(547e) A Novel Digital RTD Toolbox for Adaptive Modelling, Quality Control, and Material Traceability of Continuous Pharmaceutical Manufacturing Process

Residence time distribution (RTD) is a probability distribution function that describes how long a fluid or powder element spends inside a given operation. Currently, continuous pharmaceutical manufacturing is facing several challenges such as prediction of mixing in each unit operation as well as in an integrated line, assurance of content uniformity (CU), and tracing of materials for lots and batches identification ideally needed for product regulation and urgent re-calls [1-4]. These issues are directly related with patient safety and therefore are critical to address. The RTD model has been found in the center of all solutions to address these critical issues. However, because of different level of complexities, the accurate development and effective applications of the RTD model is still a challenging task. Therefore, a systematic toolbox is needed through which, the RTD model can be developed and deployed for varies applications.

In this work, an RTD toolbox has been developed for continuous pharmaceutical manufacturing process. The components of RTD toolbox includes, unit operation building blocks, unit operation RTD model library, calculation systems to perform varies calculations needed to develop integrated RTD based flowsheet model, miscellaneous models, and a library consisting of the integrated RTD based flowsheet model of varies manufacturing lines. The mathematical models have been developed to predict the RTD model parameters from operating conditions. The RTD toolbox is adaptive in nature and thus can be used to develop the RTD model of any continuous pharmaceutical tablet manufacturing process.

The applications of the RTD toolbox to develop the integrated flowsheet model of continuous pharmaceutical tablet manufacturing process has been demonstrated. The integrated flowsheet model is capable of predicting the mixing in each unit operation as well as its affects in final product. The model library and knowledge base are two important supporting tools for the developed toolbox. The model library consists of the RTD model of basic elements such as plug flow process, continuous stirred tank (CST), and dead zone (DZ). Subsequently, via combining these basic elements, the pharmaceutical unit operation (e.g. blender, feed frame) RTD model library has been developed. The knowledge base which has been developed through extensive experimentations consist of the RTD model parameters for a broad range of equipment’s. This knowledgebase is used to develop the additional mathematic models to predict the RTD parameters. The integrated flowsheet model of any continuous pharmaceutical manufacturing processes can be easily generated using this toolbox via drag and drop approach. The toolbox is flexible in nature, can be adapted for any continuous pharmaceutical manufacturing plant and thus should have a broad range of real time applications through distributed control system (DCS) as well as for offline research and development purposes.

The varies applications of the RTD based integrated flowsheet model has been demonstrated. Some of these applications are as follows: prediction of API composition throughout the continuous pharmaceutical manufacturing process. Analysis of effects of disturbances and measurement noise. Material traceability. The applications of the RTD based digital twin for real time diversion of tablets have been also demonstrated to assure the content uniformity of the tablets.

The objective of this presentation is two folds. First to highlight the development of the ‘novel RTD toolbox’ and then to demonstrate its applications for development of integrated RTD based flowsheet model, tablet quality assurance, and material traceability.

References

[1]. Singh, R. (2021). Predicting tablet potency in continuous manufacturing. A modular toolbox enables residence time distribution-based control for continuous pharmaceutical manufacturing. Pharmaceutical Technology. 44-48.

[2]. Singh, R. (2019). Systematic framework for implementation of RTD based control system into continuous pharmaceutical manufacturing pilot-plant. Pharma. Issue 34, 43-46.

[3]. Bhaskar, A., Singh, R. (2018). Residence time distribution (RTD) based control system for continuous pharmaceutical manufacturing process. Journal of Pharmaceutical Innovation. DOI: 10.1007/s12247-018-9356-7.

[4]. Billups, M., Singh, R. (2018). Systematic framework for implementation of material traceability into continuous pharmaceutical tablet manufacturing process. Journal of Pharmaceutical Innovation. https://doi.org/10.1007/s12247-018-9362-9.