The market for mRNA vaccines has experienced a surge fueled by the global rollout of the COVID-19 vaccines, and the potential of mRNA technology in public health opens a new frontier in medical science. To realize this potential, manufacturing partners in the mRNA vaccines and therapeutics world must keep pace with these advancements so drug developers can stay focused on developing life-changing drugs for patients who need them most.
In this article, we discuss several of the challenges of mRNA manufacturing and how partnering with a CDMO with robust analytical capabilities can empower therapeutic innovators to successfully bring treatments across the finish line.
Challenge 1: Quality mRNA analytics
mRNA therapeutics are complex to design and manufacture. From mRNA sequence engineering to fill-and-finish, mRNA therapeutic development requires precise, consistent, and exacting quality analysis. While other conventional molecules—such as mAbs—have provided enough flexibility for scientists to develop optimized and standardized analytical procedures over time, the recent emergence of mRNA as a human drug during the pandemic did not afford adequate time to develop such methods concurrently with clinical studies.
Today, this requires that therapeutic manufacturers partner with rigorous CDMOs that have established gold-standard analytical procedures to ensure satisfactory mRNA drug quality.
mrna vaccine
The market for mRNA vaccines has experienced a surge fueled by the global rollout of the COVID-19 vaccines, and the potential of mRNA technology in public health opens a new frontier in medical science. [MicroStockHub/Getty Images]
The current process of mRNA development and manufacturing generates impure byproducts that must be eliminated. Due to the intrinsic character of the enzymatic method, mRNA synthesis generates double-stranded RNA, which can trigger unwanted innate immune responses. While downstream processing will remove as much double-stranded DNA as possible, quantifying the biologically meaningful level of double-stranded RNA at the outset is a crucial metric for success in mRNA manufacturing.
Beyond double-stranded RNA quantification, CDMO partners also need to precisely assess 5′ capping efficiency and poly(A) tail homogeneity to develop processes that can support the production of the most effective and stable mRNA drug substance in a given technological circumstance. These assays may be newer, but they determine the quality of critical quality attributes of an mRNA therapeutic and cannot be overlooked if a drug substance is to be deemed safe and effective.
CDMO partners should collaborate with clients to develop new methods tailored specifically to mRNA therapeutics, ensuring consistent quality of mRNA drug substance. This partnership is an essential foundation of therapeutic excellence.
Challenge 2: Analytical support and innovative technologies
While quality-controlled manufacturing is important, innovation should also accompany manufacturing to enhance overall capability in end-to-end mRNA service. Overcoming knowledge gaps and ensuring success requires finding partners with the technologies and expertise to understand the cutting edge of innovation and how to act on it—your partner in mRNA manufacturing should be as innovative as your therapy.
Opportunities for innovation abound, from mRNA sequence optimization to stable poly(A)-tail development. Sophisticated CDMOs are committed to optimizing processes, and that includes integrating AI-based mRNA sequence design to improve expression profile and ensure developmental and manufacturing success.
Another hurdle innovative CDMOs must overcome is the intrinsically short half-life of mRNA and its fast decay. Human cells are specifically equipped with the capacity to degrade mRNA with short poly(A) tails because they are the signature of aged mRNA to be metabolized. Without stable tails protecting their body from cellular nucleases, mRNA vaccines are prone to be degraded and may not produce enough antigen to induce immunological memory.
To mitigate this risk, manufacturers must be able to elegantly design stable poly(A) tails to increase mRNA stability and therapeutic efficacy while maintaining high expression levels.
While a good partner may be innovating to make processes better, a great partner centers daily operations and innovation around client needs—driving the whole field forward with a passion for customer excellence. Some of these innovative applications in the mRNA space include using circular RNA in the production process to enhance RNA stability and cell-based analytical methods to test for immunogenicity.
Across development and manufacturing, CDMOs with innovative technology and the flexibility to adapt processes to match that technology are uniquely positioned to ensure optimal success for mRNA therapeutics. Efforts by these CDMOs to expand their understanding can help developers create higher-quality products, adapt to changes quickly, and anticipate changing technological needs.
Challenge 3: Manufacturing
Manufacturing mRNA vaccines and therapeutics involves multiple intricate steps, each with its own unique challenges and demands. Across each of these, an agile industry partner ensures valuable molecules are delivered to the market safely and quickly.
Sungyul Lee, PhD
Sungyul Lee, PhD, principal scientist and lab leader at Bio R&D, Samsung Biologics
Therapeutic mRNA manufacturing begins with in vitro transcription, in which plasmid DNA (or pDNA) is linearized and used as a template to create mRNA in a reactor at scale. Even at this very initial step, flexibility is paramount. The scale of mRNA production may vary depending on therapeutic use and developmental stage, and the CDMO partner must be able to adapt to these varying needs with a wide range of manufacturing spectrum.
The next step during mRNA manufacturing is purification. The purification steps following in vitro transcription help reduce impurities that could trigger cellular immune responses and begin to prepare the mRNA for encapsulation. CDMOs must have a diverse arsenal of purification strategies ranging from chromatography to ultrafiltration and diafiltration to be able to provide customized purification strategies optimized for each client’s unique molecular or clinical features.
mRNA therapeutic manufacturing is completed with mRNA encapsulation within lipid nanoparticles for in vivo delivery. The process of mRNA encapsulation and LNP purification requires optimized mixing geometry for a desired LNP profile and appropriate pump type to minimize the shear rate.
While the creation of mRNA therapeutics concludes with lipid nanoparticle encapsulation, fill-finish is the crucial final stage of production for mRNA-based drugs. All fill-finish steps must be completed under aseptic conditions to prevent contamination, further complicating the challenge of this critical last step. mRNA is mixed with various inactive ingredients to create a stable and effective formulation to protect the mRNA and ensure effective delivery. The final mRNA product is filled into vials or syringes, depending on the transportation method, and sealed to maintain its integrity.
Finally, products must be appropriately stored to prevent degradation—this may require below-freezing temperatures or unique environmental conditions such as humidity control. CDMO partners must obsess over these subtle intricacies to provide the quality clients need to efficiently deliver therapeutics to the market.
Partnering with a one-stop CDMO with the expertise and capabilities to drive a project from inception through scaled manufacturing at a single facility overcomes the various hurdles that may impede both timely and quality manufacturing. The mRNA development and manufacturing process can be divided between sites, often spanning the globe.
While well-intentioned, scattering the mRNA therapeutic process across time zones can cause involuntary chaos. Drug developers shouldn’t have to handle the frantic logistics of scheduling weekly development calls with an office in Boston, check-ins with the scaling team in Ireland, and separate meetings with the fill-finish specialists in Brazil.
Eunseo Lee, PhD
Eunseo Lee, PhD, director of mRNA tech transfer, Samsung Biologics
Such a disjointed approach is a recipe for miscommunication, transportation challenges, and inevitable logistical delays. Instead, wise developers should partner with CDMOs that have all of the processes required for mRNA manufacturing in a single location and a centralized and reliable support team. Reducing the number of vendors also reduces headaches and can help companies overcome many of the challenges associated with mRNA production.
No project is perfect—every development and manufacturing product has bumps in the road to completion. The trick is operating with a mindset and culture obsessed with excellence. To provide an unsurpassed level of service to clients, CDMOs must be dedicated to each individual customer’s needs and flexible enough to accommodate each client’s unique differences. From the developer side, this necessitates transparency with the CDMO partner to serve as the backbone for that excellence.
Choosing the right partner for your mRNA therapeutic
Customer needs are the most critical driver throughout the development and manufacturing pipeline, and, as we have seen, the need for robust mRNA development and manufacturing is growing. As a customer looking for an mRNA therapeutic partner, you should prioritize operational excellence. Choose flexible CDMOs committed to optimizing processes for efficiency and client satisfaction.
Your CDMO partner should also have excellence in quality and people to mitigate mRNA manufacturing risks. Quality ensures compliance with evolving regulations, while people excellence empowers the team to excel and innovate. Both qualities allow CDMOs to stay nimble and responsive to client needs.
CDMOs with the full spectrum of capabilities have the means to focus on these needs and rise to the challenges as your agile and robust partner in overcoming the challenges of bringing an mRNA product to market.
Sungyul Lee, PhD, is principal scientist and lab leader at Bio R&D, Samsung Biologics, and Eunseo Lee, PhD, serves as director of mRNA tech transfer, Samsung Biologics.