Titanium dioxide is classified as a second-class carcinogen, and EMA issued a statement on alternative materials for tablet coatings and capsule shells!

An assessment by the European Food Safety Agency (EFSA) in May 2021 revealed the possibility of genotoxicity of titanium dioxide (TiO2 ; CAS 13463-67-7) .

EMA on the subsequent request of the European Commission will delete titanium dioxide impact of drugs from the list of approved food additives feedback:

The summary is as follows:

Titanium dioxide(TiO2) is extensively used as an opacifier and colourant in medicines due

Titanium dioxide (TiO2) is widely used as an opaque agent and coloring agent in medicine due to its multiple functions

TiO2 is used very frequently in oral solid dosage forms (eg tablets,soft capsules, hard capsules, granules/powders for oral solution and oralsuspensions), in oral semi-solid dosage forms (eg oral paste, oral gel).

TiO2 is commonly used in oral solid preparations (such as tablets, soft capsules, hard capsules, granules/powders for oral solutions and oral suspensions), and oral semi-solid preparations (such as oral ointments, oral gels)

To date, no singlematerial has been identified that provides the same combination of properties that are unique to TiO2 (eg opacity,enhancing contrast, inertness, protection from UV light and the finish/smoothness of the resulting product).

So far, no single substance has been found to provide the unique combination of TiO2 attributes (such as opacity, enhanced contrast, inertness, UV protection and the resulting smoothness of the product)

Possiblealternatives identified so far include calcium carbonate, talc and starch.

Possible alternatives identified so far include calcium carbonate, talc and starch

The feasibility ofreplacing TiO2 cannot be confirmed at this stage.

The feasibility of replacing TiO2 cannot be confirmed at this stage

The direct and indirect impacts on medicines for human and veterinary use are expected to be aggravated in the scenario, where Europe would be the onlyregion globally to ban TiO2 as excipient in medicines, which would requireindustry to develop new formulations for the majority of oral solid doseproducts potentially for the EU only, with titanium dioxide continuing to beused in the majority of medicines globally.

Under this circumstance, the direct and indirect impact on human and veterinary drugs is expected to intensify.
Europe will become the only region in the world that bans TiO2 as pharmaceutical excipients.
This will require the industry to consider the majority of oral drugs that may only target the EU.
New formulations of solid preparation products are developed, and titanium dioxide continues to be used in most drugs worldwide
.

An transition period for phasing-out TiO2 in all or specificuses 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 acceptable studies required, to be followed by the necessary regulatory procedures forassessment and approval.

It is currently difficult to imagine or estimate all or specific acceptable transition periods for phasing out TiO2 in drugs covered by colorants
.
Depending on the required formulation and research level, the time required for each product may be several years, and then the necessary regulatory procedures need to be developed for evaluation and approval
.

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 salesvolume products, bee products, etc.
).

Taking into account the scale of use of this prescient need, the time and cost involved in the reformulation, and the number of products affected, we believe that any requirement to replace TiO2 in medicines will almost certainly cause a serious shortage of medicines and cause medicines to change from The EU/EEA market is discontinued/exited, which has a significant impact on patients and animals
.
Certain fragile products, such as pediatric drugs, orphan drugs, low-volume products, and bee products, are of particular concern
.

EMA stated that many manufacturers are working to develop TiO2-free formulations, including:

Tablet coatings

Tablet coating

Coating suppliers have developed titaniumdioxide free coating range.
However, these are not currently widely used and there is therefore limited information available regarding their generalsuitability for use.

The coating supplier has developed a titanium dioxide-free coating series
.
However, these are not currently in widespread use, and therefore, there is limited information about their general suitability for use
.

Capsule shells

Capsule shell

Titanium dioxide free capsule alternatives are available.

Capsule substitutes without titanium dioxide are now available
.