Modeling-based Development of an Enantioselective Hydrogenation Reaction of a Sitagliptine Intermediate

The use of process models to speed up the development and optimize the design and operation of integrated processes has increased dramatically in recent years in the pharmaceutical industry.1,2 All aspects of modeling appliance (and process simulators as well) in process development need some guidelines. That is why different regulatory agencies (such as U.S. Department of Health and Human Services, Food and Drug Administration) have developed a method for evaluating new drug applications, especially the chemistry, manufacturing, and process controls. This approach is described in relevant covering topics given by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). There is an endorsed guide for ICH implementations Q8, Q9 and Q10, describing a new scientific development approach that supplements the existing one.3 It is a concrete and practical implementation of some underlying concepts and principles outlined in quality by design (QbD) initiatives.4 The QbD initiative aims to ensure pharmaceutical product quality via scientific process understanding, risk management, critical quality attribute (CQA) control strategies, and multivariate design space definition.3–10 The QbD was described and some of its elements identified.9 Process parameters and quality attributes were identified for each unit operation. The use of QbD was contrasted with the evaluation of product quality by testing alone. The QbD is a systemic approach to pharmaceutical development. It means designing and developing manufacturing processes to ensure predefined product quality and process robustness.10 The use of mechanistic models in process development has multiple benefits. Mechanistic models enable systematic analysis of experimental data and quantification of intrinsic and/or scale-dependent process attributes. Computer aided process design and simulation tools have been successfully used in the pharmaceutical industry. Many authors have worked on modeling and developing API production process with QbD methodology, which can be referred to development of reaction kinetics of the manufacturing process of: Torcetrapib,11 Ibipinabant,12 recombinant protein13 and different drug substances,14 for the control of genotoxic impurities in the manufacturing process of a drug substance,15 as well as to the development of crystallization processes.16–18 According to current QbD FDA submission statistics, the number of QbD new molecular entity applications rises significantly.19 Modeling-based Development of an Enantioselective Hydrogenation Reaction of a Sitagliptine Intermediate