6.1.1 One way to improve viral vector performance is to engineer capsids and vectors that exhibit more desirable properties.[30][122] Most capsids used today are based on naturally occurring viruses that have less-than-optimal properties for the purposes of gene delivery.[123] Companies, including Capsida, Dyno Therapeutics, StrideBio, Revvity (formerly PerkinElmer), AskBio, and VectorBuilder, as well as various academic groups, are all working on engineered AAV capsids with improved (more targeted) biodistribution and potency, greater manufacturability, and reduced dose requirements, toxicity, immunogenicity, and other undesirable side effects. Typically, advanced technologies are applied to enable screening of often millions of capsid variants. Gene therapies based on engineered capsids are mostly in preclinical development but are showing promise, with improvements in different properties by as much as a factor of 10.[122]
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6.2.1 Viral vector purification is a critical step in manufacturing, and recent advances in purification methods have enabled more efficient and cost-effective purification of viral vectors. Ultracentrifugation has been the standard purification method for viral vectors produced at small scale. This method is not practically scalable due to the need for expensive equipment and the length of time involved. In most platform viral vector production processes today, clarification is followed by two-step chromatography purification comprising a capture step to remove process-related impurities (e.g., host cell proteins, DNA, and RNA) and an anion-exchange step to separate full capsids from partial and empty capsids.
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6.3.1 Even if 50–75 cell and gene therapies receive FDA approval by 2030, questions remain as to whether they will achieve commercial success. Safety issues with different viral vector gene delivery vehicles that have occurred in the past few years must also be addressed. Demonstration of long-term safety and efficacy must be achieved as well.
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6.4.1 The switch from predominantly adherent to mostly suspension cell culture for viral vector production had a marked impact on the scalability of cell and gene therapy manufacture, reducing the manufacturing footprint required for large-scale viral vector production and enabling the transition to ever-larger, stirred-tank bioreactors. However, the gold standard process for viral vector production is still transient three or four plasmid transfection, depending on whether you’re producing AAV or LV vectors (see above). This brings its own scalability challenges because transfection is far less efficient in suspension than adherent cell cultures.
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6.5.1 CDMOs can also reduce manufacturing costs and help innovators accelerate their path to the clinic or market by implementing platform processes for viral vector production. Traditionally, viral vector manufacture has been customized to each therapeutic. The innovator would complete the majority of their preclinical work in a particular cell line with their own custom plasmids, using a customized process and defined materials, reagents, and equipment. They would then tech transfer that custom process to the CDMO, which would perform further process development work to optimize it for large-scale production. This not only involves a tailor-made process development project for each client but also means working with different suppliers to source the reagents, raw materials, and equipment, which drastically complicates the supply chain and leaves the project vulnerable to multiple delays. Each project would also need a custom bill of materials (BoM) and other GMP documentation, and manufacturing staff would have to be retrained in the specifics of each project.
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6.6.1 One of the major limitations in viral vector manufacture for cell and gene therapies is the industry’s reliance on plasmid-based transfection to transport viral DNA and the therapeutic transgene into the cell. Until recently, plasmid supply has been a major bottleneck in cell and gene therapy production, with limited plasmid manufacturing capacity impacting supply chains and lead times for viral vector manufacture. However, in the last few years, multiple CDMOs, including Catalent, Charles River, Thermo Fisher, WuXi Advanced Therapies, Andelyn Biosciences, and the Center for Breakthrough Medicines, have started manufacturing plasmids themselves to unblock this supply, and as such it is now possible to source even off-the-shelf GMP grade plasmids in weeks, with custom plasmids produced and delivered within six months rather than the lengthy lead times quoted just two years ago.
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6.7.1 The design and quality of key raw materials (e.g., plasmids, transfection reagents) have a direct impact on the efficiency of transient transfection processes and the quality and purity of the generated viral vector products.[30]
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6.8.1 For innovators whose cell or gene therapy achieves regulatory approval, commercial viability is the final hurdle to leap on the path to success. The costs involved in manufacturing these therapies are significant, and attributing value to potentially curative therapeutics is undeniably complex, requiring the balance of factors as diverse as reduced hospitalization, remission periods, patient-reported benefits, and even the cost of managing future comorbidities if the patient’s life is extended.[146]
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6.9.1 Artificial intelligence (AI) and machine learning (ML) have the potential to help overcome challenges in the cell and gene therapy field, including their complexity and heterogeneity with respect to therapeutic approaches, the supply chain, logistics, and so on. Companies looking to leverage these digital tools for cell and gene therapy development include Modulus Therapeutics, Outpace Bio, Serotiny, Dyno Therapeutics, and Patch Biosciences.[148]
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6.10.1 Despite being the established standard for delivering therapeutic DNA to cells both in vivo and ex vivo, viral vectors do have disadvantages, of which the complexity and cost of their manufacture is only one. Other notable disadvantages include concerns around toxicity and immune response; the latter being particularly problematic for AAV-based gene therapies that can currently only be administered once, since the patient’s immune system would fight a re-dose before it had time to exert any therapeutic effect. This can also exclude some patients from even a first dose using some AAV serotypes if they have had previous natural exposure to the virus.
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6.11.1 One of the ongoing challenges in the biomanufacturing industry is a serious labor shortage. The National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) is a public–private partnership that was founded in 2017 to study, highlight, and address the challenges in the industry.[151] In 2022, NIIMBL published a study in which they surveyed manufacturers across the U.S. and found the talent shortage to be ubiquitous.[152] While the shortage is felt across all levels of biomanufacturing organizations, it is striking that only 42% of job postings for manufacturing associates require a bachelor’s degree.[152] Traditionally, firms across industries will pay relocation fees for high-level employees such as managers and above, but relocation support for entry-level employees without a college degree is rare. Companies are left, then, to recruit from local talent for entry-level manufacturing associates jobs while they simultaneously compete nationally (or even globally) for more educated talent.
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6.12.1 In the last few years, the pace of innovation in cell and gene therapy manufacturing has been unremitting, bringing several possible solutions to the challenges associated with cost-effective manufacture of advanced therapy medicinal products (ATMPs) closer to clinical reality.
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