Predicting pharmaceutical particle size distributions using kernel mean embedding

In the pharmaceutical industry, the transition to continuous manufacturing of solid dosage forms is adopted by more and more companies. For these continuous processes, high-quality process models are needed. In pharmaceutical wet granulation, a unit operation in the ConsiGmaTM-25 continuous powder-to-tablet system (GEA Pharma systems, Collette, Wommelgem, Belgium), the product under study presents itself as a collection of particles that differ in shape and size. The measurement of this collection results in a particle size distribution. However, the theoretical basis to describe the physical phenomena leading to changes in this particle size distribution is lacking. It is essential to understand how the particle size distribution changes as a function of the unit operation's process settings, as it has a profound effect on the behavior of the fluid bed dryer. Therefore, we suggest a data-driven modeling framework that links the machine settings of the wet granulation unit operation and the output distribution of granules. We do this without making any assumptions on the nature of the distributions under study. A simulation of the granule size distribution could act as a soft sensor when in-line measurements are challenging to perform. The method of this work is a two-step procedure: first, the measured distributions are transformed into a high-dimensional feature space, where the relation between the machine settings and the distributions can be learnt. Second, the inverse transformation is performed, allowing an interpretation of the results in the original measurement space. Further, a comparison is made with previous work, which employs a more mechanistic framework for describing the granules. A reliable prediction of the granule size is vital in the assurance of quality in the production line, and is needed in the assessment of upstream (feeding) and downstream (drying, milling, and tableting) issues. Now that a validated data-driven framework for predicting pharmaceutical particle size distributions is available, it can be applied in settings such as model-based experimental design and, due to its fast computation, there is potential in real-time model predictive control

Application of Iterative Robust Model-based Optimal Experimental Design for the Calibration of Biocatalytic Models

The aim of model calibration is to estimate unique parameter values from available experimental data, here applied to a biocatalytic process. The traditional approach of first gathering data followed by performing a model calibration is inefficient, since the information gathered during experimentation is not actively used to optimize the experimental design. By applying an iterative robust model-based optimal experimental design, the limited amount of data collected is used to design additional informative experiments. The algorithm is used here to calibrate the initial reaction rate of an ω-transaminase catalyzed reaction in a more accurate way. The parameter confidence region estimated from the Fisher Information Matrix is compared with the likelihood confidence region, which is not only more accurate but also a computationally more expensive method. As a result, an important deviation between both approaches is found, confirming that linearization methods should be applied with care for nonlinear models