Euro Roundup: EMA warns action against titanium dioxide will cause significant drug shortages

RoundupsRoundups | 14 October 2021 |  By 

The European Medicines Agency (EMA) has found that requiring manufacturers to replace titanium dioxide (TiO2) in medicines “will almost certainly cause significant medicines shortages and discontinuations/withdrawals ... with major implications for patients and animals.”
EMA investigated the impact of phasing out the use of the excipient at the request of the European Commission. The Commission’s request was triggered by a European Food Safety Authority (EFSA) recommendation that TiO2 is no longer considered safe when used as a food additive. EFSA reached the conclusion after finding it is impossible to rule out genotoxicity based on the current evidence. In light of the EFSA opinion, the Commission wanted to know why TiO2 is used and whether it can be replaced.
The final feedback from EMA suggests it will be hard for the industry to move away from TiO2. As EMA explains, the excipient is used “very frequently” in oral solid and semi-solid dosage forms as an opacifier and colorant, including in “many essential medicines” such as antidiabetics and antibiotics. EMA found no single material that offers the same combination of properties as TiO2.
Alternatives proposed by EMA include calcium carbonate, talc and starch but the agency identified a number of shortcomings associated with the excipients. The shortcomings include the inability to obtain sufficiently thin films, supply chain issues, mined materials with associated elemental impurity risks.
The lack of a like-for-like replacement for TiO2 means, “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,” EMA found. That work will need to happen for the approximately 91,000 human drugs that contain the excipient.
“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,” EMA concluded. EMA’s Quality Working Party found a transition period of 10 years or more would be needed.
Given the time and cost associated with reformulation, EMA anticipates a request to phase out TiO2 would cause significant shortages and withdrawals, with vulnerable types of products such as orphan drugs, pediatric medicines and other low-volume pharmaceuticals being particularly affected. EMA warned the impact will be “aggravated” if the European Union is the only region to ban TiO2 as the costs of reformulation could only be recouped in one part of the world.
EMA Report
EU health committee votes for EMA to develop drug shortage early warning system
Members of the European Parliament’s health committee have voted overwhelmingly for a package of pharmaceutical reforms that include a requirement for EMA to establish an early warning system for drug shortages.
The Committee on the Environment, Public Health and Food Safety (ENVI) considered the future of pharmaceutical policy in the EU as part of the reform agenda initiated by the Commission late last year. Responding to the Commission’s pharmaceutical strategy, ENVI’s rapporteur released a draft set of proposals earlier this year. ENVI members voted on a long list of amendments this week before holding a final vote on the report, which passed by 62 votes to 8, with 8 abstentions. 
Key recommendations of the report include steps to address the root causes of drug shortages. ENVI wants EMA, the Commission and member states to develop an early warning system “based on a transparent and centralized digital European platform.” Other recommendations include promotion of “Made in Europe” pharmaceuticals, the development of “adequate capacity for the sustainable production of active substances” and the launch of large clinical trials coordinated at the EU level.
Members of the European Parliament are set to vote on the report next month. The position taken by the Parliament will inform the Commission’s proposals for the reform of EU pharmaceutical law next year.
Press Release
‘Dramatic improvement’ in clinical trial reporting by leading EU research institutes
Leading research institutes in the EU have achieved a “dramatic improvement” in their clinical trial data reporting rates, according to a report by groups including TranspariMED.
EU guidelines have required clinical trial sponsors to publish results on a registry within 12 months of completing a study since 2014. However, earlier assessments found low reporting rates at large EU academic research institutes. With national regulatory agencies gaining the power to impose sanctions early next year, TranspariMED and its collaborators took another look at reporting rates.
The review found 21 of the 26 assessed institutes “are now clearly working to clear their backlogs of missing results.” Many results are still missing, with 28% of the due datasets being reported, but the trend is positive at all bar a handful of research centers in Italy and the Netherlands.
Medical University Vienna has uploaded 96% of its due trial results and multiple other institutes are more than half way to clearing their backlogs of unreported studies. The five centers that are yet to tackle their backlogs only uploaded a single trial result from May to August 2021.
It is unclear whether national authorities will use their powers to punish sponsors for late reporting. The Danish Medicines Agency has vowed to make use of the new powers but its peers are yet to set out their plans.
Transparency Report
EMA executes slimmed-down work plan despite allocating 9% of staff to COVID-19
EMA allocated almost 10% of its workforce to the COVID-19 pandemic over the first half of the year. The remaining staff were largely able to execute a slimmed-down work plan, although some annual actions were delayed or suspended.
When the pandemic hit, EMA mobilized 40 full-time equivalents (FTEs) to respond to the crisis. The team has almost doubled in size since then, with 79 FTEs, equal to almost 9% of EMA’s workforce, focusing on the pandemic response in the first half of 2021. EMA’s expansion covers a time in which vaccines have come to market and driven a surge in adverse event reports.
The agency expected a heavy workload related to the crisis going into 2021, leading it to trim its plans for activities beyond COVID-19, for example by stopping the work on the publication of clinical data for non-pandemic products. Even so, EMA still missed some of its shortened list of objectives.
EMA has been more active than expected in some areas. The number of individual case safety reports for centrally authorized products is now forecast to top the initial projection by 57%, giving EMA almost 1 million more submissions to process. EMA now expects to conduct 220% more good manufacturing practice inspections than originally targeted, bringing 2021 in line with earlier years.
EMA Report
Other News:
Roche has applied for EMA approval of its anti-SARS-CoV-2 antibody combination. The candidate, which originated at Regeneron, is already in use in the US. EMA could decide whether to authorize the product in the treatment of certain adults and adolescents with COVID-19 within two months as it has already assessed some data as part of a rolling review. EMA Notice
The Dutch Medicines Evaluation Board (MEB) is keeping its veterinary fees unchanged ahead of the move to a new regulatory framework next year. MEB Notice


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