Rheology by Design: A Regulatory Tutorial for Analytical Method Validation

Abstract

The increasing demand for product and process understanding as an active pursuit in the quality guideline Q8 and, more recently, on the draft guideline on quality and equivalence of topical products, has unveiled the tremendous potential of rheology methods as a tool for microstructure characterization of topical semisolid dosage forms. Accordingly, procedure standardization is a dire need. This work aimed at developing and validating a methodology tutorial for rheology analysis. A 1% hydrocortisone cream was used as model cream formulation. Through a risk assessment analysis, the impact of selected critical method variables (geometry, temperature and application mode) was estimated in a broad range of rheological critical analytical attributes—zero-shear viscosity, upper-shear thinning viscosity, lower-shear thinning viscosity, infinite-shear viscosity, rotational yield point, thixotropic relative area, linear viscoelastic region, oscillatory yield point, storage modulus, loss modulus, and loss tangent. The proposed validation of the approach included the rheometer qualification, followed by the validation of numerous operational critical parameters regarding a rheology profile acquisition. The thixotropic relative area, oscillatory yield point, flow point and viscosity related endpoints proved to be highly sensitive and discriminatory parameters. This rationale provided a standard framework for the development of a reliable and robust rheology profile acquisition.

Development, Optimization, and Evaluation of Luliconazole Nanoemulgel for the Treatment of Fungal Infection

“…e rheological properties of the gel formulations are correlated to the preparation process, the molecular weight of the incorporated polymer, and the degree of crosslinking [40]. Based on the findings of the present investigation, it could be said that the rheological property of the formulation could be easily applied topically as the increasing rate of shear to the formulation resulted in a decrease in viscosity [41]. erefore, to initiate a flow of the formulation, stress needs to be applied, which will facilitate easy spreadability over the topical area.…”

The Implications of Regulatory Framework for Topical Semisolid Drug Products: From Critical Quality and Performance Attributes towards Establishing Bioequivalence

“…Generally, the rheology of semisolid products is highly sensitive to alternations in the product microstructure, and therefore, detailed rheological characterization takes the central role in detection of the potential microstructure differences [ 22 , 24 ]. Furthermore, rheological characterization serves as a useful quality and stability indicator, which could provide additional information concerning batch variability, product sensorial properties (e.g., consistency, spreadability, and feel) and consequently patient compliance [ 22 , 25 ]. Hence, EMA defines specific rheological parameters that should be documented when characterizing the rheological profile of a given formulation.…”

“…However, currently, there are no regulatory recommendations for the standardization, i.e., formal validation of this method. Hence, Simões and coworkers [ 25 ] tried to establish a practical approach for validation of the rheological analysis, including the rheometer qualification and the validation of numerous operational critical parameters for a rheology profile acquisition. The experimental results showed that the rheology measurement method can be successfully validated, proving its suitability to determine sameness/differences between the formulations.…”

“…Likewise, obtained findings inter alia showed that geometry configuration, sample application mode and temperature are critical method variables that should be carefully optimized before each analysis. According to the risk assessment analysis, the thixotropic relative area, oscillatory yield point, flow point, and viscosity related endpoints were defined as highly sensitive and discriminatory monitoring responses [ 25 ]. Hence, it is believed that the early inclusion of rheological measurements in product manufacture would allow identifying the factors responsible for microstructure variations, which in turn would assure the satisfying product quality and reduce the overall batch variability [ 25 ].…”

From Lab to Upscale—Boosting Formulation Performance through In Vitro Technologies

“…The viscosity profile of a semisolid dosage form is highly linked with the product sensorial properties, such as consistency, spreadability and feel, which strongly impact patient compliance [11,15]. From a quality perspective, viscosity measurements can be regarded as not solely a monitoring tool during process development and stability assessment, but also as a performance indicating tool, since these attributes correlate with drug release and diffusion rate [14].…”