Strategies To Address FDA CMC Trends For mRNA Therapies

By Minghua Liu, Ph.D., Eliquent Life Sciences

mRNA-based therapies provide a promising alternative to traditional treatments, boasting simpler designs, shorter development cycles, and strong specificity in target engagement. These therapies are generally less costly and easier to manufacture. Unlike other therapeutic approaches, mRNA functions within the cytoplasm and does not integrate into the host genome, reducing the risk of insertional mutagenesis.

Currently, regulatory authorities are proactively engaging with industry stakeholders to shape comprehensive guidelines that ensure the safety and efficacy of these innovative therapies. As specific guidelines for mRNA products are still under development, companies must rely on existing regulatory experiences with biologics and cell and gene therapies to navigate this evolving area.

The discussion here is based on what we have learned from our interactions with regulators over the past two years. While the discussion primarily addresses prophylactic mRNA-LNP vaccines, many of the considerations apply equally to therapeutic mRNA-LNP applications, such as cancer vaccines. Considerations regarding the mRNA drug substance are also applicable to mRNA therapeutics utilizing different delivery vectors.

Control of Materials

Regulatory scrutiny of mRNA therapies is notably stringent due to their novelty. Agencies require comprehensive details even in early-phase IND applications, including Certificates of Analysis (CoAs) for non-compendial raw materials (e.g., RNA polymerase, NTPs, and 5’ CAP). This level of detail aligns more closely with cell and gene therapy products than with traditional biologics like monoclonal antibodies.

Detailed information about plasmid sources, construction processes (preferably supplemented by flow diagrams), key elements (e.g., promoters, enhancers, targeted gene, etc.), and complete plasmid sequences with annotations are required for IND applications. It is crucial for sponsors to assume that regulatory reviewers are not familiar with the specifics of their product during the drafting of the IND dossier. Even though the specific reviewers looking at the application file may already know the details of the process, when the sponsor thoroughly explains the process it demonstrates the sponsor's understanding of their own product, which is also very important.

Cell Banks

When it comes to the plasmid cell bank construction and characterization, the sponsor should follow the requirements in ICH Q5B and Q5D, as well as other regulatory guidance from the FDA (e.g., Points to Consider in the Characterization of Cell Lines Used to Produce Biologics, issued in 1993). It is worth mentioning that, unlike mammalian cell lines such as CHO cells where monoclonality is critical, for E. coli, the most common strain used for plasmid production, two rounds of single colony isolation and phenotypic confirmation are generally considered sufficient.

Starting Material

Determining the appropriate starting material for mRNA products should be based on the guidelines provided in ICH Q11. Whether you are using plasmid DNA or linearized DNA template as the starting material, the establishment of robust release specifications for it is critical. These specifications should encompass identity, purity, and safety parameters to comply with cGMP standards (plasmid DNA and all downstream activities), ensuring the quality of the starting material throughout the manufacturing process. The FDA's 2007 guidance on plasmid DNA vaccines for infectious diseases and ICH Q5B can serve as valuable references.

Manufacturing

Manufacturing Process

A detailed process description is critical for regulatory compliance in mRNA manufacturing, especially regarding key process parameters and in-process controls (IPCs). Recent FDA trends indicate an increasing emphasis on setting quantitative limits for all process parameters and IPCs, even during early development. These ranges can be broad initially but must be clearly defined as part of the submission. Previously, such feedback was given in Study-May-Proceed letters, but these requirements are emerging during the 30-day review period.

Specific product-related steps, such as pooling, capping, and poly-A tail addition, should be clearly outlined in the process description. For example, when pooling occurs, the details (including intermediate qualifications and container and storage information) must be included. Similarly, the methods for steps that may vary by product must be specified in the description of the manufacturing process to avoid confusion.

Process Change Management

"Nothing is permanent except change," particularly in the evolving field of mRNA drug substance and drug product manufacturing. Unlike traditional biological products, mRNA therapies are new entrants with processes that are likely to undergo significant changes throughout development. These changes can encompass scale-up activities, formulation optimizations, alterations in dosage forms, and shifts in raw materials, manufacturing equipment, or locations. Managing these changes effectively is pivotal. The approach must be tailored to the phase of development and the extent of change. Initially, simple comparability studies might suffice, but as development progresses, more rigorous assessments are required. These should:

• be underpinned by a detailed written protocol,
• include statistical comparisons of attributes before and after changes,
• cover thorough characterizations, lot releases, stability assessments, and process comparability, and
• compare degradation profiles to assess consistency.

Additionally, the significance of maintaining an adequate reserve of pre-change material for future studies cannot be overstated. This ensures that changes can be evaluated effectively even years later.

Characterization and Release Specifications

While mRNA-LNP products do share the general categories of tests, there are some requirements that are specific to this type of products.

For example, sponsors are being asked to provide residual DNA template distribution information as part of the characterization rather than the total residual DNA level. Also, because the LNP encapsulation process usually occurs during the drug product manufacturing, the drug product will need to be characterized with DP-specific tests including particle size, lipid component impurities, and residual solvents.

Additionally, detailed descriptions should be provided for analytical procedures. And when it comes to the immunogenicity potency assay for a vaccine product, details about the source and quality data for the antigen used in the test are required in the IND.

Furthermore, a newer trend we are seeing, which is similar to that of the manufacturing IPCs, is that the FDA is asking sponsors to assign quantitative criteria for lot release and to refrain from using the word “report.” They acknowledge that the ranges may be broad in early development. Again, while we used to see this as a non-hold comment in Study-May-Proceed letters, we have recently begun to receive that feedback during the 30-day review for Phase 1 INDs.

Stability Studies

When it comes to the stability studies, based on our previous experience with the FDA, we note that the reference standard lots or their source lots are required to be subjected to real-time or long-term stability studies. Potency assays should be performed at all time points, especially when the stability data are used for comparability studies. Studies under stressed conditions are not required at Phase 1, and non-stability indicating tests, such as some identity tests and endotoxin and residual solvents tests, are not needed in the stability protocols.

Novel Excipients and Regulatory Alignment

Novel excipients, such as ionizable lipids in mRNA-LNP formulations, require careful regulatory consideration. During IND stages, placement of detailed CMC information in dedicated sections is acceptable. However, BLA submissions necessitate pre-meeting alignments with the FDA. In terms of the impurity level of the ionizable lipid component, this should be supported by tox data and the actual proportion of it measured in the final mRNA-LNP drug product.

If you are using a previously approved component at a level below the approved limits, documentation such as applicable Drug Master Files and letters of authorization, together with the CoAs from vendors, may be provided in the IND dossier in lieu of a complete CMC section for this lipid component.

Platform Technology Designation

The FDA's Platform Designation Program recognizes technologies that facilitate broader drug development, such as LNP platforms for mRNA therapies. Benefits of this designation include timely regulatory feedback and the use of existing data to expedite new applications. This proactive engagement can significantly aid in navigating the approval process for novel platforms.

Conclusion

Successfully navigating the regulatory landscape for mRNA therapies demands a proactive, informed approach to documentation, comparative analyses, and regulatory communications. As the field evolves, staying ahead of regulatory expectations through strategic planning and thorough documentation will be key to successful product development and approval.

About The Author:

Minghua Liu, Ph.D., is a CMC consultant with extensive regulatory experience at Eliquent Life Sciences. At Eliquent Life Sciences, she has successfully completed over a dozen IND CMC Module 3 submissions and supported BLA filings, specializing in biologics such as mRNA-LNP, ADCs, and cell and gene therapies. Her previous roles were in regulatory compliance and quality management, and she has broad experience working with both domestic and international clients navigating regulatory challenges.