optimized quadratic model generated from the DOE results describes the inherent relationships between the input factors and droplet velocity thus providing a better understanding of the input factor influences. Overall, PDA provides a new in vitro characterization method for the evaluation of inhalation drugs through assessment of spray velocity and may assist in product development to meet drug delivery equivalency requirements.

Effects of vessel geometric irregularity on dissolution test results.

Dissolution testing of pharmaceutical products is an important technique used extensively for both product development and quality control, but there are many variables that can affect dissolution results. In this study, the effect of the inner shape of standard 1-L dissolution vessels on drug dissolution results was investigated. The geometric dimensions and irregularities of commercially available vessels (obtained from four different manufacturers) were examined using a three-dimensional video-based measuring machine (VMM). The same analyst, dissolution test assembly, and experimental conditions were used for dissolution testing involving 10 mg of prednisone tablets (NCDA #2) with dissolution apparatus 2 (paddle). Mechanical calibration of the dissolution apparatus was performed prior to dissolution testing with each set of vessels. Geometric characteristics varied within and among the sets of vessels, but the overall averages and standard deviations of dissolution results (six vessels) showed no statistical significant differences among the vessel sets. However, some dissolution differences were noted when comparing individual vessels. With these types of comparisons, the vessel concentricity, sphericity, and radius of sphere were found to possibly influence the amount of prednisone dissolved, but flatness of vessel flange, cylindricity, and circularity showed no effect on dissolution results. The study shows that VMM is a technique that could be used to qualify dissolution vessels.

In vitro dissolution of oral modified-release tablets and capsules in ethanolic media.

In 2005, Palladone, an extended-release capsule, was withdrawn from the market after clinical testing showed subjects who took the product with alcohol had increased levels of drug in their blood. To better understand this phenomenon, we studied the in vitro drug release of 27 oral modified-release products in alcohol-containing media. In 40% alcoholic medium, 9 of 10 capsules and 2 of 17 tablets show accelerated drug release. When a high percentage of the total dose is released in a short period of time, the extended-release product is then performing like an immediate release formulation. Products were also tested in 5% and 20% alcoholic media and in simulated gastric fluid (without enzyme) containing 20% alcohol. No tested capsules or tablets exhibited a significant increase in drug release in media containing only 5% alcohol. The current study indicates that in vitro dissolution may provide evidence regarding the ruggedness of formulations to ingested alcohol.

Propagation of uncertainty in nasal spray in vitro performance models using Monte Carlo simulation: Part II. Error propagation during product performance modeling.

Monte Carlo simulations were applied to investigate the propagation of uncertainty in both input variables and response measurements on model prediction for nasal spray product performance design of experiment (DOE) models in the first part of this study, with an initial assumption that the models perfectly represent the relationship between input variables and the measured responses. In this article, we discard the initial assumption, and extended the Monte Carlo simulation study to examine the influence of both input variable variation and product performance measurement variation on the uncertainty in DOE model coefficients. The Monte Carlo simulations presented in this article illustrate the importance of careful error propagation during product performance modeling. Our results show that the error estimates based on Monte Carlo simulation result in smaller model coefficient standard deviations than those from regression methods. This suggests that the estimated standard deviations from regression may overestimate the uncertainties in the model coefficients. Monte Carlo simulations provide a simple software solution to understand the propagation of uncertainty in complex DOE models so that design space can be specified with statistically meaningful confidence levels.

Release liner removal method for transdermal drug delivery systems (TDDS).

A release liner removal test is a valuable test for assessing the quality of a transdermal drug delivery system (i.e., TDDS, patch). This test measures the force required to remove the release liner from a patch. The objective of the present study was to establish sample preparation and instrument parameters for measuring release liner removal adhesion for TDDS. Ten TDDS were evaluated (six drugs for a total of 29 lots). Patches which had a rate-controlling membrane were run as-is, since they could not be cut to a precise width without sacrificing their structural integrity. Patches that were square or rectangular in shape were run as-is, and the width of these patches was determined using a digital caliper. Patches which were not square or rectangular in shape and did not have a rate-controlling membrane were cut to a precise width using a specimen cutter. Double-sided tape was used to adhere the liner side of the transdermal system to a clean stainless steel test panel. A release liner peel adhesion method for TDDS is proposed using a dwell time of approximately 3 min, a peel angle of 90 degrees , and a peel speed of 300 mm/min.

Lack of significant dermal penetration of titanium dioxide from sunscreen formulations containing nano- and submicron-size TiO2 particles.

Titanium dioxide (TiO(2)) is included in some sunscreen formulations to physically block ultraviolet radiation. A dermal penetration study was conducted in minipigs with three TiO(2) particles (uncoated submicron sized, uncoated nano-sized, and dimethicone/methicone copolymer-coated nanosized) applied 5% by weight in a sunscreen. These and control formulations were topically applied to minipigs at 2 mg cream/cm(2) skin (4 applications/day, 5 days/week, 4 weeks). Skin (multiple sites), lymph nodes, liver, spleen, and kidneys were removed, and the TiO(2) content was determined (as titanium) using inductively coupled plasma mass spectroscopy. Titanium levels in lymph nodes and liver from treated animals were not increased over the values in control animals. The epidermis from minipigs treated with sunscreens containing TiO(2) showed elevated titanium. Increased titanium was detected in abdominal and neck dermis of minipigs treated with uncoated and coated nanoscale TiO(2). Using electron microscopy-energy dispersive x-ray analysis, all three types of TiO(2) particles were found in the stratum corneum and upper follicular lumens in all treated skin samples (more particles visible with coated nanoscale TiO(2)). Isolated titanium particles were also present at various locations in the dermis of animals treated with all three types of TiO(2)-containing sunscreens; however, there was no pattern of distribution or pathology suggesting the particles could be the result of contamination. At most, the few isolated particles represent a tiny fraction of the total amount of applied TiO(2). These findings indicate that there is no significant penetration of TiO(2) nanoparticles through the intact normal epidermis.

Evaluation of droplet velocity and size from nasal spray devices using phase Doppler anemometry (PDA).

To determine aerosol deposition during the inhalation drug delivery, it is important to understand the combination of velocity and droplet size together. In this study, phase Doppler anemometry (PDA) was used to simultaneously characterize the aerosol velocity and droplet size distribution (DSD) of three nasal spray pumps filled with water. Thirteen sampling positions were located in the horizontal cross-sectional area of the nasal spray plumes at a distance of 3cm from the pump orifice. The results showed droplet velocities near the center of the spray plume were higher and more consistent than those near the edge. The pumps examined showed significant differences in their aerosol velocity at the center of the spray plume, which suggest that this metric might be used as a discriminating parameter for in vitro testing of nasal sprays. Droplet size measurements performed using PDA were compared with results from laser light scattering measurements. The ability of PDA to provide simultaneous measurements of aerosol velocity and size makes it a powerful tool for the detailed investigation of nasal spray plume characteristics.