When a substance is identified by an “E number,” the immediate assumption is often that it belongs to the category of food additives. However, some of these substances are also used in medicinal products as excipients.
Titanium dioxide (E171), aspartame (E951), sorbitol (E420), saccharin (E954), erythrosine (E127), sulphites and benzoates can all be incorporated into medicinal products, where they serve as excipients performing a variety of functions, such as opacifying agents, sweeteners, colourants, preservatives, and more.
Nevertheless, food additive and pharmaceutical excipient are not interchangeable terms. Behind the same substance lie two different regulatory frameworks, two different assessment approaches, and distinct requirements.
Similar Functions, but Two Distinct Regulatory Approaches
At first glance, food additives and pharmaceutical excipients appear to have similar definitions.
In the food sector, Regulation (EC) No 1333/2008 defines a food additive as a substance that is not normally consumed as food itself, nor used as a characteristic ingredient of food, and that is intentionally added to food for a technological purpose. Preservatives, colourants, sweeteners and antioxidants are typical examples.
In the pharmaceutical sector, Directive 2001/83/EC adopts a different and particularly broad definition of an excipient: any constituent of a medicinal product other than the active substance and the packaging materials.
In both cases, the substance may fulfil a technological function: providing colour, improving taste, stabilising a formulation, facilitating manufacturing, or enhancing preservation.
However, this is where the similarity ends.
In the food sector, the assessment primarily focuses on consumer exposure in the context of food use. Authorisation conditions, permitted product categories and maximum use levels are defined within a dedicated regulatory framework. Authorised additives must also comply with purity criteria and harmonised European specifications, notably those established by Regulation (EU) No 231/2012 laying down specifications for food additives listed in Annexes II and III to Regulation (EC) No 1333/2008.
In the pharmaceutical sector, the approach is different. An excipient is assessed within the context of the finished medicinal product, taking into account factors such as pharmaceutical quality, route of administration (oral, parenteral, inhalation, etc.), the exposed population, the administered dose and the overall benefit-risk balance of the medicinal product.
Beyond the substance itself, the requirements applicable to its manufacture and control also differ depending on its intended use. In the pharmaceutical field, excipients are subject to specific expectations regarding quality and risk management. Marketing Authorisation Holders must demonstrate that the excipients used are suitable for pharmaceutical use and that their manufacture is appropriately controlled, in accordance with European guidelines on the formal risk assessment of excipients. Other regulatory considerations may also apply, including the control of elemental impurities, nitrosamines and other potential contaminants.
These requirements further illustrate that a substance considered acceptable in a food context cannot automatically be transposed into the pharmaceutical domain.
“Authorised for Food Use” Does Not Automatically Mean “Acceptable in a Medicinal Product”
The inclusion of a substance on the list of authorised food additives does not, by itself, demonstrate its acceptability as a pharmaceutical excipient.
Why? Because the context of exposure is not necessarily comparable.
For medicinal products, several parameters must be taken into account, including the amount of excipient administered, dosage regimen and treatment duration, route of administration, characteristics of the target population, such as children, elderly individuals or patients with specific diseases, as well as the function of the excipient and its quality attributes.
The regulatory question is therefore not simply whether the substance is authorised, but rather:
“Is its use acceptable in this specific medicinal product, at this amount, via this route of administration, and for this patient population?”
This distinction can have very practical implications when preparing a marketing authorisation application (MAA), reformulating a product, changing suppliers, or assessing the compliance of product information.
Behind the Term “Excipient”: Substances That Are Not Always Inert
The term excipient is sometimes mistakenly associated with the idea of a completely inactive substance with no pharmacological effect.
In reality, certain excipients may produce known effects in specific patient populations or under particular conditions of use. For this reason, European authorities have established a list of “excipients with a known effect”, for which specific information must be provided to patients through labelling and package leaflets.
This concept is particularly interesting because it highlights one of the fundamental differences between the food and pharmaceutical sectors. In medicinal products, regulatory assessment does not stop at authorising the use of a substance. It must also ensure that patients receive all the information necessary to use the product safely.
Examples of excipients with a known effect include aspartame, sorbitol, ethanol, propylene glycol, lactose, certain azo dyes, sulphites, sodium and potassium. Their presence may require specific statements in the package leaflet to inform at-risk populations or highlight particular precautions for use.
This approach reminds us that an excipient should not automatically be regarded as entirely harmless. Even when it does not contribute directly to the desired therapeutic effect, it may raise questions relating to tolerability, patient information or risk management, which must be considered from the development phase and throughout the product lifecycle.
For pharmaceutical companies, the challenge is therefore not limited to selecting an excipient with the required technological properties. It also involves understanding the regulatory consequences of that choice, particularly with regard to quality documentation, product information and patient communication requirements.
Three Illustrative Examples
- Titanium Dioxide (E171)
Titanium dioxide is probably the most emblematic example of potential divergence between food and pharmaceutical regulatory frameworks.
For many years, titanium dioxide was used as a food colourant under the designation E171.
In 2021, the European Food Safety Authority (EFSA) concluded that titanium dioxide could no longer be considered safe as a food additive because concerns related to genotoxicity could not be ruled out. This assessment led the European Union to withdraw its authorisation for food use in 2022.
However, the substance has remained temporarily permissible for use in medicinal products because its pharmaceutical use raises different considerations. In some medicines, titanium dioxide serves not only an aesthetic purpose. Its opacifying properties can also help protect formulations from light and therefore prevent degradation.
The European Medicines Agency (EMA) has highlighted the technical challenges associated with replacing titanium dioxide, as well as the potential consequences of a widespread substitution on the quality, safety, efficacy and availability of medicinal products. European work conducted in 2024 also showed that the alternatives evaluated did not necessarily provide equivalent performance across all relevant pharmaceutical criteria.
Aspartame is best known as a food sweetener. It may also be used in medicinal products, particularly to improve the acceptability of oral dosage forms by masking the bitterness of the active substance.
However, aspartame is a source of phenylalanine, which has important implications for patients with phenylketonuria (PKU). For this reason, it is classified as an excipient with a known effect.
Within the European pharmaceutical framework, its presence requires specific information to be included in the package leaflet. This requirement applies whenever aspartame is present in an orally administered medicinal product.
The issue is therefore no longer limited to determining whether aspartame can fulfil the required technological function. Manufacturers must also anticipate patient information requirements and the resulting implications for product information.
This example illustrates how a substance that is well known in the food sector may trigger specific documentation and communication obligations in the pharmaceutical context.
Sorbitol provides another particularly relevant example.
It demonstrates how an excipient may be subject to specific regulatory requirements despite its widespread use in both food products and medicines.
Within the pharmaceutical framework, sorbitol is listed among excipients with a known effect. European guidance requires different information statements depending on the conditions of use of the medicinal product. Some of these statements relate specifically to patients with hereditary fructose intolerance, as well as potential gastrointestinal effects that may occur under certain exposure conditions.
This example illustrates that the regulatory assessment of an excipient is not based solely on its identity or long history of use. It also depends on the conditions under which the medicinal product is used and, on the information, necessary to ensure appropriate patient care.
Questions Pharmaceutical Companies Are Asking Today
When a substance is also known as a food additive, several questions may quickly arise:
- Should a change in the food regulatory status of a substance trigger a reassessment of its pharmaceutical use?
- How should the retention or replacement of an excipient be documented?
- When should a potential future regulatory risk be anticipated?
- What are the implications for marketing authorisation dossiers, variations and patient information?
- How can companies balance regulatory requirements, industrial constraints and continuity of supply?
The answers often depend on the product concerned, the regulatory context and the available data.
Where Atessia Can Help
Issues relating to excipients are rarely purely technical or purely regulatory.
They sit at the crossroads of formulation development, regulatory affairs, quality, supply chain management and product lifecycle management.
Atessia supports pharmaceutical companies in assessing the regulatory impact of excipient selection, evaluating available options, documenting decision-making processes and anticipating regulatory developments that may affect a product portfolio.
When it comes to excipients, an apparently ordinary substance can conceal a much more complex regulatory challenge than it first appears.
Article written by Lise CHOCHON, Regulatory Intelligence & Digital Marketing Coordinator
