(603e) Model-Based Comparison of Dissolution Behavior between Batch and Continuous Direct Compression Manufacturing Platforms

Dissolution testing is one of the most important release testing of tablet manufacturing to assure bioavailability of drugs. Along with the development of process analytical technology (PAT), real-time release testing (RTRt) of tablet dissolution has been attracting attention on the industry since it can reduce product lead-time significantly. RTRt is expected to be used in continuous manufacturing that is more beneficial than conventional batch manufacturing in terms of operation time, flexibility, product quality, and cost [1]. Among possible routes of continuous manufacturing, continuous direct compression (CDC) is the most preferred route in terms of process simplicity and energy consumption.

So far, numerous studies have been performed for CDC, e.g., comparison with batch manufacturing [2], the analysis of key process parameters [3], and process analytical technology (PAT) [4]. While the application of CDC has increased in the industry, batch operation may still be needed during the research and development (R&D) phase due to the limited availability of active pharmaceutical ingredients (APIs). To shift from batch to continuous manufacturing smoothly, obtained process and product quality information during R&D should be transferable to CDC lines. For example, the applicability of CDC for commercially batch-produced tablets was analyzed [5]. However, quantitative knowledge about a comparison of batch and continuous direct compression (DC) is limited toward efficient process design.

This study shows the model-based comparison of dissolution behavior between batch and continuous DC. Dissolution behavior is one of the most critical quality attributes (CQAs) and needs to be equivalent between R&D and commercial production. Tablets were produced by both batch using a Modul^TM P tablet press (GEA Pharma systems, Collette^TM, Wommelgem, Belgium) and continuous DC ConsiGma CDC-50 (GEA Pharma Systems, Collette^TM, Wommelgem, Belgium) using the same formulations to measure process performance and product quality. Ibuprofen was used as a surrogate API, whereas materials and composition ratio of excipients were varied, resulting in nine formulations. Each formulation was processed at three different hardnesses, and dissolution testing was performed with different pH values. During the operation, process performances, e.g., feed factor, main compression, and ejection forces, were monitored in addition to a near-infrared (NIR) probe placed in the feed frame to asses the blend uniformity; CQAs, e.g., dissolution, disintegration, content uniformity and hardness, were measured after the operation.

Different types of models, including statistical, empirical, and mechanistic models, have been applied to the analyses of experimental results. First, all blends were characterized by a principal component analysis (PCA) model. Then, two Partial Least Square (PLS) models were constructed to predict the blend uniformity in the feed frame prior to tableting and the content uniformity of the obtained tablets in a non-destructive manner, these models could then be linked to the dissolution behavior of the drug product. To understand the differences of dissolution behavior deeply, both empirical and mechanistic models of tablet dissolution were applied to experimental data. Finally, obtained results were further analyzed by statistical approaches.

Process responses were compared between batch and continuous DC lines. Higher ejection forces were observed for the CDC trials potentially due to different conditions of lubricant blending and compression. Several problems arose during the tableting process related to the blend properties, this required flexibility from the initial experimental plan. Additional experiments with different process settings of lubricant blending and compression can identify the cause of different ejection forces.

Comparison of the dissolution profiles obtained after batch and CDC processing gave rise to identical dissolution curves, where the standard deviation of batch trials was larger compared to the ones obtained from the CDC trials. The difference can be linked to the highly controlled environment of the continuous line, where label claims were more consistent over time. Different hardnesses and pH ranges gave rise to different dissolution, as expected. The formulation compositions also had a significant impact on dissolution profiles, where more hydrophilic filler components exhibited slower release profiles in comparison to hydrophobic filler combinations. This observation could be attributed to the water competition effect. By fitting dissolution results into empirical and mechanistic models, the differences in the values of model parameters can deepen the understanding of differences between batch and continuous DC lines as well as the impact of formulation properties and process settings. Through the analyses, key process parameters that need to be tuned from batch to CDC can be identified.

Acknowledgement: The authors would like to acknowledge, in no particular order, AstraZeneca and Janssen Pharmaceutica for their financial support and fruitful collaboration in this project.

References:
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