The Need for Innovation in the Excipient Toolkit
As bio/pharmaceutical drug development progresses and more complex molecules enter the pipeline, increased innovation and a rethink of excipient portfolios is necessary.
Pharmaceutical excipients are considered an essential part of modern drug formulation. Comprising approximately 50–90% of the finished product, excipients ensure that limitations of the API, such as poor solubility or stability, can be overcome, enabling effective performance and delivery in the end user (1,2).
However, despite the recognized criticality of excipients, true innovation within the sector has been stifled as a result of ambiguous regulatory approval processes, which typically require a novel excipient to be evaluated only as part of a final drug product application rather than through an independent pathway (3,4). Consequently, pharmaceutical companies and marketing authorization holders (MAHs) often rely heavily on traditional, well-established excipients to avoid jeopardizing drug approval timelines (2).
Innovating within Existing Boundaries
To innovate within the boundaries of existing regulations and compendial monographs, manufacturers are increasingly turning to advanced physical modification techniques that alter the solid-state properties of established excipients without modifying their molecular structure. By manipulating characteristics such as particle size distribution, morphology, porosity, and crystalline polymorphism, formulators can significantly enhance the excipient’s critical material attributes, including compactability, flowability, and dissolution kinetics (5).
For example, engineering specific polymorphic forms of mannitol (6) or modifying the porous architecture of calcium silicate (7) allows formulators to resolve complex manufacturing challenges like poor API compressibility while utilizing chemically identical materials that conform perfectly to established United States Pharmacopeia (USP) or European Pharmacopoeia (Ph.Eur.) monographs. Additionally, using quality-by-design (QbD) methodologies to characterize variability within monographed excipient lots enables manufacturers to intentionally optimize formulation performance for specific therapeutic delivery needs (8).
The Power of CoPEs
One of the most successful manifestations of physical innovation within existing chemical boundaries is the development of co-processed excipients (CoPEs), which offer manufacturers a tool to improve various functionalities, such as compressibility and disintegration, beyond what is achievable with a simple physical blend (9). From a stringent regulatory perspective, the distinction between a simple physical blend and a co-processed excipient hinges on the nature of the particle interaction and the manufacturing process.
A simple physical blend is a low-energy combination of two or more independent compendial excipients that can be separated by routine physical means, such as mechanical sieving or density-based separation. Conversely, a CoPE is defined as a highly engineered composite material containing two or more monographed or non-monographed excipients that have been physically interacting at a sub-particle level via processes such as high-shear granulation, spray drying, or co-crystallization (9,10).
The critical regulatory line is drawn at the atomic level: while the constituent components of a CoPE interact closely via van der Waals forces, hydrogen bonding, or physical entrapment to form a singular particulate system with unique synergistic properties, no new chemical covalent bonds are formed during the manufacturing process (10). As the chemical identity of each individual component remains unaltered, a CoPE is legally classified as a physical composite rather than a novel chemical entity, though it exhibits performance characteristics distinct from its individual parts (11).
Formal Risk Assessments and Guidance
To manage the filing requirements for these composite materials, the European Medicines Agency (EMA) recently published a dedicated Question and Answer document outlining a risk-based approach for quality dossiers, which represents a highly significant framework for pharmaceutical manufacturers (12). Under this risk-based paradigm, the EMA shifts the regulatory burden away from a rigid, one-size-fits-all testing protocol and instead requires the MAH to provide a comprehensive scientific justification based on the complexity of the co-processing manufacturing method and the intended function of the excipient in the dosage form.
Manufacturers must conduct formal risk assessments to demonstrate that the processing steps do not inadvertently generate novel chemical impurities, degrade the constituent materials, or alter the biopharmaceutical safety profile of the final drug product (12,13). This approach is highly important for manufacturers because it provides a predictable, scientifically logical pathway for the inclusion of advanced multi-functional excipients in regulatory submissions.
By validating that the co-processing does not alter the fundamental toxicology of the component excipients, manufacturers can use the risk-based framework to bypass expensive, time-consuming in vivo toxicological studies and, ultimately, accelerate development timelines for high-performance oral solid dosage forms (13).
Urgency for Specialized Excipient Platforms
However, the pharmaceutical landscape is increasingly transitioning from small molecule therapeutics toward biologics and advanced niche modalities, giving rise to a fundamental shift in the technical requirements for formulation design. This change has exposed gaps in the traditional excipient toolkit (14).
Missing links in the contemporary excipient toolkit include specialized, highly purified stabilizing agents capable of preventing protein aggregation, oxidation, and surface adsorption in high-concentration biologic formulations without precipitating immunogenic responses (14,16). Furthermore, the industry lacks biocompatible, biodegradable polymeric matrices tailored specifically for the intracellular trafficking and targeted cytosolic release of macromolecular payloads, such as clustered regularly interspaced short palindromic repeats-Cas9 complexes and small interfering RNA, without causing localized cellular toxicity (15).
The current reliance on a narrow selection of polysorbates and simple sugars exposes advanced therapies to severe degradation vulnerabilities, such as peroxyl radical-mediated oxidation and enzymatic hydrolysis, highlighting an urgent need for specialized excipient platforms engineered for modern macromolecular architectures (16).
Global Regulatory Fragmentation
These persistent excipient uncertainties are further amplified by the fragmented nature of global regulation, where differing requirements between international regulatory authorities frequently create commercial friction (4). To foster better alignment and ensure that an excipient innovation introduced in one geographic region is not contrary to regulations in another, closer collaboration is required by relevant stakeholders to establish a unified, independent global evaluation pathway for novel excipients (3).
By expanding precompetitive research collaborations, standardizing data requirements for toxicological qualification, and driving the convergence of regional pharmacopeial monographs through the Pharmacopeial Discussion Group (PDG), the industry can eliminate redundant testing mandates (2,17). Creating a globally recognized Master File system would allow excipient suppliers to submit confidential safety and manufacturing data once to multiple agencies simultaneously, ensuring that regulatory authorities in the United States, Europe, and Japan review identical data packages under synchronized timelines, mitigating the regulatory risk for global drug developers (17,18).
References
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Mitchell, M.J.; Billingsley, M.M.; Haley, R.M.; et al. Engineering Precision Nanoparticles for Drug Delivery. Nat. Rev. Drug Discov. 2021, 20, 101–124.
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