The In Vitro Transcription (IVT) manufacturing process classifies mRNA Therapeutics as Biologics governed by CBER, whereas synthetically manufactured siRNA, ASOs, and RNA Aptamers are regulated as Small Molecules by CDER.
Global regulatory bodies like the FDA, EMA, and WHO lack unified mRNA-specific guidelines, forcing drug developers to rely on draft standards like the USP Analytical Procedures for mRNA Vaccine Quality to define Critical Quality Attributes (CQAs).
Regional classification discrepancies create international compliance friction, as European authorities categorize therapeutic mRNA Drug Products as Gene Therapies, while the U.S. FDA excludes non-integrating mRNA Vaccines from its official gene therapy listings.
Advanced platform technologies such as Self-Amplifying RNA (saRNA) and Lipid Nanoparticle (LNP) delivery vehicles require flexible CMC (Chemistry, Manufacturing, and Controls) protocols due to complex Biodistribution profiles and non-genomic mechanisms of action.
1 Regulatory Challenges Remain
1.1 Ahe analytical requirements to release a drug product can be murky with new modalities. Although there are some established guidances for DNA products, gene-editing therapies, and chimeric antigen receptor (CAR)-T–type ex vivo gene therapies, none yet exist for release and characterization of mRNA therapies. As a result, developers are performing more tests that they will likely need (and more than were performed on COVID-19 mRNA vaccines) to ensure that their drug meets regulatory approval. With little data available, the FDA is taking a “levelheaded approach” to development of a guidance. The question of potency assays for multivariant vaccines and rare diseases has proved especially difficult for some developers to navigate.
2 Are mRNA Products a Gene Therapy?
2.1 The regulatory landscape for mRNA therapeutics and vaccines is undergoing significant discussion within the industry and is expected to evolve going forward. One key question has to do with whether mRNA products should be considered gene therapies.
2.2 Some experts believe that, on the basis of the mechanism of action of mRNA vaccines and therapeutics, they should absolutely be considered gene therapies.[1] Others argue adamantly that, because mRNA products do not alter the genome, they should not be classified as gene therapies.
2.3 Unlike in vivo gene therapies that integrate new genes into the genome to replace missing or faulty ones, mRNA directs cells via temporary transgene expression to produce proteins that fight viruses or cancer or facilitate some desired biochemical reaction that addresses a particular disease mechanism. In addition, mRNA is rapidly degraded in the body.
2.4 For this reason, the term “genetic medicine” is now frequently applied to mRNA therapeutics and vaccines.[1] Neither the United States nor the European Union has published regulatory guidance specific to mRNA drug and vaccine development. There is a WHO guidance covering mRNA vaccines that discusses “regulatory considerations regarding key aspects of the manufacture and quality control, and nonclinical and clinical evaluation, of preventive mRNA vaccines against infectious disease for human use.”[2]
2.5 Regulations vary in different parts of the world, further complicating the issue.[3][4] No mRNA-specific regulations have been issued in the United States or Europe. In the United States, the two mRNA COVID-19 vaccines were approved by the Center for Biologics Evaluation and Research (CBER), which is responsible for evaluating biologics, vaccines, and cell and gene therapies. They are not included in the agency’s list of approved gene therapies. Neither are any of the other three RNA-based therapeutics (not mRNA) approved by the agency. In Europe, RNA vaccines are regulated as vaccines, while mRNA therapeutics are classified as gene therapies.[3]
3 Initial Regulatory Guidance
3.1 Therapeutics are classified as a biologic based on how they are manufactured. For this reason, mRNA and any other RNA made by in vitro transcription (IVT) are considered biologics and therefore regulated by CBER. CBER was created to regulate therapies that are produced by biological processes and therefore known to have complex drug substance profiles. An antibody therapeutic, for example, will have numerous glycosylation isoforms in addition to a low level of chemical modification to the residues, such as oxidation and deamidation. CBER has established a regulatory strategy to evaluate these therapies for safety and efficacy, while allowing for variation within the therapeutic.
3.2 Synthetically manufactured RNAs — such as small interfering RNA (siRNA), micro RNA (miRNA), antisense oligonucleotides (ASOs), and aptamers — are regulated by the Center for Drug Evaluation and Research (CDER) because they are synthetically produced. CDER requires that every impurity in a product sample be identified and characterized. With peptides and oligonucleotides, these impurities can number in the thousands, and therefore cannot be characterized by the standards of traditional small molecules. It has yet to be determined how these synthetic RNAs can be evaluated along the same logic as biologics, which are known to have a range of modifications.
3.3 There are some regulations from the WHO and the FDA on plasmid DNA vaccines, liposome drug products, and drugs and biologics that contain nanomaterials.[3] The International Organization for Standardization (ISO) is reported to be developing a guidance on methods of analyzing mRNA–LNPs.
3.4 There are two general but very different guidance documents that can provide some assistance to mRNA developers. One was issued by the WHO and specifically covers mRNA vaccines delivered as LNPs (excluding therapeutics),[2] and the other is a draft guideline (third edition) from the USP on analytical procedures, again specifically for mRNA vaccines.[5] It has been suggested this document will be expanded to include therapeutics as well.[3]
3.5 In light of the success of the COVID-19 vaccines and the explosion of mRNA vaccines and therapeutics entering clinical development, the WHO issued some general guidance regarding the development and manufacture of mRNA vaccines (including saRNA products) in December 2021.[2] The guidance is purposefully designed to be flexible due to the fact that most processes, analytical methods, and control strategies remain proprietary. The guidance therefore emphasizes the need for developers to speak with relevant regulatory authorities regarding how their specific approaches may impact the quality, safety, and efficacy of mRNA vaccines.
3.6 The WHO guidance covers “regulatory considerations regarding key aspects of the manufacture and quality control, and nonclinical and clinical evaluation, of preventive mRNA vaccines against infectious disease for human use.”[2] Detailed information must be provided on the mRNA drug substance and the mRNA–LNP drug product, including the relevant biological characteristics; rationale for selection of target antigen(s) and any encoded proteins, such as cytokines; and reasons for the addition of any coding and noncoding sequences. The full formulation must be described, and rationales for its composition and target dosing regimen provided. Examples of analytical methods are provided for different in-process and product-release applications. The guidance also directs developers to refer to other relevant WHO guidelines, particularly those relating to GMP compliance.
3.7 The second edition of the USP guideline on procedures for mRNA vaccine quality determination was published in April 2023 (the first was published in February 2022) and includes both changes based on feedback and some additional donated methods.[5] USP is also evaluating several methods that, if applicable to a broad range of mRNA products, may be advanced as documentary standards.
3.8 More information on recommended analytical methods and techniques can be found in the April 2023 version of the USP guideline on procedures for mRNA vaccine quality determination.[5] The draft guidelines include methods to evaluate the content, identity, purity, mRNA integrity, and safety parameters of mRNA vaccines, some of which, the group says, may also apply to other mRNA therapeutics. Tables of methods for characterization and release testing for plasmid DNA, mRNA drug substance, and mRNA–LNP drug product, as well as a table on methods for mRNA production process and testing, are provided. The group continues to seek input from industry and academia and is also testing assays that could ultimately become compendial methods if they have broad applicability to many different types of mRNA products.
3.9 The overall goal is to establish “a set of analytical methods for mRNA quality to support developers, manufacturers, regulatory agencies, and national control laboratories worldwide” and “create an overall shared understanding of mRNA quality attributes, with the aim of accelerating product development, guiding successful manufacturing scale-up, and bolstering regulatory confidence in the utilization of best practices and suitable quality controls when developing and manufacturing this new modality.”[6]
3.10 A paper published by a group of European researchers summarized the regulatory requirements in the United States and Europe regarding preclinical biodistribution studies for mRNA therapeutics and vaccines.[7]
3.11 Like the WHO, the EMA is also concerned about the lack of specific guidance for mRNA vaccines in the face of the large number of candidates under development. The agency announced publication of a new concept paper in June 2023 describing its plans to issue guidance on the quality requirements for mRNA products, including “specific aspects regarding the manufacturing process, characterisation, specifications and analytical control of mRNA vaccines, as well as the definition of starting materials, active substance and finished product for mRNA vaccines.”[8]
3.12 As is the case with the WHO and USP guidances, the EMA guideline will focus solely on mRNA (including saRNA) vaccines for infectious diseases. It will include definitions of all materials, recommendations for control of starting materials, identification and control of impurities, specifications for drug substance and drug product, and potency testing and formulation strategies, among other aspects.
3.13 Additional topics to be discussed will include the development and testing of bivalent and multivalent vaccines, specifics related to saRNA– LNP vaccines, non-LNP delivery systems, and the application of platform technologies. Notably, the EMA guideline will take the WHO guidance document on mRNA vaccines “into account.”
3.14 The FDA, meanwhile, updated and finalized guidance for the development of COVID-19 vaccines, including mRNA products, in late October 2023.[9] The guidance covers considerations for the generation of chemistry, manufacturing, and controls (CMC) and preclinical data, analytical methods, clinical trials, and post-marketing studies.
3.15 Although mRNA products are quite new, the administration of hundreds of millions of doses of COVID-19 mRNA vaccines worldwide has generated a vast quantity of safety and performance information on a highly diverse population — a unique situation for any class of drug, let alone a new modality.
3.16 Despite the existence of these historic data, the approval of future mRNA vaccines and therapeutics is not expected to proceed along the same path as that of the COVID-19 vaccines.[10] The pressure of the pandemic is no longer a driver for such accelerated development. In addition, uncertainty about the basic definition of mRNA products and the absence of mRNA-specific guidelines suggest that regulatory compliance will be complex.
3.17 On the other hand, the rapid approval of updated COVID-19 vaccines targeting new variants raises hopes for accelerated pathways for platform-manufactured products, where only the mRNA sequence is changed without significantly affecting CQAs. Even so, the issuance of mRNA-specific guidelines with stricter characterization and quality requirements is expected.[1]
FAQs
Why are synthetically produced RNA therapies regulated differently than IVT mRNA products?
Synthetically manufactured RNAs like siRNA and ASOs are regulated as Small Molecules by CDER because they are chemically synthesized. Conversely, mRNA produced via enzymatic In Vitro Transcription (IVT) is classified as a Biologic and governed by CBER due to inherent biological manufacturing complexity.
Are mRNA products classified as gene therapies by global regulatory authorities?
Regulatory classification varies internationally. European regulatory agencies classify therapeutic mRNA Products as Gene Therapies, whereas the U.S. FDA excludes mRNA Vaccines from its approved gene therapy list because mRNA exerts temporary cytoplasmic transgene expression without integrating into or permanently altering the host genome.
What role does the USP draft guideline play in mRNA quality assurance?
The USP Draft Guidelines establish standardized analytical procedures for evaluating mRNA Drug Substance identity, purity, content, and structural integrity. These draft standards offer developers a common quality framework for characterization, helping accelerate clinical development and post-marketing scale-up while regulatory standards continue to evolve.
How do WHO guidelines support mRNA vaccine manufacturing and nonclinical testing?
WHO Guidelines provide a flexible regulatory framework covering manufacturing, quality control, and nonclinical safety evaluations for mRNA Vaccines. The guidance helps developers establish CMC strategies, justify antigen sequence designs, validate LNP formulations, and ensure global GMP compliance during clinical trial development.
How does the European Medicines Agency (EMA) regulate new mRNA vaccine candidates?
The EMA regulates mRNA Infectious Disease Vaccines under specific quality guidelines that account for starting material controls, impurity specifications, and LNP Delivery Systems. The agency aligns its quality standards with WHO recommendations while establishing detailed expectations for Multivalent and saRNA platform technologies.
