Publication of EMA Document on the Establishment of a Guideline on mRNA Vaccines

The published document from the European Medicines Agency addresses the need to establish a guideline on the quality aspects of mRNA vaccines. In recent years, the number of applications for clinical trials for human medicinal products as well as for marketing authorization for mRNA-containing medicinal products has increased significantly and is expected to continue to increase in the near future. From an analytical and regulatory perspective, mRNA vaccines are of interest because their classification depends on the target and/or whether they are derived by chemical or biological means. mRNA vaccines against infectious diseases must comply with the current guidelines for human vaccines. However, this new technology is not fully addressed in the existing documents. It is therefore proposed that a guideline be developed to address the specific aspects of the manufacturing process, characterization, specifications, and analytical control, as well as the definition of the active ingredient and finished product for mRNA vaccines for the prevention of infectious diseases.

The scope of the guideline will be limited to mRNA vaccines against infectious diseases (including self-amplifying mRNA). mRNA-based therapeutics do not fall within the scope of the document. For now, It is not intended to address specific requirements for mRNA vaccines for clinical trials; however, the scientific principles described may also be applied to pharmaceutical development.

Because the manufacturing of mRNA vaccines must be compliant with the general guidelines for human vaccines, special quality considerations may apply to these novel products. The proposed guideline is based on the structure of CTD Module 3, where relevant. In addition, finished product considerations (e.g., excipient selection, formulation and manufacturing aspects) relevant to mRNA-containing finished product formulations are addressed. The guide provides information and regulatory considerations on the following key aspects of manufacturing and quality control:

• Definitions of terms: Starting materials, active ingredient, finished product intermediate, excipients and finished product
• Control of starting materials
• Development of an integrated control strategy for the active ingredient and finished product
• Manufacturing process to ensure consistent quality of mRNA vaccines, based on relevant critical quality attributes (CQAs)
• Characterization approaches including investigation of impurity profile
• Contamination control strategy: process- and product-related impurities as well as other potential impurities and methods to control them
• Active ingredient and finished product specifications
• Efficacy testing: various tests may be required to control different aspects of efficacy, including functionality (e.g., mRNA expression, protein expression in transduced cells)
• Various aspects related to formulation strategies, including considerations for lipid nanoparticle (LNP) formulation and manufacturing process and stability
• Stability studies for active ingredient and finished product

Other regulatory considerations and challenges

The guidance described also addresses the following regulatory considerations and challenges:

• The development and testing of bivalent and multivalent vaccines, and modifications to existing strains of mRNA vaccine
• Self-amplifying mRNA (sa-mRNA) packaged in LNPs
• Other carrier systems (i.e., non-LNPs)

EMA is requesting assistance with this document and needs your expertise. The comment period for this document ends on September 30, 2023.

For the full original EMA document, see "Concept Paper on the development of a Guideline on the quality aspects of mRNA vaccines".