Process Modeling in Focus for EU and US Reviewers

The understanding of the potential uses and value of models in facilitating manufacturers’ development efforts and helping regulators understand their complex processes is growing.

The importance of using models as well as maintaining them was highlighted in ICH Q8. Models were recommended in the guideline, for example, as valuable tools in risk assessment, the control strategy, and design space determination and scale up.

At recent meetings, FDA and EU regulators have been discussing how to maximize the value of models in quality-by-design submissions and across the product lifecycle.

Addressing the Center for Drug Evaluation and Research’s growing experience with models at a recent conference, FDA Office of New Drug Quality Assessment  Review Chemist Sharmista Chatterjee emphasized the importance of understanding the uncertainty they contain.

“Any measurement has some uncertainty, and good understanding of that will tell us the limitations of the model and how the control strategy should be designed to prevent the associated risk. Risk depends a lot on what uncertainty is in the model.”

Chatterjee also stressed the importance of verifying models. Doing this verification “gives us an understanding of what the limitations are for the model, and how the control strategy should then be designed,” she said.

The ONDQA official stated that her office is willing to work closely with applicants prior to submission and during the review process regarding the use of models.

The use of models in regulatory submissions has also spawned questions and debate in the EU.

Models are generally initiated in product and process development at pilot scale and later transferred to manufacturing, and subject to frequent updates

The questions include how the model should be represented in the regulatory submission and which version from the development/manufacturing cycle should be submitted. Also at issue are what level of detail should be submitted, which in part depends on what the regulators request, and what data should be available for review at the manufacturing site.

[Editor’s note:  A more extended analysis of the impact of models in the EU and US is provided in the May report from IPQ on the changing CMC landscape.]