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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.
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 procedurebut 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.
What is the EU guidance on titanium dioxide? ›
(12) In light of the conclusion of the 2021 Authority's opinion about the safety of titanium dioxide (E 171) when used as a food additive, it is appropriate to remove the authorisation to use titanium dioxide (E 171) in foods. Accordingly, titanium dioxide (E 171) may no longer be used in foods.What medications have titanium dioxide? ›
- Amoxicillin Trihydrate 500mg.
- Amoxicillin trihydrate 500 mg.
- Amphetamine and Dextroamphetamine Extended Release 20 mg.
- Cephalexin 500 mg.
- Cetirizine Hydrochloride 10 mg.
- Cyclobenzaprine Hydrochloride 10 mg.
- Cyclobenzaprine Hydrochloride 10 mg.
- Cyclobenzaprine Hydrochloride 10 mg.
TiO2 is monographed in the European Pharmacopoeia and is considered to be suitable for use in the medicinal products as an excipient. Due to its unique combination of physicochemical properties, TiO2 imparts several highly desirable properties to medicinal products.What are the side effects of titanium dioxide? ›
The following acute (short-term) health effects may occur immediately or shortly after exposure to Titanium Dioxide: ► Exposure can irritate the eyes, nose and throat. since it has been shown to cause lung cancer in animals. a carcinogen.Why is titanium dioxide banned in EU? ›
EU nations are generally not allowed to set food safety standards that affect international trade on an individual basis. The concern with titanium dioxide centers on its tendency to break into nanoparticles that can accumulate in the lungs and elsewhere in the body.When was titanium dioxide declared a carcinogen? ›
In 2016, French authorities submitted a proposal to the European Chemicals Agency (ECHA) to classify titanium dioxide as a carcinogenic substance.What does titanium dioxide do to the brain? ›
This study revealed that titanium dioxide nanoparticles are neurotoxic as expressed by histological alterations, reduced cell viability, reduced acetylcholine esterase activity and induced oxidative stress by reducing glutathione activity in male Sprague Dawley rats.Does Tylenol contain titanium dioxide? ›
Tylenol Extra Strength, Rapid Release Gel, and other products contain titanium dioxide, which enhances the whiteness of paint, plastics, paper products, and certain foods and drugs, Valerie Morrison alleges in a suit filed Monday in the US District Court for the Southern District of California.What is the generic name for titanium dioxide? ›
Titanium dioxide, also known as titanium(IV) oxide or titania , is the inorganic compound with the chemical formula TiO2. When used as a pigment, it is called titanium white, Pigment White 6 (PW6), or CI 77891.Why do they put titanium dioxide in pills? ›
Titanium dioxide is an FDA approved food coloring agent commonly added to pills to make them white. Although only very small amounts are used in supplements (less than 1% of the formulation) animal studies have raised concerns that it could be carcinogenic and adversely affect the immune system and digestive tract.
Why do they put titanium dioxide in vitamins? ›
Titanium dioxide, a common non-active ingredient in many dietary supplements, is used as a white colorant and color enhancer.Why do they put titanium dioxide in medicine? ›
Thanks to its ability to scatter light and absorb UV rays, TiO2 extends the shelf-life and ensures the stability of pharmaceuticals by protecting the active ingredients against UV/light and heat degradation.Has the EU publishes official regulation on titanium dioxide? ›
All food businesses currently using titanium dioxide as a food additive have a legal responsibility to comply with the requirements of Regulation (EU) 2022/63, banning the use of titanium dioxide.Is titanium dioxide regulated by the EU for cosmetics? ›
The following year, the ECHA's Committee for Risk Assessment (RAC) classified titanium dioxide as a category 2 carcinogen. The European Commission adopted regulation 2020/217 based on this decision from the ECHA, which also classified titanium dioxide as a carcinogen.Is titanium dioxide regulated in the EU for food? ›
14 Sep 2022 --- No longer authorized as a food additive in the EU, titanium dioxide is officially banned across Europe, prompting more companies to innovate alternatives to what was once a key whitening ingredient across multiple food applications.When did Europe ban titanium dioxide? ›
The European Commission is banning titanium dioxide (E171) as a food additive in the EU, starting with a six-month phasing out period as of February 7, 2022, until August 7, 2022, after which a full ban applies.