European Commission: Lack of alternatives to TiO2 precludes ban in drugs

The European Commission has determined that there are no viable alternatives to titanium dioxide (TiO2) as an excipient in many pharmaceutical products. They also identified a risk of shortages if a ban were implemented, which could negatively impact patients due to the large number of medicinal products affected.

The decision was based on feedback received from the European Medicines Agency (EMA), which evaluated the feasibility of alternatives to TiO2 in medicinal products and considered the potential impact on medicine availability.

In November 2023, experts shared some behind-the-scenes discussions with Focus about addressing the ban. They outlined plans to issue a response and reiterated concerns regarding the high cost of reformulating drugs to use alternatives that do not contain TiO2. (RELATED: Pharma groups fight proposed ban on titanium dioxide in Europe, Regulatory Focus 27 November 2023)

The European Commission was expected to make a final decision on the ban in February 2025.

The scramble to address and find alternatives to TiO2 emanated from a May 2021 scientific opinion from the European Food Safety Authority (EFSA), which stated that TiO2, also known as E 171, is not considered safe for use as a food additive. Following this conclusion, the European Commission published a regulation in January 2022 that revoked the authorization for TiO2 as a food additive and indicated the potential for extending the ban to pharmaceuticals.

In its recent decision, the Commission decided not to extend the TiO2 ban to pharmaceuticals.

The Commission stated that “titanium dioxide has been used for decades as a whitening agent in food, a pigment in medicinal products and a UV protectant in cosmetics,” said the Commission. “Due to its high opacity and brightness, titanium dioxide is used in a very large number of medicinal products (91,000 human medicinal products and 1,600 veterinary medicinal products) as a pigment (to add whiteness or accentuate the boldness of other colours) and opacifier (to ensure that tablets have a uniform colour when manufactured).”

The excipient also helps maintain the drug’s color during its shelf life and serves as a coating to preserve the active pharmaceutical ingredient (API).

In its decision, the Commission summarized the EMA's analysis on whether titanium dioxide can be replaced, and the decision includes feedback from the pharmaceutical industry regarding questions posed by the EMA's scientific experts.

Some of the main findings of the EMA’s analysis are the following:

The uniformity of color and appearance in medicinal products can be greatly affected by the replacement of titanium dioxide. This ingredient traditionally provides opacity that helps ensure a consistent color across tablet coatings. When using alternative film coatings, the natural color of the tablet core can influence the coverage and color uniformity, which may hinder the effective coating of certain tablet formulations. As a result, alternative coatings often require more intense colors to achieve uniform coverage. Additionally, reformulating tablets to replace titanium dioxide could create challenges with patient compliance due to changes in the products’ visual appearance.
Opacity is a crucial factor influenced by the replacement of titanium dioxide. Titanium dioxide is known for delivering effective opacity even in small amounts, while alternative coatings typically need a significantly higher weight percentage to achieve a similar level of opacification. This requirement can result in longer processing times and increased costs. Additionally, the inconsistent opacity of these alternatives creates challenges, complicating the reformulation of various products.
The in vitro performance of current alternative capsule shells and coatings shows no significant differences in disintegration and dissolution compared to titanium dioxide-based counterparts, yet their long-term stability is still being investigated. There are concerns that the thicker coatings required for these alternative materials may impact the stability and shelf-life of medicinal products.

Based on this feedback, EMA concluded that “all the alternatives tested were inferior to titanium dioxide when assessed against the entire set of KPIs [key performance indicators]. Some alternatives performed well on certain KPIs but not others.”

The agency further concluded that removing titanium dioxide “is likely to be feasible for less than 5% of authorised medicines, as no simple one-to-one replacement exists, and that the same technical challenges are expected to apply to medicines currently under development.”

The Commission ruled that "in view of the EMA's findings, the Commission takes the view that the use of titanium dioxide as a colour in medicinal products, as provided for in Regulation (EU) 2022/63 amending Regulation (EU) 2022/63 amending Regulation (EC) No 1333/2008, shoud be maintained."

EMA also released a copy of EU association’s feedback on exploring alternatives to TiO2 and a summary and timelines of industry activities to identify and assess alternative coatings and capsules.

The associations that released the report included representatives from the European Federation of Pharmaceutical Industries and Associations (EfPIA), Medicines for Europe, Animal Health Europe, the International Pharmaceutical Excipients Council (IPEC) Europe, the TiO2 Alternative Consortium, the Association of the European Self-Care Industry (AESGP), Access Vetmed, and the European Confederation of Pharmaceutical Entrepreneurs (EUCOPE).

European Commission decision on TiO2, Feedback from EMA to the EU Commission, Industry associations report on Tio2 and identification of alternatives

European Commission: Lack of alternatives to TiO2 precludes ban in drugs

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