New Approach Methodologies for Novel Excipients: Current Status and Outlook

Regulatory support for New Approach Methodologies is growing rapidly. For excipients, however, acceptance remains largely case-specific and linked to the medicinal product. The opportunity today is to use NAMs, read-across and existing data to build a more relevant safety argument and to focus any remaining animal studies on genuine uncertainties.

Why this matters

New drug products increasingly depend on excipients that improve solubility, stabilize proteins and nucleic acids, control release or enable new routes of administration. Yet a new excipient is normally assessed within a medicinal-product application rather than approved independently. The first drug developer using it therefore carries much of the regulatory risk.

New Approach Methodologies, or NAMs, could help reduce this barrier. FDA defines NAMs broadly as innovative methods and strategies that include human-based in vitro systems, in silico modelling and other platforms that can improve the relevance of nonclinical evaluation [1]. The toolbox also includes read-across, physiologically based pharmacokinetic modelling, organoids, microphysiological systems, omics, artificial intelligence and integrated weight-of-evidence assessments.

NAMs should not be treated as a menu of animal-free tests. Their value lies in combining different evidence streams to answer a clearly defined safety question.

United States: strong momentum, but an excipient gap remains

FDA’s Roadmap to Reducing Animal Testing in Preclinical Safety Studies, published in April 2025, describes a staged transition toward computational models, organ-on-chip systems, advanced in vitro assays and human data [2]. In March 2026, FDA issued draft guidance describing general principles for validating and reporting NAMs used in drug development [3].

FDA has also published examples of nonclinical programmes in which NAMs or reduced animal testing may be acceptable. Importantly, the agency states that this inventory excludes studies related to impurities and excipients [4]. The wider policy change therefore does not automatically create an accepted NAM pathway for novel excipients.

The principal FDA guidance dedicated to excipient safety remains the 2005 guidance on nonclinical studies [5]. It provides a useful framework, but predates modern read-across, microphysiological systems and AI-supported toxicology.

The Novel Excipient Review Pilot Program, launched in 2021, was an important step. It allowed a small number of manufacturers to request review of an excipient before its inclusion in a particular drug formulation [6]. It was not, however, a general approval system. The safety conclusion still depends on the route, dose, duration and intended patient population.

Europe: policy is moving faster than the excipient pathway

Directive 2010/63/EU establishes replacement, reduction and refinement of animal use as a legal objective [7]. EMA supports this through its 3Rs Working Party, expert networks and horizon-scanning activities. These initiatives recognize both the potential of NAMs and the remaining problems, including inconsistent terminology, limited reference datasets and uncertain performance standards [8].

On 1 September 2026, EMA launched a voluntary data submission pilot. Companies, laboratories and method developers can submit NAM data independently of a marketing-authorisation application and receive individual regulatory feedback. The feedback is non-binding and non-decisional, but the programme gives European regulators access to data they would not normally see. Submissions are expected until the third quarter of 2027, followed by a lessons-learned report [9].

The current general European guideline for excipients became effective in January 2008, and novel excipients are still assessed within the medicinal-product dossier [10]. A newer EMA Q&A for co-processed excipients, effective from August 2026, introduces three risk categories and corresponding dossier expectations [11]. This is primarily a quality document, but its tiered approach could become a useful model for other types of excipient innovation.

The European Pharmacopoeia has already demonstrated that replacement is possible for a well-defined endpoint. It removed the rabbit pyrogen test from 57 texts and introduced a risk-based choice of suitable in vitro methods. The revised texts became applicable in July 2025 [12].

A practical NAM toolbox for excipients

A credible programme should begin with the material and its intended use, not with the test technology.

1. Define the context of use. Specify the grade, route, maximum daily exposure, treatment duration, patient population and expected local and systemic exposure.
2. Characterize the material. Relevant attributes may include molecular-weight distribution, substitution pattern, particle properties, residual reagents, catalysts, impurities, degradation products and batch variability.
3. Collect prior knowledge. FDA’s Inactive Ingredient Database provides information on previous approved use by route and dosage form [13]. It is a starting point, not an automatic safe-use limit. Food, cosmetic, clinical and pharmacopoeial experience may also contribute.
4. Use computational methods. The OECD QSAR Toolbox supports analogue identification, grouping and data-gap filling. The OECD assessment framework requires documentation of the endpoint, model, applicability domain, underlying data and prediction uncertainty [14,15].
5. Select targeted tests. In vitro, in chemico and microphysiological methods should address remaining questions such as irritation, sensitization, genotoxicity, barrier effects, cellular stress, inflammation or metabolism.
6. Integrate the evidence. The final output should connect identity, existing data, read-across, experimental findings, exposure margins and uncertainty in one auditable weight-of-evidence assessment.

Read-across and bridging

Read-across may be particularly useful because many innovations are new grades, modified forms or combinations of established materials rather than completely new chemical entities. Similar names are not enough. The bridge must consider composition, physicochemical properties, impurities, metabolism, degradation, toxicokinetics and route of administration.

For a new grade within an established family, analytical comparability and manufacturing history may provide the main bridge. A new use requires attention to changes in route, dose, duration and population. A chemically modified grade requires evaluation of the degree of modification, metabolites and degradation products. For a co-processed excipient, the safety history of the individual components remains relevant, but possible process-induced changes, interactions and new impurities must also be addressed.

A new chemical entity will normally require the broadest integrated programme. NAMs and read-across can make that programme more focused, but are unlikely to remove every conventional requirement immediately.

Where to find data

Useful official starting points include FDA’s Inactive Ingredient Database [13], the OECD QSAR Toolbox [14], the NIH Integrated Chemical Environment, EPA’s CompTox Chemicals Dashboard and CAMERA, the US collection of alternative methods with regulatory relevance [16–18]. These resources support scoping and data-gap analysis. They do not replace supplier information, batch data or confidential studies held in a Drug Master File.

Outlook and call to action

The direction is clear, but the transition will be gradual. Over the next few years, regulators are likely to receive more submissions combining NAM and conventional data. This will help define contexts of use, performance standards and acceptable uncertainty. Read-across and analytical bridging should become increasingly important for new grades and modified members of established excipient families.

The excipient community now needs a tiered review pathway that distinguishes among new grades, co-processed excipients, new uses, chemically modified materials and new chemical entities. A standardized bridging table should show the source and target materials, their similarities, relevant differences and residual uncertainties. Confidential manufacturing and toxicology data could remain protected in a master file, while a public conclusion identifies the recognized conditions of use.

International alignment is equally important. Common terminology, reporting templates and data standards would allow a well-supported excipient assessment to be reused across products and regions.

NAMs are no longer a theoretical ambition. They are entering regulatory practice. For novel excipients, they will initially supplement existing evidence and reduce unnecessary animal studies rather than replace every study. That is still meaningful progress. It can improve human relevance, reduce development risk and create a more realistic pathway for excipient innovation.

References

1. US Food and Drug Administration. New Approach Methodologies. 2026.
2. US Food and Drug Administration. Roadmap to Reducing Animal Testing in Preclinical Safety Studies. 2025.
3. US Food and Drug Administration. General Considerations for the Use of New Approach Methodologies in Drug Development. Draft guidance. 2026.
4. US Food and Drug Administration. CDER Streamlined Nonclinical Studies and Acceptable NAMs. 2026.
5. US Food and Drug Administration. Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients. 2005.
6. US Food and Drug Administration. Novel Excipient Review Pilot Program. Federal Register. 2021.
7. European Parliament and Council. Directive 2010/63/EU. 2010.
8. European Medicines Agency. Horizon scanning: Identifying emerging trends. 2025.
9. European Medicines Agency. Voluntary data submission pilot to advance innovative alternatives to animal testing. 2026.
10. European Medicines Agency. Guideline on excipients in the dossier for application for marketing authorisation. Revision 2. 2007.
11. European Medicines Agency. Questions and answers regarding co-processed excipients. 2026.
12. European Directorate for the Quality of Medicines & HealthCare. Replacement, Reduction and Refinement of animal testing: latest achievements.
13. US Food and Drug Administration. Inactive Ingredient Database.
14. Organisation for Economic Co-operation and Development. OECD QSAR Toolbox.
15. Organisation for Economic Co-operation and Development. (Q)SAR Assessment Framework. 2023.
16. National Toxicology Program. Integrated Chemical Environment.
17. US Environmental Protection Agency. CompTox Chemicals Dashboard.
18. National Institutes of Health. CAMERA.

By Philippe Tschopp
Philippe Tschopp writes about pharmaceutical excipients, formulation and oral drug delivery, with a focus on excipient functionality, practical formulation considerations and lesser-known material properties.

Disclaimer

This article is based on publicly available information and industry sources at the time of writing and supported by AI. While every effort has been made to ensure accuracy, completeness, and fair representation, the author does not guarantee that all information is current, error-free, or reflective of the latest developments.

The content is provided for informational and educational purposes only and does not constitute technical, regulatory, or commercial advice. No liability is accepted for decisions made based on this material. Readers are encouraged to consult the original manufacturers and official sources to verify details before making professional or business decisions.