Industry’s Perspective on Challenges Assessing the in Vivo Impact of Removing Titanium Dioxide (TiO2) from Drug Products

The European Commission (EC) has tasked the European Medicines Agency (EMA) to provide a recommendation towards the acceptability of titanium dioxide (TiO₂) in pharmaceutical products by early 2024 to inform on final decision in early 2025[1]. Unlike the already implemented ban of TiO₂ in foods, removing this excipient from pharmaceutical products will likely have significant impact on the pharmaceutical industry, regulatory agencies, and patients. This commentary explores the challenges facing the pharmaceutical industry tasked with supporting the development and registration of TiO₂ free (TF) drug products. Specifically, justification of formulation changes and potential impact to in vitro and in vivo performance, as well as differences in global regulatory comparative dissolution requirements to justify changing to TF drug product are discussed. Particularly, the uncertainties around how a formulation change such as removal of TiO₂ from immediate release solid oral dosage forms will be viewed in Europe compared to other regions is discussed. To respond to these challenges and avoid disruption to the medicines supply chain in case in vitro data such as dissolution is either too challenging or insufficient to justify changing to TF product, pharmaceutical companies may have to decide if the level of risk is worth the effort needed to reformulate, develop, and register a new TF product.

Introduction

In 2022, the European Commission (EC) delisted titanium dioxide (TiO2, specifically grade E171) as a food additive due to potential consumer health concerns raised by the European Food Safety Authority (EFSA). Because E171 is also an excipient present in many medicinal products, EC had tasked EFSA and the European Medicines Agency (EMA) in 2018 to make a recommendation on the future use of E171 in medicines by April 2024. Banning E171 from the list of approved excipients would affect over 91,000 medicinal products currently available in the EU. If the EC was to decide that all of these medicinal products can no longer contain TiO2, then industry would have to identify and implement suitable alternatives. This would require significant efforts towards manufacturing changes following applicable regulations, which could lead to drug shortages and impact public health which is concerning to EMA1 as well as industry. To date, according to a number of renown toxicologists who recently presented their findings at various conferences including a workshop sponsored by the Pharmaceutical Quality Research Institute (PQRI), there is no compelling evidence that E171 is unsafe in foods or medicinal products. In a recent on-line publication, the U.S. FDA acknowledged that in their current opinion, there is no evidence that TiO2 is unsafe in foods.

In medicines, TiO2 is widely used as an excipient in tablet film coatings and capsule shells for a variety of functions. For example, TiO2 in tablet film coating is mainly used as an opacifier to eliminate or significantly reduce photodegradation of the active pharmaceutical ingredient (API), enhance product appearance by masking API color, and provide enhanced identification and differentiated appearance of commercial products. In addition to effectively blocking UV and visible light from causing API degradation, TiO2 is also used in capsules to over encapsulate clinical trial materials and comparators. Because of the important function TiO2 plays in pharmaceuticals, simply removing it will likely compromise the critical quality attributes of many drug products. Based on discussion between members of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), many companies are currently proactively working with their excipient suppliers to identify TiO2 free (TF) film coating or capsule alternatives. Despite these efforts, an alternate material that is approved for use in pharmaceuticals and has the same unique properties of TiO2 has not yet been identified. As a result, the amount of film coating needed to provide equivalent masking of API color and acceptable tablet appearance will likely increase. Second, photostability of the product could potentially be compromised, leading to further need to increase the amount of coating on the tablet. This increase in film coating and corresponding increase in manufacturing processing time has potential to impact dissolution performance of the tablet. For example, the increased thickness of the film coating could increase the disintegration time of the tablet, which could impact dissolution particularly at earlier timepoints. Additionally, many potential TF coating systems being considered contain CaCO3 as alternate opacifier, which has potential to alter the microenvironment pH of the tablet and affect solubility of the API and dissolution profile. Changing the composition and amount of the coating will likely require manufacturing process changes, which could result in increased moisture content and water activity of the tablet, which could then impact dissolution performance at release and/or during storage. Higher moisture content could also lead to increased levels of drug impurities, microbial growth, and/or solid form changes on stability which can also impact dissolution. In a worst case, these changes in product disintegration and/or dissolution could negatively impact in vivo performance. Given these complexities, switching to TF film coating could be high risk and not straightforward, particularly since demonstration of equivalent dissolution performance is usually required for tablets and capsules.

Thus, restriction of TiO2 in pharmaceutical products could significantly impact drug availability due to reformulation challenges, manufacturing changes, unknown and potentially complex supply chains, and regulatory compliance with current development and post approval regulatory requirements. Pharmaceutical companies are closely monitoring the ongoing discussion of how the EC will regulate the use of TiO2 in pharmaceutical products. As mentioned earlier, if TiO2 is banned in pharmaceutical products, approximately 91,000 currently approved commercial drug products in Europe, the majority of which are tablets for oral ingestion, will be directly impacted. An indirect global impact will also exist as many companies use the same product globally. In addition, products in the development pipeline will also be significantly impacted. Changes to formulation composition or manufacturing process could negatively impact product quality. The risk of these changes having an impact on dissolution rate and extent of drug release needs to be assessed for each product. Restricting the use of TiO2 in pharmaceutics is likely to cause a surge in regulatory submissions ranging from simple annual product updates to complex prior approval supplements or supplemental submissions. IQ published a review paper in August 2022 to describe the process by which titanium dioxide is manufactured and its functionalities to pharmaceutical products. The IQ review paper concluded that there is currently no replacement material which could address both current and future toxicological concerns of Regulators and the functional needs of the pharmaceutical industry and patients. A recently published case study paper further confirmed this assessment. Complementary to the IQ review and case study papers, this commentary focuses on the in vitro dissolution and potential in vivo data that will likely be required by several regulatory agencies to assess the impact of replacing or removing TiO2 from drug products in clinical development and on the commercial market. Solid oral dosage forms, specifically tablets, are the primary focus of this commentary because this type of dosage form makes up the majority of the potentially impacted products in Europe.

Read more on the industry perspective on the TiO2 here

Andreas Abend, Diana Sperger, Dorys Argelia Diaz, Ruiqiong Guo, Regina Reul, Sy-Juen Wu,
Industry’s Perspective on Challenges Assessing the in Vivo Impact of Removing Titanium Dioxide (TiO2) from Drug Products,Journal of Pharmaceutical Sciences,2024,ISSN 0022-3549,
https://doi.org/10.1016/j.xphs.2024.08.002.