Excipients: New opportunities for complex challenges – USP’s approaches

Abstract

The quality of excipients is important since they can make up to about 90% of the total mass/volume of the drug product. Traditionally, excipients specifications were established with a focus on quality for intended use in the drug product and less on excipient composition, and physical and chemical properties, however, the increasing demand for high quality excipients used in the development of nanomedicines and novel delivery systems requires higher quality and purity, e.g., use of phospholipids in development of Covid-19 vaccine nanomedicine delivery systems. USP is collaborating with stakeholders to address the lack of standardized test methods for complex/polymeric type excipients (e.g., phospholipids/LG polymers) offering new solutions and help with excipient compositional and variability issues along with associated environmental aspects. By expanding its offerings through its “emerging standards” new model for stakeholder engagement, USP is more flexible in its solutions offerings that favor earlier interaction in the genesis of quality standards in a more iterative way. This publication will provide an overview of evolving compendial approaches (e.g., standalone chapters) and expanded solutions and offerings (use of analytical reference materials (ARMS), associated application (App) notes, and technical guides).

Introduction

Excipients are important components of medicines that may constitute up to 90% of the total mass/volume of the drug product. They are essential for medicines to function in the body and can cause harm to patients if their quality is poor. Misidentification of high-risk excipients used in pediatric medicines due to adulteration by diethylene glycol (DEG) and ethylene glycol (EG), and contamination of alcohol-based hand sanitizers with methanol are just two recent examples of incidents that have resulted in numerous poisonings and fatalities worldwide [1], [2], [3], (Table 1). The pharmaceutical market has become truly globalized, with manufacturers increasingly operating across multiple countries and multiple supply chains with highly variable technical and regulatory capabilities, as evidenced during the COVID-19 pandemic. At the same time, a large pipeline of new medicines is in development, with a marked shift towards new and increasingly complex and advanced therapies and modalities. Advances in science, engineering, and software technologies, from gene sequencing, process engineering, and analytical technologies to data modeling and analytics, are continuing to transform the drug development process and accelerate the introduction of innovative and unique products. The industry is also seeing the increasing adoption of new manufacturing approaches, such as continuous and “on-demand” manufacturing and the use of advanced data and analytical technologies to monitor and measure product quality throughout the manufacturing process. Today’s rapidly changing, and increasingly complex pharmaceutical landscape requires new approaches to the development of public quality standards [4]. Recognizing this fact, the United States Pharmacopeia (USP) is focused on building trust in the supply of safe, quality medicines by being a definitive source of quality standards [5], [6].

Traditionally, excipient specifications were established with a focus on determining a suitable quality for the intended use or function in the drug product, with less emphasis on excipient composition and variability. Starting in 2005, in response to stakeholder needs, the USP Excipients Expert Committee’s (EC) focus expanded to include both introduction and modernization of official quality USP-NF excipient standards to provide better characterization methods and an enhanced understanding of composition, variability, and performance. This renewed approach helps ensure that excipients are fit for purpose and addresses potential threats from the complexities of the global supply chain. Furthermore, the introduction of advanced analytical techniques is helping provide standardized methods and materials that address stakeholders’ needs concerning excipient quality, composition, and variability. The updated USP Excipient Request for Revision Guidelines and the Excipient Nomenclature Guideline streamline and expedite the USP standard-setting and naming processes, making it more efficient and beneficial to USP stakeholders [7], [8].

In 2022, USP proposed “emerging standards” as a new model for stakeholder engagement that favors earlier interaction in the genesis of quality standards in a more iterative way [4]. Furthermore, the emerging standards / iterative standard development approach provides a path forward for USP to better support novel excipients development and address the challenges faced by stakeholders at the exploratory and innovation stage of development, since novel excipients have no prior use in drugs or foods and are not yet eligible for National Formulary (NF) admission. USP is continuously evolving its standards in response to stakeholder input and advances in technology and regulatory science. Advanced methodologies for compositional testing of complex/polymeric-type excipients are being introduced in new compendial monographs and general chapters or revisions thereof, as well as in other approaches and solutions discussed below. These include USP Analytical Reference Materials (ARMs) and resources like case studies, technical guides, and Application Notes (Apps), as tools to help address the lack of standardized methods and materials for quality testing throughout product innovation, development, and manufacturing lifecycle.

The article serves as an overview of USP’s strategies and approaches to addressing complex challenges in the use of excipients in medicines highlighting key directions and activities underway in collaboration with global stakeholders.

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Catherine Sheehan, Tong (Jenny) Liu, Peng Zhang, Hong Wang, Anni Chang, Excipients: New opportunities for complex challenges – USP’s approaches, European Journal of Pharmaceutics and Biopharmaceutics, Volume 223, 2026, 115045, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2026.115045.

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