Large-scale mRNA vaccine production is still a relatively new phenomenon. The first mRNA vaccines approved for human use, Moderna and Pfizer’s COVID-19 vaccines, became available in 2021. Two years later, the biopharmaceutical industry has learned valuable lessons about optimizing the production of mRNA — and there is growing enthusiasm among the biopharma community about new applications for mRNA therapeutics, including personalized cancer vaccines and vaccines for infectious diseases ranging from HIV to Zika virus and influenza.
Samsung Biologics, a contract development and manufacturing organization (CDMO) that helped manufacture Moderna’s COVID-19 mRNA vaccine, has been on the leading edge of this movement to advance mRNA vaccine production in recent years.
After providing fill/finish services for Moderna in 2021, the CDMO completed the first commercial-scale mRNA vaccine production run at its newly constructed end-to-end mRNA suite in 2022, providing both drug substance and drug product services for a COVID-19 vaccine developed by GreenLight Biosciences.
Scientists and executives at Samsung Biologics have made a concerted effort to address the challenges still facing mRNA vaccine production, applying new innovations in mRNA technology along with lessons learned from the company’s experience as a manufacturer of monoclonal antibodies at a variety of scales.
In a recent webcast, Pierre Catignol, executive vice president and head of manufacturing, and Eunseo Lee, Ph.D., a senior specialist focusing on mRNA technology transfer and lipid nanoparticle manufacturing, explained some of these challenges along with how Samsung Biologics’ mRNA vaccine production strategies are designed to overcome them, emphasizing agility and expertise grounded in experience.
Agile mRNA Vaccine Production
The mRNA vaccines produced to protect against COVID-19 infections had to be manufactured at scales large enough to meet the demand of a global pandemic. However, the scale may be as small as a single personalized mRNA cancer vaccine catered to an individual’s unique needs.
Manufacturers of mRNA vaccines should develop agile capabilities that can adapt to various scales depending on a partner’s needs. And as Catignol and Lee emphasized, in addition to manufacturing capabilities at a variety of scales, CDMOs should have expertise in a variety of mRNA technologies and manufacturing strategies.
“To offer multiple modalities to numerous clients, manufacturing flexibility in various types of RNA payload and analytic formulation techniques is a key component,” said Lee.
MRNA vaccine production generally requires the linearization of circular plasmid DNA molecules, which are transcribed to mRNA molecules designed to instruct the body to produce an antigen-targeting protein. This coding process demands an expert understanding of the molecular structure of the mRNA required, as well as the technologies available and the in vitro process of designing and testing code sequences.
“Coding sequence design can be based on literature and open-source data such as Eterna. Since billions of sequences can be augmented in the optimization of coding and noncoding sequences, [artificial intelligence] is a rising star in the targeted design to predict the durability of drugs from the secondary structure analysis,” explained Lee.
Crucially, the mRNA molecules must be encapsulated in lipid nanoparticles to ensure stability. Additional steps may be needed to prevent immunogenicity, an immune response to the vaccine that could weaken its effectiveness.
Other factors that need to be considered include cold chain storage, the chromatography and diafiltration process required for purification, and the pump mixing technology used for LNP encapsulation.
As Catignol explained, Samsung Biologics has worked to develop a flexible, end-to-end mRNA vaccine production process to accommodate the complex variety of factors that need to be considered and adapted to different mRNA projects.
“We have on-site in Korea a [Manufacturing Science and Technology] lab with various related equipment at small scale, from 100 milliliter up to 10 liter, and we have a good manufacturing practices manufacturing facility [that is] large scale with all related equipment. And in this facility, we can produce up to 200-liter scale batches.
“We started current GMP mRNA drug substance manufacturing last April 15, 2022. We now offer a full end-to-end service package from pDNA manufacturing, including pDNA linearization, mRNA synthesis, mRNA purification, LNP formulation,” he continued. “We are doing drug product too — with fill and finish services, with lipid or freeze-dried forms, labeling and packaging, QC testing, and QA batch release.”
The Importance of Expertise
One of the main takeaways of Catignol and Lee’s presentation was that hiring a team with expertise across a variety of areas is crucial to the success of a CDMO’s mRNA vaccine production strategy. The process requires knowledge of DNA sequencing and transcription techniques, the enzymes and nucleotides needed for purification, and the formulation and encapsulation processes for LNPs.
In addition, the CDMO must have expertise in aseptic fill/finish processes used to produce the final drug product, which requires precise clean room conditions and handling to avoid contamination and degradation.
There are also more general industry factors to consider, such as knowledge of the approval process and how to best navigate the regulatory environment, as well as optimal approaches to technology transfer. Catignol stressed that this particular sort of expertise is tied to Samsung Biologics’ experience as a leading producer of monoclonal antibodies for over a decade.
“[Our] mRNA laboratory allows us to leverage our great experience during the last 10 years in tech transfer process development and characterization. Mainly, all these competencies have been acquired for monoclonal antibodies.”
He went on to explain that the CDMO has mRNA vaccine production technology transfer capabilities in in vitro transcription and LNP processes, as well as the ability to perform gap assessments, lab-scale verification runs, cleaning verification and validation-related studies, and non-GMP analytical testing.
Samsung Biologics recently put these capabilities to the test with the first commercial-scale run of its new end-to-end mRNA vaccine production suite, manufacturing 650 grams of mRNA for GreenLight Biosciences’ COVID-19 vaccine. The run was completed just seven months after the initial technology transfer.
Lee noted that the mRNA synthesis reaction for the GreenLight project had a titer of 12 grams per liter at a commercial scale, and this titer is comparable to a small-scale production, highlighting the efficiency of the process. She explained that the mRNA’s LNP encapsulation percentage was also comparable to a small-scale production.
Looking forward, Catignol and Lee were optimistic about Samsung Biologics’ ability to continue to build on its foundation in mRNA vaccine production.
“Samsung Biologics recently invested $50 million on a drug delivery platform,” said Lee. She explained that the platform utilizes “molecular profiling and advanced analytics on natural nanoparticles and information molecules. This will lay the groundwork for establishing a platform of mRNA technology and expand the service scale as a CDMO company.”
“As a leading company, our core strength comes with our people. We have top-class talent continuously joining Samsung Biologics, enabling us for all future multimodality challenges,” Catignol said. “Regarding mRNA in particular, we have mRNA-dedicated teams and experts to answer all your questions and take care of your product. We have a full scope of services and we have all flexible scales from laboratory to commercial. We can tailor according to your needs. We have a proven quality track record at the highest standard with more than 150 approvals from over 25 health authorities from our history of monoclonal antibodies.”
