4.1.1 There are many naturally occurring modalities of RNA, and so it is no surprise that more natural and synthetic modalities are being explored to create more efficacious and safer therapies. Eukaryotic cells are known to produce circular RNAs (circRNA), for example, but most lack the necessary features for translation. Engineering of these endogenous circRNAs can potentially yield circRNAs capable of protein expression but without the instability challenges of linear mRNA. When the RNA is circularized by introduction of covalent bonds in vitro, the need for the 5'cap and potentially the poly-(A) tail are eliminated because there are no free ends that can serve as substrates for exonucleases. The result is a longer in vivo half-life, more in vitro stability, and potentially a simpler manufacturing process than with linear mRNA.[46] A group of collaborators in China published data demonstrating that a COVID-19 vaccine based on circRNA and delivered within LNPs exhibited a strong cellular response with higher and more sustainable antigen production than its linear counterpart.[47]
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4.2.1 Compared to viral vectors that can be exquisitely selective in their targets, lipid nanoparticles are not particularly good at targeting specific cells. Much work is ongoing by many different groups to improve the selectivity and specificity of targeting LNPs to the desired cells. Methods often include incorporation of an antibody or other ligand into the particle.[49]
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4.3.1 While in vitro transcription (IVT) is the predominant process for clinical and commercial mRNA manufacturing, there are alternative methods that may be used under certain circumstances. Automated, solid-phase synthesis leveraging phosphoramidite chemistry is widely used for the production of shorter RNA molecules (<100 nt).[4] Longer mRNA molecules can be synthesized, however, by ligating smaller RNA units, but the key ingredients are costly.
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4.4.1 Production of mRNA by IVT can be platformized, with only the genetic sequence of the DNA template needing to change to allow manufacture of different mRNA products.[53] In addition, cell-free synthesis avoids the complexities and impurities associated with cell culture processes.[54]
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4.5.1 While IVT of DNA templates to mRNA drug substances is a simpler process than cell culture for production of traditional biologics, downstream purification has yet to be optimized. Product losses can be as high as 50%.[61] Although this yield is exceptional by comparison to protein biologics, with the possible exception of antibodies, manufacturers and innovators are always striving to improve yields in an effort to reduce costs. Impurities, such as residual DNA, RNA polymerase and other reagents, DNA fragments, incomplete mRNA transcripts, posttranscriptional variants, immunogenic dsRNA, elemental impurities, endotoxins, and so on, must be removed.[4][20][49] Notably, a lack of regulatory guidance concerning residual impurities means that overpurification may be commonplace today, adding time and cost to production processes.[62]
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4.6.1 Degradation of mRNA is a concern in production, during off-line analysis, and during distribution. In addition to RNA-degrading enzymes (RNases) that are ubiquitous in the environment, mRNA can be degraded by heat and exposure to shear forces. While it is possible to produce the mRNA drug substance and drug product at different production sites, limiting the number of freeze–thaw steps during shipment and handling is highly recommended.[64] For that reason, growing numbers of mRNA producers are establishing end-to-end capabilities, including pDNA manufacturing.
4.6.2 Regardless of the overall manufacturing strategy, it is essential to have stringent controls in place to ensure that no temperature or shear excursions occur that can result in loss of mRNA product.[64] Streamlined processes with minimal processing times also contribute to greater yields of higher-quality product. Careful control of process parameters during LNP formation is also essential to avoid mRNA degradation and ensure formation of nanoparticles with the desired composition.
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4.7.1 One of the biggest challenges to large-scale mRNA manufacturing is access to a reliable supply of high-quality, GMP-compliant raw materials. Regulatory authorities today expect that not only critical raw materials but also important ancillary materials meet GMP requirements. For mRNA manufacturing, there are several specialized ingredients with few suppliers that offer GMP-grade material in large quantities. The list includes specialty nucleoside triphosphates (NTPs), enzymes, capping reagents, and cofactors for the IVT reaction and often proprietary lipids for LNP generation.[49][61]
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4.8.1 Large-scale manufacture of mRNA–LNPs poses a unique challenge for biologics production facilities because it requires large quantities of flammable solvents, which are uncommon in cell culture and most other biologics processes apart from yeast fermentation. Specific safety measures are required, including appropriate containment infrastructure, proper operator training, and safe disposal of solvent waste. Each of these precautions adds to cost and complexity.[65]
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4.9.1 Given the fact that, once developed, an mRNA process can be applied for the production of many different therapeutics and vaccines based on different genes of interest (GOIs), generating an integrated, continuous, and highly automated version should be feasible, which would potentially have a dramatic impact on process economics.[49]
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4.10.1 When planning the production of protein biologics, developers and manufacturers face challenges in securing a reactor of the right size, available on the required schedule, at a CDMO with sufficient expertise to manage the project. As more therapeutics for more precise populations enter development, developers of all modalities are shifting their focus to manufacturing scheduling logistics, combined with rightsized but smaller-scale production.
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