RNA-based therapies: Aligning CMC strategies with “borrowed” FDA regulatory guidance

This blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.

Published June 30, 2025 

RNA-based therapies represent a rapidly evolving and promising field, as evidenced by the recent success of mRNA vaccines and the growing pipeline of RNA therapeutics. However, this innovative landscape presents specific chemistry, manufacturing, and controls (CMC) challenges and opportunities for developers: 

• The CMC regulatory framework for these therapies is still in flux, with guidance often borrowed from related fields such as gene therapy and vaccine development
• The complex nature of RNA therapeutics demands careful attention to phase-appropriate CMC strategies, from initial molecule selection and design through to large-scale manufacturing and quality control

Like most novel modalities, RNA therapies often originate in an academic setting, then transitioned to research and development in a biotech setting for process and analytical development, and eventual scale-up manufacturing. A therapy that appears promising in an academic setting needs to be carefully adapted for further CMC development, which requires meticulous planning, as well as adequate time and resource allocation. 

This blog describes the status of RNA therapies and provides specific recommendations for aligning phase-appropriate CMC strategies in the context of evolving regulatory guidance for the development of these therapies.

Current RNA therapeutics landscape

RNA therapies encompass a range of innovative approaches, which can be broadly classified into four classes: 

1. Agents of RNA interference (RNAi): Small interfering RNA (siRNA) and microRNA (miRNA) that interact with target messenger RNA (mRNA) to either degrade it or block its translation, effectively turning off the expression of an associated gene 
2. Anti-sense oligonucleotides (ASO): Short, synthetic nucleic acid strands designed to bind to specific RNA sequences and modulate gene expression
3. RNA aptamers: Engineered RNA molecules that can bind to specific targets with high affinity and selectivity, similar to antibodies
4. Messenger RNA (mRNA): Used to instruct cells to produce therapeutic proteins, as exemplified by the COVID-19 vaccines

To date, the United States (US) Food and Drug Administration (FDA) has approved 23 RNA-based therapies, and 20 of these approvals have come since 2016 (Figure 1). ASO-based therapies have emerged as the predominant class, not only as the most approved products, but also representing significant number of therapies in various stages of preclinical and clinical development.¹ Currently, there are more than 200 ongoing clinical trials focused on RNA therapeutics. 
 

Figure 1: Current FDA-approved RNA-based therapies^2,3

Bridging the gaps in regulatory guidance specific for RNA therapies

While the pharmaceutical industry investment in RNA therapeutics is increasing, the CMC regulatory landscape presents challenges. The US FDA still needs to establish clearer guidance and frameworks to support the continued growth and potential of RNA-based treatments.  

Current regulatory frameworks

RNA therapies are subject to different development pathways depending on their regulatory classification. For example, in the US, some RNA therapies are classified as ‘biologics’, while others are ‘small molecules’: 

• RNA therapies classified as biologics: The FDA classifies RNA-based therapies as ‘biologics’ when they are derived from human, animal, or microorganisms using biotechnology. These include mRNA vaccines and cell and gene therapy (CGT) products, including those utilizing viral vector delivery systems for certain RNA-based therapies. These are regulated as biological drugs under a Biologics License Application (BLA).
• RNA therapies classified as small molecules: The FDA classifies those RNA therapeutics as ‘small molecules’ that are of low molecular weight and are chemically synthesized. Therefore, synthetically manufactured RNAs, including siRNAs (small interfering RNAs) are categorized as ‘small molecules’.

Currently, there is no overall regulatory guidance for CMC development of RNA therapies.  Instead, developers are encouraged to follow regulatory guidance for human gene therapy products^4,5,6, and additional guidance for specific product types. For instance, RNA-based vaccine developers should refer to vaccine development guidelines^7,8, while ASO developers can leverage ASO-specific guidance for CMC recommendations.⁹

Additionally, there is a need for harmonization of RNA therapeutics definitions and guidance among regulatory agencies. For example, for the COVID-19 vaccine Spikevax™, four components in the lipid nanoparticle, SM-102, PEG2000-DMG, 1,2-distearoylsn-glycero-3-phosphocholine and cholesterol, are designated as “drug substances” by the FDA, while the EMA designates these as “novel excipients”. These differences in drug component designation have important implications for both manufacturing and assessment by regulatory authorities. Furthermore, these differences can become impediments in acquiring simultaneous approvals from multiple regulatory agencies.

Thus, a need for regulatory guidance specific to RNA therapeutics seems evident, as well as harmonization of best practices and quality-related CMC activities. 

CMC strategies in the absence of specific guidance 

(i) Adapt existing guidance to develop a product-specific optimized approach

Some of the general CMC guidelines can be adapted to develop CMC strategies for RNA therapies. Along with regulatory considerations, an optimized CMC approach is crucial to ensure the safety, efficacy, and consistency of these novel treatments. 

RNA therapeutic development and manufacturing involves five critical stages. Each stage can be optimized by following a product- and phase-specific plan:

1. RNA sequence design

• Design target-specific RNA sequence (e.g., siRNA, mRNA, miRNA)
• Incorporate chemical modifications to enhance stability and reduce off-target effects

2. RNA synthesis

• Utilize in vitro transcription (IVT) methods to produce the RNA molecule using a DNA template and RNA polymerase enzyme (for ASO synthesis, solid-phase phosphoramidite chemistry is used)
• Optimize reaction conditions to maximize RNA yield and purity

3. Delivery system development

RNA-based therapies require the safe and efficient delivery of RNA, which can be challenging due to RNA instability and immunogenicity, rapid clearance from the blood by the kidneys and liver scavenger receptors, as well as cellular uptake and endosomal escape. These hurdles can be addressed during early stages of development by chemically modifying the RNA and by using improved delivery carriers. 

• Select a suitable delivery vehicle like lipid nanoparticles (LNPs), viral vectors, or other nanoparticles to encapsulate the RNA and facilitate cell entry
• Engineer the delivery system to target specific cell types and tissues
• Optimize formulation parameters for stability, efficacy, and minimal toxicity

4. Scale-up manufacturing

• Streamline the transition and adaptation of the process from small-scale laboratory production to large-scale manufacturing using bioreactors and optimized downstream processing steps 
• Ensure consistency in product quality and potency across different production batches

5. Quality control and characterization

• Implement rigorous quality control measures throughout the production process to monitor RNA purity, integrity, and potential contaminants
• Utilize analytical techniques like capillary electrophoresis, HPLC, and mass spectrometry to assess RNA quality and sequence accuracy

(ii) Establish a CMC strategy appropriate to the phase of development

Designing a phase-appropriate CMC strategy is key to early success in compliance with regulatory requirements, and prudent investment of resources. Based on our experience of partnering with sponsors, and leveraging our vast experience in cell and gene therapy development, we recommend the following:

• Focus on IND-enabling CMC activities first
  • Process characterization and validation can be deferred to later stages, since this is required only for clinical trial material (CTM) used for the pivotal (licensure-enabling) studies
  • Method validation can be initiated after Phase 1, since Phase 1 CTM need not be released using validated methods. Late-stage long-term stability should be initiated using validated methods to avoid variability
• Develop platform technologies to support the portfolio
  • Wherever applicable, platform technologies should be developed – during, before or after the lead program is developed – and employed to save time and costs. For example, analytical methods developed for one program could be applicable to other programs in the pipeline

Conclusions 

The evolving CMC regulatory framework with a continuously expanding pipeline of RNA therapeutics presents interesting manufacturing challenges and opportunities for developers.  As developers establish phase-appropriate CMC strategies for their products that align with available regulatory guidance, they also seek to incorporate innovative approaches that regulatory agencies will accept. For these reasons, engaging early with governing agencies is very important. For example, leverage INTERACT and pre-IND meetings with the FDA to address critical questions, to make informed decisions about time and resource allocation.  

Also important is leveraging external partners [Contract Development and Manufacturing Organizations (CDMOs) and Clinical Research Organizations (CROs)] for their expertise and experience. CDMOs and CROs gather a substantial amount of manufacturing, clinical, and regulatory experience through working on multiple and diverse RNA-based product programs.

Leveraging CDMO and CRO broad experience early can greatly minimize trial-and-error in one’s own program. External partners also have established quality and supply chain systems that can save time and effort.

Parexel is well-positioned to help you navigate the complex CMC landscape of RNA-based therapies. Our Regulatory Consulting CMC team comprises both former industry and regulator experts, who have developed, advised on, and critically assessed a range of RNA therapy types. We will guide you through the planning and execution of your CMC activities, as well as negotiations with regulatory authorities. Our extensive experience positions us to provide informed recommendations in areas where formal guidance is lacking. Please get in touch; we are always available to discuss how to accelerate your RNA therapy development.  

References

1. Zhu, Y., Zhu, L., Wang, X. et al. RNA-based therapeutics: an overview and prospectus. Cell Death Dis. 13, 644 (2022)
2. https://www.fda.gov/vaccines-blood-biologics/center-biologics-evaluation-and-research-cber-product-approval-information 
3. https://www.fda.gov/drugs/drug-approvals-and-databases/resources-information-approved-drugs
4. Human Gene Therapy Products Incorporating Human Genome Editing; Guidance for Industry (Jan 2024)
5. Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs); Guidance for Industry (Jan 2020)
6. Potency Assurance for Cellular and Gene Therapy Products; Draft Guidance for Industry (Dec 2023)
7. Manufacturing Considerations for Licensed and Investigational Cellular and Gene Therapy Products During COVID-19 Public Health Emergency; Guidance for Industry (Jan 2021)
8. Development and Licensure of Vaccines to Prevent COVID-19 (Oct 2023)
9. Investigational New Drug Application Submissions for Individualized Antisense Oligonucleotide Drug Products for Severely Debilitating or Life-Threatening Diseases: Chemistry, Manufacturing, and Controls Recommendations, Guidance for Sponsor-Investigators (Dec 2021)

Disclaimer: Parexel provides the information contained in this document for educational purposes only. The information does not constitute legal or regulatory advice. Readers should not act upon this information without seeking advice from professional advisors. 

Return to Insights Center