The European Federation of Pharmaceutical Industries and Associations (EFPIA) is stressing that food, chemical, and environmental legislation should be developed and implemented with the impact on medicines in mind and that EMA and other regulatory authorities and stakeholders need to be more directly engaged to make sure that the outcomes align with the EU’s healthcare objectives.
While expressing strong backing for the environmental/green goals that Europe is pursuing, industry is proposing that the same scientific evidence and benefit-risk principles critical in other aspects of medicines evaluation should be deployed in ensuring that safe, high-quality medicines remain available and can still be manufactured in Europe.
IPQ’s five-part story explores the intensifying dialogue at industry/regulator forums on how to bring more medicine regulatory input into designing and implementing constructive and viable environmental policies that do not carry with them unintended consequences counterproductive to the health enhancement goals.
• PART I: The Need for Pharma Stakeholder Engagement
The story begins with a call from EFPIA for input and support from the medicine regulatory network in Europe’s effort to achieve its environmental goals. The need for more effective communication across environmentally-related legislative efforts about their potential impact on medicines was a key theme at a session of the March 2023 DIA Europe conference.
At the session, EDQM shared its experience in working collaboratively with European and international regulatory stakeholders on N-nitrosamines in accord with the unfolding science and the need to preserve patient access to critical medicines.
Included in this part of the story is the late April release by the European Commission of a proposal for revising pharmaceutical legislation, which has implications for environmental risk assessments and CMC/GMP expectations.
• PART II: EU PFAS Action and Pharma Mitigation Needs
Part two then explores the implications for the pharmaceutical industry of a proposal under review at the European Chemicals Agency (ECHA) restricting the use of per- and polyfluoroalkyl substances (PFAS) — the so-called “forever chemicals.” Industry shared its concerns in an updated EFPIA position paper released in June.
ECHA held a webinar in early April to explain the dimension of the global environmental and health threat of PFAS and why an intensive crackdown in Europe under its Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) regulation is warranted. A Q&A after the webinar presentations delved further into the proposal, its exemption provisions, and the consultation process on it that extends through September.
The pharma concerns were also discussed at the March DIA EU legislative landscape session and in association responses submitted by EFPIA and others, including BioPhorum and IPAC-RS, as of June to the consultation.
The Part II coverage concludes with a review of environmental efforts related to PFAS in Canada, the US, and the UK.
• Part III: Industry and EMA on F-gases and Hydrofluorocarbons in Inhalation Products
The third part of the story then focuses on the issues involved with F-gases and hydrofluorocarbon propellants in inhalation products as EU’s green goals are being pursued. At the March DIA session, industry experts presented compelling data on the minimal environmental impact of the medicine propellant usage and the threat to the supply of inhalation products if the current legislative language and its broad restrictions were enacted in that context.
Also reviewed is the April EMA guidance on the replacement of propellants and comments submitted collaboratively by industry on the guidance.
• PART IV: DIA Europe Legislative Session Panel Discussion
Part IV centers around the panel discussion at the DIA Europe session on the potential impacts in the medicine regulatory arena of the EU environmental/chemical legislative developments. Session co-chairs were Roche’s Markus Goese and GSK’s Matt Popkin, who co-lead the EFPIA Manufacturing Quality Expert Working Group.
Further explored in the dialogue were some of the key presentation topics, including: ● communication across regulatory networks ● the PFAS situation, and ● F-gases and HFC replacement. Also receiving attention were: ● the need for regulatory flexibilities and expedited pathways ● the influence of media and politics on decision-making, and ● global timelines for the changes needed to adapt to new requirements.
• PART V: Intensified Industry Dialogue on TiO2 and Nanoparticles Ahead of More EMA Review
The last part focuses on the intensified industry dialogue around the use of titanium dioxide in pharmaceuticals and the collaborative efforts to address EU safety concerns about nanoparticles.
A June PQRI Workshop brought together experts from TiO2 suppliers, innovative pharma, generics manufacturers, capsule suppliers, and toxicology science with the aim of bringing data and benefit-risk considerations to bear on influencing the regulatory processes and decision-making. The workshop highlighted the research being done to feed into EMA’s ongoing review. Discussed were: ● new safety information ● other global regulator assessments ● TiO2 alternatives, and ● the impact of TiO2 replacement on product quality, resources, and availability. IPQ coverage includes the generic manufacturer perspective and discussion of the issues around iron oxide – another excipient under review for nanoparticle safety.
Also reviewed is how the EU pharma legislative proposal alters the way approved colorants in foods and pharma are linked and provides EMA the authority to make its own determinations on colors.
[EDITOR’S NOTE: In view of the urgency of the communication process on the issues involved and PQRI’s engagement with them, Part V is being made openly available and appears in full below. Part V builds on IPQ’s coverage of TiO2 discussions that took place at the May Excipient World conference, which was released on June 11, 2023 and is also openly available.]
Intensified Industry Dialogue on TiO2 and Nanoparticles Ahead of More EMA Review
The dialogue around the EU action on titanium dioxide (TiO2) use in foods and medicines and the broader EU safety concerns about nanoparticles continued at a two-day Product Quality Research Institute (PQRI) workshop held in Bethesda, Maryland in mid-June.
Because of a link between food and pharma legislation in Europe, an EU regulation removing TiO2 from the list of authorized food additives could result in it not being allowed in pharmaceuticals, unless a second review by the EMA – to be completed by April 2024 – provides sufficient justification for its continued use. Industry input to the updated EMA review is due by November 2023. [Part V builds on IPQ’s TiO2 coverage released on June 11, 2023.]
The PQRI workshop provided an opportunity for experts from excipient suppliers, innovative pharma, generics manufacturers, capsule suppliers, and toxicology science to share and discuss details of ongoing collaborative efforts to provide the necessary data and justification for the ongoing EMA review.
Established in 1999 with FDA backing, PQRI provides a forum for industry, agency and academic experts to share knowledge and collaborate on research projects in support of science-based approaches to CMC/quality regulation and guidance. PQRI’s mission, the institute stresses, “is singularly relevant given the current rapid growth in new and varied drug product modalities, advancements in manufacturing paradigms, and the ever-increasing need for efficient but high quality research, development and manufacturing frameworks.”
Along with FDA, organizations in the non-profit consortium include the US Pharmacopeia (USP), Health Canada, the International Pharmaceutical Excipients Council of the Americas (IPEC-Americas), the International Pharmaceutical Aerosol Consortium on Regulation & Science (IPAC-RS), the Parenteral Drug Association (PDA), and the Consumer Healthcare Products Association (CHPA).
Opening the workshop, industry consultant and IPEC-Americas QbD/Composition Committee Chair Dave Schoneker outlined the workshop’s objectives and the plan to develop a white paper from the outcomes based on discussions in breakout sessions.
How Did This TiO2 Issue Arise?
The workshop began with an overview of the history, current status of TiO2 in Europe, and concerns related to nanoparticles given by Colorcon QA & RA Manager and IPEC-Europe Board Member Kevin Hughes, and Lonza Regulatory Affairs Associate Director Bram Baert.
Baert outlined the properties of titanium dioxide that make it useful as a white pigment and opacifier, pointing out that titanium is “one of the most common metals on earth,” and that TiO2 occurs naturally in different crystalline forms.
Pure TiO2 is obtained by extraction from the mineral ilemenite, and two grades are available for commercial use: ● pigment grade µm-size particles with a brilliant white appearance, mainly used for coloring, and ● nano-grade particles sized less than 100nm, transparent, with improved UV scattering and absorbing properties – commonly used in paints, catalytic coatings, plastics, paper, cosmetics, and food.
Baert then explained the background to the EU legislative system and the interplay between the European Commission, European Council and European Parliament and the bodies responsible for chemical, cosmetic, food and pharma regulations.
Describing the history of titanium dioxide reviews since first being approved by FDA in 1966, Hughes gave a detailed timeline of the safety debates and reviews in Europe over the years.
In particular, he noted the public and political will building against titanium dioxide in 2018 and the French law on agricultural practices and food published that year, resulting in a ban on TiO2 in France – which has been applicable since January 2020, based on “the precautionary principle.”
An opinion on TiO2 (E 171) published by the European Food Safety Authority (EFSA) in 2019 originally proposed a revised specification including controls on particle size and particle distribution in order to limit nano content, and also tighter heavy metal limits.
However, the final EFSA opinion published in May 2021 concluded that “E 171 can no longer be considered as safe when used as a food additive.”
Hughes noted the “strong political will” to ban E 171 and that Members of the European Parliament “argued strongly” for a complete ban in the EU. A regulation was subsequently approved to remove titanium dioxide (TiO2) from the list of authorized food additives from January 2022.
The regulation calls on the pharmaceutical industry to accelerate R&D on alternatives and to replace TiO2 in both new and already authorized products, unless “objective, verifiable reasons” can be provided for the lack of feasibility of doing so.
TDMA Analyzes EFSA TiO2 Opinion
A critique of the EFSA opinion on the safety of TiO2 in foods followed, provided by the Titanium Dioxide Manufacturers Association (TDMA) Scientific Committee Chair David Lockley. The TDMA represents TiO2 manufacturers from across Europe.
Lockley reviewed the scientific aspects and concerns around the EFSA opinion, including test materials not being representative of the E171 grade used in foods, and studies that were dismissed or not considered.
TDMA scientists concluded that EFSA “gave undue weight to results of in vitro genotoxicity studies that do not represent dietary intake of E171” and did not give appropriate weight to results of “compelling in vivo genotoxicity studies.”
Lockley remarked that EFSA nano guidance was applied to E171 in “unusual circumstances,” noting that E171 is a specific form of TiO2 and the EFSA guidance relates to different forms.
He emphasized that EFSA’s position is not shared by other regulatory authorities and highlighted an ongoing review of TiO2 by the Joint FAO-WHO Expert Committee on Food Additives (JECFA), the global food additive regulation coordinator. In response to a November 2022 call for data, TDMA submitted a “comprehensive dossier” of over 200 pages and has also shared that dossier with other authorities. The JECFA opinion is expected in 2024.
Lockley also mentioned that a new study, led by the Japan National Institute of Health Sciences, evaluated nanoparticulate TiO2 and found no adverse effects. The Japanese Ministry of Health, Labour and Welfare, which has medicine oversight, is beginning a formal review of TiO2 (E 171) in July 2023.
Closing his presentation, Lockley highlighted the wide use of TiO2 in cosmetics, toys, food contact materials, and medicines, including packaging as well as formulated tablet and capsule products. TDMA has submitted updates to the EMA about scientific developments and aims to submit results of genotoxicity studies and outcomes of reviews by other regions for the agency’s review beginning in November.
Toxicologists Present New TiO2 Safety Information
Three presentations on new TiO2 safety inform-ation closed out the first morning of the workshop, covering: ● a review of the genotoxicity data available ● a weight of evidence review of the carcinogenicity of TiO2, and ● an evaluation of the immunologic and intestinal effects of dietary E 171 consumption.
Regarding genotoxicity, consultant David Kirkland presented the results of a panel of experts from genetic toxicology, general toxicology, bioavailability, carcinogenicity, and nanoparticle characterization, who reviewed and weighted 337 data sets and concluded that the data did not support a direct DNA-damaging mechanism for TiO2.
University of Nebraska Medical Center Professor of Oncology Samuel Cohen then presented a review of carcinogenicity data on TiO2 since 1979, including more recent studies considered in the EFSA opinion, and concluded that E 171 is not carcinogenic when administered orally.
Michigan State University Institute for Integrative Toxicology Assistant Professor Lance Blevins followed with data showing that none of the immune alterations reported in a key study in 2017 by French researchers Bettini et al were observed when E 171 was administered in food – a “more realistic context” than the sonicated TiO2 administered in water used by the previous researchers.
Blevins then discussed the 2017 Nature Scientific Reports open-access paper by Bettini et al, which has been a focus of the debate around the safety of titanium dioxide nanoparticles and E 171, and the relevance of different experimental study designs.
In his presentation, he posed the questions: ● Should regulatory decisions be made using studies with a questionable experimental design? ● If an agent produces a statistically significant change in a biological endpoint, should the change immediately be interpreted as an “adverse effect?” ● How should animal models of disease be used in assessing toxicity and in making regulatory decisions, and ● Is a harmonized framework for assessing the toxicity of nanomaterials needed?
A scientific paper on the work by Blevins and a team of researchers including University of Nebraska Medical Center’s Cohen was published in 2019. [Links to the Kirkland, Bettini and Blevins papers are provided below.]
Health and Environment Alliance Comments on Industry-backed Study
The study by Blevins and his team was made available in time for consideration at a September 2019 meeting of the European Commission working group on food additives and member states to discuss the French ban on E171 in foods.
A release by the European not-for-profit organization Health and Environment Alliance (HEAL) followed shortly after, raising concerns about the study, which the organization pointed out, received financial support from three industry groups – the Grocery Manufacturers Association (GMA), the Titanium Dioxide Manufacturers Association (TDMA), and the International Association of Color Manufacturers (IACM) – “which all have substantial commercial interests in the outcome of the decision at stake.”
HEAL also questioned some aspects of the methodology and asked EFSA, the EC, and member states to take a “precautionary approach” in their upcoming discussions on the toxicity of E171. They urged the decision-makers to uphold the French ban on E171. [A link to the HEAL release is provided below.]
The alliance argued that: ● E171 did not meet any of the three conditions that are necessary to authorize food additives – safety, technological need, and benefits for consumers ● the French experience showed that manufacturers can easily remove E 171 from their products, and ● all Europeans deserve the same high level of protection.
Notably, the final EFSA opinion published in May 2021 makes it clear that its evaluation is only related to the risks of TiO2 being used as a food additive, and “not to other uses.”
By contrast, as discussed at the IPEC-Americas Excipient World conference and the PQRI workshop, the use of titanium dioxide as an opacifier and colorant in medicinal products does serve a technological need, benefits patients, and is considered safe at the levels ingested. And, as already acknowledged by EMA, it cannot be easily removed or replaced (see IPQ June 11, 2023).
Effect on the Microbiome is Drawing More Attention
The impact on gut microbiota is getting more attention in health impact assessments in general and is another consideration coming into play in assessing TiO2 and other pharma formulation materials.
The Kirkland 2022 paper notes that the use of titanium dioxide as a food colorant has “dramatically increased” since the end of the second world war with cheaper mass production techniques and increased availability of processed foods. It can be found as a whitener in dairy products such as milk and cream, coffee whitener, sweets, chewing gum, and sauces.
In its 2021 opinion, EFSA included updated dietary survey data from across Europe to estimate a consumption of titanium dioxide in foods of up to 30mg/kg body weight in maximally exposed children.
Some of the studies considered by the EFSA panel included analyses of gut microbiota changes in response to exposure to E 171 or TiO2 nanoparticles.
One of these studies, published in 2019 by an Australian team based at the University of Sydney, noted that E171 is a whitening agent present in over 900 commonly consumed food products. The findings, the study abstract states, “collectively show that TiO2 is not inert, but rather impairs gut homeostasis, which may in turn prime the host for disease development.”
However, EFSA commented that since there is no consensus on quantifying the extent of gut microbiota changes and when such changes should be considered adverse, no conclusions could be made regarding related effects on health.
FDA Reassesses TiO2 and Finds No Safety Concerns
In the afternoon session of day 1 of the PQRI workshop, Schoneker presented the perspectives of FDA and other regulators on TiO2 safety.
He pointed out that FDA’s Center for Food Safety and Applied Nutrition (CFSAN) had asked toxicologists, chemists and nanomaterial experts to re-evaluate the safety of TiO2 in food following publication of the EFSA opinion. CFSAN also discussed the issue with Health Canada.
FDA reviewed the information available, including that submitted to and analyzed by EFSA, and requested evidence that material used in a 1979 cancer study was representative of currently used TiO2 material. TDMA performed nanoparticle analysis to confirm that it was.
Schoneker shared a January 2023 FDA communication to the TDMA – highlighting the section provided below:
Schoneker also remarked that FDA has publicly stated that it does not have a safety concern and does not plan to take any action to ban or restrict its use, also that the agency had no plans to publish a formal report “unless a Citizen’s Petition is filed” since it felt TiO2 was safe in the past and the agency’s re-evaluation did not change this position. This message was reiterated in an October 2022 FDA “NanoDay Symposium.” [A link to the recording of the relevant section is provided below.]
UK FSA Interim Report Highlights “Risk-Averse” EFSA Opinion
When the UK Food Standards Agency (FSA) began a review of the EFSA opinion in May 2021, it asked for input from the Committees on Toxicity (COT) and Mutagenicity (COM) of Chemicals in Food, Consumer Products and the Environment.
COT and COM are independent bodies providing advice to government departments and agencies on potential toxicity, mutagenicity and genotoxicity of chemicals, the general hazards and risks associated with their use, and recommendations for further studies.
At the PQRI workshop, Schoneker highlighted the UK review references to statements that: ● “the weight of evidence did not support the conclusions drawn by EFSA” ● the EFSA conclusion is “highly risk-averse based on the weak evidence available, and it might create unnecessary concern to the public,” and ● the committees were “uncomfortable with EFSA’s binary communication on a dataset with a lot of uncertainties.”
He noted that a formal position from the COT and FSA is expected in July 2023. He also pointed to the Joint Food and Agriculture of the United Nations/WHO Expert Committee on Food Additives (JEFCA) review expected in 2024.
Canada, Australia and New Zealand Explain Different Opinions to EU
In June 2022, Schoneker pointed out, Health Canada (HC) also published a “state of the science” review of data on titanium dioxide used as a food additive, explaining to consumers why the agency came to a different opinion than the EU.
In an April 2023 communication, HC acknowledges that “recent analyses of food-grade TiO2 samples have found that a significant proportion of particles may be within the nanoscale,” and that these may have unique physical and chemical properties.
The agency also commented on the updated safety assessment of TiO2 in Europe, noting that the EU experts considered new toxicity studies and concluded that, although there were no immediate health concerns, due to uncertainties around the safety of TiO2 nanoparticles its use in foods could no longer be considered safe.
“While the conclusions of the EU expert panel were considered in this report,” HC said, its Food Directorate “conducted its own comprehensive review of the available science. This included evaluating new scientific data that addressed some of the uncertainties identified by the EU expert panel and were not available at the time of their review.”
The HC communication outlines points made in the TDMA analysis and maintains that “there is no conclusive evidence that the food additive TiO2 is a concern for human health,” based on a review of relevant scientific data. However, the agency will continue to review the emerging science on the safety of TiO2 as a food additive and “may revisit our position if new scientific information becomes available.”
Schoneker noted that in September 2022, the Food Standards Australia and New Zealand (FSANZ) authority published a review carried out following the EFSA opinion, which also included “new scientific data that addressed some of the concerns raised by EFSA.”
FSANZ point out that “in line with the outcomes of recent reviews conducted in the UK and Canada,” they found no safety concerns.
[Editor’s Note: Reviews of TiO2 food safety risks by the UK, Canada, and Australia and New Zealand in the wake of the EFSA 2021 opinion are appended below.]
Other Regions Follow EU’s Lead and Ban TiO2 in Foods
Continuing his presentation, Schoneker pointed out that many regions follow and implement EU regulations and that some countries had already implemented a ban on TiO2 in foods following the EU ruling, including Switzerland, Israel, and Yemen.
Meanwhile, he remarked, Brazil and the Gulf Cooperation Council, including Saudi Arabia, have indicated their intention to follow the ban but have delayed implementation awaiting their own evaluations or those of JECFA.
Argentina, Japan, and Thailand are other regions evaluating whether to institute a TiO2 ban. South Korea notified an intention to ban E 171 in January 2023, with a deadline for comments of April 1, 2023.
In the US, recent non-governmental organization (NGO) activity includes a February 2023 Assembly Bill in California to prohibit the manufacture, sale, or distribution of food products containing five additives, including TiO2.
Schoneker noted that the ban would come into effect in January 2025 if passed and that similar bills have been filed in New York and New Jersey.
In addition, a petition has been filed to the FDA by a group of NGOs to repeal approval of TiO2 use in foods.
Color Additive Petition Filed with FDA
Following Schoneker to the podium, Jay West from the Titanium Dioxide Stewardship Council (TDSC) delved into more detail on the US activities relating to TiO2.
The TDSC, under the umbrella of the American Chemistry Council, is the US counterpart of the TDMA, which itself is part of the European Chemical Industry Council. TDSC represents TiO2 manufacturers and was formed to promote the safe use of TiO2 through research, product stewardship, advocacy and outreach.
West explained that a Color Additive Petition was filed with FDA in April 2023 by the Environmental Defense Fund, Center for Food Safety, Center for Science in the Public Interest, and the Environmental Working Group.
“Recent scientific studies raise serious questions,” the petition states, “such that there is no longer the legally required ‘convincing evidence that establishes with reasonable certainty that no harm will result from the intended use of the food additive.’” It points out that “FDA has not reviewed the safety of synthetic TiO2 since 1973.”
The petition also points out that “nanoparticles – unlike their larger counterparts – are more likely to bypass the body’s natural defenses in the gastrointestinal tract and be absorbed into the bloodstream where the nanoparticles can reach other organs and may cause harm.”
Regarding the FDA’s statement affirming the safety of TiO2 following their review of the EFSA opinion, the petitioners “respectfully disagree,” and request the agency to undertake a “more detailed and rigorous analysis.”
TDMA Outlines New Science Program for TiO2
At the PQRI workshop, David Lockley, Chair of the TDMA Scientific Committee, and consultant David Kirkland then outlined the approach that the TDMA was taking in light of the EFSA opinion, noting that a 13.5 million Euro science program had already been launched in 2018 to address emerging concerns.
They commented that a Genotoxicity Working Group has now been convened to address concerns raised by EFSA, which will be chaired by Kirkland and take input from experts and regulators.
The working group plans to keep engaging with regulatory agencies in the effort to have its work considered in the upcoming reviews by EMA and JEFCA.
A 200-plus page dossier has already been circulated by TDMA to JEFCA and global regulators, and the association is advocating for the European Commission to trigger a re-review of the science.
The studies that are planned to address the “novel approach” taken in the EFSA opinion and fill in perceived gaps were described in detail, and the speakers concluded by reiterating the intention to ensure that “relevant science on E 171” is considered by all stakeholders.
IQ Consortium Highlights Technical Need for TiO2 in Medicines
The second day of the PQRI workshop focused mainly on the use of titanium dioxide in pharmaceuticals and the technical challenges of trying to use alternatives.
Bristol Myers Squibb (BMS) Senior Scientific Director Mike Tobyn began by presenting work done and subsequently published by the IQ Consortium Titanium Dioxide Working Group on the role of TiO2 and the requirements for replacing it in oral solid dosage forms. [A link to the IQ Consortium TiO2 paper is provided below.] Tobyn co-chairs the IQ TiO2 group and is also a member of the USP working group on physical test methods for excipients and of the editorial board of the Handbook of Pharmaceutical Excipients.
His presentation concentrated on the technical details of E 171 and the alternatives, addressing: ● what E 171 is and its properties ● how it is used in oral solid dosage forms ● the properties of potential alternatives, and ● the consequences of replacing E 171 with alternatives.
Regarding physical properties, Tobyn highlighted the high stability and low reactivity of E 171 grade TiO2, its low solubility, physical stability under pharmaceutical use, white, lustrous color, and particle size ideal for blocking visible light. The opacity of E 171 is due to its high refractive index, which is separate from UV absorption, he noted.
E 171 is currently used in about two-thirds of all oral solid dosage forms in Europe – providing protection of active ingredients through its UV and visible light-blocking properties, and having an easy-to-swallow, smooth finish. Importantly, it also provides a mechanism for unique identification and batch-to-batch consistency and is being increasingly used in product identification and anti-counterfeiting measures.
In terms of unique identification, Tobyn outlined the criticality for patient safety by reducing risks of: ● product mix-up during manufacturing ● receiving falsified products ● medicines misadministration, and ● not being able to identify medication in cases of emergency. The properties of E 171 also allow for “visionary applications of UV laser printing,” he added.
He pointed out that current alternatives are not as “technically efficient” as E 171. Most of the analysis on alternatives has focused on approved ingredients because the path for novel materials exceeds the timelines required to provide additional data to EMA. Materials tested have lower protection from UV and lower refractive index, with no capacity for “laser activation.”
Other disadvantages include sourcing of materials and potential contaminants that need to be considered, also the “intrinsic link” between particle size and efficiency. E 171 has dimensions of less than 1 µm, but not less than 100nm, which means that “it is not a nanomaterial by this definition.” Alternatives need to be used at “significantly greater levels” to achieve similar effectiveness – but with changed characteristics of the dosage form.
Highlighting the consequences of replacing E 171 in capsules and tablets, Tobyn stressed the likelihood of thicker coats/capsule shells and requirements for extensive reformulation and validation of production and analytical methods. As a pharmacist, he also emphasized the need for education programs to explain the changes in appearance to patients and carers.
In summary, he pointed to the benefit-risk imbalance of replacing E 171, which has been used successfully for many years in the majority of solid oral dosage forms, with replacements of lower performance and possible liabilities, including safety, that may emerge in the future. He concluded by acknowledging the collaboration with IPEC, TDMA and EFPIA in the IQ Consortium effort.
Perspectives Shared on Tablet Coating and Capsule Manufacturing
Following Tobyn’s review, a deeper dive into the implications of replacing TiO2 in tablet coating was provided by Colorcon Regulatory Affairs and Quality Assurance Manager Kevin Hughes on behalf of his company and other film-coating suppliers including JRS, Seppic, Ashland, Biogrund and Evonik.
Hughes walked through the possible alternative opacifiers and cross-industry efforts to investigate their use in different formulations. The results clearly demonstrated the challenges in achieving: ● the same opacity levels ● color matching ● color stability ● similar disintegration/dissolution characteristics, and ● properties of functional coatings.
Lonza Regulatory Affairs Capsules and Health Ingredients Head Bram Baert then gave a presentation on the challenges and opportunities from a capsule shell producer point of view involved in replacing titanium dioxide in hard capsules.
Noting that capsules have “a wide range of customization possibilities” for both visualization and functionality, he stressed that TiO2 is “more than just another colorant” – offering full masking of the capsule fill and protection of ingredients susceptible to light degradation in addition to visual identity characteristics.
Echoing the comments made by Tobyn, Baert outlined the wide range of materials Lonza had considered in their search for a suitable alternative, weighing up the advantages and disadvantages of each. “Looking at the combined technical and regulatory requirements,” he remarked, “the only viable TiO2 alternative for oral dosage forms is calcium carbonate.”
While calcium carbonate is an authorized colorant in both Europe and US, it has the limitation of having a lower refractive index than TiO2, requiring a greater amount to achieve opacity. Phosphate salts, meanwhile, offer an innovative new concept to achieve both similar color and opacity, but have the disadvantage of not being explicitly listed as food colorants or color additives in the EU or US.
Ending in a similar fashion to Hughes, Baert concluded that there are potential alternatives to TiO2, but not a 1:1 match. Different degrees of opacity and whiteness can be achieved and the general performance of capsules can be preserved, but solutions are technically challenging and not broadly applicable. Finally, the regulatory acceptability of alternatives is not as broad as with TiO2.
Pharma Manufacturers Discuss the Impact of Replacing TiO2
The impact of replacing TiO2 on product quality, resources and availability was then discussed by three major pharma companies: Eli Lilly, Merck, and Pfizer.
Eli Lilly Senior Director Jason Melnick shared some examples of technical challenges in drug projects with titanium dioxide alternatives – homing in on color matching and tablet appearance, including considerations around debossing, texture and disintegration that his team had experienced.
For hard capsules, he pointed out the different levels of opacity of alternatives, lack of global acceptable, surface differences leading to difficulty in imprinting, and that blinding of clinical materials may be difficult. The colors available for markings of dosage forms will also become limited, he noted.
Next, Merck Senior Principal Scientist Andreas Abend focused on the impact of film coating changes on product quality, in terms of analytical tests, specifications, and formulation bridging.
The impact on existing analytical methods, he commented, depends on the phase of development – with early phase having little impact, late phase having medium/high impact, and commercial phase having high impact. In addition to the revalidation and method transfer implications, for commercial products those changes would have to be filed in all markets where products are approved.
He stressed that current internal and external analytical resources would be unlikely to meet demand.
A drug product stability mitigation strategy would also be needed, resulting in increased filing, review and approval processes. Abend outlined the bridging studies required during product development when considering different strategies for regional markets – whether to have one global TiO2-free product or different products for different markets.
Pfizer Material Science Head Bruno Hancock then continued the evaluation of different options for phasing out TiO2 from existing medicines – from removing/replacing TiO2 to withdrawing products from the market – and considered those options from a global supply perspective, taking into account technical challenges, business challenges, and patient impacts.
In addition to points raised by previous speakers, Hancock emphasized the importance of the relationship with suppliers, noting that film coating pre-mixes and capsule shells are “almost always purchased from third-party vendors” and that medicines manufacturers are reliant upon these suppliers to develop TiO2-free options.
Many of these suppliers, he remarked, are small companies with limited resources. Developing new film coating and capsule formulations “requires highly specialized skills, which are in limited supply.” And a close partnership between finished product manufacturers and suppliers is needed to establish which coatings or capsules will work for each different product.
Hancock finished by highlighting some “great unknowns,” including: ● EU/EMA expectations for safety data on other excipients ● whether existing approved products would be “grandfathered in” or authorizations revoked ● circumstances for TiO2 continued use in medicines where benefits are greater than risks ● EMA’s plans and timelines for reviewing hundreds of updated MAAs ● plans to minimize drug shortages in Europe, and ● whether other major markets will restrict the use of TiO2 in medicines.
TiO2 Restriction Would be Especially Challenging for Generics
The generic drug manufacturer’s perspective of a potential TiO2 ban was shared by Teva Product Science in Environment, Health, Safety and Sustainability Senior Director David Cragin, who gave a talk prepared jointly with his European colleague, Regulatory Policy & Intelligence EU Senior Director Britt Vermeij. [Cragin’s full remarks are appended below.]
Cragin emphasized that Medicines for Europe, EFPIA, and the Association of the European Self-Care Industry (AESGP) collaborated in putting the presentation together.
He pointed out that Medicines for Europe companies supply “about 67% of all medicines in Europe,” which is “very significant,” although less than in the US, where generics represent “about 90% of prescriptions.”
Referring to the presentation by Lonza’s Baert, Cragin highlighted the advantage TiO2 offers in being insoluble in water. “Politicians and the public recognize that most of us have drugs in our bathrooms. And TiO2, because it is insoluble in water, tends to maintain tablet integrity much better in humid conditions than those replacements do.”
He commended the IQ Consortium for the work presented by BMS’ Tobyn, noting that Pfizer’s Hancock and Lilly’s Melnick were also co-authors on the published outcome paper.
“If you haven’t read it, read it. It is an excellent paper. And the key conclusion is that there is no system or material that could address both current and future toxicological concerns of regulators and the functional needs of the pharmaceutical industry and patients – so a crucial message for us to bring forward.”
Economic Burden Underscored by Teva Figures
Cragin then focused on the real impact to generic manufacturers, referring to the Teva Environment, Social and Governance 2022 report for relevant data.
As of 2022, “Teva has 2088 generic drugs in its portfolio. So when we talked about reformulating products, think about the challenge of reformulating 2088, or some significant fraction of that.”
Noting that Teva produced 76 billion tablets and capsules in the last year, Cragin invited participants to consider the impact of additional coating time on production capacity.
He then linked those figures to the impact on affordable healthcare and the challenges being experienced “in every country of the world.” Generic drugs, he noted, play a key role in affordable healthcare, and while withdrawing products has not been discussed within the TiO2 group at Teva, “it is a reality that that would happen.”
Turning to bioequivalence issues, Cragin referenced the presentation by Merck’s Abend and expanded further based on his own experience from previous roles – emphasizing the need to know “with certainty” about the impact of reformulation on drug bioavailability.
He then moved on to consider the timelines and testing requirements involved in reformulation, again referring to the numbers of products and economic impact. Drawing attention to a 2022 survey of pharmacies across Europe, he stressed the likelihood that a TiO2 ban would increase the risk of drug shortages.
In summary, he called out some key messages from the industry collaboration and suggested that generic drugs could be “a key part of our advocacy approach in terms of why this is not appropriate, why this is not practical and there are no safety or other reasons why we should change TiO2.”
Nanoparticle Concerns Expand to Other Excipients
In the last formal presentation of the PQRI workshop, EMD Serono/Merck KGaA Chemical and Preclinical Safety Department Senior Toxicologist Thomas Broschard discussed the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) concerns about nanoparticles and another colorant on their list for review, iron oxide, E 172.
Broschard addressed: ● the ANSES nanomaterial list and iron oxide ● the EFSA opinion and timetable of activities ● toxicology studies performed by an industry consortium ● EFSA request for clarification ● particle characterization studies, and ● some concluding comments. [Broschard’s full remarks are appended below.]
Noting that the ANSES nanomaterial list had been mentioned several times, he explained that there were actually two lists – one of substances used in foods where “the presence of manufactured nanomaterials has been proven,” and a second list, where the presence is suspected but not confirmed after review of the literature and data. Titanium dioxide, iron oxide, calcium carbonate, and other common excipients are included in the first list.
Broschard then homed in on iron oxide (E 172), giving examples of its use in foods and explaining the different versions – red iron oxide, yellow iron oxide, and black iron oxide.
In its opinion on E 172 in 2015, EFSA raised concerns about nanoparticles. The authority recommended that particle size/distribution be included in the specifications and that toxicity studies be performed to confirm the safety of E 172 in the three versions in foods.
In 2017, an E 172 consortium was set up to support the required financing and organization of the studies. Schoneker later explained that this had taken a lot of effort and convincing of pharma manufacturers and suppliers about the criticality of the issue. It was unlike other consortia for sharing information because in this case, a “sizable fee” was involved to fund “millions of dollars’ worth of toxicity studies.”
Broschard described in detail the studies undertaken and submitted to EFSA in March 2020.
EFSA published a guidance document on particle characterization in June 2021. The following November, Broschard explained, the agency requested that the consortium provide additional data demonstrating: ● that the test materials used in the safety studies included the fraction of small particles, and ● the adequacy of the existing toxicity and genotoxicity studies for covering the hazard assessment of the fraction of small particles.”
A teleconference with EFSA followed in February 2022 in which the consortium presented its proposals for new studies. Another program was started later in the year to look at particle characterization and nanoparticle fraction percentages – mainly involving Venator and Merck KGaA. Additional analytical investigations showed that the percent nano fraction in the different test item formulations was comparable to or exceeded the “real samples,” which included capsule shells.
Broschard noted that responses were submitted to EFSA in December 2022 and that the agency had hoped to give an opinion in 2023, but the response is now expected in 2024.
In summing up the events, he acknowledged the collaborators in the EBRC laboratories who performed the toxicity studies and Jones Day management consultancy for organizational help with the consortium.
In his comments following Broschard’s presentation, Schoneker commended the color and pharma manufacturers for supporting the toxicity work with the necessary resources, remarking that a lot of materials on the ANSES list “don’t have suppliers who have that kind of reach.” He also noted that in many cases, “the pharmaceutical market and even the food market for some of these materials are rather minor compared to what they sell in the industrial world.”
Breakout Sessions Enabled Deeper Dive
Breakout sessions held at the end of each day enabled further discussions on the topics covered, with the first session focusing on safety and communication to the public and healthcare professionals, and the second focusing on reformulation of products and engagement with regulatory agencies.
One of the topics discussed was around potential hazard versus real risk “with realistic levels of exposure,” rather than considering hazard potential based on unrealistic levels of TiO2 shown to have genotoxic effects.
It was noted that JECFA is expected to propose an acceptable daily intake (ADI) following its review of TiO2. TDMA has proposed a 1000mg/kg body weight per day as a starting point, and FDA currently has a limit of 1% by weight in foods.
When discussing the EFSA opinion, the breakout session attendees suggested that resources would be best expended on preserving use of TiO2 in medicines rather than revisiting the decision on use in foods.
Involving patient advocacy groups in the dialogue would be helpful, it was pointed out, once they are informed about the possible impact on the availability of medicines.
The expansion into other global regions of the concern about the safety of TiO2 in foods was also considered. Attention was given to the role of the media and legal cases and their influence on decision-making by politicians (see Part IV of this story). Ideas for how scientists and manufacturers could counteract this influence through other channels of communication were offered, including how to explain in lay terms the concept of “weight of evidence.”
More details of the work being carried out by individual companies were shared, with an agreement that calcium carbonate was the only real alternative to TiO2 – possibly used as a blend with isomalt. However, there was concern expressed about introducing other excipients, for which safety issues may be raised in the future with a consequent need for further reformulation.
Additional concerns that were brought up included the unknown risks with scaleup and acceptability of “increasingly speckled appearance” in countries where aesthetics are critical – for example, Japan.
Comments were made that further engagement, discussion and advice from EMA would be appreciated – especially in view of the resources invested so far with reformulation efforts and the challenges involved with planning for supply during transition phases and the timing of global dossier submissions. The inclusion of pharmacopeias in the TiO2 dialogue was also recommended.
Collaborations, Communication and Dialogue Continue Apace
EFPIA, Medicines for Europe and the OTC organization AESGP collaborate and actively engage with EMA via its Quality Working Party on topics including TiO2 and PFAS (see Part II). The EFPIA working group on titanium dioxide is chaired by GSK’s Matt Popkin.
A high-level summary of the PQRI workshop has been published and also planned are: ● a white paper for consideration by EMA ● a scientific paper of proceedings, and ● communications to consumers, patients and healthcare professionals. In addition, a recording of the workshop is available (see link below).
Another key outcome of the workshop was that PQRI representatives were invited to present a summary of the discussions to the International Pharmaceutical Regulators Programme (IPRP) Nanomedicines Working Group.
IPRP was created in 2018 to establish a forum for its regulatory members and observers to exchange information on issues of mutual interest and enable regulatory cooperation. [A link to the IPRP webpage is provided below.]
Members include individual regulatory authorities such as FDA, EMA, Japan PMDA, UK MHRA and Korea MFDS, as well as regional cooperative organizations such as the Asia-Pacific Economic Corporation (APEC), Association of Southeast Asian Nations (ASEAN), Gulf Health Council (GHC), Pan-American Health Organization (PAHO), and the South African Development Community (SADC).
The European Directorate for the Quality of Medicines and Healthcare (EDQM) and WHO are observers, and EDQM Director Petra Doerr was elected chair of the IPRP Management Committee in June. Doerr previously served as WHO Regulatory and Safety Head.
Proposed EU Pharma Legislation Addresses Colors in Medicines
The background and status of TiO2 (E 171) in Europe were discussed by Colorcon’s Kevin Hughes and Lonza’s Bram Baert in the opening presentation of the PQRI workshop. It was noted that the final EC decision on the use of E 171 in medicines was expected in February 2025.
The two speakers expressed concern that the current “direction of travel” in Europe is toward the removal of TiO2 from medicines, citing: ● the EC regulation removal of E 171 from the list of approved colors ● the regulation’s stressing of the “critical importance” for the pharma industry to look for alternatives to E 171 and the need to provide “objective and verifiable reasons” for not replacing it, and ● the EMA Q&A outlining the relevant variation procedures.
Potentially countering this “direction,” they noted, is the proposed revision of the EU pharmaceutical legislation and its preamble sections, which discuss the use of colors in medicinal products.
The wording allows for EMA to carry out its own assessment on the use of a color in medicines in the case that color is removed from the approved list of food additives – “taking into account the EFSA opinion and its underlying scientific evidence, as well as any additional scientific evidence and giving particular consideration to the use in medicines.” Significantly, a new process for establishing a separate list of colors approved for use in medicines is outlined in the proposed regulation (see below).
At a June 2023 European Compliance Academy webinar on the new EU legislation, Federal Association of Drug Manufacturers Consultant Fatima Bicane commented that, although the planned date for the new regulations coming into force is Q4 2024, due to expected debate and delays as it moves through the legislative process, a more likely date is 2026 or even 2027 (see Part I of this story).
● Kirkland et al 2022 genotoxicity of TiO2 review
● Bettini et al 2017 Nature paper on TiO2
● Blevins et al 2019 Food and Chem Toxicology paper
● HEAL release on E 171
● FDA NanoDay Symposium Session 3
● IQ Consortium Titanium Dioxide Paper 2022
● Teva 2022 ESG Report
● IPRP website
● PQRI workshop recording
● EFSA 2015 opinion on iron oxides
● EFSA 2021 updated opinion on titanium dioxide
● EFSA 2021 guidance on risk assessment of nanomaterials