EMA’s Feedback: On Replacing Titanium Dioxide (TiO₂) in Medicinal Products: Critical Challenges, Limited Alternatives (Human & Veterneary)

Sharan Murugan
Aug 6
3 min read

The European Medicines Agency (EMA) submitted its updated report to the European Commission (EC) evaluating the feasibility of replacing titanium dioxide (TiO₂) in medicinal products. This request came in light of the Regulation (EU) 2022/63, which set a provisional timeline and prompted a review by February 2025.

Background & Regulatory Context

Titanium Dioxide (TiO₂) is widely used in medicines—over 91,000 human and 1,600 veterinary products across the EU include it. TiO₂ plays essential roles such as:

Providing opacity to protect from light degradation
Ensuring product uniformity
Enhancing shelf life
Facilitating coating consistency and dissolution

TiO₂ remains provisionally authorised in EU medicines due to concerns about immediate shortages if withdrawn.

The 2021 EMA report led to continued authorisation specifically to prevent disruptions to medicine supply.

The EMA’s latest (2024) review was performed at the EC’s request and with deep industry engagement, re-considering alternatives, technical feasibility, and the impact on public health. Titanium dioxide (TiO₂) is under scrutiny for replacement in medicinal products due to rising safety and regulatory concerns, particularly in the European Union. Here are the main reasons driving this trend:

Why TiO₂ Needs to Be Replaced

Reason	Details
Genotoxicity concerns	Inability to rule out DNA damage risk
Carcinogenicity (inhalation)	Classified as possible human carcinogen by IARC
EU regulatory bans and reviews	Banned as food additive; pharmaceuticals under scrutiny
Precautionary principle	Move to minimize uncertain risks
Pressure for harmonization	Align food and medicine excipient regulation in EU
Voluntary reformulation trend	Some companies proactively replacing TiO₂
Patient acceptance	Growing skepticism about TiO₂-containing drugs

In essence, TiO₂ is targeted for replacement due to regulatory, scientific, and perception-driven risks—despite the technical challenges involved.

Key Challenges Identified by EMA

Feasibility of Substitution: Current data show that less than 5% of medicinal products could be feasibly reformulated without TiO₂. In most products, TiO₂ is technically essential to maintain quality, efficacy, and safety.
Alternatives Tested: Industry explored over 20 potential excipients. However, none matched TiO₂’s performance. Issues included poor light protection, inconsistent color, and manufacturability limitations.
Manufacturing Burden: Reformulation would increase processing times, require major investment in coating equipment, and raise costs substantially.
Shelf-Life & Safety Risks: Alternative coatings provided inferior photostability, which may lead to degradation of light-sensitive APIs, requiring stronger packaging or reduced shelf life.

Timelines:

For a simple, low-risk reformulation: ~3 years/prod. (immediate-release tablet, minimal changes, no bioequivalence studies)
Complex or high-risk reformulation: ~5 years/prod. (needs light-protection, modified/controlled-release, coloured coatings, bioequivalence, or toxicology data on the excipient)
A typical company: Will need 7–12 years to reformulate their portfolio—longer for larger entities.
A full transition in Europe: Estimated >12 years, even under ideal conditions due to concurrent regulatory and manufacturing constraints.

Summary Table: TiO₂ vs Common Alternative Options

Attribute	Titanium Dioxide (TiO₂)	CaCO₃ / Fe₂O₃ / HPMC / PVA (Alternatives)
Opacity/Photoprotection	High	Lower; thicker coatings needed
Colour uniformity	Excellent	Poor, especially for coloured products
Manufacturability	Predictable, robust	Higher variability, slower process, increased complexity
Shelf-life	Optimized	Often shorter due to less effective light protection
Patient adherence	High (easy identification)	Lower (colour changes, product confusion possible)
Regulatory status	Global acceptance	Variable; Fe₂O₃ limited intake, not globally approved
Technical risk	Low	High – more excipients, risk of instability

Consequences of TiO₂ Removal

Regulatory Overload: Reformulating every TiO₂-containing product would trigger massive post-approval variation filings and regulatory bottlenecks.
Product Shortages: A rushed or mandatory ban on TiO₂ could lead to withdrawal or unavailability of numerous medicines in the EU.
Long Transition Timelines: Even under optimal conditions, 4–6 years would be needed to reformulate each product, with a total transition period exceeding 12 years for entire portfolios.