In order to produce pharma-grade hyaluronic acid, the process requires a high degree of process understanding and documentation. Therefore the process development work is very extensive and consists of several phases. Firstly, during PAR (proven acceptable range) studies, single parameter experiments are performed. Secondly, during PC/NOR (process characterization/normal operating range) multiple parameter/interaction studies are done. Thirdly, scale dependent parameters are investigated at full manufacturing scale in order to get a comprehensive understanding of the full-scale production process. Finally, the process needs to be validated and shown to be robust and reproducible.
In this work, we describe the different approaches during the stages of the development process, where at first relatively simple experiments are performed for getting a basic understanding of the importance of each process parameter. Afterwards more advanced experiments are performed using a DOE (Design of Experiment) set-up, where the interaction between important process parameters is determined. And finally at scale experiments are described to show the effect of viscosity and mass transfer differences at scale that are very dependent on the tank geometry and cannot be simulated in a down-scale model.