EMA feedback to the EC request to evaluate the feasibility of alternatives to replace TiO2 in medicinal products and its possible impact on the availability of medicines

Last updated: 8 August 2025

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Date	Update(s)
8 Aug 2025	New sub-section ii) Commission staff working document on the use of titanium dioxide in medicinal products added under the heading 6 August 2025

The information for this post has been obtained from the report (of 1 April 2024) with the title above, published on 6 August 2025. Whilst the executive summary from the report is reproduced at the end of this post, It is important to read the full report in order to get a clear understanding of the subject matter.

On the basis of the analysis by the European Medicines Agency (EMA) on titanium dioxide (TiO2) provided to DG SANTE on 8 September 2021 (see links to report and blog post below), the Commission proposed that TiO2 remains provisionally on the list of authorised additives to allow its use in medicinal products as a colour.

EMA’s report (see blog post on this report) on pharmaceutical aspects on impact of removal of TiO2 on medicines concluded that it was not possible at that stage to replace TiO2 without impacting on the quality, safety and efficacy of medicinal products and thus also the availability of medicines in the EU.
Therefore, the decision was made primarily to avoid shortages of medicinal products that could impact public health.

14 January 2022

These measures were formalised in Regulation (EU) 2022/631 (the Regulation), adopted on 14 January 2022.
Under Article 3 of the Regulation, a review clause was foreseen to allow the Commission to re-evaluate the situation within 3 years after the date of entering into force of the Regulation, i.e. by 7 February 2025, on the basis of an updated assessment by the EMA in April 2024.
The Regulation also gives a clear sign that the pharmaceutical industry should make any possible efforts to accelerate the research and development of alternatives to replace TiO2 in both new and already authorised products, and to submit the necessary changes to the terms of the marketing authorisations concerned.

July 2022

The EMA published technical and procedural guidance on the replacement/removal of titanium dioxide (TiO2) in medicines. You can view it on this page.

5 August 2023

On 5 August 2023, the European Commission (EC) requested the EMA to provide an updated analysis with the aim to understand the feasibility of alternatives to replace TiO2, without negatively impacting the quality, safety and efficacy of medicines; and if the feasibility was confirmed, the impact on the availability of medicinal products, taking into account the number of medicinal products in which TiO2 is used.
EMA were also asked to take into account considerations to help define a reasonable transition period for the phasing out of TiO2 in all or specific uses in medicines covered by the scope of colouring matters.
To support the analysis, the Agency was asked to seek the input from industry stakeholders.
For this purpose, the EMA organized a joint meeting with QWP, CMDh/CMDv, EC and Interested Parties (EU trade industry associations) on 16 October 2023 with the aim to learn of Industry’s latest developments concerning replacing/removing TiO2 in medicinal products.
A list of questions was prepared and addressed by AESPG, EFPIA, Medicines for Europa, TiO2 Alternatives Consortium, IPEC Europe, EUCOP, AnimalhealthEurope, and AccessVetmed industry trade associations. Responses to these questions are provided in Annex I.

What were the questions asked at the meeting of 16 Oct 2023?

Question 1: The feasibility of alternatives to replace TiO2, without negatively impacting the quality, safety and efficacy of medicines.
Question 2: If the feasibility is confirmed, the impact on the availability of medicinal products, taking into account the number of medicinal products in which titanium dioxide is used. EMA should also take into account considerations to help define a reasonable transition period for the phasing out of TiO2 in all or specific uses in medicines covered by the scope of colouring matters.

February 2024

Annex I – Use of titanium dioxide as excipient in human and veterinary medicines and identification of alternatives – Industry feedback to QWP experts / EMA questions – Final report February 2024 published on 6 August 2025

6 August 2025

i) Report of 1 April 2024 published

The responses to the questions asked at the meeting of 16 October 2023 were included in the report of 1 April 2024 which was published on 6 August 2025.

An expert group composed of Quality Working Party (QWP) experts and relevant EMA experts and Committee members prepared the responses.
The report was endorsed/adopted by CHMP, CVMP, CMDh, CMDv and QWP in March 2024.

The executive summary from the report is reproduced below.

Executive summary:

TiO2 is present in approximately 91000 Human medicinal products and 1600 Veterinary medicinal products on the EU market.
In many medicines the use of TiO2 as an excipient is critical to safety and efficacy (e.g. as an opacifier to protect from light and prevent degradation of the active substance, or to enable tablet dissolution).
Removal of TiO2 is likely to be feasible for less than 5% of the medicines.
Extensive studies have been done by the pharmaceutical industry to investigate possible alternatives involving 20 possible excipients. All of the 20 alternatives were inferior to TiO2 based on the entire set of KPIs. Significant challenges around manufacturability and photostability were observed.
The investigations performed by the pharmaceutical industry thus far have confirmed EMA’s interim conclusion in 2021 that it is not technically feasible to replace TiO2 in all medicines, without negatively impacting the quality, safety and efficacy of the vast majority of those medicines.
The same technical challenges are expected to apply to new products under development. Given the widespread use and acceptability of TiO2, it is the material of choice in coating materials, capsules, etc. This means that it is included very early on in product and formulation development and clinical studies on these investigational medicines. Its removal from medicines under development is expected to raise the same technical challenges as for authorised medicines.
The technical challenges identified by industry are considered to be a realistic representation of the situation.
Attempts to replace TiO2 will present significant logistical challenges for industry for both authorised products and products under development. Capacity issues for industry and regulators will also arise. These multifaceted challenges are considered highly likely to result in withdrawal of products, unavailability of products while changes are undertaken and increased time in bringing new medicines to market. Severe shortages for European patients and animals can be anticipated.
It should be highlighted that any requirement to make available TiO2 free medicines would only be proposed in the EU/EEA and not globally. Accordingly, companies would have to create EU/EEA only supply chains, processes and dossiers. This will add to the potential that products may be subject to shortages or discontinued because of the cost and complexity of maintaining them on the EU/EEA market.
In the hypothetical scenario that an alternative for TiO2 is identified, Industry estimates that timelines for reformulation of individual products would vary from 4 to 6 years depending on complexity and risks associated with reformulation and considering regulatory filings. This would mean that a typical pharmaceutical company would spend at least between 7 to 12 years for reformulation of their portfolio, given the large volume of products affected. Submission of post-approval variation procedures for so many products would further prolong the time needed due to capacity constraints within the EU regulatory network.
EU Regulatory experts have concluded based on the investigations reviewed that, in the hypothetical scenario that an alternative for TiO2 could be identified, a transition period of more than 12 years would be required for the phasing out of TiO2 in medicines.

Source: EMA

ii) Commission staff working document on the use of titanium dioxide in medicinal products

The document with the above title was published on 6 August 2024. You can view it here.

The Commission Staff Working Document confirms that titanium dioxide should continue to be allowed in medicines, following the updated analysis (at i) above) of the European Medicines Agency of April 2024.

Source: European Commission