Effects of process parameters on tablet critical quality attributes in continuous direct compression: a case study of integrating data-driven statistical models and mechanistic compaction models

Abstract

Continuous manufacturing of oral-dosage drug products is increasing the need for rigorous process understanding both from a process design and control perspective. The purpose of this study is to develop a methodology that analyzes the effects of upstream process parameters on continuous tablet compaction and then correlates associated upstream variables to the final tablet attributes (e.g. relative density and hardness). The impact of three process parameters (system throughput, blender speed, and compaction force) on tablet attributes is investigated using a full factorial experimental design. As expected, the compaction force was found to be the most significant process parameter. However, importantly, throughput was discovered to have a non-negligible impact which was previously unaccounted for. This impact is proposed to be related to differing levels of powder pre-compression. An empirical model for this relationship is regressed and incorporated into a flowsheet model. The flowsheet model is then used to develop an in silico design space which is compared favorably to that built from experiments. Moreover, in the future, the in silico design space based on the validated flowsheet model can provide better manufacturing flexibility and make control strategy development simpler.

Keywords:

• Continuous direct compression
• design space
• model simulation
• tablet compaction

Acknowledgements

A license for the gSOLIDS process modeling software has been provided by Process Systems Enterprise (Ltd.) for the simulation work. The authors are grateful for the MODDE software license used for this research and provided by Satorius Data Analytics.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was financially supported by the U.S. FDA cooperative research project [5U01FD005294]. The project is also partially supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.