A Breakthrough Born in Crisis and the Race to Deliver It at Scale
During the COVID era in early 2020, while scientists across the globe raced to create a COVID-19 vaccine, a technology that many once considered an idea — mRNA therapy — suddenly gained global spotlight.
The beauty of mRNA is that it helps our own cells to make the proteins we need to defend ourselves. No pieces of virus. No weakened germs. Just a clear set of instructions, written in nucleotides and delivered into the body with precision.
The science was elegant, but making mRNA at a scale the world needed was not simple. Scientists already knew how to create mRNA in the lab using in vitro transcription (IVT). But turning that into a product safe and pure enough for the global population required more than knowledge. It needed specialized facilities, trusted systems, and partners who could turn this promise into something real.
That is where CRDMOs stepped in, not just as service providers but as true partners in this global effort. We built facilities, enabled scientists to trace and remove even the smallest impurities, and improve every step of the process from preparing the DNA template to capping, purification and lipid formulation (LNP). It was the beginning of a new way to treat and prevent disease.
Today, mRNA is no longer only about vaccines. It is being explored for cancer treatments, rare genetic disorders, and even ways to help the body repair itself. The question now is no longer whether it works but whether we can make it quickly, safely, and on a scale that matches the need.
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Overview of mRNA Synthesis
Messenger RNA or mRNA, functions as a messenger that carries the genetic information from the DNA for building proteins required for critical biological processes and functions. Let us look into mRNA synthesis in greater detail.
1. Design and Template Preparation
The discovery stage in mRNA synthesis focuses on innovative approaches to designing novel sequences for therapeutic applications. In addition to codon optimization, significant effort is invested in discovering optimal untranslated regions (UTRs) that enhance ribosome engagement and translation initiation for protein synthesis. Advanced computational tools explore secondary RNA structures that can positively or negatively affect stability and translation efficiency. Moreover, research is increasingly directed toward developing sequence elements that evade innate immune sensors like toll-like receptors, thus minimizing inflammatory responses. At the template level, new plasmid designs are made to simplify downstream processes by integrating proprietary promoters or unique restriction sites to ensure clean linearization; that facilitate rapid and efficient IVT.
2. In Vitro Transcription (IVT)
Discovery activities in IVT involve exploring new enzymatic variants of RNA polymerases with improved fidelity and reduced propensity to generate double-stranded RNA contaminants. Research institutions and companies collaborate to discover modified nucleotide analogs that enhance the therapeutic properties of mRNA by minimizing immune activation while maximizing expression efficiency. Another focal area is the discovery of novel co-transcriptional capping analogs or enzymatic capping methods that generate uniform Cap structures more efficiently, which are crucial for translational efficiency.
3. Post-Transcriptional Processing
Recent discoveries in post-transcriptional modification emphasize novel enzymatic strategies for poly(A) tailing, focusing on the precise control of tail length and sequence uniformity, which are critical for sustained protein expression and mRNA stability. Additionally, cutting-edge research examines enzymatic or chemical modifications at specific internal positions within the mRNA transcript, aiming to modulate immunogenicity and enhance translation without compromising safety.
4. Purification
Discovery research in purification technologies is moving toward novel chromatographic resins specifically engineered to selectively remove double-stranded RNA impurities or incomplete transcripts while preserving the desired single-stranded mRNA product. Researchers are investigating affinity chromatography systems utilizing nucleic acid-binding ligands that preferentially retain intact, capped, and correctly-tailed mRNA. Innovative nonchromatographic methods, including novel membrane filtration and precipitation-based approaches, are also being explored to simplify purification workflows and improve scalability, yield, and cost-effectiveness.
5. Formulation
The formulation of mRNA into lipid nanoparticles (LNPs) has moved beyond traditional lipids to discover new classes of ionizable lipid structures that enhance cellular uptake and endosomal escape more effectively. Research groups are actively synthesizing novel biodegradable lipids with superior safety profiles and reduced immunogenicity, addressing issues associated with long-term & repeated dosing.
6. Quality Control and Release
Discovery-based initiatives in quality control are developing sophisticated analytical techniques that offer deeper insight into mRNA structure, heterogeneity, and stability. Advanced mass spectrometry methods, single-molecule sequencing, and novel imaging techniques are being discovered and refined to accurately detect even minute impurities or structural deviations within mRNA preparations. Emerging bioinformatics tools enhance the predictive power of analytical datasets, supporting early detection of potential issues and enabling rapid decision-making for further optimization of mRNA manufacturing processes.
Overview of Services Provided by CDMOs and CRDMOs in mRNA Synthesis
Sequence Optimization and Bioinformatics
CDMOs and CRDMOs assist in creating ideal mRNA sequences by optimizing codons, predicting potential immune reactions, and selecting effective UTRs. Their teams use specialized bioinformatics tools to design sequences that maximize protein expression and therapeutic efficacy. They also guide clients through early decisions about structural and functional RNA elements, ensuring the designed mRNA has optimal stability, translation efficiency, and safety profiles for therapeutic purposes.
In Vitro Transcription Support
Organizations offer advanced enzyme platforms and transcription systems customozed to individual project needs. They test and integrate modified nucleotides, innovative capping techniques, and new transcription methodologies. Their research teams continually refine transcription processes to improve mRNA purity and boost yields, ultimately ensuring a high-quality, cost-effective therapeutic-grade product suitable for clinical use.
Advanced Purification Technologies
CDMOs specialize in developing robust purification processes that eliminate contaminants, such as double-stranded RNA and residual nucleotides. They experiment with customized chromatography resins, affinity purification systems, and novel filtration methods designed specifically for mRNA molecules. This support allows clients to achieve the regulatory-grade purity and consistency needed to advance their mRNA therapeutics toward clinical trials and market approval.
Formulation and Delivery Innovations
CDMOs and CRDMOs provide extensive expertise in developing LNP formulations and exploring other novel delivery systems. They test new biodegradable lipids and polymers to improve cellular uptake, minimize immune responses, and enhance therapeutic performance. Their formulation experts help identify stable, scalable, and efficient delivery methods, enabling clients to rapidly transition promising formulations into preclinical and clinical studies.
Comprehensive Analytical and Regulatory Services
Organizations offer advanced analytical capabilities to thoroughly characterize and validate mRNA products, ensuring they meet all regulatory standards. Their services include high-resolution purity assessments, structural analysis, stability testing, and potency evaluations. Additionally, they help prepare detailed regulatory documentation for submissions to authorities, providing strategic guidance and compliance expertise to facilitate smooth progress through clinical development and regulatory approval stages.
What Aurigene Offers
Tailored mRNA Synthesis Services
- Integrated high-quality Non-GMP plasmid DNA production suites (including E. coli clone development, cell banking, fermentation, and plasmid purification).
- Non-GMP IVT mRNA production labs with controlled & RNAse-free environments.
- Advanced analytical platforms:
- Nanodrop (A260/A280)
- TapeStation for purity, integrity, and length confirmation
- LC-MS for capping efficiency and poly(A) tail analysis
- SE-HPLC, RP-HPLC, IEX, and affinity systems for assessing purity
- ELISA for dsRNA analysis
- DLS for size, PDI, and zeta potential of LNPs
- HPLC for lipid content
- Endotoxin testing
- Dedicated mRNA-LNP formulation analytics facility with stability testing, encapsulation efficiency measurement, and potency testing in different cell lines.
- Custom mRNA synthesis by in vitro transcription (IVT) for applications from screening to preclinical research.
- Integrated plasmid preparation and supply of essential enzymes and reagents.
- High-throughput gene synthesis, codon optimization, and cloning support.
- Flexible IVT options:
- Transcription from plasmids, PCR products, or cDNA
- Conventional mRNA, self-amplifying RNA (saRNA), or circular RNA
- Promoter choice (T7 or SP6)
- Unmodified or modified mRNA (e.g., Pseudo-UTP)
- Multiple 5′ capping strategies (ARCA, CleanCap, Vaccinia system) with Cap0, Cap1, or Cap2
- Poly(A) tail integration (template-derived or enzymatic).
- mRNA purification using reverse phase, affinity, and ion-exchange methods, with gram-scale capabilities.
- mRNA formulation development and characterization (LNP-based and small-scale development).
- Comprehensive plasmid and mRNA analytics including residual DNA, host RNA, endotoxin, protein content, bioburden, and immunogenicity testing.
- mRNA-LNP formulation analytics (encapsulation efficiency, size, lipid content, potency, and stability).
- Experienced scientific teams with deep expertise in mRNA therapeutics, formulation, and analytical development.
- Proven ability to integrate discovery-scale R&D with scalable manufacturing for mRNA.
- Flexibility to tailor workflows to specific client requirements and production scales.
- In-house skill sets covering RNA biology, analytical chemistry, process engineering, and regulatory standards.
- End-to-end support—from sequence design to high-quality mRNA production and advanced characterization.
Resources
mRNA Production
Aurigene partners with innovators to accelerate mRNA therapeutics from concept to clinic. Learn more from Aurigene’s mRNA services flyer.
mRNA Technology and the Brief History of New Vaccine
Decades of research, pioneering discoveries, and scientific perseverance have turned mRNA from a laboratory curiosity into a foundation for life-saving vaccines. This article traces that journey—from early challenges in stability and delivery, to the breakthrough modifications that enabled the record-time development of COVID-19 vaccines, and the ongoing efforts toward vaccines for influenza, Zika, HIV, and cancer. Read the full story here: mRNA Technology and the Brief History of New Vaccine.
Manufacturing Strategies for mRNA Therapeutics
Platform and Process Approaches
mRNA manufacturing predominantly uses an enzymatic IVT platform rather than traditional cell-based production. This approach enables rapid prototyping and scalability because it bypasses the complexities of cell culture. Manufacturers often select between batch manufacturing and continuous manufacturing. Batch systems allow for well-defined checkpoints and are easier to validate, while continuous systems offer a faster turnaround, improved productivity, and reduced downtime.
Scalability and Flexibility
Modern strategies emphasize single-use systems, which minimize cross-contamination risks and simplify cleaning validation. These disposable technologies are complemented by modular facility designs, allowing rapid capacity expansion when demand surges, such as during a pandemic. CDMOs and CRDMOs often invest in platform-based manufacturing, where established processes can be quickly adapted to new mRNA constructs, significantly shortening development timelines.
Integration with Formulation
Unlike many biologics, mRNA therapeutics require immediate integration with delivery technologies. Manufacturing strategies often link mRNA synthesis directly with LNP formulation suites. This integration reduces handling steps and improves overall product stability, ensuring the mRNA is encapsulated in a protective matrix as soon as it is synthesized and purified.
Quality Aspects in mRNA Manufacturing
Control of Raw Materials
High-quality, GMP-grade raw materials are foundational. Enzymes like T7 RNA polymerase, nucleotides (including modified ones), and capping reagents must be sourced with strict supplier qualification programs. Incoming materials undergo identity testing, impurity profiling, and functional assessments to ensure they meet predefined specifications.
Process and Product Testing
During manufacturing, quality assurance teams monitor critical parameters such as temperature, pH, and enzyme activity. In-process testing identifies contaminants like double-stranded RNA (dsRNA) or truncated transcripts early, allowing timely intervention. Purification steps, such as chromatography or filtration, are validated to consistently remove these impurities.
Analytical Characterization
Finished mRNA is extensively characterized to confirm its identity, integrity, and functionality. Techniques include HPLC for purity, capillary electrophoresis for size distribution, mass spectrometry for sequence verification, and cell-based potency assays. Long-term stability studies, conducted under various storage conditions, establish shelf life and guide cold chain requirements.
Regulatory Landscape for mRNA Therapeutics
Regulatory Guidelines and Standards
Agencies such as the European Medicines Agency (EMA) and the U.S. FDA have issued dedicated guidelines for mRNA vaccines and therapeutics, which outline requirements for manufacturing controls, impurity thresholds, and comprehensive risk assessments. For instance, the EMA guideline on quality aspects of mRNA vaccines calls for detailed documentation on sequence design, capping efficiency, poly(A) tail characterization, and residual DNA content.
Documentation and Validation
To comply with regulations, manufacturers must provide a complete Chemistry, Manufacturing, and Controls (CMC) package. This includes descriptions of raw material controls, process validation data, analytical methods, and stability protocols. Regulatory bodies also require evidence that each step of the process is reproducible and does not introduce safety risks.
Global Harmonization and Compliance
With mRNA therapies expanding worldwide, manufacturers must navigate regional differences in regulatory expectations. Harmonizing data packages for submission to multiple authorities (EMA, FDA, PMDA, etc.) is an important focus. Many CDMOs offer specialized regulatory support teams to guide sponsors through these evolving pathways, ensuring smooth interactions with agencies.
Limitations and Challenges in mRNA Manufacturing
Product Stability
One of the biggest limitations is mRNA’s inherent instability. Without protective measures, it quickly degrades due to ubiquitous RNases and temperature fluctuations. This necessitates stringent cold-chain storage, often at ultralow temperatures, which can pose logistical challenges for global distribution.
Process Complexity and Impurities
Manufacturing processes must be finely tuned to minimize impurities such as dsRNA, which can trigger strong immune responses. Advanced purification technologies, like affinity chromatography and novel membrane filters, are often needed, adding cost and technical complexity.
Scale-Up and Supply Chain Issues
Scaling from lab to commercial volumes is not straightforward. Small changes in reaction volumes or mixing dynamics can affect yield and product quality. In addition, sourcing GMP-grade enzymes, modified nucleotides, and lipids consistently at scale remains a bottleneck for many developers, sometimes leading to supply chain delays.
Regulatory and Cost Considerations
Because regulatory guidelines are still evolving, developers often face uncertainties about long-term expectations for analytical methods, impurity thresholds, or post-approval changes. These factors, combined with high development and operational costs, can make mRNA projects financially challenging, particularly for smaller companies.
Future Outlook
The mRNA field is moving rapidly from an emergent technology to a mature cornerstone of modern biopharma. Below is an in-depth look at these key future outlook points, organized by major themes shaping the global mRNA synthesis and manufacturing landscape.
Evolving CDMO and CRDMO Landscape
The landscape for CDMOs and CRDMOs is shifting rapidly as mRNA technologies mature. Service providers are now building advanced facilities that integrate research, process development, and large-scale production under one roof. Many are also expanding geographically to meet regional demand, setting up manufacturing hubs in Europe, North America, and Asia. Analysts from EY and other market intelligence firms note that CDMOs with prior experience in nucleic acid therapeutics are attracting the most interest, as their platforms can be adapted quickly to new mRNA constructs.
Future-oriented CDMOs are investing in digital manufacturing technologies, implementing real-time data monitoring, predictive maintenance, and AI-driven quality control. These innovations not only reduce operational costs but also ensure consistent product quality. The market is seeing increased consolidation, with mergers and acquisitions enabling mid-size players to acquire specialized capabilities, such as proprietary lipid nanoparticle formulation technologies or unique purification methods.
Growth Prospects for mRNA Synthesis and Manufacturing
Projections from recent industry reports suggest that the global market will continue to expand at a compound annual growth rate of ~4% through 2032, with some forecasts indicating even higher growth in specific regions like North America and Asia–Pacific. This growth is being driven by an increase in research programs, the broadening of mRNA applications beyond vaccines, and improved access to manufacturing technologies.
Investment trends show that large pharmaceutical companies and emerging biotech firms are allocating significant budgets to develop in-house expertise while also entering long-term contracts with specialized CDMOs. The move is not only about increasing production capacity but also about improving turnaround time for new product launches. Governments are also stepping in with funding to establish domestic mRNA manufacturing facilities, reducing dependence on international supply chains. This public-private cooperation is expected to create a more resilient global mRNA ecosystem.
Expanding Therapeutic and Vaccine Applications
mRNA therapeutics are extending far beyond their initial focus on infectious diseases. Currently, personalized cancer vaccines are a major area of research, with several candidates in late-stage clinical trials. These vaccines are designed to encode patient-specific tumor antigens, stimulating the immune system in ways that were not possible with conventional approaches. Additionally, researchers are exploring mRNA therapies for cardiovascular diseases, where mRNA could be used to express growth factors that repair heart tissue after injury.
Studies published in peer-reviewed journals highlight promising developments in using mRNA to code for monoclonal antibodies directly inside the body, offering a potentially faster and more flexible way to treat rare genetic disorders. Self-amplifying mRNA platforms, which allow smaller doses to achieve the same effect as larger conventional mRNA doses, are under active investigation. This could significantly reduce production costs and expand access to mRNA-based treatments in low-resource regions.
Raw Materials, Supply Chains, and Innovation
Securing a stable supply of high-quality raw materials remains a priority. The pandemic underscored vulnerabilities in global supply chains, leading companies to adopt dual-sourcing strategies and build inventory buffers. Manufacturers are working closely with suppliers to qualify new vendors of enzymes, nucleotides, and cap analogs to ensure redundancy. The United States raw materials market alone is projected to reach over a billion dollars in the next decade, with similar growth expected globally.
Innovation in raw materials is also shaping the future. Companies are designing new ionizable lipids that improve tissue targeting and reduce inflammatory responses. Some are exploring biodegradable lipid systems that break down more efficiently after delivery, minimizing potential long-term side effects. Research into thermostable formulations is accelerating, to produce mRNA products that can be stored and transported at higher temperatures, significantly reducing the cost and complexity of global distribution.
Regulatory Evolution and Global Alignment
Regulatory frameworks for mRNA therapeutics are evolving quickly to keep pace with innovation. Agencies such as the EMA and FDA are actively engaging with manufacturers to refine guidelines for process validation, impurity thresholds, and post-approval changes. The EMA’s most recent draft guidelines emphasize comprehensive characterization of the mRNA molecule, including verification of cap structure, poly(A) tail uniformity, and dsRNA levels. Manufacturers are expected to provide detailed risk assessments and robust analytical data to demonstrate consistency.
Global alignment efforts are also gaining momentum. International regulatory workshops encourage harmonization of requirements, allowing companies to prepare a single data package for submission to multiple agencies. This trend is particularly important for smaller biotech firms, as it reduces the time and cost associated with bringing products to market in different regions. CDMOs are increasingly offering regulatory consulting as part of their services, helping clients navigate these complex pathways with confidence.
Emerging Business Models and Investments
The surge in interest around mRNA therapeutics is leading to new business models in the industry. Venture-backed startups are focusing on niche mRNA therapies and partnering early with large CDMOs to access specialized manufacturing. Larger pharmaceutical companies are adopting hybrid models, building limited in-house capacity while outsourcing large-scale production to trusted partners. This dual strategy enables rapid scaling during clinical trials and commercial launches without overcommitting capital expenditure.
The financial outlook is optimistic, with significant investment flowing into both established players and newcomers. Many companies are exploring strategic collaborations, joint ventures, and licensing agreements to accelerate innovation. These partnerships often combine proprietary delivery systems with mRNA platforms, creating differentiated products that can capture specific market segments. Analysts predict that as more mRNA-based treatments receive approvals, investment in infrastructure and talent will continue to grow, reinforcing mRNA as a central pillar of the biopharmaceutical industry.
