A Rapidly Maturing Regulatory Framework
The approval of the first mRNA COVID-19 vaccines in late 2020 was a watershed moment for LNP-based medicines and for the regulatory agencies that oversee them. Within the space of two years, both the FDA and EMA moved from limited experience with LNP products to reviewing and approving the most widely administered pharmaceutical products in history. The data generated during that period, on LNP characterisation, stability, immunogenicity, and manufacturing, has fundamentally shaped the expectations that regulators now bring to new LNP development programmes.
The regulatory frameworks for nanomedicines continue to evolve, and developers entering the field in 2026 face a more defined but also more scrutinised path than those who filed the first LNP programmes a decade ago. This article outlines the current regulatory expectations for LNP-based therapeutics at both the FDA and EMA.
Key Regulatory Guidance Documents for LNP Developers
| Document | Agency | Relevance to LNP Programmes |
| Guidance for Industry: Drug Products, Including Biological Products, that Contain Nanomaterials (2022) | FDA | Defines nanomaterial scope; addresses CMC characterisation expectations including particle size, surface properties, and stability |
| Reflection Paper on Nanotechnology-Based Medicinal Products for Human Use (EMA/CHMP/79769/2006 and updates) | EMA | Foundational guidance on physicochemical characterisation and non-clinical testing expectations for nanomedicine products |
| ICH Q8(R2) Pharmaceutical Development | ICH | Quality by Design framework applicable to LNP development; design space and control strategy concepts |
| ICH Q2(R2) Analytical Validation | ICH | Validation requirements for LNP-specific analytical methods including encapsulation assays and particle characterisation |
| FDA mRNA Product-Specific Guidance | FDA | Product-specific guidance documents for mRNA vaccines and therapeutics addressing CMC and non-clinical requirements |
| EMA Guideline on Excipients in the Dossier for Application for Marketing Authorisation | EMA | Relevant to novel lipid excipients used in LNP formulations that are not covered by existing compendial monographs |
CMC Expectations for an LNP IND or IMPD Filing
Drug Substance: The Nucleic Acid Payload
For mRNA-based LNP products, the mRNA is the drug substance, and the LNP is the drug product formulation system. The mRNA drug substance section of Module 3 must address the mRNA sequence and structure including the 5-prime cap, UTR design, and codon optimisation strategy, the manufacturing process for in vitro transcription, the impurity profile including residual template DNA, truncated transcripts, and dsRNA, and the analytical methods used to characterise sequence integrity, purity, and potency. FDA’s guidance on mRNA drug substance CMC provides the current framework for these requirements.
Drug Product: The LNP Formulation
The drug product section must describe the LNP composition including the identity and grade of each lipid component, the drug-to-lipid ratio, and the buffer system. Novel ionisable lipids that are not described in the current literature or approved products require a more detailed justification of their physical and safety properties. The manufacturing process description must cover the microfluidics or extrusion process, the critical process parameters and their ranges, and the in-process controls applied at each step.
Characterisation: The Critical Quality Attributes
Regulators expect a comprehensive physicochemical characterisation package covering at minimum particle size and PDI, encapsulation efficiency, zeta potential, lipid composition (identity and purity of each lipid component), mRNA integrity, and potency by in vitro translation assay. The method used to measure each CQA must be described, and where the method is not a compendial or established published method, abbreviated validation data supporting fitness for purpose is expected at the IND or IMPD stage.
Stability: Supporting the Clinical Trial Duration
The stability data submitted with an IND or IMPD must cover the duration of the intended clinical trial, including a margin for shipping and site storage. For LNP products stored at minus 20 or minus 80 degrees Celsius, the stability programme must include data at the intended long-term storage condition and, ideally, at an intermediate temperature to demonstrate the impact of inadvertent excursions. Accelerated stability data at minus 20 degrees Celsius for products stored at minus 80 degrees Celsius is increasingly expected by regulators as an indicator of the stability margin.
The Novel Excipient Question
Many of the ionisable lipids used in current LNP programmes are proprietary compounds not described in pharmacopoeial monographs or in the composition of previously approved products. Regulators classify these as novel excipients and require a more comprehensive safety and characterisation package than would be required for an established excipient. For Phase I filings, the FDA and EMA have accepted abbreviated novel excipient packages that focus on physicochemical characterisation and the non-clinical toxicology data generated in the IND-enabling studies. The full novel excipient justification is required at the NDA or MAA stage.
How Ardena Supports LNP Regulatory Filings
Ardena’s regulatory team works alongside its nanomedicine formulation scientists at Oss to build CMC packages for LNP-based IND and IMPD filings. The team has experience preparing Module 3 sections for both mRNA LNP and small molecule LNP products, and can advise on the current FDA and EMA expectations for characterisation data, novel excipient justification, and stability programme design.
