Industry's perspective on challenges assessing the in vivo impact of removing titanium dioxide (TiO) from drug products.

The European Commission (EC) has tasked the European Medicines Agency (EMA) to provide a recommendation towards the acceptability of titanium dioxide (TiO) in pharmaceutical products by early 2024 to inform on final decision in early 2025[1]. Unlike the already implemented ban of TiO in foods, removing this excipient from pharmaceutical products will likely have significant impact on the pharmaceutical industry, regulatory agencies, and patients. This commentary explores the challenges facing the pharmaceutical industry tasked with supporting the development and registration of TiO free (TF) drug products. Specifically, justification of formulation changes and potential impact to in vitro and in vivo performance, as well as differences in global regulatory comparative dissolution requirements to justify changing to TF drug product are discussed. Particularly, the uncertainties around how a formulation change such as removal of TiO from immediate release solid oral dosage forms will be viewed in Europe compared to other regions is discussed. To respond to these challenges and avoid disruption to the medicines supply chain in case in vitro data such as dissolution is either too challenging or insufficient to justify changing to TF product, pharmaceutical companies may have to decide if the level of risk is worth the effort needed to reformulate, develop, and register a new TF product.