IPEC is Helping Marshal Expertise Across Stakeholders to Forestall a Potential Titanium Dioxide Ban in Pharmaceuticals

Deeper Dive Workshops Will be Held in June

A deeper dive will be taken into the global regulatory and technical issues surrounding the use of TiO2 in pharmaceuticals and the consequences of trying to replace it at a Product Quality Research Institute (PQRI) hybrid workshop being held in Bethesda, Maryland on June 13-14. The meeting will be chaired by IPEC-Americas Science and Regulatory Policy Vice Chair David Schoneker.

The workshop will begin with an overview of the potential EU ban on TiO2 in pharmaceuticals by representatives from IPEC-Europe and the Titanium Dioxide Manufacturers Association (TDMA).

The first day will then focus on the safety issues involved, with sessions focused on: ● the latest TiO2 genotoxicity and carcinogenicity information, and ● the global assessment of TiO2 safety, with reviews of FDA and other regulator perspectives and their lack of findings of concerns, efforts in the US to ban TiO2 in various states through a color additive petition, and TDMA’s new science program for TiO2.

The day will conclude with parallel breakout small-group discussions on the safety of TiO2 with PQRI’s regulatory members, which include FDA and Health Canada.

Day two sessions will cover: ● TiO2 use and currently available alternatives ● the impact of replacing TiO2 on product quality, resources, and availability, and ● “what could be next” – focusing on the EU concerns around nanoparticles. Perspectives will be given by innovator, generic, and OTC drug companies, CMOs, and suppliers. Participants will then discuss their experiences in evaluating alternatives in breakout groups.

PQRI’S DESCRIPTION OF THE WORKSHOP OBJECTIVE

The objective of this workshop is to bring together material suppliers, the pharmaceutical industry, and regulatory experts to discuss the impact removing titanium dioxide would have along with the benefits and challenges of the alternatives to titanium dioxide for use in solid oral dosage forms. This workshop will address the following key areas:

  • Build awareness for the industry by giving an overview of the issue, an interpretation of the data related to TiO2 safety, and the potential impact a ban on titanium dioxide would have on patients.
  • Overview of what is happening globally because of the EU regulation.
  • Present the technical challenges that pharmaceutical companies are likely facing when trying to formulate new and reformulate existing drug products with the currently available alternatives.
  • Discuss alternatives for oral solids and oral suspensions.
  • Identify areas that need further research to support technical initiatives related to possible additional safety study requirements to support continued safe use of TiO2 or technologies related to the use of TiO2 alternatives where desired.
  • Possible classification of titanium dioxide as something other than a colorant

IPEC Europe is also co-hosting a conference with the International Association for Pharmaceutical Technology (APV) on June 20-21 in Brussels. The focus of this event will be on nanoparticles in excipients and their impact on pharmaceuticals, with particular attention on titanium dioxide and iron oxides.

The conference program notes that the ban on TiO2 as a food additive in Europe has “highlighted the need for a comprehensive understanding of the global regulatory environment regarding the presence of nanoparticles in food additives and excipients.” The meeting will provide updates on the current situation and address technical and regulatory issues in particle size measurement and processing and the performance of TiO2-free tablet coatings and capsules.

 

European Food Safety Authority Updates Opinion on TiO2

In May 2021, the European Food Safety Authority (EFSA) published an updated scientific opinion on the safety of titanium dioxide as a food additive, taking account of new information, including concerns about nanoparticles.

Following its review, EFSA concluded that, “based on all the evidence available, a concern for genotoxicity could not be ruled out, and given the many uncertainties, [titanium dioxide] can no longer be considered as safe when used as a food additive.”

The opinion makes clear that the evaluation is related to the risks of TiO2 being used as a food additive, and not to other uses. Furthermore, EFSA clarifies that “any legislative or regulatory decisions are the responsibility of the risk managers – the European Commission (EC) and EU member states.” [A link to the EFSA opinion is provided below.]

In EU legislation, the use of excipients in a medicinal product is generally evaluated as part of the overall benefit-risk profile of the product. However, for colors, only those that are in the approved list of food additives can be used.

Following the EFSA opinion, the European Commission decided to move forward in removing TiO2 from the list of authorized food additives, and in May 2021 requested EMA to provide a report to the EC on the extent of use of TiO2 in medicines.

EMA Surveys Industry and Highlights Magnitude of Replacement Burden

The aim of the EMA analysis was to: ● define the technical purpose of titanium dioxide in medicinal products ● investigate the feasibility of using alternatives without negatively impacting the quality, safety, and efficacy of medicines, and ● outline considerations to be taken into account to define a transition period for phasing out the excipient.

As part of this analysis, the agency was asked to seek input from industry stakeholders. In July 2021, a joint response for human medicines was provided by the Association of the European Self-Care Industry (AESGP), the European Federation of Pharmaceutical Industries and Associations (EFPIA), and Medicines for Europe. In the same timeframe, Animal Health Europe and the European Group for Generic Veterinary Products provided a combined response for veterinary medicines.

EMA’s report to the Commission was completed in early September 2021, with industry responses provided as annexes.

The 11-page EMA report, compiled by the Quality Working Party (QWP), EMA staff, and its committees, outlines the list of questions sent to the trade associations, summarizes their responses, and provides perspectives and data collected from across the EU regulatory network.

In the Executive Summary (provided below), the agency explains that TiO2 is used extensively for multiple purposes in medicines, including many essential medicines, and that to date, no other material has been identified that serves all the functions of TiO2.

Furthermore, replacing TiO2 would require individual assessment for each product, the report stresses, pointing out that an estimated 91,800 are currently on the EU market, according to industry figures. The implications for regulatory agency resources, lengthy timelines of phasing out the excipient, and potential shortages of medicines are clearly articulated.

EMA’s SUMMARY OF THE IMPACT ON DRUG PRODUCTS OF
DISALLOWING TiO2 USE

Below is the Executive Summary from the September 2021 EMA report to the EU Commission on the impact on pharma of disallowing TiO2 use. Minor formatting changes have been made by IPQ. [Links to the full report and annexes are provided below.]

 

  • Titanium dioxide (TiO2) is extensively used as an opacifier and colourant in medicines due to its multiple functionalities1.
  • TiO2 is 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). It is present in many essential medicines for human [use] 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.
  • To date, no single material has been identified that provides the same combination of properties that are unique to TiO2 (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).
  • 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.
  • 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 only region globally to banTiO2 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 titanium dioxide continuing to be used in the majority of medicines globally.
  • 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.
  • Considering the scale of the use of this excipient, the time and costs involved in their formulation 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.

1 Approximately 91,000 human medicinal products and 800 veterinary medicinal products contain TiO2 in the EU according to EU Trade Associations (see Annex I and II).

 

Industry Questions Justification for Taking on Reformulation Burdens

In the comments submitted in response to the EMA survey, the industry groups stressed the “highly advantageous” formulation characteristics of TiO2, noting that a European Pharmacopoeia monograph exists for TiO2 use as an excipient.

On the feasibility of alternatives to replace TiO2 without impacting negatively the quality, safety, and efficacy of medicines, they pointed out that, to date, no single material equivalent to TiO2 has been identified and that a suitable alternative would have to: ● have similar pharmaceutical properties – for example, opacification, stability, and degradation protection ● be a simple chemical substance that has similar physicochemical properties, including chemical inertness ● be compatible with the other components of the pharmaceutical product, and ● have an acceptable safety profile.

The potential bottlenecks and capacity issues within the EU regulatory network, the EMA report points out, include a likely increase in pre-submission interactions on scientific, regulatory, and procedural aspects at both the national and European level.

In estimating the post-approval workload involved in transitioning away from TiO2, EMA performed an analysis of variation procedures carried out under the centralized procedure for applications between 2018-2020. The analysis, EMA indicated in the report, “clearly demonstrates that a change in excipient is rarely submitted as a low-risk Type 1A variation,” and that variations to replace TiO2 are likely to be submitted as grouped variations “with consequential complexity in the submission and assessment.”

In view of the industry and regulatory reformulation burdens, “resource prioritization should be carefully considered taking into account the regulatory environment and balancing the anticipated benefit with other concurrent issues” – for example, nitrosamines, the COVID-19 pandemic, and challenges or threats at the time. Given these burdens, EMA maintains, a requirement to replace TiO2 will “almost certainly cause significant medicines shortage on the EU market.”

The report acknowledges that industry would likely prioritize high-volume products, and not necessarily products for medical need, and that there is currently no mechanism available to regulators to dictate the priority of products to be reformulated.

 

EC Makes a Temporary Provision for Use of TiO2 in Medicines

In spite of the concerns detailed in the EMA report about the implications for pharmaceuticals, the European Commission went ahead and developed a regulation to remove TiO2 from the list of approved food additives, which came into force in January 2022.

The regulation does allow for a temporary, specific provision for use of the colorant in medicines, pending the development of alternatives or submission of compelling evidence on the lack of feasibility of replacing TiO2.

In the preamble to the regulation, the Commission explains the background to its decision-making, including the rationale for and findings of the European Food Safety Authority review on the safety of titanium dioxide as a food additive.

Referring to the conclusion of the EFSA 2021 opinion, the EC goes on to say that titanium dioxide “may no longer be used in foods,” but that since EFSA “did not identify any immediate health concern…and in order to allow for a smooth transition” foods already manufactured with TiO2 could “continue to be marketed until their date of minimum durability or ‘use by’ date.”

The preamble then turns to the use of approved food additives as colors in medicinal products.

Referenced are the EMA report findings on: ● the scale of the use of titanium dioxide ● the volume of products impacted ● the impact on global supply chains, and that a requirement to replace it “would almost certainly cause significant medicines shortages on the Union market.”

In view of the EMA findings, the EC decided that TiO2 should “remain provisionally on the list of authorized additives” to allow its use in medicinal products as a colorant.

However, the preamble states, “it is of critical importance that the pharmaceutical industry makes any possible efforts to accelerate the research and development of alternatives,” and to submit the necessary variations. “In the absence of such efforts,” competent authorities may request “objective and verifiable reasons explaining the non-feasibility of the replacement.”

The Commission said that it will review the situation on maintaining TiO2 or delete it from the list of food additives “for exclusive use as a color in medicinal products” within three years of the regulation date.

The decision will be based on an updated assessment by EMA to be provided by April 1, 2024, which should take into account: ● progress made to develop alternatives to TiO2 for use in new medicines and replacement in authorized products, and ● possible impacts on quality, safety, and efficacy – as well as availability – of medicinal products.

MEDICINAL PRODUCT DISCUSSION IN EU TIO2 REGULATION PREAMBLE

The following are clauses 16-18 in the preamble to the January 2022 Commission regulation amendment on food additives regarding titanium dioxide. Clauses 15-18 are the relevant sections of the preamble relating to the use of TiO2 in medicines. Clause 15, not included below, basically reiterates the findings in the September 2021 EMA report, which are provided in the report’s executive summary included above. Minor formatting changes have been made for readability. [A link to the full regulation is provided below.]

 

(16) On the basis of the EMA scientific analysis, and in order to avoid shortages of medicinal products that could have impacts on public health, titanium dioxide (E 171) should remain provisionally on the list of authorised additives to allow its use in medicinal products as a colour, pending the development of adequate alternatives to replace it while ensuring the quality, safety and efficacy of the medicinal products concerned. During this time, titanium dioxide (E 171) should however be included in the list of colours that may not be sold directly to consumers.

(17) It is of critical importance that the pharmaceutical industry makes any possible efforts to accelerate the research and development of alternatives that would be used as a replacement for titanium dioxide (E 171) in medicinal products, and to submit the necessary variation to the terms of the marketing authorisations concerned. In the absence of such efforts, competent authorities may request the concerned stakeholders to submit objective and verifiable reason explaining the non-feasibility of the replacement.

(18) The Commission is committed to review the necessity to maintain titanium dioxide (E 171) or otherwise delete it from the Union list of food additives for exclusive use as a colour in medicinal products within three years after the date of entering into force of this Regulation.

This review should be based on an updated assessment of the EMA to be performed before 1 April 2024.

It should take into account the progress made during this period to develop alternatives to titanium dioxide (E 171) in medicinal products both for new products and for replacing it in authorised products, and possible impacts on quality, safety and efficacy, as well as on the availability of medicinal products.

Where replacement of titanium dioxide (E 171) in medicinal products has not taken place or been initiated within this period, only objective verifiable reasons related to the lack of feasibility of its replacement should be taken into account.

 

EMA Publishes Guidance on Replacement of TiO2

As a follow-up to the EC regulation, in July 2022, EMA published technical and procedural guidance on the replacement/removal of titanium dioxide in medicines.

The guidance explains the background to the TiO2 regulation and its implications for pharmaceutical companies.

It then goes on to address: ● what to do as an applicant with a new marketing authorization (MA) that contains TiO2 ● what to do as a holder of an MA for a product containing TiO2 ● scientific data requirements to remove/replace TiO2, and ● regulatory pathways to support a change in excipients to remove/replace TiO2.

The guidance points to the need for MA holders of TiO2-containing products to “make all possible efforts to accelerate” the R&D on alternatives, and strongly encourages manufacturer collaboration, especially for similar products.

 

IPEC Panel Discussion Stresses Need for Action

At the May 2023 IPEC-Americas Excipient World Conference, leaders from excipient and drug product manufacturers echoed the need for collaborative action in providing data for the second EMA review – in their case, to ensure that titanium dioxide remains available for use in medicine formulations.

The panelists additionally highlighted the need for managing the expanding and increasingly global issues developing out of the EFSA review.

Without directly referencing the 2021 EMA report on the earlier industry feedback, the panelists reinforced the concerns highlighted in that report about the magnitude of the burden that a ban on TIO2 use in medicines would create for both industry and regulators. In addition, they stressed the lack of a safety rationale that would justify such an expenditure of resources.

Participating in the panel discussion were: ● IPEC leader Dave Schoneker ● AbbVie CMC Regulatory Affairs Associate Director Joanne Wakeman ● JRS Pharma Senior Technical Sales Representative Allison Labriola, and ● Colorcon Product Development Manager Daniel To. Moderating the discussion was Amgen Senior Principal Scientist Ron Kelly, who serves on the IPEC-Americas Executive Committee and leads its Nitrosamine Cross-functional Team.

 

Misconception that EFSA Cited a Safety Problem with TiO2

Kelly opened the session by asking panelists to share their background and experience with titanium dioxide, then gave the floor to Schoneker to provide an overview of the TiO2 issue and the current situation.

From his in-depth knowledge and involvement in the topic, Schoneker was able to give additional color to the information available in published European documents. [The full panel discussion is appended below.]

He pointed to a common misconception that EFSA had indicated there was a safety problem with TiO2, whereas the agency actually pointed to “data gaps” on some unique grades of TiO2 that are not used in drugs and foods – “entirely different than saying we have looked at the data and we have a safety concern.”

After outlining the situation in Europe, Schoneker went on to describe what was happening globally in relation to titanium dioxide – citing the countries that had also reviewed safety data on TiO2 and concluded there was no safety concern.

However, he also called out regions like the Middle East that follow EU regulations and were thinking of implementing a ban on the back of the EFSA report. Closer to home, he shared some recent developments in the US states of California and New York, where advocacy groups were petitioning for a review of TiO2 safety in foods.

Kelly then raised the “worst-case scenario” of a ban on TiO2 in pharmaceuticals and asked the other panelists about alternatives.

Colorcon’s To explained that most companies had unsuccessfully tried calcium carbonate as a one-to-one replacement. He described the efforts his company had undergone to find alternative opacifiers – looking through “hundreds of materials, hundreds of formulations” but finding nothing close to titanium dioxide for the functions needed. JRS’ Labriola agreed that it is “the best thing at being white and opaque.”

AbbVie’s Wakeman pointed to the results of her company’s trials with available alternative coatings, which demonstrated that a much higher weight gain was required for similar opacity. She emphasized that often the bottleneck of manufacturing is the coating, so increasing the time for coating “will have some implications” in addition to the challenges of matching the appearance of products.

 

What is the Real Scope of the Issue?

In answer to Kelly’s question on the scope of the issue and if the industry might be overreacting to it, Schoneker underscored the figure of 91,000 drug products containing TiO2 in Europe alone. “In effect, this issue,” he commented, “will affect billions of patients – one material.”

Additional considerations, he stressed, were the analytical challenges, economic impact, and real risk to patients from product withdrawals where the economics do not justify reformulation “for essentially a non-safety issue.”

IMCD’s Joe Zeleznik raised the concern about bioequivalence studies being required in certain cases, which led to a discussion around different levels of regulatory burden and costs of reformulating individual products. Comments followed about the levels of activity in co-development and preferences for TiO2 replacements or TiO2-free products.

Regulatory capacity was highlighted as a major concern, given the potential for EMA and global regulatory agencies to have to review thousands of post-approval changes. Schoneker asked if this indirect impact was justified. From the audience, BASF’s Sandip Tiwari concurred that this justification “is the real issue.”

BMS’ Alex Bilogur, who chairs the New Jersey Pharmaceutical Quality Control Association, drew attention to the role that politics and the media had played in influencing the European decision to ban titanium dioxide in foods, and asked whether similar situations could play out in other regions.

Schoneker agreed about the political “firestorm” – meaning that “science may, at the end of the day, not matter.” IFF’s Priscilla Zawislak, current President of the IPEC Federation Board, also underscored the importance of political as well as scientific advocacy.

Schoneker expressed optimism that the new EU Pharma legislation may allow EMA to make a decision on a colorant that is different from the food regulations, but cautioned that “obviously, we have a lot of information to provide them.”

Returning to politics, FinnBrit consultant and IPEC Foundation Chairman Chris Moreton asked about the position of the UK Food Safety Agency and whether there were any consequences related to Brexit.

Schoneker pointed out that the interim UK position was that there was no safety concern and that criticism had been forthcoming from the UK on the EFSA report. However, he suggested that Brexit could play a part politically because of trade negotiation considerations, noting that a final decision is expected in July.

To put the safety concern in perspective, Schoneker pointed out that, with most people having eaten TiO2 every day of their lives for 100 years, “it is the largest human clinical study in world history outside of drinking water” – with no adverse events directly tied to TiO2.

By contrast, for the alternatives there is “nowhere close to the amount of data. So we are going to go again from a situation of no risk with great human experience to back it up to completely unknown situations – maybe based on a rat study that somebody did with a poor study design.”

 

Nanoparticle Concern May Implicate Other Excipients

Later in the panel discussion, there was a focus on potential further excipient safety reviews being on the table with the increased attention on nanoparticles – especially in France, where the TiO2 study informing the EFSA review was carried out and where the definition of ‘nano’ differs from other regions.

Iron oxides and calcium carbonate are two substances on a list of 37 due for review – indicating, Schoneker commented, that TiO2 could be the “tip of the iceberg” in terms of excipients being investigated for safety issues of nanoparticles. JRS’ Labriola voiced concern about the impact a ban on iron oxides would have on the choices of colors and the ability of patients to differentiate products.

Lubrizol’s Meera Raghuram pointed out that the ANSES reviews are focused on nanoparticles in foods and that, rather than being “alarmist,” industry should take a proactive approach to collecting and sharing data in the pharma context.

A discussion followed on the collaborative industry initiatives and the upcoming PQRI and APV/IPEC Europe meetings.

Collaborations highlighted were: ● the IPEC-Americas TiO2 Working Group ● the IQ Consortium ● a pharma industry consortium convened to work on data to provide to EMA a new science program developed by the Titanium Dioxide Manufacturers Association (TDMA), and ● a joint association team bringing in all the major trade associations across the dietary supplement, food, and pharma arenas to share information and align on moving forward.

[CLICK HERE for the full panel discussion at the IPEC Excipient World session on TiO2.]

 

LINKS:

 EFSA opinion on the safety of TiO2 when used as a food additive (May 2021)

 EMA feedback to the EU Commission on titanium dioxide use in medicines (September 2021)

●  EMA report Annex I: response from industry (human medicines) (July 2021)

●  EMA report Annex II: response from industry (veterinary medicines) (July 2021) 

●  EU Commission Regulation 2022/63 on titanium dioxide (January 2022)

●  EMA guidance on replacement/removal of TiO2 in medicines (July 2022)

●  PQRI June Workshop on TiO2 Global and Regulatory Challenges

●  APV/IPEC Europe Conference on Nanoparticles in Excipients

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