BioPharm International - September 2022

BioPharm International - September 2022

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6 BioPharm International ® Emerging Therapies 2022 eBook cells. This process and the associated shipping of collected viruses can be complex, requires many chemicals, and might take many months. In comparison, mRNA vaccines are cell-free and grown from a DNA template. This template can be sent electronically and synthesized quickly. • Safety. In traditional vaccines, collecting and growing vast quantities of a virus can be dan- gerous, whereas no virus is needed for mRNA vaccines. mRNA is non-infectious. Because it does not enter the nucleus, there is no concern for DNA integration. • Ef ficacy. T he mech a n i sm s for del iver y of mRNA allow for stabilit y and increased cell delivery efficiency. This increases the amount of spike protein produced—compared to tra- ditional vaccines—and enables an effective immune response. • Flexibility and cost. In traditional vaccines, each vaccine needs a bespoke manufacturing process. mRNA vaccines can be scaled and stan- dardized quickly; therefore, minimal changes will be needed to the manufacturing process; thus, reducing overall cost. These are some of the characteristics that make this technolog y promising for some of the world's most challenging infectious diseases, like the f lu, zika virus, and potential new pandemics. The ad- vances made in mRNA vaccines for infectious dis- eases are renowned, but less is known about the new therapeutics being developed by reimagining what is possible with existing technologies. In vivo gene-edit- ing techniques are becoming more common. RNA cell therapy is often selected as a more stable alternative to CAR-T therapy, and mRNA can be used to deliver the sequence of an antibody as an alternative to viral vectors. In addition, mRNA therapeutics are being re- searched for use in allergen-specific immunotherapy and agriculture to replace pesticides. Clustered reg- ularly interspaced short palindromic repeats-based gene editing opens new pathways, gene-modified cell therapies open new modes of action, and mRNA is the way to access these modes. Hurdles ahead Despite the clear advantages of m RNA, there are some obs t ac les to overcome. Wit h t he scope of such a wide range of scales, it's impor tant to rec- og n i ze t h at t he broad spec t r u m of appl icat ion s and their needs will have an impact on the man- ufact ur ing st rateg y adopted. T he biopha r ma in- dustr y needs to establish a development toolbox that is fit for its pur pose. Legacy methods are de- signed and optimized for monoclonal antibodies or traditiona l vaccines, rather than m RNA, lead- ing to bottlenecks in manufacturing. (See Figure 1 for the range of molecules in clinical development). In addition, process is central to biomanufactur- ing. The elements of process, facility, resources, and infrastr ucture are integrated and inf luence each other. Holistic solutions and incorporating these el- ements can reduce project risks, stabilize costs, max- imize capacity, and help speed up time to market. Few manufacturers are equipped to handle all parts of this process, and distributed processes are leading to bottlenecks in logistics and the supply chain. Challenges and bottlenecks in the development of key materials, processes, and manufacturing are contributing to cha l lenges researchers and dr ug developers are facing. mRNA and viral vector-based t herapies rely on pla sm id DNA (pDNA), a nd t he good manufacturing practice (GMP)-qualit y sup- ply has been significantly strained. Using cell-free technologies to generate pDNA is a possible solution that could reduce process timelines and improve product quality. Drug developers and manufacturers will need to work collaboratively to address the challenges of the in-vitro transcription process. This part of the process can be costly because it is so complex and requires the careful addition of multiple diverse components to the pDNA template. All reactions are currently batch-based; therefore, developing alternate reac- tor designs that reduce the inventor y of expensive raw materials could make a significant difference in productivity and costs. Purification can be more challenging for mRNA molecules. Due to their size and var ying impurity profiles, they do not interact well with traditional chromatography resins. Flexibility in purification technologies—i.e., allowing process development scientists to mix and match media based on the spe- cific characteristics of the molecule—could help al- leviate this problem. Encapsulation using lipid nanoparticles is another critical step in mRNA processing. The lipid nanopar- ticles used in m RNA deliver y protect t he nucleic acid from degradation as the therapeutic makes its way through the patient's body. The lipids must be dissolved in an organic solvent, which is typically [T]he potential for mRNA technology to transform global healthcare is enormous.

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