PBBK BE WAIVER BCS CLASS IV POST APPROVAL CHANGE

[raaju42-creator]

Question to the community:

We have made formulation/process changes to an already approved drug product intended for the EU market. The drug substance is BCS Class IV, and one of the formulation changes was the addition of an antioxidant to mitigate a nitrosamine-related risk.

We have also generated multimedia dissolution data, and the post-change formulation demonstrates comparable dissolution performance to the approved/reference product across the relevant media.

We are exploring whether a mechanistic PBPK/PBBM approach could be used to support a regulatory justification for waiving an in-vivo BE study.

I would appreciate input from colleagues experienced with PBPK/PBBM and EU regulatory submissions on:

1. How would you structure the PBPK/PBBM model for this type of formulation change?
2. What clinical/reference data would be required to develop, verify, and qualify the model?
3. How can the observed multimedia dissolution profiles be incorporated into the model to demonstrate that the formulation change does not meaningfully affect systemic exposure?
4. For a BCS Class IV drug, what level of model verification and sensitivity analysis would regulators typically expect?
5. Can PBPK/PBBM realistically provide sufficient evidence to support a BE waiver, or would it generally be considered supportive evidence alongside comparative dissolution and other data?
6. Are there any EU/EMA precedents or regulatory guidance where PBPK/PBBM has been successfully used to support a post-approval formulation change without conducting an in-vivo BE study?

I would particularly appreciate practical experience with EMA scientific advice, variations/post-approval changes, and PBPK-based biowaivers for BCS Class II/IV compounds.