EMA – Concern on the safety of titanium dioxide could result in reformulation of drug products in Europe (updated on August 10, 2022)
Since 2020, titanium dioxide (TiO2) has been the subject of concern about its safety for use as a food additive in Europe. In May 2021, an assessment by the European Food Safety Authority (EFSA) concluded that issues related to the genotoxicity of titanium dioxide particles could not be ruled out and it can no longer be considered safe when used as a food additive.
Although EFSA’s opinion affected directly only foods, this issue raised discussions about the use of titanium dioxide in other products, including medicines, as it is extensively used as an opacifier and colorant in medicines, especially in solid and semi-solid dosage forms.
On May 17, 2021, the European Commission (EC) requested the European Medicines Agency (EMA) to provide an analysis aiming to define the technical purpose of titanium dioxide in medicinal products; the feasibility of alternatives to replace it without negatively 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 requested to seek input from industry stakeholders and provided a list of questions that were answered by Human Industry trade associations (AESPG, EFPIA, and Medicine for Europe). These answers were evaluated and compiled by a team composed of experts from the Quality Working Party (QWP), relevant EMA departments, and committees, and resulted in the Report called “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 authorized food additives on medicinal products”.
In this Report, it is possible to see that associations mentioned that several open questions need to be answered in order to inform the assessment of the benefit/risk profile of the presence of TiO2 in medicines. Possibly, the main one is the potential for any prohibition on the use of TiO2 to affect the availability of drug products in the EU.
Also, according to EMA’s final report, given a large number of impacted products, it will not be possible to perform the assessment for all products simultaneously and the definition of a prioritization list of product reformulations will be necessary. This will increase the overall time needed for implementation. Prioritization by the Pharmaceutical industry is likely to be focused on high-volume products, and not necessarily on products for medical needs and there is currently no mechanism available for regulators to dictate the priority of products to be reformulated.
As a result, the industry estimates the deadline from 3 to 5 years to reformulate individual products and from 3 months to 1 year for approval of individual changes by the Sanitary Authority. Considering these timeframes and the volume of products involved, estimates from 7 to 12 years are not considered unreasonable. Therefore, the QWP concluded that a transition period of 10 years or even longer would be necessary for the elimination of TiO2 in drug products.
The alternatives proposed by EMA for reformulating the products include replacing titanium dioxide with calcium carbonate, talc, or starch, however, the agency has identified a series of deficiencies associated with the excipients. Deficiencies include the inability to obtain sufficiently thin films, supply chain problems, extracted materials with associated elemental impurity risks, among others.
The lack of an identical replacement for TiO2 means that “each affected drug product will need an individual review and evaluation, which will require investigation of alternatives, product reformulation, generation of new data related to manufacturing, dissolution, stability, etc. and potentially new clinical data”, concluded EMA. This work will need to consider the approximately 91,000 medicines for human use that contain the excipient.
Due to the time and costs associated with reformulation, EMA anticipates that the request to eliminate TiO2 would cause significant shortages and withdrawals for some products or classes considered “vulnerable”, such as orphan drugs, pediatric drugs, and other low-volume pharmaceuticals, which would be particularly affected. EMA warned that the impact will be “aggravated” if the European Union is the only region to ban TiO2, as the cost of reformulation could only be recovered in one part of the world.
In July 2022, the authority EMA published on its website a Q&A section related to the replacement/removal of titanium dioxide in human and veterinary medicines. Find below a summary of the published questions/answers:
1. What does Commission Regulation (EU) 2022/63 on TiO2 mean for pharmaceutical companies developing and/or maintaining an authorization of medicines for human and veterinary use?
The Regulation foresees that TiO2 remains for the time being on the list of authorized additives to allow its use in medicinal products as a colorant, in order to avoid shortages that could impact public health, since the replacement requires investigation and testing of suitable alternatives. However, the regulation provides a review clause after 3 years of entering into force and the companies should already accelerate the Research and Development in order to provide alternatives to the excipient in both new and already authorized products.
2. What should I do if I am an applicant of a new MAA that contains TiO2?
If the applicant has submitted the MA application or is close to submitting it, for the time being, the drug product composition may include TiO2. If applicants decide to replace or remove TiO2, this should either be done prior to applying for marketing authorization or via a variation procedure (i.e. after marketing authorization is granted), but not during an ongoing marketing authorization procedure. It is important to mention that changes in the composition of medicines to replace/remove TiO2 will require new formulations to be developed, and the impact of this change on the product should be properly assessed.
3. What should I do if I am a MAH of a MA containing TiO2?
MAAs and MAHs are reminded to make all possible efforts to accelerate the research and development of alternatives and to replace TiO2 in their authorized products. Therefore, it is essential that manufacturers collaborate with each other regarding research and development of alternatives for replacement, especially when it comes to replacing TiO2 for similar products.
4. What are the scientific requirements to remove/replace TiO2?
Scientific data requirements to support a change in excipient(s) to remove or replace TiO2 vary between products and depend on the function of TiO2 in the individual medicine. Each medicinal product will need an individual review and assessment, which will require investigation of alternatives, reformulation, generation of new quality data (e.g., related to manufacture, dissolution, stability etc.), and potentially new clinical data (e.g., new bioequivalence studies).
5. What are the regulatory pathways to support a change in excipients to remove/replace TiO2 in medicinal products?
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 on the type of change, type of product, and the potential impact of the proposed change to the quality, safety, and efficacy of the product. However, other changes may also be associated and should be submitted together as a grouped variation. Work-sharing and collaboration among marketing authorization holders and national competent authorities should be explored.
Access the Q&A section through the link: https://bit.ly/3SzttjY (updated on August 10, 2022)
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