In September 2021, the European Medicines Agency (EMA) provided final feedback was provided to the European Commission (EC) on its request to evaluate the impact of the removal of titanium dioxide from the list of authorised food additives in medicinal products.
It is worthwhile reading the entire feedback document if only to appreciate the complexity of such a change.
About titanium dioxide
Titanium dioxide (E 171) is authorised as a food additive in the EU according to Annex II of Regulation (EC) No 1333/2008. Historically, there is a legislative link allowing the use of colourants listed in Annex II to Regulation(EC) No 1333/2008 in human and veterinary medicinal products without further justification.
Due to its opacity, whiteness, chemical inertness, and the protection it provides from UV light, titanium dioxide (TiO2) is a widely used excipient in pharmaceuticals. TiO2 is odourless and tasteless, and as such has no negative impact on palatability.
Timeline of deliberations concerning TiO2
The safety of the food additive TiO2 (or E171) was re-evaluated by the European Food Safety Authority (EFSA) ANS Panel in 2016 under Regulation (EU) No 257/2010, as part of the re-evaluation programme for food additives authorised in the EU before 20 January 2009.
In its 2016 opinion, the ANS Panel recommended new studies be carried out to fill the gaps on possible effects on the reproductive system, which could enable them to set an Acceptable Daily Intake (ADI). Uncertainty around the characterisation of the material used as the food additive (E 171) was also highlighted, in particular with respect to particle size and particle size distribution of titanium dioxide used as E 171.
EFSA statement on review performed by ANSES
In 2019, EFSA published a statement on the review of the risk related to the exposure to food additive titanium dioxide (E171) performed by the French Agency for Food, Environment and Occupational Health Safety (ANSES).
In its statement, EFSA highlighted that the ANSES opinion reiterated the uncertainties and data gaps previously identified by EFSA and did not present findings that invalidated the Authority’s previous conclusions on the safety of titanium dioxide.
Netherlands NVWA opinion
In 2019, the Netherlands Food and Consumer Product Safety Authority (NVWA) also delivered an opinion on possible health effects of food additive titanium dioxide, which highlighted the importance of examining immunotoxicological effects in addition to potential reprotoxicological effects.
EFSA opinion on the safety of TiO2
On 6 May 2021, the European Food Safety Authority (EFSA) published its opinion on the safety of food additive Titanium dioxide (TiO2), recommending that on the basis of all currently available evidence along with all uncertainties, in particular the fact that genotoxicity could not be ruled out, TiO2 can no longer be considered as safe when used as a food additive.
EC request to EMA to provide an analysis on TiO2
On 17 May 2021, the European Commission (EC) requested the 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.
A group composed of Quality Working Party (QWP) experts and relevant EMA departments and Committees prepared the responses to the EC request.
The following questions were addressed:
- Question 1: Define the technical purpose of TiO2 in medicinal products, the scope, and the functions of TiO2
- Question 2: Feasibility of alternatives to replace TiO2 if at all possible, without impacting negatively the quality, safety and efficacy of medicines.
- Question 3: If the feasibility is confirmed, consideration to be taken into account 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.
EMA feedback to the EC
Below is a snapshot of the of the responses/feedback (to the questions) provided by the EMA to the EC.
Titanium dioxide (TiO2) Uses
Titanium dioxide is:
- extensively used as an opacifier and colourant in medicines due to its multiple functionalities.
- 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).
- 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), oromucosal, sublingual, transdermal and vaginal use.
Identification of alternatives that that provides the same combination of properties that are unique to TiO2
- To date, no single material has been identified (e.g. opacity, enhancing contrast, inertness, protection from UV light and the finish/smoothness of the resulting product).
- Separating out the different functionalities of TiO2 for those medicinal products in which it serves more than one function is difficult or might not be possible at all.
- 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).
Feasibility of replacing TiO2
- The feasibility of replacing TiO2 cannot be confirmed at this stage.
- 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), which subsequently will all have to be assessed by the national competent authorities and EMA.
Potential impacts on medicines for human use from banning the use of TiO2 as an excipient in medicines in Europe only
The direct and indirect impacts on medicines for human use are expected to be aggravated in the scenario, where Europe would be the only region globally to ban TiO2 as excipient in medicines, which would require industry to develop new formulations for the majority of oral solid dose products potentially for the EU only, with TiO2 continuing to be used in the majority of medicines globally.
Is there an acceptable transition period for phasing out TiO2 in all or specific uses in medicines?
An acceptable transition period for phasing-out TiO2 in all or specific uses in medicines covered by the scope of colouring matters is currently difficult to envisage or estimate. The time needed to reformulate each individual product could be several years depending on the level of formulation and studies required, to be followed by the necessary regulatory procedures for assessment and approval.
Scope for medicines shortages if reformulation of products is undertaken to replace TiO2
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 almost 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.