Table 6.

Challenges in global regulatory harmonization: divergent perspectives on design space (case study of FDA vs. EMA).

Aspect	FDA (U.S.)	EMA (EU)	Harmonization Gaps and Implications
Regulatory Framework	Emphasizes risk-based flexibility under ICH Q8-Q11. Supports post-approval changes within design space without prior approval.	Stricter predefined data requirements for design space validation. Requires prior approval for major changes, even within design space.	Conflict: FDA’s “enabled flexibility” vs. EMA’s cautionary approach delays global dossier alignment.
Design Space Acceptance	Encourages broader design spaces with multivariate interactions (e.g., dissolution and compression). Case: Approved design space for a modified-release tablet with 3 CPPs.	Prefers narrower, parameter-specific ranges (e.g., granulation moisture as standalone CPP). Case: Rejected a design space model due to insufficient interaction data.	Impact: Sponsors must generate region-specific data, increasing R&D costs.
Change Management	Allows real-time monitoring (PAT) to justify adjustments within design space (e.g., blend uniformity via NIR).	Demands extensive stability data for post-design space changes (e.g., 12-month real-time stability).	Delay: EMA’s data requirements prolong time-to-market for multinational products.
Data Requirements	Accepts mechanistic models (e.g., PBPK) to support design space boundaries.	Prioritizes empirical data over predictive models for biologics (e.g., mAb aggregation risks).	Inconsistency: Model-informed approaches face EMA skepticism, hindering innovation adoption.
Communication	Open dialog via QbD pilot programs and pre-submission meetings.	Relies on formal scientific advice with limited iterative feedback.	Barrier: Asymmetric communication channels complicate global strategy alignment.

Case examples: Sections in Regulatory Information and Dissolution Methods Database, Food and Drug Administration (.gov): approved a design space for oncology tablets integrating dissolution and hardness CPPs (2019). EMA: rejected a biosimilar design space due to insufficient glycosylation control data (2021).