Advanced Therapy Medicinal Products (ATMPs), medicines based on genes, tissues or cells, offer groundbreaking new opportunities with the potential to transform the way diseases are treated. Unlike traditional medicines, ATMPs treat the cause of diseases by repairing, replacing, or regenerating organs, tissues, cells, genes and metabolic processes in the body. Often these products are given as a single treatment with potentially curative benefits. 
 
ATMPs can be classified into three main types of medicine: Gene therapy that contain genes that lead to a therapeutic, prophylactic or diagnostic effect; Somatic-cell therapy that contain cells or tissues that have been manipulated to change their biological characteristics or cells or tissues not intended to be used for the same essential functions in the body; and tissue-engineered medicines that contain cells or tissues that have been modified so they can be used to repair, regenerate or replace human tissue.
 
The safety and efficacy of ATMPs are determined by the quality attributes of the manufacturing process, such as starting and raw materials, as well as how the manufacturing process itself is designed and controlled. As such, manufacturing equipment plays an integral role.
 
Marie Jourdan, Vice President, Marketing & Product Management, Univercells Technologies, discusses manufacturing challenges, the latest advances in manufacturing equipment, and adoption of production innovations and new technologies. –KB 
 
Contract Pharma: What are the pharma/biopharma trends impacting manufacturing equipment? 
 
Marie Jourdan: When considering Advanced Therapies, the growing and advancing pipeline of candidates in development and clinical stages requires adequate manufacturing capacities to deliver on expected demands. There has been a continued push towards integrated continuous processing solutions to leverage advantages in process economics. 
 
Within Gene Therapy (GT) candidates, we see the applications evolving, which also impacts the type of manufacturing approach that will work. The first wave of GT products uses local injection and have small target populations while the “second wave” of GTs have larger indications and systemic delivery therapies with various targets such as Duchenne’s muscular dystrophy, Parkinson’s disease. This unprecedented variety results in logs differences in production demands, calling for new, flexible manufacturing technologies that can meet production needs. Beyond capacity, increasing functional titers and yielding higher quality of virus offers an answer to both quantity and quality (efficacy / safety) concerns.
 
The rise and initial promise of new modalities such as exosomes, mRNA-based vaccines and GTs has recently drawn more attention to the biopharma industry. However, such new modalities come with specific manufacturing requirements and new challenges which need to be considered during technology and process design. It is the role of technology providers to anticipate such industry trends and innovate in parallel to quickly offer purposely designed manufacturing technologies, which will bring an essential lever to accelerate access of these therapies to customers.
 
Many therapies require scale to treat populations or patients, or to accommodate rapid responses, such as with the pandemic. High-capacity, easily scalable manufacturing technologies are still impacted by supply chain issues in the industry, which has recently included scarcity of single-use components. Manufacturers require more reliable, sustainable, and easy-to-deploy production capacity. This is challenging suppliers to leverage integrated single-use systems that reduce the number of intermediate steps and thus the usage of corresponding hold bags and manifolds.
 
Moving forward, the final step is addressing in-line analytics approaches to ensure safe, high-quality results throughout development and production.
 
CP: What are some of the latest advances in manufacturing equipment? 
 
MJ: At Univercells Technologies we are purposely designing manufacturing platforms for advanced therapies, re-thinking process architecture to amplify the benefits of process intensification and integration. Our technologies are built to enable a smaller facility footprint and optimize CAPEX combined with drastic cost efficiencies that reduce overall COGS. The use of automated, closed platforms reduces manual operations, increasing process reliability and batch-to-batch consistency by minimizing risks of errors, deviations, and lost batches from human operators.
 
The NevoLine Upstream platform offers a total solution by chaining the fixed-bed scale-X bioreactor with in-line clarification and concentration steps to deliver concentrated bulk harvest within a 3m² automated footprint. Continuous manufacturing principles were deployed to combine upstream (cell culture and virus production) and midstream unit operations (clarification, in-line concentration) steps into an automated, closed environment.
 
Within the NevoLine platform, or in benchtop systems, scale-X bioreactors are available from R&D to commercial scale to ensure streamlined scale up and tech transfer from process development to market. A structured fixed-bed design promotes homogeneity with low-shear to increase specific viral productivity. Scaling is based on bioreactor height and diameter with constant compaction for linear volume/surface ratio. Simpler process transfer is achieved with three step optimizations compared to traditional technologies that have complicated, multi-step processes that are costly to scale.
 
The advanced product design of the scale-X bioreactor portfolio has already shown significant gains in bioproduction efficiency. Several projects have demonstrated productivity increases in the scale-X compared to stirred-tank and packed-bed bioreactors. 
 
Similar principles are being applied to other emerging applications like a purposely built platform for mRNA modalities which will undoubtedly contribute to promoting the safe and efficient production and delivery of these therapies.
 
CP: What capabilities do clients look for in manufacturing equipment?
 
MJ: Advanced Therapies customers are most concerned with quality, scalability, and sustainability.
 
Developers and manufacturers require high-quality material with reliable producibility. This means they need a well-characterized environment for cell growth with reproducible high performance, a high level of automation, and in-line PAT within a closed system to ensure integrity and robustness. 
 
There is also demand for scalable capabilities, both in the light of speed to clinic and speed to large-scale, global production. The immediate need to scale-up to large capacities has dictated some process and technology choices. Many manufacturers are using established suspension-based equipment in the upstream, requiring adaptation of processes and expression systems while others are branching out to explore adherent alternatives. In the downstream, we see the need for a transition from centrifugation to chromatography technologies.
 
Most importantly, customers need sustainable, reliable production for the life of each process. Available technologies and analytics should help to drastically cut development and manufacturing costs while increasing quality and safety. 
 
CP: What specific manufacturing challenges do clients look to overcome?
 
MJ: In the upstream, advanced therapy developers and manufacturers need to increase specific cell productivity and functional titers, while lowering manufacturing costs especially linked to DNA, reagents. 
 
The most discussed downstream challenge in viral production remains the need to separate full and empty capsids.
 
These challenges can vary as new modalities come with their specific needs and challenges, reagents costs in mRNA processes, analytics tailored to exosomes manufacturing.
 
CP: Where does the industry stand with adopting production innovations or new technologies?
 
MJ: The industry has been pushing for a wide adoption of continuous manufacturing technologies for viral processing, however this remains bound to innovations and improvements in related technologies (PATs, stable producer cell lines, etc). There are many companies leading the way and working on delivering these next-generation tools and processes which will be instrumental in deploying continuous processing. 
 
As technology developers, our team is continuously seeking to accommodate new developments and lead the way towards the next generation of fully integrated manufacturing platforms. We work to understand the concerns of our customers in evaluating and adopting innovative technologies, which is why remain focused on fully characterizing our solutions and demonstrating performance and reliability for a broad range of applications.