In 2021, the European Food Safety Authority (EFSA) investigated the safety of the white coloring agent titanium dioxide (TiO2) and concluded that the substance should not be considered safe as a food additive due to uncertainties around possible inflammation and neurotoxicity. On the basis of new data and strengthened methods EFSA scientists could not rule out a concern for genotoxicity and consequently they could not establish a safe level for daily intake of TiO2 as a food additive.
The US FDA reviewed the findings of EFSA’s 2021 Opinion on TiO2. The FDA notes that EFSA’s 2021 Opinion continued to confirm no general and organ toxicity and no effects on reproductive and developmental toxicity. The US FDA has assessed the safety of TiO2 pigment as a color additive in food, drug and cosmetic applications (intended for use around the eye), and as an ingredient in sunscreen products. For use in foods, the FDA categorizes TiO2 as Generally Recognized as Safe (GRAS) at a maximum 1 percent by weight. For drugs, the color additive TiO2 may be used for coloring ingested and externally applied drugs generally, in amounts consistent with good manufacturing practice.
In the EU, the phasing out period for TiO2 came to a halt on August 7, 2022. Manufacturers will no longer be allowed to place food containing TiO2 (such as chewing gum, and white decoration on cakes and pastries) on the market. After that date, it can still be in the store until the shelf life has expired. So, the food industry needs to change their product formulations and find good alternatives for TiO2 (E171).
Titanium dioxide is also used as an excipient in medicinal products, e.g., film-coated tablets, pellets and capsule shells.
Compared to other excipients, TiO2 allows for a thinner, less fragile outer layer of the tablet. This ensures that the active substance of the drug becomes available quickly after oral administration. TiO2 thus aids in preserving the safety, efficacy and quality of the product over its’ shelf life by supporting the physical integrity of the product and/or is a stabilizer for photosensitive formulations by protecting other UV sensitive ingredients from degradation when exposed to visible light.
The approval of coloring agents/dyes in medicines is currently linked to the approval as a food additive. It is unclear whether it is feasible to replace TiO2 in medicines. There are not immediately good alternatives available with the same, unique combination of properties. Particular concerns have been raised about the impact on appearance (loss of opacity and strength), light resistance and/or the need for increased film coating quantities. Possible alternatives identified so far are:
These possible alternatives should be re-examined for their impact on the quality, safety and efficacy of the newly formulated medicines.
The removal or replacement of TiO2 may go beyond a simple change and constitute a product/ process re-development to a greater or lesser extent.
It can be envisaged that variations may need to be submitted for currently registered film-coated tablets, pellets, and capsule shells in the EU as a direct consequence of implementing the excipient change. EMA has therefore provided potential regulatory pathways to support the removal/ replacement of TiO2 in medicinal products. Changes anticipated are for example:
It is recommended that all variations that are a consequence of the removal or replacement of TiO2 are submitted together as a grouped variations in the EU. The assessment by Health Agencies could take an estimated 7 to 12 years for the sheer number of drugs.
Given the diverse opinions about TiO2, ProPharma Group provides a comprehensive suite of interrelated services that are cost-effective and efficient to meet your project or program needs. We can support you with:
Using our flexible skillset and universal understanding of process and product lifecycle management, we work with your team to determine your project’s key milestones and provide scalable project management support.
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