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Process intensification involves the miniaturization of equipment while retaining process throughput and performance. The pharmaceutical industry can benefit from this approach especially during drug product development, where the availability of active pharmaceutical ingredients (API) is often limited. It reduces the need for process scale up, as equipment used during product development and commercial production is identical. However, applications of process intensification for processing pharmaceutical powders are limited so far. Here we show that semi-continuous mini-blending can be utilized for process intensification of blending of API and excipients. Uniform blending at commercially relevant throughputs was achieved through mini-blends with a volume of less than ten liters. Our results demonstrate that blending speed, cycle time and blender fill level can be optimized without compromising blending performance. Acceptable blend uniformity is obtained over a broad range of operating parameters, by choosing the right excipients. The optimized throughput of the mini-blending process is in line with the desired throughput of a commercial Continuous Direct Compression (CDC) process.

Developing a robust roller compaction process can be challenging, due to the diversity in process parameters and material properties of the components in a formulation. A major challenge in dry granulation is the reduction of tablet strength as a result of re-compaction of the materials. The aim of this study is to investigate the impact of excipient type and particle size distribution on tablet tensile strength after roller compaction. Lactose monohydrate, anhydrous lactose and microcrystalline cellulose with different particle sizes are roller compacted at varying specific compaction forces. Granules obtained are compressed into tablets to evaluate the reduction in tablet strength upon increasing the specific compaction force. The impact of particle size of the starting material is shown to be vastly different for the three types of excipients investigated, due to the differences in mechanical deformation mechanisms. The presence of rough surfaces and a high degree of fragmentation for anhydrous lactose appears to be beneficial for compaction and re-compaction process. Additionally, the particle size of anhydrous lactose hardly affects the tensile strength of tablets, which can be beneficial for the robustness of a roller compaction process.

The material properties of excipients and active pharmaceutical ingredients (API's) are important parameters that affect blend uniformity of pharmaceutical powder formulations. With the current shift from batch to continuous manufacturing in the pharmaceutical industry, blending of excipients and API is converted to a continuous process. The relation between material properties and blend homogeneity, however, is generally based on batch-wise blending trials. Limited information is available on how material properties affect blending performance in a continuous process. Here, blending of API and excipients is studied in both a batch and a continuous process. Homogeneity of the resulting mixtures is analyzed, which reveals that the impact of material properties is very different in a continuous process. Where parameters such as particle size, density and flowability have significant impact on blending performance in a traditional batch process, continuous blending is more robust resulting in uniform blends for a large variety of blend compositions.

Risk control for nitrosamine impurities in drug products is currently a major challenge in the industry. Nitrosamines can form during drug product manufacturing and storage through the reaction of nitrites with amine-containing APIs or impurities. The level of nitrites in excipients and the rate of reaction often control the build-up of nitrosamine. Although the variability in nitrite levels across excipient types and suppliers is well recognized, the impact of excipient selection on the level of nitrosamine formed has not been systematically studied. This gap of knowledge is addressed in the current work. We present theoretical case studies of formulations where microcrystalline cellulose (MCC), or lactose supplier, or superdisintegrant type are changed in pursuit of lower levels of nitrite. The impact of the average, maximum, and minimum levels of nitrites in each excipient on nitrosamine formation in the dosage form is calculated. The input data for this calculation are the formulation composition, nitrosamine molecular weight (MW), percentage of conversion, and nitrite levels per excipient. The percentage of conversion (based on the formulation and manufacturing variables) and nitrite levels were taken from the recent literature. We show that changing the supplier of a single excipient, or of the three most critical excipients, can reduce nitrosamine formation by up to −59% and −89%, respectively. We also show that high-risk formulations, e.g., high MW nitrosamines, high dosage weights, and high percentages of conversion (e.g., wet granulation), can often be de-risked below regulatory acceptable daily intake via careful excipient selection. Finally, we provide an open-access tool that enables users to calculate the theoretical formation of nitrosamines in their specific formulations. This calculation template can be used for (i) the preliminary screening of the risk of nitrosamine formation in drug products and (ii) the preliminary assessment of the impact of excipient selection for risk mitigation.