Continuous manufacturing can be benefited by the use of the Quality by Design (QbD) strategy for robust process development and by the use of Process Analytical Technology (PAT) for real-time process monitoring and control. A successful implementation of QbD and PAT for continuous processes relies on a robust and information-rich process model as a basis for process understanding, monitoring, and control. Compared to first principles and other empirical models, a latent variables-based process model is capable of decomposing multidimensional process data into a few orthogonal latent variables and of providing accessible process understanding/visualization and control within the latent variable space. This study is an extension of our group's earlier effort (Liu et al., J Pharm Innov 6:170-180, 2011) to explore the utility of latent variables-based process modeling in pharmaceutical manufacturing processes. The case presented here is the first application of latent variables-based modeling to a reaction process in small-molecule active pharmaceutical ingredient route synthesis, i.e., a continuous-flow hydrogenation. A particular reactor configuration and operation was used in this proof-of-concept study. It was found that time-variant profiles of pressure in the flow tube reactor served as an effective indicator of gas-liquid interaction within the reactor, thus determining process outcomes, i.e., the extent of reaction and enantiomeric excess (ee), given the importance of process set points. In addition, a design space of process parameters predicted to produce optimal outcomes, i.e., extent of reaction greater than 98 % and ee higher than 93 %, was established in order to provide a flexible operation space for performing the reaction with desired process outcomes. The capabilities of latent variables-based process modeling have been well demonstrated as applied to a continuous-flow hydrogenation reaction, regarding its improved process understanding and the potential for process optimization & control as well. Future efforts will be focused on continuing understanding of the capabilities and limitations of such a methodology on a fully-automated control scheme for continuous flow reaction.

• Lilly Research Laboratories

• PAT
• Modeling
• API

1. API
2. continuous manufacturing
3. Design space
4. hydrogenation
5. Latent-variable modeling
6. modeling
7. pat
8. Research Article