The success of mRNA vaccines in the COVID-19 pandemic has accelerated interest in mRNA technology in vaccine and drug development. Can continuous mRNA manufacturing be a potential solution to address production bottlenecks and ​facilitate​ capacity ramp-up? 

By Patricia Van Arnum, Editorial Director, DCAT, pvanarnum@dcat.org 

Continuous manufacturing: where the industry stands 
Although batch manufacturing is the dominant form of manufacturing in the bio/pharma industry, continuous manufacturing, whether of the active pharmaceutical ingredient (API) or drug product, continues to make inroads as companies advance select projects. A potentially new application in continuous manufacturing is in the advanced therapy ​medicinal​ product (ATMP) space, specifically mRNA continuous manufacturing, where researchers and the industry are collaborating to advance this technology.  

In general, continuous manufacturing involves the continuous feeding of input materials into, the transformation of in-process materials within, and the concomitant removal of output materials from a manufacturing process. This description may apply to an individual unit operation, such as tableting in solid-dosage manufacturing, perfusion in biomanufacturing, and flow chemistry in the manufacture of small-molecule APIs. It can also involve integrated aspects of a continuous manufacturing system in which two or more unit operations are directly connected, such as various unit operations in solid-dosage manufacturing, upstream and downstream bioprocessing in biomanufacturing, and the full synthesis of a given API.  

With the industry’s installed manufacturing base still in batch manufacturing and further investment required in equipment, analytical technology, such as process analytical technology (PAT), and technical training for continuous manufacturing, the industry has been proceeding on a measured basis in adopting continuous manufacturing. However, with the potential for improved process control and reduced and more flexible manufacturing footprints, bio/pharmaceutical companies continue to evaluate continuous manufacturing for the production of both APIs and drug products. 

To make investment in continuous manufacturing, the industry needs regulatory support to ensure that a change from batch to continuous manufacturing would not impede the regulatory filing for a given product. The US Food and Drug Administration (FDA) has long supported continuous manufacturing and has taken steps to facilitate the bio/pharmaceutical industry’s implementation of continuous manufacturing. The FDA first put forth its support for continuous manufacturing in 2002 with the agency’s initiative, Pharmaceutical Current Good Manufacturing Practices for the 21st Century, as a means to modernize pharmaceutical manufacturing and enhance product quality. This initiative included putting forth a science- and risk-based approach to pharmaceutical manufacturing and regulatory oversight through a Quality-by-Design approach as well as by encouraging new technologies, such as PAT and continuous manufacturing. 

FDA’s Center for Drug Evaluation and Research (CDER) continued that support through the establishment in 2014 of the Emerging Technology Program (ETP) to promote and facilitate the adoption of innovative approaches to pharmaceutical project design and manufacturing. ETP is a collaborative program where industry representatives can meet with Emerging Technology Team members to discuss, identify, and resolve potential technical and regulatory issues regarding the development and implementation of a novel technology prior to filing a regulatory submission to address concerns that bio/pharmaceutical companies may have in  developing new technologies that could result in delays while novel regulatory challenges are considered.  

CDER’s counterpart, the Center for Biologics and Research (CBER)), which regulates biologic products, has a similar mechanism, the CBER Advanced Technologies Team to provide an interactive mechanism to promote dialogue, education, and input between CBER and prospective innovators/developers of advanced manufacturing and testing technologies. In addition, CBER has awarded several grants and contracts to support research projects to study and recommend improvements for the advanced manufacturing of biological products, including the investigation and development of innovative monitoring and control techniques. The funded research addresses knowledge and experience gaps identified for emerging manufacturing technologies and ​supports​ the development and adoption of such technologies in the biological product sector. 

Continuous mRNA manufacturing: the next frontier 
In this context, a consortium led by researchers at the Massachusetts Institute of Technology (MIT) announced last year (2023),  a three-year, $82-milion award from the FDA, through CBER, to develop a pilot-scale system for the first fully integrated, continuous mRNA manufacturing platform.  

Messenger RNA, or mRNA, carries instructions that cells use to make proteins. Scientists have studied mRNA for decades, but its use in developing successful COVID-19 vaccines has spawned great interest in mRNA technology, not only for use in vaccines, but also mRNA-based therapeutics. Like the production of many other biologics, the current production of mRNA is batched and requires many steps that can create bottlenecks in its production. Continuous mRNA manufacturing has the potential to mitigate those bottleneck​s​ and help meet the growing demand for mRNA material and make it easier to ramp up production quickly, for example, in the event of a pandemic or other public health emergency. 

With the funding from the FDA, MIT has formed the Center for Continuous mRNA Manufacturing, led by Richard Braatz, the Edwin R. Gilliland Professor in MIT’s Department of Chemical Engineering and the principal investigator for the project. The engineering challenges will be tackled by researchers at MIT as well as collaborators at Penn State University, led by Professor Andrew Zydney, and Rensselaer Polytechnic Institute, led by Professors Steven Cramer and Todd Przybycien. A substantial portion of the project has been subcontracted to ReciBioPharm, the biologics business unit of Recipharm, a Stockholm, Sweden headquartered CDMO.  

The new research program builds on the success of the Novartis–MIT Center for Continuous Manufacturing, a $85-million program that ran from 2007 to 2019, which developed and demonstrated the first bench-scale integrated continuous manufacturing system of both the API and drug product, a so-called “blue-sky vision” for continuous manufacturing.   

The main goal of the work of the Center for Continuous mRNA Manufacturing is to advance the field of mRNA therapeutics by providing a continuous manufacturing template for companies to follow while facilitating collaboration throughout the biopharmaceuticals industry. The research team will also work closely with the FDA to ensure the pilot-scale system adheres to cGMP and informs regulatory strategies. MIT is focusing on experimental innovation and ReciBioPharm is implementing the attenable and GMP-level manufacturing program. Work at MIT and ReciBioPharm is already underway to develop automation and advanced controls for quality assurance and improve midstream processing. 

The path to continuous mRNA manufacturing 
Under the program, ReciBioPharm is responsible for the development of a GMP production train that can produce 0.5-40 g/day of RNA drug product (in vitro transcription [IVT] through fill–finish). “But the broader intent of this project is to advance RNA manufacturing far beyond what exists today in the realm of intelligent manufacturing,” explains Aaron Cowley, Chief Scientific Officer, ReciBioPharm. “So, while we are charged with developing a continuous process, we are layering in advanced process control via complex machine learning and inline process analytical tools. The result is a rapid, intensified manufacturing process from IVT through fill–finish that produces high-quality and better characterized lipid nanoparticle (LNP)-encapsulated xRNA in days—including analytical testing and product release. This is a drastic change from current batch processes which can take weeks to months to complete manufacturing and release testing.”

Cowley explains th​at​ there are distinct technical challenges in developing a continuous mRNA manufacturing process compared to continuous manufacturing processes for other APIs and drug products. “With small molecules or biologics, there are clearly defined quality attributes that have been established over decades of batch manufacturing and commercial production. In the ATMP [advanced therapy medicinal products) space, we are dealing with constructs that are vastly more complex and physically much ​larger​. The greater complexity and inherent variability of manufacturing nucleic acids requires a larger number of quality attributes compared to less complex modalities. The measurements, analytical tools and analytical development are far more complex than traditional CQAs [critical quality attributes] for biologics. Nucleic acids are a new modality, and there is not yet a consensus on characterization.  Due to the urgent need for vaccines during the COVID-19 pandemic, products were rushed to market without robust product definition. Currently established assays are offline and post-reaction. Our system brings eyes into the manufacturing line to provide real-time data with no process down time.” 

Cowley explains that the pilot system for the continuous mRNA project is designed to be indication-agnostic, but the intent is to bring this innovation to the broader ATMP space. “Within the next year, we will be able to manufacture GMP-grade messenger-, self amplifying-, circular- RNA drug products for personalized cancer vaccines, immunotherapies, gene therapies, preventive medicine, hot-zone infectious disease outbreaks, and for other endemic disease vaccines, such as flu vaccines.” 

ReciBioPharm’s Cowley outlined what a continuous mRNA ​manufacturing​ process would entail. “[It] begins with digital process simulation—this software is built upon complex chemometric modeling, advanced analytic methods, and digital twins for each unit operation. It will generate optim​i​zed process parameters, assist in target formulation, and determine the manufacturability of the construct in real time without the need for expensive early-stage process development labor force, lab space, and equipment infrastructure,” he says. “If required, our system will be able to affirm simulations via scale-down studies or rapidly produce research-use-only (RUO) material for client use. From then on, rapid GMP manufacturing is possible via flexible equipment capable of producing GMP material for clinical or commercial scale demands. With continuous manufacturing, scaling is a factor of time (number of days), and not increasing volume through validating a whole large scale manufacturing train.”