Titanium dioxide (E171) and its role in formulation -

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By David Harris (MSD), Jason Melnick (Eli Lilly), Jonathan Kaye (GSK), Mike Tobyn (Bristol-Myers Squibb) ACR-801

Titanium dioxide (E171) and its role in formulation -

In this article Mike Tobyn from Bristol Myers Squibb, Jonathan Kaye from GSK, David Harris from MSD and Eli Lilly’s Jason Melnick discuss the role of E171 (titanium dioxide) in the identification of solid oral dosage forms.

The ability to uniquely identify oral solid dosage (OSD) forms has been recognised by regulatory authorities worldwide as one of the mechanisms to reduce medication errors and to detect falsified medicines. Changes in the appearance of medicines has been identified as a factor in patient compliance and, therefore, clinical outcomes.

In the development of a new drug product, it is necessary that each dosage form or strength incorporates mechanisms that enable its unique identification. The ability to identify medicines is regarded, in European Medicines Agency (EMA) guidance,1 as a key mechanism for reducing medication errors: elderly patients frequently use multiple medicinal products (polypharmacy) which may in itself cause adherence problems which may be partly overcome by the pharmaceutical design of the medicines used (eg, a wider range of colours, sizes and tablet shapes is known to assist the recognition of medicines and hence to reduce the risk of errors).1

Once on the market, unique identification is a key mechanism for helping to prevent and identify falsified medicines. Falsified medicines present significant risks to patients, and their identification and removal is a key goal of healthcare regulators throughout the world.2 Having unique, difficult‑to‑falsify features makes the medicines supply chain safer.

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As the need to rapidly and uniquely identify a solid oral dosage form is a vital part of product development, several mechanisms to achieve those goals have been endorsed by the pharmaceutical industry and regulators.

E171, a specific grade of titanium dioxide currently acceptable worldwide in medicines, is a key component of most OSD forms, as it has a unique (in the pharmaceutical armoury) set of properties. These properties allow it to protect the active pharmaceutical ingredient (API) from UV and visible light while being chemically inert; factors which are important in producing a stable product with an appropriate shelf life. E171 can be used in a range of tablet coatings and in capsule shells (of gelatine or hypromellose composition). These exceptional properties are complemented by E171’s ability to provide white, bright colour or easily combine with other colourants to create an array of vivid colours and shades. It is highly effective as an opacifier at low solids loading and can be effective in thin coats. These features make E171 an important enabler of unique, visible identification of oral solid dosage forms.

Hypromellose capsules opacified without E171. From left to right: empty / filled with white powder / filled with orange pellets / filled with black pellets. Photos courtesy of Lonza.

Recently the European Commission (EC) required the removal of E171 from foods intended for sale in the EU. This was not based on an adverse finding of safety with respect to E171, but the absence of a finding of complete safety by the European Food Safety Authority (EFSA).7 Foods manufactured after August 2022 for sale in Europe cannot contain E171. Uniquely in the EU, only colourants approved for use in food can be used in medicines. Therefore, the EC has further requested that pharmaceutical companies “make all possible efforts to accelerate the research and development of alternatives and replace titanium dioxide in both new and already authorised products”. This guidance would affect a majority of the available OSD form medicines in Europe.8

Under Regulation 2022/63, the EC is due to re‑evaluate by early 2025 the exemption that allows ongoing use of E171 as a colour in pharmaceutical formulations. This will be based on the EMA’s re‑evaluation (due in Q1 2024) of the impact of E171’s removal and the feasibility of alternatives to replace it. Subsequent to the EFSA assessment and the publication of 2022/63, other regulatory authorities have reviewed the safety of titanium dioxide and the EFSA opinion and have indicated that they do not believe any changes to its status in food or medicines are warranted.

As an opacifier (which is different to its function as a colourant), E171 acts as an enabler of the unique identification of dosage forms. The mechanisms for this benefit include:

If E171 is removed as an option for inclusion in OSD forms, it is important that any alternative retains as many of the properties outlined above as possible to maintain the uniqueness of these dosage forms. In addition, it would be preferable for any alternative to be inert and usable in the same settings as are currently deemed suitable for formulations containing E171. As it stands, none of the materials currently identified as potential replacements have the ability to block UV to the same extent as E171, and have a significantly lower refractive index than E171,9 implying that like‑for‑like replacement will not be possible. This puts the UV protection provided by E171, and the colour and hiding capacity provided by the tablet coat or capsule shell, at risk.

The EC is due to re-evaluate by early 2025 the exemption that allows ongoing use of E171 as a colour in pharmaceutical formulations

Initial colour palettes provided by suppliers indicate that the range of colours possible using currently identified replacements is different from that currently available using E171; thus colour matching with current presentations may not always be possible. The palette may have a sufficient range of colours for new medicines, but colour matching with the current systems may be difficult to achieve. This could be significant when trying to replace E171 in medicines already on the market.

At a recent APV conference on the challenges relating to the replacement of E171, reports of initial solid dosage forms made with the early formulations of E171-free coating systems indicates that some of these systems demonstrate fading over time. Data also indicates that the new coating systems, which either need a higher solid content or a longer application time, do not adhere to the dosage form as well as E171-based formulations. There can also be a lack of visual colour uniformity on the tablets, particularly on the sharp edges of the dosage form. These complications of using E171-free coatings systems may end up narrowing the ranges of possible tablet shapes and debossed features.

How to optimise production by using the correct tablet tooling

Recent innovation with alternative opacifying technologies demonstrates that equivalent whiteness and light protection in the capsule could be achieved with materials other than E-171, but these solutions are not fully developed and do not currently have regulatory clearance. New printing inks are being developed to replace those containing E171, to replicate the identification function for dosage forms, but not all colours currently on the market can be replicated yet, and white inks will remain a specific problem. There is currently no alternative identified that allows for the laser activation of the material as an identification mechanism for the dosage form.

Innovations in the market are inevitable and welcomed. However, a timeline for their introduction to meet potential delisting of E171 will need to be developed and agreed by the industry and regulators since the feasibility, as direct replacements of E171-free colour mixtures and capsule shells has not been confirmed at this stage.10

The authors are grateful for the help provided by Liz Meehan (AstraZeneca) and Bruno Hancock (Pfizer) in preparing the article. The help and support of Kevin Hughes, Jason Teckoe (Colorcon), Bram Baert and Ljiljana Palangetic (Lonza) is gratefully acknowledged.

Mike Tobyn is a Senior Scientific Director at Bristol Myers Squibb, where he has worked for 17 years. He is a Pharmaceutical Materials Scientist and leads a transatlantic group studying and understanding API and excipient properties in OSD forms. Mike is a member of the USP Expert Panel on Methods for Testing Excipients.

Jonathan Kaye is a Scientific Team Leader at GSK, where he has worked for 15 years. He works in the R&D drug product development group, specialising in oral dosage forms. Jonathan is a qualified pharmacist in the UK, registered with the General Pharmaceutical Council.

Jason Melnick is a Senior Director at Eli Lilly and Company where he has worked for 26 years. He is a member of the global Technical Services and Manufacturing Sciences group supporting the development, technical transfer and manufacturing of OSD forms.

David Harris is a pharmaceutical scientist at MSD with over 30 years of industrial experience. He is a Principal Scientist specialising in the development of OSD forms of new chemical entities.

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