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6 Pharmaceutical Technology ® | BioPharm International ® Bio/Pharma Outsourcing Innovation February 2025 PharmTech.com ing its fourth year of financial drought, which has been one of the biggest challenges lately to bring- ing next-generation therapies to market. "Whilst next-generation technologies are incredibly exciting in their potential, these really require, for the first time, excellence in drug development to be combined with excellence in manufacturing," Pashazadeh says. Speaking specifically on nucleic acid-based therapies, Bernard Sagaert, CEO of etherna, emphasizes that the challenges are still big, even after the success of the COVID-19 vaccines. The challenges on the RNA front are tied in with RNA quality, where sometimes an inferior quality of RNA is used, which always leads to project failure in discovery or preclinical stages, cost of goods, or duration of expression, he explains. "On the deliv- ery side, targeted expression and off-target expression reduction, balancing immune expression (regulate up or down, or be immune-neutral), and stability are the main challenges. All of these challenges can be differ- ent based on the therapeutic area where the products need to be used, whether it is in prophylactic or ther- apeutic vaccines, autoimmune diseases, gene editing, oncology, protein replacement, etc.," Sagaert says. Meanwhile, other challenges include technical and regulatory complexities, such as optimizing gene-ed- iting precision and efficiency, ensuring scalable and cost-effective manufacturing, navigating complex reg- ulatory requirements, and addressing safety and ethi- cal considerations. "Overcoming these hurdles requires broad scientific expertise, strong analytical capabilities, and strategic collaborations among key 'players' to accel- erate development while minimizing risks," says Paule. Complexity of manufacturing For the most part, it is the complexity of manufac- turing involved in next-generation biotherapies that drives outsourcing in this sector. "These therapies re- quire specialized expertise in areas such as gene and cell therapy production, advanced analytics, and reg- ulatory compliance—expertise that many biopharma companies do not have in-house. Of course, everyone would love to do everything in-house, but the amount of initial investment needed, the need for speed in de- velopment, cost efficiency, and enhanced scalability are the main factors driving outsourcing," says Paule. "A certain level of complexity multiplies directly in line with" the scale of manufacturing capacity," adds Jason Jones, global business development lead, Cellu- lar Origins. Jones explains that if processes are com- plex, variable, and expensive when manufacturing 1000 doses of a next-generation therapy, then these processes will be 100x more complex, variable, and expensive if they are continued to be produced the same way as production scales up 100x. "Undoubtedly, expert contract manufacturers could offer the space, technologies, and systems to assist multiple therapy developers reach these levels over individual companies taking on the challenge, each in their individual way, reinventing the wheel each time. Undoubtedly, tech transfer will become more chal- lenging with more complex processes conducted at a greater scale, but full and robotic automation, such as that which we are progressing at Cellular Origins, can assist a seamless transfer with completely standardized processes and digital transfer of identical processes across multiple sites," states Jones. "Certainly any con- tract manufacturing embracing full automation will have a lot to offer therapy developers struggling to scale out their own manufacturing, and those that embrace it first will benefit from first mover advantage." Un like sma ll-molecule moda lities, remarks Sa- gaert, these biotherapies come with their own spe- cia lities wit h regards to manufacturing, process optimization, and quality control development and analy tics. These requirements make it extremely difficult for a company that is technology agnostic to have expert teams in all areas. "Being able to rely on a partner that understands the technology and its capabilities and challenges unburdens those compa- nies from those challenges," he explains. Jon Ellis, CEO, Trenchant BioSystems, points out that the CGT sector has tried to create solutions to its own manufacturing problems. "Whilst automated solutions are being created, the current market provision leaves much to be desired," he remarks. "Vein-to-vein timelines are still over six weeks, and costs continue to spiral." However, Ellis cautions that, although collabo- ration was touted as the solution to these problems, automated solutions have only led to an addition of machines that are only capable of doing specific tasks in the overall processes. This challenge makes it im- portant to create an end-to-end manufacturing plat- NE X T-GENERATION THERAPEUTICS It is the complexity of manufacturing involved in next- generation biotherapies that drives outsourcing in this sector.