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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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).

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).

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.

Transdermal delivery of fentanyl from matrix and reservoir systems: effect of heat and compromised skin.

The United States Food and Drug Administration (FDA) has received numerous reports of serious adverse events, including death, in patients using fentanyl transdermal systems (FTS). To gain a better understanding of these problems, the current research focuses on the in vitro characterization of fentanyl reservoir (Duragesic) and matrix (Mylan) systems with respect to drug release and skin permeation under conditions of elevated temperature and compromised skin. In addition, different synthetic membrane barriers were evaluated to identify the one that best simulates fentanyl skin transport, and thus may be useful as a model for these systems in future studies.

Propagation of uncertainty in nasal spray in vitro performance models using Monte Carlo simulation: part I. Model prediction using Monte Carlo simulation.

Design of experiment (DOE) methodology can provide a complete evaluation of the influences of nasal spray activation and formulation properties on delivery performance which makes it a powerful tool for product design purposes. Product performance models are computed from complex expressions containing multiple factor terms and response terms. Uncertainty in the regression model can be propagated using Monte Carlo simulation.

Particle size determination of sunscreens formulated with various forms of titanium dioxide.

Background: There has been some apprehension expressed in the scientific literature that nanometer-sized titanium dioxide (TiO(2)) and other nanoparticles, if able to penetrate the skin, may cause cytotoxicity. In light of a lack of data regarding dermal penetration of titanium dioxide from sunscreen formulations, the Food and Drug Administration Center for Drug Evaluation and Research initiated a study in collaboration with the National Center for Toxicology Research using minipigs to determine whether nanoscale TiO(2) in sunscreen products can penetrate intact skin. Four sunscreen products were manufactured.

Vibration effects of lab equipment on dissolution testing with USP paddle method.

Environmental vibration induced by laboratory equipment, building construction, or even by the analysts themselves is one of the more complicated factors affecting dissolution testing. It is difficult to control and/or calibrate by mechanical means or performance-based methods. In this study, dissolution apparatus vibration levels were measured in the frequency range from 10 to 270 Hz along all three axes using commercially available, single-axis accelerometers.

Reservoir based fentanyl transdermal drug delivery systems: effect of patch age on drug release and skin permeation.

Purpose: To understand and evaluate the stability and skin permeation profiles of fentanyl reservoir systems as a function of patch age.

Methods: Drug release and skin permeation studies were performed using a modified USP apparatus 5 with a novel sample preparation technique.

Results: The amount of fentanyl present in the EVA/adhesive layer (EAL) increased from about 17% of label claim (LC) at 5 months to 25% LC at 22 months.