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Analytical Procedures for mRNA Vaccine Quality (Draft Guidelines)- 2nd Edition

Type of Posting: General Announcement
Posting Date: 28-Apr-2023 
Input Deadline: 25-Jul-2023 
Expert Committee: Biologics Monograph 3 – Complex Biologics & Vaccines 

Proposed Title:  Analytical Procedures for mRNA Vaccine Quality (Draft Guidelines) – 2nd Edition

Suggested audience: Suppliers and manufacturers of mRNA vaccine drug substances, contract manufacturing organizations, drug testing organizations, regulatory agencies, and QA/QC specialists.

Background and objective:  The global mRNA therapeutics market is expected to expand tremendously in the next ten years due to its benefits, including being more effective, faster to design and produce, as well as more flexible compared to traditional approaches. mRNA-based therapeutics and preventatives are in development for a variety of refractory diseases, including infectious diseases, metabolic genetic diseases, cancer, and cardiovascular diseases.

Creating shared understanding is critical to advancing adoption of this technology. To address the need, USP is developing a set of analytical methods for mRNA quality to support developers, manufacturers, regulatory agencies, and national control laboratories worldwide. The goal is to create a shared understanding of mRNA quality attributes overall, which aims to accelerate product development, guide successful scale-up of manufacturing and fuel regulatory confidence that manufacturers are employing best practices and appropriate quality controls when using this new modality. 

In February 2022, USP released the first version of the draft guidelines to solicit feedback from global stakeholders on the included methods, and to encourage submission of any alternative methods and additional supporting documentation. The original draft guidelines included methods adapted from publicly available sources and vetted by a USP scientific expert committees on biologics, which included representatives from industry, government, and academia. The document also incorporated best practices described in two of USP’s existing standards on vaccines in the United States Pharmacopeia—National Formulary, General Chapters <1235> Vaccines for Human Use—General Considerations and <1239> Vaccines for Human Use—Viral Vaccines

USP has received public comments on the first version of the mRNA draft guidelines from a variety of stakeholders, as well as several method donations. In this second version, public comments have been addressed and donated methods have been added. 

To further support the quality and consistency of analytical methods used for mRNA-based vaccines and therapies, USP has initiated evaluation of several methods in USP laboratories, with the goal of qualifying and/or validating these methods. In some cases, where the method is applicable to a broad range of mRNA products, methods may be advanced as documentary standards (for example general chapters with validated methods). These proposed compendial methods would be published in our Pharmacopeial Forum for public comment prior to publication in USP-NF. In other cases, where standardization is more challenging due to the variety of mRNA products in development, methods and other associated information may be published outside of the compendial process (e.g., draft guidelines, technical notes, or scientific publications).

Proposal and stakeholder engagement:  Additional collaboration is needed. To advance these draft guidelines, we invite industry, academic and government experts with experience or interest in mRNA vaccines and technology to provide feedback on the methods detailed in these draft guidelines and recommend additional information to support the understanding of mRNA quality. We encourage the submission of any alternative analytical methods as well as supporting documents (e.g., validation documentation). By collaborating with USP, participants play an active role in shaping standards and solutions that contribute to building the supply of safe, effective, quality medicines that people around the world can trust. 

Preliminary outline of the proposed guidelines: The following table outlines the proposed methods for testing for plasmid DNA prior to release. Additional tables have been added for assessing quality attributes for drug substance and drug product. The draft guidelines include methods to evaluate the content, identity, purity, mRNA integrity, and safety parameters. Some of these methods may also apply to other mRNA therapeutics.

For more information and to download the draft guidelines please click here.

Deadline for Submitting Comments
USP welcomes your feedback and encourages you to submit your supporting data within 90 days from the post of this announcement by email as described below.

Submitting your comments 
Please submit your comments and supporting documents to

USP contact information
For further information, please contact Sarita K. Acharya, Principal Scientist, USP Biologics, or

USP looks forward to continued engagement from industry, regulators, and other stakeholders.