By George Todorov, MS, and Catherine Jomary, PhD

It is difficult to overstate the potential for emerging cell and gene therapies, yet we put lives at risk as supply chains remain vulnerable to disruption. While other therapies may have provided hype in the past, cell and gene therapies offer the first hope of truly curative treatment for several intractable diseases such as B cell malignancies, hemophilia, spinal muscular atrophy, ocular disease, and many other life-threatening rare diseases. Unfortunately, as this industry segment grows, the current global supply chain faces a menagerie of constraints exacerbated by geo-political issues and the COVID-19 pandemic. Thus the supply of life-saving cell and gene therapies is under constant threat. 

We foresee vulnerabilities across the supply chain – some are already known, while others have yet to reveal themselves. Eliminating risk to the supply chain will require the development of a robust network of suppliers that will allow cell and gene therapies to thrive. Fortunately, existing computational and machine learning tools can help predict vulnerabilities and uncover opportunities to strengthen the industry at points along the entire supply network. Alternatively, through inaction, we may deprive this nascent therapeutic industry of the stability it requires to mature. 

In-vivo/ex-vivo gene and cell therapies such as AAV and CAR-T products require GMP-grade essential raw materials and reagents, which will be at risk from supply chain shortages. That is not the only risk, however, as critical starting materials, such as cell banks and plasmid DNA, will consume raw materials for manufacturing. 

Advances in single-use equipment have offered a sustainable solution for manufacturing these novel products, but single-use materials also provide a potential point of disruption in the process. Cell and gene therapies require an array of single-use consumables, including bioreactor bags, tubing assemblies, and bio-containers for process manufacturing, storage, and filling. Single-use equipment and consumables are also critical for manufacturing other products, such as monoclonal antibodies. To increase manufacturing product turnover, contract manufacturing and development organizations  (CMOs and CDMOs) producing cell and gene therapy and biologics products have moved to using single-use equipment to reduce the cost and time for equipment installation and remove the costly and time-consuming cleaning requirement for traditional hardwall equipment. We can appreciate that the manufacturing of starting materials, reagents, and drug products depends on a standard supply of single-use components, media, and raw materials that serve the entire pharmaceutical industry. 

The industry has become increasingly reliant on these materials but has inadvertently created a delicate balance in the supply chain that can be easily interrupted. For example, global shortages of platinum-cured silicone tubing could potentially halt the production of GMP-grade plasmid DNA and cell banks. The results can be devastating, ultimately delaying the life-saving therapy patients desperately need.  
To ensure we accommodate the growing demand for these novel therapies, the industry needs to invest heavily in manufacturing capacity and increase the number of suppliers for crucial goods. In addition, the industry may also need to invest in innovating alternative materials from which those essential goods are made as a measure against future shortages. Simply building new facilities is not enough, however, as the industry must consider developing a resilient reconfigurable supply chain network that will reduce the impact of disruption from the loss of any individual supplier. 

A more resilient supply chain network will require certain factors for success, many of which are unknown – but not unknowable. For example, it is critical to determine the optimal manufacturing capacity level, raw materials, and consumable stock control based on patient demand forecast. 

With such knowledge, the development of robust supply lines becomes much more solvable through machine learning and the power of iterative simulation. We could see, for example, the interdependence of multiple supply chain factors through models generated with discrete event simulation software. We could then create intelligent logistics management tools to coordinate the different networks of multiple supply chains. Advances in IT and machine learning should also be leveraged to develop holistic management tools that can anticipate the entire bill of materials spanning raw materials production to final drug product filling and shipment of cell and gene therapy products. 

We see today how disruptions in the production of computer chips have a disproportionate effect on numerous industries. Waiting on the delivery of a new car for lack of a chip is inconvenient. Waiting on the delivery of a therapeutic for want of key raw material is intolerable. Instead, we must use the tools available to strengthen the supply lines where we can and know when to innovate on new materials or strategies where disruption is inevitable.  

Read the article in Cell & Gene.