Article pubs.acs.org/OPRD
Model Driven Process Design and Development for a Continuous Process Sze-Wing Wong,* K. Derek Berglund, and Shekhar K. Viswanath Small Molecule Design & Development, Eli Lilly and Company, Indianapolis, Indiana 46285, United States ABSTRACT: This paper presents a case study where kinetic models were used to drive process development of an amination reaction in a continuous process. The kinetic model was first used to optimize the process by minimizing impurity formation. Then, the kinetic parameters were put into a two-in-series CSTR (continuous stirred tank reactor) model and a separate PFR (plug flow reactor) model to guide reactor selection and optimize the reactor design. Once the model predictions were validated with experimental data, the simulated impurity profile from each reactor type was compared. While the results showed that both reactors delivered similar impurity profiles at steady state, the model was used to conduct perturbation analysis on the two reactors to assess the impurity and operational control strategy. The simulations showed that the CSTR can tolerate a process upset time up to 10% of its residence time with materials meeting product specification as compared to the PFR. Since the CSTR offers additional buffering capacity during process upsets due to the dilution effect inside the reactors, the project team selected the CSTR as the final reactor choice. This case study shows that a kinetic model can positively impact development of a continuous process even at an early development phase, which is consistent with quality by design (QbD) principles.1 Most importantly, the model can simulate various perturbation scenarios to provide understanding of the process dynamics and provide guidance in determining the process operational boundaries with computer simulations. This resulted in substantial savings in cost of material, development time, and resources. To our knowledge, this is the first example of utilizing a model for continuous reactor selection in the pharmaceutical industry where the reactor choice was based on its ability to tolerate process upsets rather than the impurity profile obtained.
■
INTRODUCTION There are two main reasons why the pharmaceutical industry has traditionally been focused on batch process manufacturing. First, given that the pharmaceutical industry is heavily regulated, a batch process helps simplify quality control in which the quality of the active pharmaceutical ingredient (API) can be tested at the end of each individual batch. Second, the typical product life cycle of an approved pharmaceutical product is relatively short with 10−12 years of sales. As a result, the commercialized process is typically designed to fit into existing batch equipment in order to minimize capital investment. Given the industry-wide 76% attrition rate of compounds in development, there is a big driver to make stage-appropriate investments in process research.2 This creates drivers to enable process development under highly accelerated timelines after clinical proof-of-concept is achieved (
