Since the thalidomide disaster, ensuring that medicines are safe before they are approved for sale to the public has become one of the most important tasks of regulatory agencies.

However, while most people are familiar with clinical trials and how they are used to assess safety and efficacy of new medicines (technically, the active ingredients), excipient safety is rarely featured, and has remained a mystery.

In this short article, we will explain how the safety of different pharmaceutical excipients, such as parabens and vaccine adjuvants, is assessed by pharmaceutical scientists today.

What is excipient safety?

Whether a particular excipient is safe or not depends on what safety actually means. The commonly agreed definition of safety is the absence of undesirable pharmacodynamics effects (adverse and side effects) that a particular substance exerts on the physiological function of the living organism upon exposure within its therapeutic range.

Excipient toxicity, another closely related term to safety, and often used interchangeably, actually refers to the degree a material is poisonous, i.e its ability to cause injury.

Undesirable effects include sensitization, allergic reactions, anaemia, jaundice, kidney damage, nerve damage, interference with vision, blood cell count, et cetera.

It is important to also note that safety and toxicity depend on many other factors, not just the dose, duration or route of exposure of that material, per se. This is sometimes referred to as the intrinsic safety/toxicity.

Some excipients subtly alter physiological properties, such as increased gastrointestinal motility, permeability of membranes, metabolism and excretion. This type of toxicity is known as extrinsic.

Examples of undesirable effects in commonly used excipients are shown in the table below.

Safety of an excipient is formally assessed by monitoring its effects on vital systems, in particular, the cardiovascular, the central nervous and respiratory systems.

A material’s toxicity will depend on a variety of factors, including the dose of the substance, duration and route of exposure.

For a long time, excipients were considered inert substances, included in products to facilitate production and/or improve convenience during use.

This definition, in the strictest sense, now only applies to natural, simple substances, such as honey, simple sugars and other substances that are well characterised and known to be inert.

The importance of safety

Modern pharmaceutical products are anything but simple mixtures; they are complex engineered products in which several ingredients are combined to produce specific characteristics.

Many of these complex materials have the potential to adversely affect consumers, particularly if used in large quantities.

For this reason, there is a process for ensuring that the safety of every ingredient in the formulation is well studied and mapped out.

Safety is especially important since excipients are often present in very high proportions relative to the active ingredient.

But safety is also dependent on the way a product is handled, for instance during formulation or manufacturing, it may be exposed to high heat or humidity, leading to an increase in the probability to generating secondary products and impurities to be introduced into the product.

During use, the patient may not store is correctly, leading to further degradation to produce toxic impurities.

Excipients may also interact with the medicinal agent, other excipients in the formulation, the container or the atmosphere, leading to many more undesirable effects.

Thus, safety and toxicity of the pure substance as well as any degradants must be known, both by regulatory agencies and product manufacturers, and rightly so, by the public who are the ultimate users of medical products.

Methods used to assess excipient safety

Mapping out the intrinsic and extrinsic safety, as well as understanding potential risks and post-approval monitoring are what constitute the universe of excipient safety assessment.

Some of the tests and investigations conducted on excipients to understand their instrinsic and extrinsic toxicological profiles are shown in the infographic below.

Note that many of these resemble those tests done on new chemical entities:The challenge for this approach, however, is that there can be no end to it – rather like the proverbial length of a piece of string.

This problem (of unending safety assessment) can be overcome by adopting a risk-based view of safety; by seeking to understand and address any potential risks during the life history of the material, from the earliest stages of synthesis, through to product development, launch and use.

Risk-based assessment of safety

A risk-based approach to safety and toxicity requires manufacturers of the excipient and medical products to adhere to good manufacturing practices (GMPs) when handling excipients, very much similar to those for active ingredients and follow guidelines set by regulatory agencies.

Some of the requirements from regulatory agencies include routine testing of excipients to ascertain and verify a material’s identity, purity, traceability of batches, and quality, which are all important determinants for safety and efficacy of the product.

The particular safety assessment pathway taken is largely dictated by precedence of use. The exact requirements depend on the regulatory agencies, which operate under different rules.

For practical reasons, we’ll focus on three regulatory agencies: the US Food and Drug Administration (FDA), the European Medicines Agency, and the Japanese Ministry of Health, Labour, and Welfare:

Excipients with precedence of use

If an excipient has already been used in an approved pharmaceutical product, is a food additive, or any product with human exposure, that is, where previously safety tests were carried out, it is considered to have precedent.

Such materials are already registered for use and may be included in official pharmacopoeia or compendia.

The US Food and Drug Administration (FDA) has an excipient database (FDA Inactive Ingredients Database) which lists all excipients and their precedence of use.

There is also the United States Pharmacopoeia and National Formulary that carries monographs of approved excipients for use there. You can click here to access the Inactive Ingredients Database.

Related post:

• Full list of excipients Generally Recognised As Safe

The European Medicines Agency does not have a list of ingredients; however, individual member countries have compendia that list approved materials and their routes of administration.

In France, for instance, this is the “Dictionnaire Vidal,” and in Germany the “Die Rote Liste”. The European Pharmacopoeia, just like the USP-NF carries monographs of excipients approved across the bloc.

In Japan, the Japanese Ministry of Health, Labour, and Welfare has a precedence of use compendium known as the Japanese Pharmaceutical Excipients dictionary, and the Japanese Pharmacopoeia. Both show the different excipients that have been previously used in drug formulations in that country, with the description of their characteristics, and the maximum dose used in the different administration routes.

Excipients with no precedence of use

Excipients that have never been used in any products and therefore have no safety assessments undertaken formally are considered novel excipients.

Novel excipients are materials being used in a drug product for the first time or a new route of administration.

In other words, they are not included in the Inactive Ingredient Database, United States Pharmacopeia-National Formulary (USP-NF), European Pharmacopoeia, Japanese Pharmacopoeia, or other compendia, including the “Handbook of Pharmaceutical Excipients.

Also, approved excipients that have undergone chemical modification, however minor, are considered novel excipient by regulatory agencies.

For these materials, there are several guidelines in operation by respective regulatory authorities before they can be permitted for use in medicines.

For instance, the US FDA requires nonclinical and clinical assessments to be undertaken. These studies not only aims to assess the excipient’s intrinsic safety but also the extrinsic Safety profile.

For further reference, please see USP-NF 26 General Chapter <1074 > “Excipient Biological Safety Evaluation Guidelines”, and IPEC’s New Excipient Evaluation Guidelines.

The excipient manufacturer is expected to develop full safety information recommended in the guidelines, based on the material’s future use and dosage form.

The battery of tests to be conducted are described in these guidelines.

Excipient Safety Assessment: Two common Questions

Pharmacopoeia: Are excipients required to be listed in the pharmacopoeia?

A common question that often arises is whether an excipient is required to have a monograph before it can be commercialised. The simple answer is no. There is no regulatory requirement for a monograph.

However, it is always preferable to present an excipient with a monograph or a complementary document that is relevant, because it means that such a material has established quality specifications for pharmaceutical use.

If the excipient is present in several pharmacopoeias, the manufacturer is expected to ensure conformity for all monograph requirements, present in all pharmacopoeias, before its commercialization to the global market.

The manufacturer demonstrates that methods used to test the material are valid and provide assurance that the excipient, when tested by these methods, conforms to all requirements.

When the excipient is not present in any pharmacopoeia or other monograph in a compendium, the manufacturer can establish an own specification, based on a similar monograph present in the pharmacopoeia.

Pharmacopoeia: Can excipients with no monographs be used in medicines?

An excipient that is not written in any pharmacopoeia can be used in a drug product, even if there is no monograph. However, regulatory authorities normally require a detailed evaluation of the excipient’s safety and toxicity, which can be an expensive endeavour.

If there is no monograph available, a specification can be based on the manufacturer’s own experience and in the chemical and physical properties of the excipient according to the intended use of administration.

Inclusion of a novel material into the pharmacopoeia depends on its commercial importance and its use in a pre-approved drug product.

In this case, both the excipient manufacturer and medicinal product manufacturer can request regulatory agencies or the national pharmacopoeia commission to draw up a new monograph, provided the novel excipient has received approval through its use in a marketed drug product.

At this stage, the novel excipient is considered approved for use by the stated route of administration and in the stipulated dosage levels as in the approved drug.

What about Drug Master Files?

The first step to introduce a new excipient in the market is the determination of its functionality, route of administration, identification, and stability of the intended API for a drug formulation.

Once these steps are all set, a document with all information known as a Drug Master File (DMF), or European Certificates of Suitability (CEP) is created.

This document provides all the technical information such as specifications and test methods for raw materials, in-process testing, the finished excipient product, manufacturing process, safety, packaging details, and content label.

In the United States, the supplier submits the DMF to FDA, which is held in confidence by the administration. In Europe, the DMF only exists for APIs and is not available for excipients.

CEPs are used for pharmaceutical excipients, which may be treated in two ways: CEPs for excipients listed in Ph. Eur and CEPs for excipients not listed in the Ph. Eur.

Other supplementary tests for assessing safety

Excipient assessments for generic drug products

During generic product development, the sponsoring company may choose to use excipients that are different from the innovator formulation either because of a change in route of administration or dosage forms.

In this case, the formulations and or route of administration are different but the API is already established and known.

In both cases, excipients will be selected based on the function they perform, compatibility with the API and other formulation components and any other considerations, such as cost, material availability and the company’s own experience and preferences.

Regulatory approval will only be granted if it’s established that the excipients are suitable to be used in the new formulation, via the intended route of administration or the dosage form specified for the new drug product.

Investigations of Excipient – API Incompatibilities

Since some excipients react with and can modify excipients or the API, additional compatibility studies between excipients and APIs are mandated. Such reaction products may be harmful or alter the stability of the API.

There are many ways excipient compatibility studies can be done, the most common ones being differential scanning calorimetry (DSC) or isothermal calorimetry, using simple blends of the excipient and API in simple ratio.

Thus, assessing the nature of these interactions therefore aims to select only materials that are compatible with the drug and will not compromise the stability or safety of the formulation. If incompatibilities are established, the formulation team will aim to alleviate the incompatibilities.

Presence of impurities and residual solvents

The presence of impurities and solvents in the product formulations need to be identified and controlled within specified limits. Impurities and solvents can be introduced during the material’s manufacture, product formulation or production.

Residual solvents are classified into three main groups, depending on their toxicity and potential harm:

Class 1 solvents are to be avoided in the formulation because they are known or suspected carcinogens and hazardous to the environment. Examples of Class 1 solvents include carbon tetrachloride and benzene.

Class 2 solvents are to be limited because while being non-genotoxic are suspected to have neurotoxicity or teratogenicity, or suspected to be causative agents of the same. Examples of Class 2 solvents include acetonitrile, methanol and dioxane.

Class 3 solvents have low toxic potential to humans however, they may be limited in terms of the total quantities allowed in the formulation. Examples of Class 3 solvents include ethanol, acetone and ethyl acetate.

Excipient stability studies

Excipient stability studies are carried out with the aim of determining whether the material maintains its quality over the time period it is used. The excipient will be studied under various environmental conditions, such as high temperature, light and humidity.

A major objective of excipient stability studies is to determine the expiry date or re-test period, which refers to the time period within which the raw material is expected to remain within specification, and therefore, safe for use in the drug product. A material that has expired and or has not been re-tested is not safe for use, and should be destroyed.

Market surveillance

The final, and by no means the least aspect of safety assessment is market surveillance post-launch of the product onto the market, whereby healthcare professionals and the public report any side and adverse effects encountered into a central database. The data are then collated and analysed for patterns and trends that might point to previously unreported toxicity to ensure the product is withdrawn before it can harm more people.

The significance of market surveillance is evident when you consider the fact that twenty percent of adverse effects and toxicities are discovered during this phase of market surveillance.

Conclusions on excipient safety

For a long time only the quality, efficacy, and safety of the API was considered as the most important aspects of a new medicine.

This approach has now changed, and manufacturers are required not only to study an excipient’s safety but they must also justify its inclusion in a product.

Any ingredient used in the product must be beneficial and help optimize the performance of the product, both during the manufacture and also during use.

The process of assessing safety involves a battery of established tests that determine the physiological effects of the material, including potential effect on the cardiovascular, respiratory and central nervous system.

In addition, any interactions with other components in the product must be studied and understood fully.

The rule of the thumb is to simplify formulations as much as possible and reduce the number of excipients to those that are absolutely necessary.

Sources used

American Academy for Paediatrics: Committee on Drugs. ‘Inactive’ ingredients in pharmaceutical products update (Subject review). Pediatrics 1997;99(2):268–278. Available at: http://pediatrics.aappublications.org/content/99/2/268.long (accessed August 2021)

Turner MA, Duncan JC, Shah U et al. Risk assessment of neonatal excipient exposure: lessons from food safety and other areas. Adv Drug Deliv Rev 2014;73: 89–101. DOI:10.1016/j.addr.2013.11.003

C.L. Winek, History of excipient safety and toxicity, Drugs and the pharmaceutical sciences, 103 (2000) 59-72. PMID: 27262205. DOI: 10.1016/j.xphs.2016.03.019

Substances that are established components of human or animal food can, upon qualification by a scientific committee, be granted GRAS status.

For pharmaceutical excipients, GRAS status represents an interesting class of materials for product formulators since their safety profile is already considered and sufficiently known.

In this post, we will review the ins and outs of GRAS listed excipients and summarise their implications when it comes to inclusion in products, especially if they are intended for use in the United States of America.

What is the GRAS Excipients List?

“GRAS” is an abbreviation used by the US FDA for food ingredient or additives that the agency has deemed safe. It stands for Generally Recognized As Safe.

The basis for GRAS is sections 201(s) and 409 of the Federal Food, Drug, and Cosmetic Act, under which these substances are reviewed and approved by the FDA.

Typically, any substance that has undergone the required safety assessment by a team of experts and deemed not to cause harm when used as intended can be added to the GRAS ingredients list.

This allows the manufacturers of such materials to assign GRAS status to the material.

Alternatively, a material that was in use in the human diet before 1958, and used in such significant quantities across the population of the United States without any safety concerns. may be assigned GRAS status.

Excipients are a diverse group of ingredients other than the active ingredient(s) added to medicines, medical devices, some cosmetic products or nutraceutical food supplements.

They perform specific functions, such as promoting the product’s stability, bulk or ease of use.

Any food ingredient on the FDA’s GRAS List that is also approved for use as an excipient is a GRAS Listed excipient, provided it is manufactured and used in accordance with the provisions of sections 201(s) and 409 of the Federal Food, Drug, and Cosmetic Act.

Note that all excipients need to meet minimum safety requirements before they can be used in products for use by the public.

There are several certification schemes around the world, including the listing in an official pharmacopoeia, such as the United States Pharmacopoeia as well as country compendia or lists, such as the Japanese Pharmaceutical Excipients list.

Purpose of the GRAS List

The main purpose of the GRAS list is to speed up the approval and market introduction of new products and to reassure the public that the products they are consuming are safe and wholesome.

Even though the FDA has premarket approval responsibilities over food additives, a company can add an ingredient into human food products without first seeking the agency’s approval provided the ingredient has GRAS status for the intended use.

Picture a situation where regulatory agencies such as the US FDA needed to assess every ingredient de novo each time new products were launched onto the market?

Not only would this be demanding in terms of human resources for regulatory agencies but it would put strain onto new product manufacturers who would need to resubmit data on these ingredients.

Highly repetitive and unnecessary, and would slow down innovation.

Instead, having a pre-approved list of excipients permits manufacturers and scientists to create new products and meet new demands by easily incorporating these materials into their products without having to apply for fresh approvals.

History of GRAS Status

In 1958, the US Congress passed the Food Additves Amendment to the FD&C Act as a response to widescale public outcry on the rising use chemicals in food products.

The basic tenet of this law was to mandate that before any substance could be added to food products or used in food processes, companies had to demonstrate to the FDA that the substance was safe.

The FDA was required to define the conditions under which substances were to be used. Congress also stipulated mechanisms and pathways for demonstrating safetyestablished. You can read more about this topic through this link.

Suffice to say, Congress adopted a two-step definition of food additives. The first step covers substances that become components of food while the second is for substances generally recognised by experts to be safe.

GRAS Listing Process

Any material that is not a food additive and is not required to be approved through the food additive process can be added to the GRAS List provided the necessary assessments have been undertaken.

The process of GRAS listing is schematically illustrated below:

Currently GRAS Listed Excipients

There are currently just over 370 substances with GRAS status, a number of which are also approved excipients with monographs in the USP-NF, Ph.Eur or JP.

Typically, GRAS Listed excipients include natural, synthetic or semi-synthetic materials. A list of these GRAS-listed excipients, links to their descriptions and uses is shown below:

Is GRAS List regularly updated?

The GRAS List is constantly under review. A material on the list can indeed be removed and its status revoked by the FDA. This happened in the past when partially hydrogenated fats were removed from the list in 2015 by the FDA.

What is the SCOGS Database?

The SCOGS Database permits the public to find and read for themselves the different opinions and decisions made by the FDA and its experts (in reality, the data is limited to the period between 1972 and 1980) about the safety of over three hundred ingredients.

Click here to access the SCOGS Database.

Conclusion

So there you have it. Excipients that also have GRAS status essentially means that their use is not subject to pre-market review by the FDA for their intended use determined by an expert scientific committee.

The GRAS framework provides an additional safeguard for public welfare, by requiring manufacturers to provide information needed by regulators and consumers, regarding safety of ingredients added into consumer products.

Sources Used

To ensure our content is accurate and scientifically sound, Pharmacentral implements a strict referencing policy. We only use peer-reviewed studies and reputable academic sources and authors.

Personal opinions and anecdotes are not used.

• T.G. Neltner, N.R. Kulkarni, H.M. Alger, M.V. Maffini, E.D. Bongard, N.D. Fortin, E.D. Olson, Navigating the U.S. Food Additive Regulatory Program, Comprehensive Reviews in Food Science and Food Safety, 10 (2011) 342-368.
• https://www.fda.gov/food/food-ingredients-packaging/generally-recognized-safe-gras

As pharmaceutical companies move increasingly toward changing production methods from batch to continuous processing, there is a need to re-evaluate the types and formulations of the excipients used. Within a continuous process, conventional monofunctional excipients must be added through individual feeders, potentially creating multiple sources of variability. In contrast, a single high-functionality co-processed excipient requires only one feeder, thus enhancing product performance while minimizing variability. This article discusses some benefits of continuous manufacturing and reports on the evaluation of a co-processed excipient composite comprising binder-filler, lubricant, superdisintegrant and glidant, used in tablet production. Click here to download this technical guide.

Benefits of Using High-Functionality Excipients in a Continuous Manufacturing Process PDF