Pharma groups fight proposed ban on titanium dioxide in Europe

Correction: An earlier version of this story misstated when a Ti02 ban could take effect. Regulatory Focus regrets the error. Also, the impact of the reformulation was clarified on 30 November
 
Pharmaceutical industry groups are working to submit comments to the European Medicines Agency (EMA) to oppose a proposed ban on the use of titanium dioxide (TiO2) in Europe. The European Commission is expected to make a final decision on the ban in February 2025.

These actions were prompted by a scientific opinion from the European Food Safety Authority (EFSA) in May 2021 that concluded that TiO2 (also known as E 171) is not considered safe when used as a food additive. Shortly after, in January 2022, the European Commission published a regulation removing the authorization for TiO2 as a food additive and opening up the possibility of extending the ban to pharmaceuticals.

Experts recently described to Focus some of the behind-the-scenes discussions about addressing this ban and reiterated concerns on the high cost of reformulating drugs with TiO2-free alternatives. They also stated that European regulators’ concerns about TiO2 in food and pharmaceuticals is not shared by other health authorities.

The Commission, in its 2022 regulation, said it would “review the necessity to maintain titanium dioxide (E 171) or otherwise delete it from the Union list of food additives for exclusive use as a colour in medicinal products within three years.” The review will be informed by an assessment by the European Medicines Agency (EMA) that is expected to be completed by 1 April 2024.

At this year’s Excipient World conference in National Harbor, MD, panelists said that the ban would have a grave impact and lead to drug shortages (RELATED: Experts: Potential EU ban on titanium dioxide would threaten access to drugs, Regulatory Focus, 9 May 2023).

EU regulators have been quiet

Jason Melnick of Eli Lilly and Company said that EU regulators have been quiet on this issue since the January 2022 regulation was promulgated. “We are not seeing a lot of information from either the EMA or the European Commission at this point,” he said.

However, he said in July 2022, EMA published a question-and answer document on using TiO2 in pharmaceuticals.

In response to the proposed ban, Melnick said the IQ consortium, of which Lilly is a part, has been monitoring the global reactions to the ban. Melnick pointed out that a number of countries, including Health Canada, Australia, New Zealand and FDA disagree with the EU’s stance on TiO2.

The IQ Consortium is also collaborating with the International Pharmaceutical Excipients Council (IPEC) group in the US and the EU to collect responses on the proposed ban and to draft feedback prior to the EMA’s 2024 deadline.

Dave Schoneker, president and owner of Black Diamond Regulatory Consulting, who has been working with IPEC on TiO2, said the non-profit Product Quality Research Institute (PQRI) is also involved in this issue. In June 2023, PQRI held a meeting on TiO2 to discuss the safety and formulation implications of the proposed ban that included pharmaceutical manufacturers, TIO2 suppliers and toxicologists.

PQRI is drafting a position paper based on the conclusions from the June meeting and will submit this information to EMA prior to the April 2024 deadline. The paper is expected to assert the safety of TiO2, the lack of alternatives to TiO2 and the barriers to reformulating products without TiO2.

Potential for large-scale drug shortages

Experts reiterated that, if enacted, the ban will create drastic drug shortages and affect a multitude of authorized pharmaceuticals.

Schoneker said about two-thirds of all solid oral dosage forms on the market in Europe contain titanium dioxide, making it the most-used excipient in drug products, “probably more than water.” He added that the 91,000 affected drug products would not be reformulated if TiO2 was banned.

“If Europe thinks they have a drug shortage problem today, they ain’t seen nothing yet. This would create the largest drug shortage situation if they actually banned it,” Schoneker said. “I’m not sure [regulators] understand that all these products will not be reformulated, period.”

The ban would have a particular impact on niche products, including older products, low-margin products, pediatric drugs and orphan drugs since the cost would be too high to reformulate these products. The ban would have less of an impact on newer drugs and high-margin products, Schoneker said. Rather than reformulate certain products, manufacturers are likely to simply withdraw from the European market, he added.

Kevin Hughes, a board member of IPEC Europe, said one of the unanticipated consequences of the proposed ban is that manufacturers would have to submit a major variation, or a Type 2 variation, to support the excipient change of going to a TiO2-free product. Such a reformulation would necessitate the filing of an additional 7,000 variations each year and it would take EMA approximately 12 years to review all the changes, he said.

No scientific justification

Looking at the big picture, Hughes said the EFSA 2021 opinion lacked a scientific justification to support the ban. “When you look at it, the EFSA opinion 2021, it did not identify any specific safety issues. There was a lack of data around genotoxicity. They could not prove it was harmful, but they could not prove it was safe,” he said.

As such, the European Commission invoked the “precautionary principle” and proposed to ban the ingredient altogether rather than risk its continued use in pharmaceuticals, Hughes explained. He added that other regulators, including the UK and Japan “disagreed with the EFSA report. They disagreed with the conclusions and the precautionary approach that the EU used.”

Canada, Australia, New Zealand and the US have stated that TiO2 as a food additive does not pose a risk to human health, according to Hughes.

Schoneker agreed that the European Commission is an outlier in this area. “The bottom line is that there is no scientific explanation to support the ban, it is a farce,” he said. “There is absolutely no scientific justification for them taking this position,” he said.

Schoneker added that European regulators are unnecessarily scaring the public. “The Japanese conducted a similar study and found no safety problems with TiO2,” he said.