New Questions and Answers from the EMA regarding Titanium Dioxide in Medicines

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The EMA published new questions and answers concerning titanium dioxide and its replacement or removal in medicines on 1 July 2022. There were five questions and answers in all, and they appeared in the section "Quality of medicines questions and answers: Part 2" on the EMA website. They serve as guidance ("Technical and procedural guidance") for marketing authorisation holders and applicants on how to replace titanium dioxide in medicines using other excipients or how to remove it completely. After having been prepared by EMA's Quality Working Party (QWP) the questions and answers document was discussed with the pharmaceutical industry in early May and commented by it. After consulting the CMDh the document was published on the EMA website.

The CMDh supports the guidance and advises marketing authorisation holders to take due notice of the document's recommendations in the pharmaceutical development of their products.

Background

Titanium dioxide (E 171) is used extensively as food additive in the food industry and as colourant, opacifier and protection from UV radiation in the pharmaceutical industry. The use of food additives is regulated by Regulation (EC) No 1333/2008. Directive 2009/35/EC and restricts the use of such substances as colourants in medicinal products for human use and in veterinary medicinal products to those substances which are approved for the use as food additives according to Regulation (EC) No 1333/2008. Article 32 paragraph 1 of this Regulation stipulates that food additives which were permitted before 20 January 2009 shall be subject to a new risk assessment. Hence, this requirement was also valid for titanium dioxide as most commonly used colourant in pharmaceutical products.

The European Food Safety Authority (EFSA) published the scientific opinion "Safety assessment of titanium dioxide (E171) as a food additive" on 6 May 2021. In this opinion the authority concludes that a genotoxic potential cannot be excluded for titanium dioxide. On request of the European Commission the EMA provided a scientific analysis on the use or avoidance of titanium dioxide in medicinal products on 8 September 2021. In this opinion the EMA recommends that titanium dioxide remains for the time being on the list of authorised additives to avoid shortages of medicinal products and hence a threat to the public health. Such a critical situation would arise if the replacement of titanium dioxide by means of alternative excipients requiring comprehensive and time-intensive testing of the medicinal products as regards quality, safety and efficacy would have to be carried out immediately.

Commission Regulation (EU) 2022/63 amending Annexes II and III to Regulation (EC) No 1333/2008 was published in the Official Journal of the European Union on 18 January 2022. Annex II supplements indications for the ban of titanium dioxide in certain food categories as well as its continued inclusion in the list of substances authorised for the use in medicinal products. The Regulation also places the obligation on the European Commission to evaluate within three years of the date of entering into force of the Regulation the necessity to maintain the authorisation of titanium dioxide or to delete it from the list of Regulation (EC) No 1333/2008. This review should be based on an updated assessment of the EMA to be performed before 1 April 2024.

Despite the provisional authorisation of titanium dioxide in the pharmaceutical sector the pharmaceutical industry is called to search for alternatives for titanium dioxide and to check their use. The guidance consisting of five questions and answers "Replacement/removal of titanium dioxide (TiO2) in medicines. Technical and procedural guidance" is supposed to assist marketing authorisation holders and applicants in this regard.

The following is a summary of the answers to the questions.

1. What does Commission Regulation (EU) 2022/63 on TiO2 mean for pharmaceutical companies developing and/or maintaining an authorisation of medicines for human and veterinary use?

The answer to this question contains (as was already described above in the section "Background") a short chronological summary of what led to the ban of titanium dioxide in food. It concludes with the call to the pharmaceutical industry to make all possible efforts to accelerate the research and development concerning the replacement of titanium dioxide in both new and already authorised products.

2. What should I do if I am an applicant of a new MAA that contains TiO2?

In case the medicinal product is in the development stage or the application for a marketing authorisation is close to submission titanium dioxide must not be replaced. However, if applicants decide to replace or remove titanium dioxide, this should either be done prior to applying for marketing authorisation or directly after marketing authorisation is granted via a variation procedure but not during an on-going marketing authorisation procedure. Replacing or removing the titanium dioxide will require new product formulations to be developed. For this the requirements according to the Note for Guidance on development pharmaceutics (CPMP/QWP/155/96) or the Note for Guidance on Development pharmaceutics for veterinary medicinal products (EMEA/CVPM/315/98) have to be observed. In cases where a novel excipient is used, full details of the manufacture, characterisation and relevant safety data should be provided.

3. What should I do if I am an MAH of a MA containing TiO2?

The answer to this question refers to the explanations to the questions 2 and 4 and repeats the request to make all possible efforts to accelerate the research and development of alternatives for titanium dioxide. In this context it is furthermore called for an enhanced cooperation between the different manufacturers.

4. What are the scientific data requirements to remove/replace TiO2?

It is distinguished between two cases:

• Titanium dioxide is incorporated only to improve the appearance of the medicinal product and can be deleted in the formulation.
  In this case it is sufficient to compare the dissolution profile of the new product formulation with the profile of the product in the old composition. Furthermore, stability studies according to the ICH/VICH Guidelines are required.
• Titanium dioxide is replaced with another recipient.
  In this case numerous data must be submitted, such as
  - studies to demonstrate the compatibility of the new excipient with the active substance and any other excipients in the formulation
  - bioequivalence studies
  - data to demonstrate that the new excipient does not interfere with the finished product specification test methods
  - where the medicinal product is sensitive to light, and titanium dioxide has so far protected against light, proof that precautions have been taken to preserve the quality of the medicinal product (such as change of the primary container)
  - demonstration that the differentiation between strengths is not affected and no negative impact on taste acceptability occurs.

5. What are the regulatory pathways to support a change in excipient to remove/replace TiO2?

The very detailed answer to this question is formulated separately for human medicinal products and for veterinary medicinal products. Central document (for human medicinal products) is the Regulation (EC) No 1234/2008 (Variations Guideline). The categories of variations for a change of the excipient in the finished product described in this Regulation have to be observed. Furthermore, other variations may be necessary as a consequence of implementing the excipient change, such as changes

• in the shape or dimensions of the product 
• in the analytical test for the finished product 
• in the finished product specification 
• to the manufacturing process and in-process controls 
• in the packaging of the finished product 
• in product shelf life and storage conditions.

The categorisation of these variations has to be carried out according to the Variations Guideline. All variations should be submitted together as a grouped variation. Work-sharing and collaboration among marketing authorisation holders and national competent authorities should be explored.