Effect of tablet press residence time distribution on material traceability in a continuous direct compression process via mini-batch blending – part 1: corroboration and application

Abstract

Continuous Direct Compression via Mini-Batch Blending (CDC via MBB) is gaining traction as an innovative manufacturing technology in the pharmaceutical industry. According to the Roche design, mini-batches (MBs) are sequentially fed and blended, remaining separate until they come into contact with one another in the hopper above the tablet press after the first diversion point. Material tracking is crucial for understanding how unexpected disturbances propagate through a CDC via MBB line. While tracking is straightforward for separate MBs, assessing the residence time distribution (RTD) in the tablet press becomes necessary after the first diversion point. In this study, a methodological framework is presented where a RTD was characterized experimentally using a tracer (tartaric acid) step change, transmission Raman spectroscopy and in-silico modelling using Discrete Element Method (DEM) simulations.

The experimental results indicated intermixing between adjacent MBs. The RTD-based simulations enabled the quantification of intermixing, revealing that the produced tablet consisted of a blend of multiple MBs at any given time during the characterization of the tablet press. Further simulations based on the corroborated RTD enabled testing of the sampling and disturbance management strategies. The RTD models were used to compare conservative and smart material diversion strategies. It was established that the smart strategy significantly reduced the amount of non-conforming material after minor disturbances. Understanding the process dynamics based on the RTD characterization of the tablet press allows for the development of sampling and material diversion strategies during the CDC via MBB drug product process development. Insights from this work can be applied to other tablet press variants as discussed in Part 2 of this study.

Introduction

Continuous Direct Compression via Mini-Batch Blending (CDC via MBB) is a technology that is increasingly gaining interest in the pharmaceutical industry (Leuenberger); (Warman et al., 2023); (Jaspers et al., 2023); (Blackwood et al., 2019); (Chatterjee, 2012) It consists of small-scale batch feeding and blending operations (1–2 kg at a time) that are carried out repeatedly and that generate a series of so-called mini-batches (MBs) that are fed into a continuously operating tablet press (Warman et al., 2023); (Bautista et al., 2022).

CDC via MBB offers typical benefits of continuous manufacturing, such as eliminating scale-up activities and gaining intrinsically enhanced process control and understanding due to higher data availability (Na et al., 2025); (Waněk et al., 2024). It also has a clear advantage over a CDC line with fully continuous blending, allowing for a simpler (i.e., closer to the batch process) control strategy (Bautista et al., 2022); (Macchietti et al., 2024) This is achieved by replacing continuous powder feeding (often the culprit in process disturbances) with gravimetric dosing, a good blending performance of the high-shear blender and simplified process dynamics, leading to good material traceability (Jaspers et al., 2023); (Bautista et al., 2025).

Clearly, material traceability is critical in a pharmaceutical setting. In fact, according to the ICH Q13 guideline (Step), one fundamental building block of continuous manufacturing is understanding the disturbance propagation through unit operations, which is the basis for “the identification of risks to product quality and the development of an appropriate control strategy.” This guideline also recommends characterizing the residence time distribution (RTD) to enable the development of sampling and diversion strategies (Tian et al., 2017); (Bhalode et al., 2021); (Engisch and Muzzio, 2016). A notable example of how this can be applied is the study by García-Muñoz et al (García-Muñoz et al., 2018). The authors developed a flow sheet model to represent the dynamics of a CDC line. They characterized the RTD and then showed that the model could be used to identify if disturbances from the feeders can be mitigated in the line. The results were presented graphically using the so-called funnel plot (Moreno-Benito et al., 2022). The model was also applied to provide calculations supporting the choice of sampling rate and size of the averaging window for an NIR instrument. This modeling approach to studying the impact of the combined effect of feeder disturbances and RTD in the blenders has become state of the art in CDC technology as shown in Tian et al. (Tian et al., 2019).

In the case of CDC via MBB, there is a diversion point after the MBB until which each MB is independent from the subsequent and adjacent MBs before the material is transferred to the tablet press. A diversion point in a continuous production process is a location where non-conforming material can be removed or discharged without halting the main process. Therefore, in this first part of the line, the material traceability is trivial and the quality of each MB can be determined without taking any process dynamics into account. In the current study, we focus on examining the process dynamics via the RTD characterization in the second part of the line, between the diversion point after blending and the point of compression. Our motivation was to address unexpected events due to which non-conforming material is not discarded at the diversion point (e.g., due to the use of excipients with different material properties that could affect the MB blend uniformity or due to the avalanche of API and/or excipients at the end of feeding that might not be registered by the loss-in-weight (LIW) sensor, leading to an inaccurate evaluation of the MB composition). Our process dynamics study aims to elucidate the damping effect of upstream disturbances in the line caused by mixing between MBs, which is termed “MB intermixing”. The intermixing happens after the diversion point in the hopper above the feed frame and in the feed frame feeding and recycling chamber.

The RTD characterization can be performed experimentally by changing the API concentration at the inlet to the tablet press hopper while monitoring the API concentration in the tablets (Tian et al., 2017); (Lee et al., 2021); (Janssen et al., 2023). This is often accomplished by introducing a pulse in the inlet API concentration, in which case the RTD can be obtained directly from the outlet concentration (Cundall and Strack, 1979). Alternatively, the cumulative RTD can be obtained based on the outlet concentration if a step change in the API concentration is introduced at the inlet. In any case, determining the RTD experimentally requires time, materials and equipment availability. In this work, the RTD of the feed frame was evaluated using Discrete Element Method (DEM) (Siegmann et al., 2020) simulations and corroborated against the experimental results. A DEM simulation considers the motion of powder particles, in our case, through the tablet press (Jajcevic et al., 2024a); (Jajcevic et al., 2024b); (Toson and Khinast, 2019). In principle, this method solves Newton’s equations of motion for every powder particle, and the RTD is calculated by monitoring the residence time of each particle (Jajcevic et al., 2024a); (Siegmann et al., 2021); (Naranjo Gómez et al., 2024); (Toson et al., 2021). It is widely used in the pharmaceutical industry to track material flow (Rosas et al., 2023); (Kureck et al., 2019).

The results were then used to choose an appropriate sampling frequency and simulate “what-if scenarios”, i.e., to develop a strategy for handling the material rejection/diversion. Rosas et al. (Boehling et al., 2021) already applied such an approach in a CDC line using the RTD as a soft sensor to predict the tablet API concentration and the trigger rejection if the limits were exceeded. To the authors’ knowledge, in the present study, a related approach has been applied to the CDC-MBB approach for the first time.

This paper is divided into two parts. The first part (this paper) focuses on the tablet press available at Roche and characterizes it both experimentally and via DEM. The experimental characterization of the RTD is described, and the results were applied to corroborate the RTD obtained via the DEM. Next, material tracking simulations were performed and considerations in terms of frequency of sampling, material tracking and discarding strategy were made for a CDC via MBB process connected to the characterized tablet press. The second part of this paper (Part II) shows how this approach was rolled out to analyze five other tablet press designs and models, for which the process dynamics were characterized only in-silico. The process dynamics characterization via DEM simulations is described in detail, and the results obtained for the various tablet presses are compared in terms of their consequences for the CDC via MBB operation.

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Peter Boehling, Johan Remmelgas, Johannes Poms, Rúben Martins Fraga, Manel Bautista, Michela Beretta, Johannes G. Khinast, Emmanuela Gavi, Effect of tablet press residence time distribution on material traceability in a continuous direct compression process via mini-batch blending – part 1: corroboration and application, International Journal of Pharmaceutics, Volume 692, 2026, 126656, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2026.126656.

Read also our introduction article on DC Excipients here: