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14 Pharmaceutical Technology ® Trends in Manufacturing eBook May 2024 PharmTech.com MultiModal autologous cell therapies. The challenge is crafting a manufacturing plan that supports one's business without attempting to become a one-size-fits-all solu- tion for every need. Market drivers The forecasted growth of the cell and gene therapy (CGT) market is significant. The ATMP space, where CGT continues to ser ve as the primar y catalyst for growth, is predicted to grow at a compound annual growth rate of 39.4% for the period from 2024 until 2030 (2). In this growth projection, cell therapies account for 15% of the growth and gene therapies account for another 30% of growth, with many of these products advancing out of early-stage clinical manufacturing toward commercialization (2). Ju s t a s t he 1990's l a rge-molec u le m a rket saw a "fork-in-the-road" decision regarding single vs. multi-product manufacturing and the technologies to implement (3), the ATMP space is grappling with critical questions around asset size, cost, technology implementation, f lexibility, scale, and many others. Transitioning to a multimodal manufacturing strat- egy could very well emerge as the most prudent busi- ness and operational solution. Another key driver fueling the multimodal manu- facturing discourse is the rapid pace of advancement in research, developing different modes of therapy to address multiple human therapeutic targets. Combi- nation therapies using multiple therapeutic modal- ities have elevated anti-cancer activit y while low- ering doses of agents, thus reducing side effects (4). As previously referenced, gene editing tools such as clustered regularly interspaced palindromic repeats (CRISPR)-Cas, transcription activator-like effector nu- cleases (TALENs), and base editing have brought about multiple therapeutic solutions that are being provided for chronic diseases and oncolytic cancer treatments, as well as advanced chimeric antigen receptor T cell (CAR-T) and T-cell receptor (TCR) therapies. T he resu lts f rom t hese development act iv it ies could pave the way to a number of different manu- facturing platforms, including: • Viral vectors • Cell therapies • Messenger RNA (mRNA) • Plasmid production as starting materials • Lipid nanoparticle (LNP) formulation • Oligonucleotides. Looking back again at the history of mAb produc- tion, one of the key challenges was the delicate bal- ance of securing the manufacturing capacity when required, while being mindful of the cost of the man- ufacturing enterprise asset and the time needed to bring it online. There was no universal solution to manufacturing multiple products in the same facil- ity. Variability in technologies, equipment, scale, and facility attributes had to be addressed. These are the same challenges facing the biopharma industry today. Multimodal manufacturing challenges The foundation elements of any biomanufacturing enterprise are consistent: the process, the facility, and the infrastructure, as defined in Figure 1. Each of these elements must focus on a risk-based approach to design that aligns the attributes of the product, the process, and the facility (5). For different modalities, there will be a number of facility design challenges that will be driven by these attributes. Along with these design challenges, there will also be pressure for the design team to address f lexibility needs as the product pipeline may shift due to future product manufacturing needs. Segregation strategy Segregation strategy is driven by product protection. Presently, product protection focuses on establishing methods that yield a closed, validatable process that mitigates product contamination risk. But the reality today is that not all process unit operations are closed, so the traditional approaches to segregation strategy still apply, such as physical segregation, environmen- tal segregation, temporal segregation, procedural segregation, and virtual segregation. Looking at physical segregation, the modality will impact the attributes of the design as noted below: • Plasmids. Plasmids are used in many CGT appli- cations as both starting materials and some in- termediates. The plasmid DNA (pDNA) is readily isolated from bacterial cells and engineered to express the protein(s) of interest in a mamma- lian host cell. However, microbial fermentation operations, used in production of the pDNA, in- troduce a potential manufacturing contamina- tion risk. The facility design must address these h igher conta m inat ion r isk s, necessitat ing a higher biosafety level, and a level of segregation Transitioning to multimodal manufacturing could emerge as the most prudent business and operational solution.