Selection of an appropriate tracer to measure the residence time distribution (RTD) of continuous powder blending operations

Abstract

Residence time distributions (RTDs) are quickly becoming an important component of the quality control strategy for continuous manufacturing (CM) of pharmaceutical products. However, methodologies for determining RTDs, including appropriate selection of tracers and proper processing of RTD data, have not been fully developed, and there is potential to improve current methods.This work aims to implement protocols for tracer selection and establish a methodology for the determination and quantitative comparison of RTD curves obtained by the pulse method. We used an extensive material property data library and multivariate analyses to select appropriate tracers for active pharmaceutical ingredient (API) of interest. Tracer performance was evaluated in two continuous blenders using pulse input experiments. The equivalence of RTDs obtained from the API and the tracer was examined for formulations with widely different blend flow properties.For the most suitable tracer candidate, material properties were determined for mixtures with different API concentrations to ensure that blend properties containing varying amounts of tracer along the RTD profile remained similar to those of the target formulation. It was observed that even small changes in the physical properties of the target formulation would result in a different tracer RTD. This observation emphasized the importance of preserving the physical properties of the blend when characterizing the dynamical behavior of a unit operation.Further, the RTD of the tracer and the API in the blender were characterized under three different base flow properties. The outcome of these experiments enabled a fair side-by-side comparison of RTDs obtained using pulses of either API or tracer for powders with a varying range of properties. In finding an appropriate tracer, RTD profiles were compared quantitively using different methods. Multivariate analysis of variance (MANOVA) was shown to be a suitable tool for RTD profile comparisons.