CFD-DEM investigation of the effects of aperture size for a capsule-based dry powder inhaler.

Capsule based dry powder inhalers (DPIs) often require piercing of the capsule before inhalation, and the characteristics of the apertures (punctured holes) affect air flow and the release of powders from the capsule. This work develops a numerical model based on the two-way coupling of computational fluid dynamics and discrete element method (CFD-DEM) to investigate the effect of aperture size on powder dispersion in the Aerolizer® device loaded with only carrier particles (lactose). Powders (carrier particles) in the size range 60-140 µm (d50: 90 µm and span: 0.66) were initialized in a capsule which had a circular aperture at each end. Boundary conditions corresponding to an air flow rate of 45 L/min were specified at each inlet to the mixing chamber (i.e., a total flow rate 90 L/min), and a capsule spin speed of âˆ¼ 4050 rpm. The velocity magnitudes inside the capsule were considerably lower than those in the mixing chamber in the vicinity of the rotating capsule, with the exception of the capsules featuring 2.5 mm and 4 mm apertures. Larger apertures reduced the capsule emptying time and increased the particle evacuation velocity; the fluid drag force on the particles issuing from the capsule peaked for an aperture of 1.3 mm. Inside the capsule, particle-particle (PP) collisions were more frequent than particle-wall (PW) collisions due to high concentration of powder, but PP collisions had smaller (median) impact energy than PW collisions. Larger apertures resulted in fewer collisions in the capsule with higher PW and virtually unchanged PP collision energies. Outside the capsule (i.e., in the inhaler mixing chamber), PW collisions occurred more frequently than PP collisions with median collision energies typically two orders of magnitude higher than inside the capsule. Larger apertures resulted in more collisions with slightly reduced collision energy, but this effect plateaued for aperture sizes larger than 1.3 mm. Powder dispersion, expressed as the fine particle fraction (FPF) of the powder, was predicted using an empirical equation based on carrier PW collisions. Therefore, consistent with the model prediction of the effect of aperture sizes on the chamber collision frequency, FPF increased with aperture size but plateaued beyond 1.3 mm.

Regulatory Experience with Continuous Manufacturing and Real Time Release Testing for Dissolution in New Drug Applications.

Regulatory submissions involving the use of continuous manufacturing (CM)1 and/or real-time release testing for dissolution (RTRT-D) to the United States Food and Drug Administration (FDA) were identified spanning several years. The submissions were for orally administered IR tablets and they were examined from a biopharmaceutics perspective to highlight commonly occurring issues which the FDA's assessment teams identified with the proposed use of CM and/or RTRT-D. The objective of this study is to provide recommendations for best practices that will help advance the field by (i) generating greater opportunities for (drug) Applicants2 to benefit from the implementation of advanced manufacturing approaches, (ii) improving high quality regulatory submissions involving CM and RTRT-D, and thus (iii) lessening the regulatory review burden. This paper has identified several common deficiencies, such as inadequate strategies for stratified sampling of drug product (DP) units, inappropriate design of experiments (DoE), inability of the proposed RTRT-D model to account for dissolution variability and to predict the entire time course of dissolution, insufficient documentation, and unsuitable in vitro dissolution methods.

The role of capsule aperture size on the dispersion of carrier-based formulation at different air flowrates.

The effect of capsule aperture size on the aerosol performance of lactose blend formulation was studied using Foradil® (containing 12 µg of formoterol fumarate (FF1) and 24 mg of lactose) dispersed with a powder inhaler Aerolizer® at increasing air flowrates. Apertures sizes of 0.4, 1.0, 1.5, 2.5, and 4.0 mm were introduced at the opposite ends of the capsule. The formulation was dispersed into a Next Generation Impactor (NGI) at 30, 60 and 90 L/min, with the fine particle fractions (FPFrec and FPFem) measured by chemical assay of FF and lactose using high-performance liquid chromatography. Particle size distribution (PSD) of FF particles dispersed in wet media was also characterized by laser diffraction. FPFrec showed a stronger dependency on the flowrate than the capsule aperture size. The most efficient dispersion was achieved at 90 L/min. At a given flowrate, FPFem remained broadly constant across different aperture sizes. The laser diffraction studies demonstrated the presence of large agglomerates.

Best Practices in the Development and Validation of Physiologically Based Biopharmaceutics Modeling. A Workshop Summary Report.

This workshop report summarizes the proceedings of Day 2 of a three-day workshop on "Current State and Future Expectations of Translational Modeling Strategies toSupportDrug Product Development, Manufacturing Changes and Controls". From a drug product quality perspective, physiologically based biopharmaceutics modeling (PBBM) is a tool to link variations in the drug product quality attributes to in vivo outcomes enabling the establishment of clinically relevant drug product specifications (CRDPS). Day 2 of the workshop focused on best practices in developing, verifying and validating PBBM. This manuscript gives an overview of podium presentations and summarizes breakout (BO) session discussions related to (1) challenges and opportunities for using PBBM to assess the clinical impact of formulation and manufacturing changes on the in vivo performance of a drug product, (2) best practices to account for parameter uncertainty and variability during model development, (3) best practices in the development, verification and validation of PBBM and (4) opportunities and knowledge gaps related to leveraging PBBM for virtual bioequivalence simulations.

Dissolution and Translational Modeling Strategies Toward Establishing an In Vitro-In Vivo Link-a Workshop Summary Report.

This publication summarizes the proceedings of day 2 of a 3-day workshop on "Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development." Patient-centric drug product development from a drug product quality perspective necessitates the establishment of clinically relevant drug product specifications via an in vitro-in vivo link. Modeling and simulation offer a path to establish this link; in this regard, physiologically based modeling has been implemented successfully to support regulatory decision-making and drug product labeling. In this manuscript, case studies of physiologically based biopharmaceutics modeling (PBBM) applied to drug product quality are presented and summarized. These case studies exemplify a possible path to achieve an in vitro-in vivo link and encompass (a) development of biopredictive dissolution methods to support biowaivers, (b) model-informed formulation selection, (c) predicting clinical formulation performance, and (d) defining a safe space for regulatory flexibility via virtual bioequivalence (BE). Workflows for the development and verification of absorption models/PBBM and for the establishment of a safe space using dissolution as an input are described with examples. Breakout session discussions on topics, such as current challenges and some best practices in model development and verification, are included as part of the Supplementary material.

Application of an NLME-Stochastic Deconvolution Approach to Level A IVIVC Modeling.

Stochastic deconvolution is a parameter estimation method that calculates drug absorption using a nonlinear mixed-effects model in which the random effects associated with absorption represent a Wiener process. The present work compares (1) stochastic deconvolution and (2) numerical deconvolution, using clinical pharmacokinetic (PK) data generated for an in vitro-in vivo correlation (IVIVC) study of extended release (ER) formulations of a Biopharmaceutics Classification System class III drug substance. The preliminary analysis found that numerical and stochastic deconvolution yielded superimposable fraction absorbed (Fabs) versus time profiles when supplied with exactly the same externally determined unit impulse response parameters. In a separate analysis, a full population-PK/stochastic deconvolution was applied to the clinical PK data. Scenarios were considered in which immediate release (IR) data were either retained or excluded to inform parameter estimation. The resulting Fabs profiles were then used to model level A IVIVCs. All the considered stochastic deconvolution scenarios, and numerical deconvolution, yielded on average similar results with respect to the IVIVC validation. These results could be achieved with stochastic deconvolution without recourse to IR data. Unlike numerical deconvolution, this also implies that in crossover studies where certain individuals do not receive an IR treatment, their ER data alone can still be included as part of the IVIVC analysis.

Computational fluid dynamics simulation of hydrodynamics in USP apparatus 3-the influence of dip rate.

PURPOSE: This study investigated the influence of dip rate on USP Apparatus 3 hydrodynamics in the presence of a solid dosage form (e.g. tablet) using Computational Fluid Dynamics (CFD) simulations. The primary variables of interest were the liquid phase velocity in the computational domain and wall shear stresses on the tablet surfaces. METHODS: Geometry building and model setup were based on a number of simplifying assumptions. Computational grid-independent solutions were achieved for dip rates ranging from 5 to 10 dips per minute (dpm). RESULTS: For all cases studied, the hydrodynamics exhibited a periodicity dictated by the dip rate. Cycle-to-cycle variations were found to be negligible. Higher velocities were predicted in the wake of the tablet and they peaked at midway positions both during the up- and downstrokes of the cylinder. Three sub-regions of velocity were identified inside the reciprocating cylinder. Results also showed localized vortices/recirculations specific to the up- and downstroke, in addition to local stagnation zones. The wall shear stresses and velocity magnitudes scaled proportionately with increasing dip rates while exhibiting qualitatively similar behavior in their spatial and temporal distributions. CONCLUSIONS: Based on the predictions of the 2D axisymmetric CFD model, the hydrodynamics in USP Apparatus 3 is characterized by complex and periodic flow structures.

Modeling of pharmacokinetic systems using stochastic deconvolution.

In environments where complete mechanistic knowledge of the system dynamics is not available, a synergy of first-principle concepts, stochastic methods and statistical approaches can provide an efficient, accurate, and insightful strategy for model development. In this work, a system of ordinary differential equations describing system pharmacokinetics (PK) was coupled to a Wiener process for tracking the absorption rate coefficient, and was embedded in a nonlinear mixed effects population PK formalism. The procedure is referred to as "stochastic deconvolution" and it is proposed as a diagnostic tool to inform on a mapping function between the fraction of the drug absorbed and the fraction of the drug dissolved when applying one-stage methods to in vitro-in vivo correlation modeling. The goal of this work was to show that stochastic deconvolution can infer an a priori specified absorption profile given dense observational (simulated) data. The results demonstrate that the mathematical model is able to accurately reproduce the simulated data in scenarios where solution strategies for linear, time-invariant systems would assuredly fail. To this end, PK systems that are representative of Michaelis-Menten kinetics and enterohepatic circulation were investigated. Furthermore, the solution times are manageable using a modest computer hardware platform.

Analysis of level A in vitro-in vivo correlations for an extended-release formulation with limited bioavailability.

A two-stage, numerical deconvolution approach was employed to develop level A in vitro-in vivo correlations using data for three formulations of an extended-release oral dosage form. The in vitro dissolution data for all formulations exhibited near-complete dissolution within the time frame of the test. The pharmacokinetic concentration-time profiles for 16 subjects in a cross-over study demonstrated notably limited bioavailability for the slowest formulation. These data were used as the basis for the IVIVC model development. Two models were identified that satisfied the nominal requirements for a conclusive internal predictability of the IVIVC, provided that all three formulations were used as internal datasets. These were a simple linear model with absorption cut-off and a piecewise-linear variable absorption scale model. A subsequent cross-validation of the models' robustness indicated that neither model predicted satisfactorily the pharmacokinetic characteristics of all formulations in a conclusive manner. The piecewise-linear variable absorption scale model provided the most accurate results, particularly with respect to the prediction of the slowest formulation's pharmacokinetic metrics. But this latter model also involved additional free parameters compared with the simple linear model with absorption cut-off. It is argued that more complex IVIVC models with extra parameterization require comprehensive validation to ascertain the accuracy and robustness of the model. In order to achieve this, it is necessary to ensure a complete suite of supporting datasets for internal and external validation, irrespective of the mathematical approach used subsequently to develop the IVIVC.

Classification of the flow regimes in the flow-through cell.

This paper examines the dissolution apparatus referred to as the flow-through cell from an engineering fluid mechanics viewpoint. The analysis demonstrates that laminar flow predominantly occurs in the standard operation of this apparatus. It is argued that fully turbulent conditions are unlikely. Consequently, the phrases 'open column' and 'packed column' are suggested as technically more accurate terms for its operational characteristics than the conventionally referenced 'turbulent mode' and 'laminar mode'. Examples of flow profiles are given to show that the criterion of a "sinusoidal" input flow profile required by USP is not a sufficiently accurate characterization at the inlet as numerous profiles can be conceived which have the same average flow rate. The rationale of pulsating flows versus constant, steady flows is discussed. Examples of how references to turbulence in the dissolution-related literature can lead to ambiguities and/or inconsistencies are highlighted.

Mathematical modeling of the fluid dynamics in the flow-through cell.

The fluid dynamics in the flow-through cell (USP apparatus 4) has been predicted using the mathematical modeling approach of computational fluid dynamics (CFD). The degree to which flow structures in this apparatus can be qualified as 'ideal' both spatially and temporally has been assessed. The simulations predict the development of the velocity field in this apparatus for configurations with and without beads during the discharge stroke of the pump. When the cell is operated only with the red ruby bead ('open column' mode), highly non-uniform flow is predicted just downstream of the bead in the latter stages of the pump's pulse. In contrast, a strong degree of profile uniformity and symmetry is predicted throughout the entire pulse in the region of the tablet holder for both standard configurations involving beads. However, noticeable differences in the tablet shear stress distribution are predicted at times when the same instantaneous inlet flow rates are being pumped through the apparatus. This effect is caused by flow separation in the velocity boundary layer formed around the tablet under the influence of an adverse pressure gradient, an effect not predicted with constant (non-pulsating) flow. While the degree of tablet erosion correlates with the average flow rate, during a particular pulse both the free-stream velocity and the boundary layer thickness are also influential.