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By Sebastian Almeida, Director, CMC, Akron Biotech; Lloyd Jeffs, Director, Clinical Manufacturing Solutions, Precision NanoSystems; John Harmer, Head of Marketing, Aseptic Filling, and Katarina Stenklo, Enterprise Solutions Activation Leader, Cytiva

After more than a year of enduring myriad economic and social disruptions and a devastating loss of life from the COVID-19 crisis, the pharmaceutical industry was able to deliver its first tools in the fight against the pandemic. The catalyst for this milestone was the rapid development of innovative vaccines. The emergency use authorization (EUA) of the Moderna and Pfizer-BioNTech vaccines, which offer 94% efficacy for fully vaccinated adults, was impressive.¹ Both vaccines rely on messenger RNA (mRNA), which delivers instructions to human cells on how to fight COVID-19 through a biological Trojan horse. The ability to “program” mRNA with genetic code to treat/prevent disease has been known for decades with clinical testing of some mRNA vaccines underway even prior to the rise of COVID²; however, challenges associated with transitioning mRNA into a drug product and an industry averse to change have historically hindered its potential.

Fast forward to late 2020, when the urgency to stop the spread of coronavirus led to the groundbreaking EUAs for the Moderna and Pfizer-BioNTech COVID-19 vaccines. Now, the success of the mRNA vaccine market—recently projected to reach $127³ billion by 2027³—is fueling high demand for mRNA, which has resulted in a critical need to address mRNA manufacturing bottlenecks. Innovation and expertise in multiple areas of the industry are available to address these issues, clearing a path for the rise of mRNA therapeutics to treat other indications as well. As manufacturers across the industry continue to pursue mRNA-based therapies, it is important they understand the challenges they may face in their journey and what solutions could help overcome them.

An mRNA Bottleneck: Yesterday’s Facilities Cannot Manufacture Tomorrow’s Products

As the industry raced to answer the call for a COVID-19 vaccine, it seemed, at least to those unfamiliar with mRNA, that the clinical success and expedited production of the Moderna and Pfizer-BioNTech vaccines were nothing short of a marvel of modern medicine. Public perception was that vaccines cannot be made in a matter of months, or even years,  of development and clinical testing before they can be safely manufactured to meet large-scale demand. And considering the lengthy timeframes it took for the medical community to respond to infectious diseases in the past, such as smallpox and influenza,⁴ even industry experts were skeptical in the early stages of the pandemic about whether vaccine manufacturers could produce an approved vaccine quickly enough to change the course of the COVID-19 outbreak. And under typical circumstances, their concerns would’ve been justified.

Traditional viral vector production, where animal cell culture infected with a weakened virus is grown in chicken eggs or a fermenter, can take four to six weeks to achieve adequate biomass to begin manufacturing, with an additional week needed for growth and production.⁵ However, this months-long process can be reduced to just minutes with mRNA, due to its reliance on an in vitro cell-free transcription reaction. Eliminating the reliance on live-attenuated or viral-vectored vaccines during development and manufacturing offers several advantages to safety, speed, cost, and efficacy. Reaping the benefits, though, is possible only with access to critical raw materials and flexible facilities armed with specialized equipment and expertise.

For Moderna, which had never produced or sold a commercial drug prior to receiving the EUA for its COVID vaccine, this meant relying on a web of outsourcing partners to scale up production.⁶ This approach is inherently risky and can reduce speed to market if there isn’t seamless coordination among all partners. And in the end, Moderna is ultimately responsible for ensuring its vaccine is made in compliance with regulatory requirements, which can be challenging when production doesn’t occur in-house. Even Pfizer ran into complications when working with BioNTech to manufacture its vaccine, as they faced a supply shortage of key raw materials and starting components.⁷ Therefore, if you’re interested in or already pursuing mRNA-based therapies and vaccines, you cannot rely on traditional, often rigid, manufacturing platforms and filling operations for the production of mRNA. Instead, you must work with solutions that are designed to support the unique characteristics and manufacturing needs of the mRNA workflow. To understand why this is important, consider the most critical areas of the mRNA workflow and why flexibility is necessary for success.

Using Flexibility To Navigate The Complex Workflow For mRNA

Batch size for mRNA is one of the crucial considerations and can vary based on a company’s strategy, the therapeutic type, and target patient population. For example, current mRNA vaccines are generated in large batches and then filled in single units, whereas mRNA-based personalized therapies are produced in a large number of smaller batches. It is essential to establish a flexible platform, such as the Cytiva FlexFactory single-use platform, that can adapt to scale and product modality with minimal downtime. Independent of scale, the mRNA manufacturing site design is unique. Each phase of the complex workflow requires separate suites for production of various key starting materials and components as well as the careful completion of critical process steps. Since mRNA is a cell-free process, it is incredibly challenging to manufacture in facilities where traditional mammalian cell culture systems are in operation and may present contamination risks. Alternatively, if you do not have the ability or capacity to execute the mRNA workflow in-house, you can work with an outsourcing partner. Yet, given the rising demand for mRNA manufacturing capabilities, you will likely need to get in line with your competitors.

For example, plasmid DNA (pDNA), which provides the DNA template for gene expression during the cell-free process of in vitro transcription (IVT), is an essential building block to produce the viral vectors needed for cell and gene therapies. With both markets on the rise, demands for production of high quality pDNA are increasing, and the industry is facing limited availability with long lead times for this crucial ingredient. Research-grade pDNA is an alternative option, but the methods to produce it are not validated, resulting in varying product quality from batch to batch as well as the potential risk of cross contamination due to less rigid cleaning requirements in research laboratories.

Modular facilities, such as the Cytiva KUBio modular environments, which are capable of rapidly deploying GMP-level manufacturing capabilities, are one solution to overcome the shortage in pDNA supply and address the unique needs of mRNA across its entire workflow. These predesigned, prefabricated manufacturing platforms offer a quicker route to operational availability as well as rapid product changeover and reduced cleaning requirements through the use of single-use technology (SUT). As opposed to constructing a dedicated greenfield production facility for the mRNA workflow that would likely take years to build, a new modular facility can be up and running in about 12 months. Akron Biotech recently announced its use of Cytiva’s FlexFactory single-use platform for the manufacture of pDNA, which it sees as an opportunity to support innovative therapies with scalable solutions.⁸ Utilizing FlexFactory Figurate automation and connectivity, Akron Biotech is able to maintain GMP compliance using a fully validated manufacturing platform that facilitates regulatory filings. This is critical in an evolving area of the industry where both manufacturers and regulatory authorities are continuing to learn and grow. By eliminating the burden of legacy facilities and embracing a digitized, standardized solution, Akron Biotech is able to position themselves for a place in a growing field of novel therapeutics.

Encapsulating mRNA For Potent Delivery

One of the biggest technical challenges in developing mRNA therapies is encapsulation using specialized lipid nanoparticles, which both protect the mRNA and enable delivery to the targeted cell cytoplasm. Conventional methods for encapsulation present considerable challenges for maintaining the efficiency of mRNA manufacturing, such as limited control over particle size; significant batch-to-batch variability; substantial material loss from low encapsulation efficiency; and a labor-intensive production process that is difficult to scale up.⁹ Outside of manufacturing, encapsulation is critical for establishing the potency of the mRNA drug by providing appropriate targeting and release.

Consistency in particle size requires a technology that ensures robust and reproducible lipid nanoparticle production that can control how the environment and concentration of RNA and lipids come together to form the final particle. Microfluidics, a standard tool in development settings, offers this control by using non-turbulent, time-invariant mixing conditions to create highly reproducible mRNA lipid nanoparticles. Microfluidics technology offers encapsulation efficiency of >90% throughout manufacturing.¹⁰ Using technologies, such as Precision Nanosystems’ NxGen platform, microfluidics is now available at manufacturing scales. Next, tangential flow filtration is used to remove the ethanol as well as any unwanted solvents and then replace them with the desired buffer for storage. Finally, any bioburden that is in the bulk mRNA lipid nanoparticle formulation is removed through sterile filtration, ensuring sterility and preserving the inherently unstable mRNA molecule.

Protecting the mRNA molecule in the final stages of production will also drive storage stability, another challenge in the mRNA workflow. Ultra-cold chain requirements for mRNA have made widespread distribution of the Moderna and Pfizer-BioNTech COVID-19 vaccines difficult and costly. An ultracold storage box for the -20 C and -70 C temperature requirements, respectively, typically cost between $10,000 and $20,000.¹¹ Recent readiness assessments for COVID-19 vaccine distribution found that only about 50% of countries assessed had the cold chain capacities necessary to deploy them.¹²

Another way to protect mRNA stability is by reducing the risk of microbial contamination during fill finish using advanced technologies that eliminate human intervention, such as robotic aseptic filling systems utilizing SUT. Traditional filling machines require downtime for cleaning and sterilization, which is not feasible for small batch processing, where flexibility and speed are key. For example, the science of mRNA allows a company to target multiple development candidates just by changing the payload of the RNA within the lipid nanoparticle to deliver a different outcome or treat a different indication. Standardized robotic filling systems that rely on presterilized, disposable components within a closed system, such as the Cytiva Microcell vial filler, facilitate faster product changeover and enable improved process control by limiting exposure to any external forms of contamination, regardless of the processes and formulation used upstream.¹¹ This means you can quickly produce your full product portfolio in any dosage presentation as needed, driving clinical candidates forward faster and ultimately improving speed to market. There is also a reduction in startup time, with robotic filling systems requiring only six months to one year for installation as opposed to the 18 to 24 months needed for conventional systems.

mRNA Readiness From Idea To Injection

While the need to move quickly to slow the pandemic required utilization of traditional and less efficient processes and technologies, a limitless future for mRNA means exploring new and innovative solutions that can open the door for improvement in many areas. Progress is being made across the entire workflow, with an increased focus on securing starting materials, optimizing large-scale manufacturing platforms, and improving technical skills for mRNA process development and manufacturing. As you consider your strategy and the tools you’ll need to be successful, look for experienced and knowledgeable vendors that have already begun to equip their arsenal with products designed to accommodate the mRNA workflow from idea all the way to injection. Doing so will position you at the forefront of this biopharmaceutical revolution, where mRNA is emerging as an unstoppable force in fighting and preventing disease around the world.

References

1. Center for Disease Control. (May 7, 2021). Effectiveness of Pfizer-BioNTech and Moderna Vaccines Against COVID-19 Among Hospitalized Adults Aged >65 Years – United States, January-March 2021.

2. Kwon, Diana. (November 25, 2020). The Promise of mRNA Vaccines. The Scientist.

3. Globe News Wire. (June 23, 2021). Global mRNA Vaccines Market to Reach $127.3 Billion by 2027.

4. Colarossi, Natalie. (July 18, 2020). How long it took to develop 12 other vaccines in history. Business Insider.

5. Verga, David. (February 10, 2021). mRNA and the future of vaccine manufacturing. PATH.

6. Trefis Team, Great Speculations. How Is Moderna’s Vaccine Production Scaling Up?. Forbes.

7. Langreth, Robert. (December 3, 2020). Pfizer Scaled Back 2020 COVID-19 Vaccine Production Targets From 100 Million to 50 Million Doses. Time.

8. Akron Biotech. (October 2020). Akron Biotech Acquires Cytiva FlexFactory for the Manufacture of Plasmid DNA.

9. Precision Nanosystems. Areas of Interest: Messenger RNA. 

10. Precision Nanosystems. (2020). Accelerating the Development of Transformative Nanomedicines with NxGen Microfluidics Technology.

11. Chakamba, Rumbi. (May 13, 2021). The cold chain storage challenge. Devex. 

12. Cytiva. Meet the SA25 Aseptic Filling Workcell.

The post Increasing mRNA Capabilities and Capacity For Growing Market Needs appeared first on GEN - Genetic Engineering and Biotechnology News.

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