What are the latest developments in mRNA manufacturing ?
Products based on messenger RNA are of great therapeutic interest in form of vaccines or as treatment option for e.g., cancer or infectious, metabolic or rare diseases. Especially, the fast development of safe mRNA-based vaccines against the SARS-coronavirus type 2 (CoV2) boosted the scientific and public interest in mRNA-based vaccines. However, there are certain bottlenecks, which need to be overcome to successfully implement a mRNA manufactering that can generate large amounts of mRNA-based therapeutics, that could be used in the clinic. These bottlenecks are mainly, the lack and costs of raw materials, the need of ultra-cold storage to ensure product stability, and the lack of contract manufacturing organization with expertise and size for large scale production of mRNA. Nevertheless, mRNA-based products could be generated faster, cheaper, and less risky compared to classical products. Additionally the global, public interest in mRNA-based therapeutics increased since the successful generation of mRNA-based SARS-CoV2 vaccines. Thus, pressure is created to find cost-effective and safe solutions to tackle the hurdles of mRNA-based product manufacturing. Our healthcare team explored these hurdles and potential solutions coming from new trends in biomanufacturing.
There are two levels on which these hurdles could be addressed: Either by altering the mRNA modality towards self-amplifying or trans-amplifying mRNA or by optimizing and innovating the mRNA manufacturing process. Here, we focus on solutions based on new trends in biomanufacturing rather than on different mRNA modalities. Continuous manufacturing of mRNA therapeutics under Pharma Industry 4.0 principles could solve the bottlenecks associated with mRNA-based product manufacturing, that are not related to the chemical properties of the mRNA molecule itself.
Continuous mRNA manufacturing and Industry 4.0
Continuous manufacturing means for mRNA-based therapeutics, that the different reactions of the in vitro transcription, purification and encapsulation of the mRNA are compartmentalized and linked together.
MRNA-based therapeutics consist of the biological active mRNA and a carrier, which ensures stability and intracellular deliverability of the mRNA molecule. The messenger RNA itself is most commonly generated in a process called “in vitro transcription”, mimicking the natural process of transcription in the human body. The DNA coding for the protein of interest is transcribed into mRNA by specific enzymes. Afterwards, the mRNA is purified and encapsuled (most often) in lipid nanoparticles (LNPs). These different steps are the same for any new mRNA-based product – only the DNA encoding for the protein of interest is specific for each product.
The comparable simple and standardized manufacturing steps of mRNA therapeutics making it attractive for continuous manufacturing under Industry 4.0 principles, which would improve quality control and material usage, as well as minimize waste. Continuous manufacturing describes a manufacturing process, in which the raw materials/the substrates are continuously fed into the manufacturing process, while the product is continuously removed from the system, these flowing manufacturing process could be performed automated and also digitalized (Industry 4.0 principles).
Continuous manufacturing means for mRNA-based therapeutics, that the different reactions of the in vitro transcription, purification and encapsulation of the mRNA are compartmentalized and linked together. Strategies for in situ product removal, substrate feed, product recovery strategies and free raw material retrieval would allow for recirculation and re-use of compounds, which would decreasing costs and amount of raw materials.
Learn more about our experience in Industry 4.0 >
Intensified purification process thanks to multimodal chromatography
The trend of using multimodal chromatography (separation of molecules based on multiple physiochemical properties of the molecule of interest and the chromatography matrix in one purification step) instead of various, classical chromatography steps during the downstream manufacturing processes is described over the last decade for the generation of protein-based biopharmaceuticals, but it is also of interest for mRNA manufacturing. In a scenario, in which the generated messenger RNA is purified and free raw materials are continuously recovered, multimodal chromatography allows an intensified purification process, which could then be automated and integrated in a continuous manufacturing process. Details about the chromatographic setup and purification process of already existing mRNA therapeutics are not (yet) disclosed with the public. However, multimodal chromatography based on e.g., CaptoCore (Cytiva) or Primesep SB (SiELC), is described to be used in the purification of biotherapeutics and could also be used in the purification of mRNAs.
Automated and digitalized mRNA manufacturing
To be able to generate millions of doses of their mRNA vaccine against SARS-CoV2, Pfizer used continuous manufacturing to accelerate the production by relying on a continuous technique for controlling encapsulation of mRNA in LNPs. The Chinese biopharmaceutical company Walvax Biotechnology, supported by experts from the American manufacturing-technology supplier Honeywell implemented intelligent manufacturing technologies into their messenger RNA vaccine production site to enable digital operations at their facility to produce millions of mRNA vaccine doses per year. Only one example how Walvax’ mRNA-based therapeutic manufacturing could benefit from digitalization is by the generation of digital twins. In a digitalized production process, all manufacturing data are collected and fed into a data center. This collection of data could be used to build a digital twin of the manufacturing process. Altered configurations of the manufacturing process to improve it and increase efficiency could be tested in a digital twin before and then uploaded into the production process without the need of reassigning.
Other mRNA-therapeutics producing companies follow different approaches by not generating large amounts of mRNA-based products, but rather small quantities of personalized mRNA therapeutics. The German biopharmaceutical company CureVac is currently working in collaboration with Tesla Grohmann Automation on the development of a mobile, fully automated and standardized mRNA-therapeutic manufacturing platform – The RNA Printer® – for the generation of smaller quantities for personalized therapeutic approaches. While, the California-based biopharmaceutical company Nutcracker Therapeutics is focusing its mRNA production for personalized medicine on the use of biochips in a fully automated and isolated manufacturing pathway.
MRNA-based therapeutics are of great interest for the pharmaceutical industry, but also for the broad society, as they are among others a promising treatment modality in oncology, as well as for e.g. respiratory diseases. Major hurdles, which are associated with the manufacturing of mRNA-based products, are about to be overcome. Since, the overall trend in biopharmaceutical production of continuous manufacturing under Industry 4.0 principles could also be applied for mRNA manufacturing leading to higher production efficiency and improved raw material utilization. Alcimed is closely following the rapid developments in this field and is ready to support you on these topics!
About the author,
Frederike, Consultant in the Alcimed’s Healthcare team in France
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