Abstract
In this case study, we present an approach for employing modeling to help define the design space for a reaction with potential to generate an impurity that could impact the quality of an API. Our approach broadly consisted of (1) evaluating the reaction parameters that can affect the critical impurity level to develop appropriate assumptions for a mechanistic model, (2) developing and evaluating a mechanistic model to predict the formation of the critical impurity, (3) defining a design space based on the model output to reduce in practice the acceptable parameter space to a practical number of parameters, and (4) verifying the design space through experimental testing. This work resulted in a verified design space that can be practically employed and includes wide parameters ranges for manufacturing flexibility.
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Acknowledgements
We would like to acknowledge Maurico Futran, Sushil Srivastava, Jean Tom, Robert Waltermire, and Jason Sweeney for their support, guidance and helpful discussions. We would also like to acknowledge Justin Burt, Jale Muslehiddinoglu, Antonio Ramirez, Nicolas Cuniere, Jing Liang, Praveen Sharma, Alice Yang, Christopher Wood, Process Research and Development Operations, and Swords Technical Operations for their contributions. We would also like to acknowledge Joe Hannon and Andrew Bird of Scale-up Systems Ltd. for their helpful discussions and support with DynoChem®.
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Hallow, D.M., Mudryk, B.M., Braem, A.D. et al. An Example of Utilizing Mechanistic and Empirical Modeling in Quality by Design. J Pharm Innov 5, 193–203 (2010). https://doi.org/10.1007/s12247-010-9094-y
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DOI: https://doi.org/10.1007/s12247-010-9094-y