A combination of rapid sterility methods with the industry-standard compendial method should ensure maximum safety.
Multimodal manufacturing is a strategic approach that harnesses the power of diverse manufacturing methods to optimize and streamline the production process, specifically within the realm of human therapeutics in the advanced therapy medicinal products (ATMP) space. This concept involves integrating different manufacturing techniques and platforms to improve efficiency, reduce costs, and enhance the overall quality of the manufacturing process and the eventual therapeutic product slated for licensure.
In a White House report, Bold Goals for US Biotechnology and Biomanufacturing, a prominent objective is to test and de-risk new biomanufacturing practices for next-generation biotechnology products in commercial manufacturing facilities. The growing focus on cell-based therapies, a key component of the next generation of human therapeutics, has led many organizations to focus their development efforts on a multitude of platforms.
Multimodal is not new. For the ATMP space, it was identified back in 2017 as a viable manufacturing option for clinical needs. In the context of the biotechnology ATMP space, multimodal manufacturing techniques are being applied to optimize the production of complex biological compounds and therapies that are studied in multi-omic research, such as gene editing.
In reality, many contract development and manufacturing organizations have been operating in a quasi-multimodal manner for decades. Multimodal can include vaccines, monoclonal antibodies (mAbs), viral vectors, plasmids, allogeneic cell therapies, and autologous cell therapies. The challenge is crafting a manufacturing plan that supports one’s business without attempting to become a one-size-fits-all solution 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 serve as the primary catalyst for growth, is predicted to grow at a compound annual growth rate of 39.4% from 2024 until 2030.
In this growth projection, cell therapies account for 15% of the growth and gene therapies account for another 30%, with many of these products advancing out of early-stage clinical manufacturing toward commercialization.
Just as the 1990s large-molecule market saw a decision point regarding single vs. multi-product manufacturing and the technologies to implement, the ATMP space is grappling with critical questions around asset size, cost, technology implementation, flexibility, scale, and many other factors. Transitioning to a multimodal manufacturing strategy could emerge as the most prudent business and operational solution.
Another key driver fueling the multimodal manufacturing discourse is the rapid pace of advancement in research, developing different modes of therapy to address multiple human therapeutic targets. Combination therapies using multiple therapeutic modalities have elevated anti-cancer activity while lowering doses of agents, thus reducing side effects.
As previously referenced, gene editing tools such as clustered regularly interspaced palindromic repeats (CRISPR)-Cas, transcription activator-like effector nucleases (TALENs), and base editing have brought about multiple therapeutic solutions for chronic diseases and oncolytic cancer treatments, as well as advanced chimeric antigen receptor T cell (CAR-T) and T-cell receptor (TCR) therapies.
The results from these development activities could pave the way for a number of different manufacturing platforms, including:
- Viral vectors
- Cell therapies
- Messenger RNA (mRNA)
- Plasmid production as starting materials
- Lipid nanoparticle (LNP) formulation
- Oligonucleotides
Looking back at the history of mAb production, one of the key challenges was the delicate balance of securing the necessary manufacturing capacity while being mindful of the cost of the manufacturing enterprise asset and the time needed to bring it online. There was no universal solution to manufacturing multiple products in the same facility. 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 foundational elements of any biomanufacturing enterprise remain consistent: the process, facility, and infrastructure. Each of these elements must focus on a risk-based approach to design that aligns the attributes of the product, process, and facility.
For different modalities, there will be a number of facility design challenges driven by these attributes. Along with these design challenges, there will also be pressure for the design team to address flexibility 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. However, not all process unit operations are closed, so traditional segregation strategies still apply, including:
- Physical segregation
- Environmental segregation
- Temporal segregation
- Procedural segregation
- Virtual segregation
The modality will impact the attributes of the design, such as:
- Plasmids – Used in CGT applications, plasmid DNA (pDNA) is isolated from bacterial cells and engineered for mammalian host expression. Microbial fermentation operations introduce contamination risks, requiring higher biosafety levels and segregation strategies.
- Viral Vectors – Used for genetic payload delivery, viral vectors require enhanced containment, mirroring viral clearance activities for mAbs. Facility design must account for increased contamination risks.
- LNPs – Used in mRNA delivery, LNPs stabilize and protect mRNA. The segregation strategy would align with general segregation and flow requirements.
- Oligonucleotides – Used in gene and protein expression, oligo manufacturing presents challenges due to solvent use, requiring strategies for handling hazardous process waste.
HVAC Design & Area Classification
For many ATMP facilities, a key challenge is pinpointing risk mitigation strategies targeting contamination control. A direct outcome of these efforts is the potential reduction of area classifications within manufacturing spaces, simplifying segregation strategy and optimizing HVAC system design.
By minimizing HVAC design criteria and reducing area classifications through system design optimization, each modality can be grouped under a simplified classification approach:
- Grade B – Cell therapy
- Grade C – Gene therapy, LNPs
- Grade D – Plasmids, mRNA, oligonucleotides
A Multimodal Design Approach
A multimodal manufacturing facility refers to an asset that can accommodate different manufacturing processes and platforms. Organizations such as contract manufacturing organizations (CMOs) must carefully assess their strategic goals, market dynamics, and technological competencies when considering multimodal facilities.
Key considerations include:
- Speed to market – Multimodal facilities allow for faster adaptation to product demands.
- Cost efficiency – Selecting the most cost-effective manufacturing method per product optimizes operational expenses.
- Market flexibility – Facilities can pivot to evolving industry needs.
- Supply chain resilience – Having multiple in-house manufacturing options minimizes disruptions.
- Innovation potential – Integrating diverse techniques can provide a competitive edge.
Multimodal manufacturing is becoming a cornerstone of the ATMP sector. As industry leaders increasingly harness its potential, it promises to enhance efficiency, innovation, and responsiveness to evolving market demands.
