European Medicines Agency (EMA) has published Questions and Answers related to the technical and procedural replacement/removal of titanium dioxide (TiO₂) in medicinal products for human and veterinary use.

Questions and Answers address the following topics:

• meaning of Commission Regulation (EU) 2022/63 on TiO₂ for pharmaceutical manufacturers of medicinal products for human and veterinary use;
• guidance for applicants of a new MAA that contains TiO₂;
• guidance for MAH’s of a MA containing TiO₂;
• scientific data requirements to remove/replace TiO₂;
• regulatory pathways to support a change in excipients to remove/replace TiO₂ in medicinal products.

Billev Pharma East can support you

• during the research and development of alternatives to replace TiO₂ (literature review, preformulation studies, compatibility, and stability studies)
• during revaluation of manufacturing process and analytical procedures  
• with the evaluation of performance of reformulated medicinal products (evaluation of dissolution and bioequivalence results)
• during the compilation of registration dossiers (variation classification, amendment of the relevant sections of the dossier, application submission, alignment with regulatory agencies)

Commission Regulation (EU) 2022/63 of 14 January 2022 amending Annexes II and III to Regulation (EC) No 1333/2008 of the European Parliament and of the Council as regards the food additive titanium dioxide (the Regulation) entered into force following its publication in the Official Journal of the European Union on 18^th January 2022. The Regulation foresees titanium dioxide (TiO₂) remains for the time being on the list of authorised additives to allow its use in medicinal products as a colourant. One of the reasons for that decision is to avoid shortages of medicinal products containing (TiO₂) as this could impact public health and animal health and welfare. The replacement of TiO₂ requires investigation and testing of suitable alternatives to ensure that quality, safety, and efficacy of medicines are not negatively affected. The Regulation is applicable to all medicinal products containing TiO₂ independent of its pharmaceutical form.

The Regulation also foresees a review clause after three years, meaning that the Commission will re-evaluate the situation within 3 years of the date of entering into force of the Regulation, based on an updated assessment by the EMA which is to be provided by April 2024. It further calls on the pharmaceutical industry to make all possible efforts to accelerate the research and development of alternatives and to replace TiO₂ in both new and already authorised medicinal products.

In May 2021, European Food safety Authority (EFSA) published a scientific opinion on the Safety assessment of titanium dioxide (TiO₂) as a food additive, which concluded that based on all evidence available, a concern for genotoxicity could not be ruled out. In the same month, the European Commission (EC) requested EMA to provide an analysis with the aim to define the technical purpose of TiO₂ in medicinal products, feasibility of alternatives to replace it without negative impacting the quality, safety, and efficacy of medicines and if confirmed, considerations to be taken into account to define a transition period for phasing out this excipient. To support the analysis, the Agency was asked to seek the input from industry stakeholders. Response of the three European associations representing the human medicines manufacturers (AESGP, EFPIA, Medicines for Europe) Use of titanium dioxide as excipient in human medicines as feedback to the Quality Working Party (QWP) of EMA in relation to the opinion of European Food Safety Agency (EFSA) on Titanium Dioxide (TiO₂) as food additive (E171) and its impact on human and veterinary medicinal products was submitted in July 2021. Final feedback from European Medicine Agency (EMA) to the EU Commission request to evaluate the impact of the removal of titanium dioxide from the list of authorised food additives on medicinal products was issued in September 2021.

Considering the scale of the use of this excipient, the time and costs involved in the reformulation and the volume of products impacted, it is considered that any requirement to replace TiO₂ in medicines will certainly cause significant medicines shortages and discontinuations/withdrawals of medicines from the EU/EEA market with major implications for patients and animals. Particular concerns arise in relation to certain vulnerable classes/types of products such as paediatric medicines, orphan medicines, low sales volume products, bee products, etc.). The data requirements when replacing an excipient are elaborated in the Note for Guidance on development pharmaceutics (CPMP/QWP/155/96) and in the Note for Guidance on Development pharmaceutics for veterinary medicinal products (EMEA/CVMP/315/98). These guidelines state that the choice and characteristics of an excipient should be justified with respect to its purpose in the medicine and that the quality of the excipient should be guided by its role in the formulation and the proposed manufacturing process. In cases where a novel excipient is used (i.e. an excipient used for the first time in a finished product, or via a new route of administration in the EU), full details of the manufacture, characterisation and relevant safety data should be provided. Industry estimates for reformulation of individual products vary from 3 to 5 years and regulatory estimates to approve individual changes are 3 months to 1 year. Taking these timeframes and the volume of products involved into account, the industry estimates of 7-12 years are not considered unreasonable.

What is titanium dioxide?

• TiO₂ is listed in European Pharmacopeia as a white or almost white powder, practically insoluble in water and does not dissolve in dilute mineral acids. It is a simple chemical substance and is widely available.
• Due to its unique combination of physicochemical properties, TiO₂ imparts several highly desirable properties to medicinal products. It is widely used in tablet coatings where it can act to prevent light transmission, moisture absorption and improve opacity. Whilst other excipients can also be used for the same purposes in tablet coatings, where due to its physicochemical properties, TiO₂ enables the application of a thinner, less brittle coat compared to other excipients, thereby imparting all of these desired quality attributes whilst still allowing rapid bioavailability of the actives once the product is ingested.
• TiO₂ is used very frequently in oral solid dosage forms (e.g. tablets, soft capsules, hard capsules, granules/powders for oral solution and oral suspensions), in oral semi-solid dosage forms (e.g. oral paste, oral gel). It is present in many essential medicines for human including antidiabetics, antibiotics and others and several veterinary medicinal products. TiO₂ is also present in dosage forms administered via routes other than oral, e.g., products for cutaneous, inhalation (capsule shells), oro-mucosal, sublingual, transdermal and vaginal use.

Based on the currently available data, no single material has been identified that provides the same combination of properties that are unique to TiO₂. A suitable alternative would have to have similar pharmaceutical properties (opacification, stability, degradation protection) and physicochemical properties (chemically inert) and have an acceptable safety profile. Possible alternatives identified so far include calcium carbonate, talc and starch. A number of disadvantages have been identified with these alternatives (e.g. inability to obtain sufficiently thin films, supply chain issues, mined materials with associated elemental impurity risk). Given the widespread use of TiO₂ in different dosage forms, a single replacement excipient cannot be identified. Each affected medicinal product will need an individual review and assessment, which will require investigation of alternatives, product reformulation, generation of new data related to manufacture, dissolution and stability etc. and potentially new clinical data (e.g. generation of bioequivalence studies). Following aforementioned activities, subsequent approval by way of variation would be required before the reformulated product could be brought to the market.

With respect to the potential impact of the removal of TiO₂ would have on the quality, safety and efficacy of medicines the following potential direct impacts have been identified:

• technical reformulation and manufacturing challenges, potential new analytical methodologies, potential incompatibilities, shorter shelf life at least temporarily until all stability studies are performed.
• potential bioequivalence issues due to changes in formulations (thicker coatings etc.) and unanticipated changes to benefit-risk determinations arising from use of alternatives.
• any new alternative colourants would need to be added to the Food Additives positive list in Regulation 1333/2008.

Way forward

• alternative excipients with similar function’s must be identified and an evaluation conducted of their physicochemical properties and how these may influence the product manufacturability, stability and clinical performance (e.g. bioavailability). A compatibility study to demonstrate the compatibility of the new excipient with the active substance(s) and any other excipients in the formulation must be conducted;
• once compatibility is demonstrated, prototype formulations need to be prepared and an evaluation made of whether the change’s has any impact on the finished product quality and  manufacturability. The results from these investigations are taken into consideration to select the prototype(s) formulations for further development and the need for further changes evaluated (e.g. optimization of the quantity of the excipients, or replacement by other excipients);
• evaluation of performance (dissolution, bioavailability) of the selected prototype’s; for some products bioequivalence studies need to be performed.
• Manufacturing process re-evaluation vis-à-vis the introduced formulation changes and the necessary technology transfer (scale up), including process validation are the next steps;
• The analytical methods (QC methods, in-process controls) will have to be adjusted or replaced and validated in order to ensure their suitability for use with the new composition;
• Finally, stability studies of the new formulation need to be conducted to support the changes to
• the product composition (and possibly to the manufacturing process) and to establish the appropriate shelf life for the new formulation;
• From the regulatory point of view, the EC variation classification guideline includes a classification for such a change (B.II.a.3). The conditions and documentation to be supplied differ depending of the type of change, type of product, role of the excipient in the formulation and the potential impact of the proposed change to the quality/safety/efficacy of the product.
• In addition to the main variation change required, i.e. B.II.a.3. change in the composition (excipients) of the finished product, for coated tablets and capsules, it is likely that variation B.II.a.4 “Change in coating weight of oral dosage forms or change in weight of capsule shells” may also be required. This change may be a type IA, IB or II, depending on the type of product and fulfilment of the guideline conditions.