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Growth in cell and gene therapies puts pressure on the raw materials supply chain.
Materials sourcing for cell and gene therapies is a complex, precise process that requires organization and adherence to pharmaceutical guidelines. Experts discuss the challenges developers must work to overcome while suggesting steps for further improvement, less risk, and better cooperation with the supply chain.
When discussing the precautions needed when sourcing materials for cell and gene therapies, vice-president of Scientific Affairs and Business Development for TrakCel, Matthew Lakelin, stresses the importance of following best practices. “These include ensuring that those suppliers have adequate stocks to maintain your peaks and troughs in demand and also ensuring that those suppliers have the ability to hold specific batches for your batch numbers and lot,” he says. “There is a paucity of viral vector manufacturers at the moment, putting real pressure on supply lines associated with these raw materials. Finding and obtaining these products can be challenging especially due to the custom nature of the manufacturing exercise.”
Lakelin notes that the collection process is crucial. “For autologous products, it is important to ensure consistency in the collection process used to obtain starting material. [Consistency] can be achieved by providing standard operating procedures at collection centers and using orchestration software to manage the process,” Lakelin says. “For allogeneic products where a key raw material will be human cells, it is recommended to use a recognized sourcing partner. Using a specialist significantly decreases the risk associated with these raw materials and also gives you the widest number of options available for these products.”
Ezequiel Zylberberg, PhD, vice-president of Product Development and Planning at Akron Biotech, suggests cell and gene therapy developers take a risk-based approach to sourcing ancillary materials while keeping industry guidance documents in mind.
“[Sourcing] entails the systematic identification, analysis, evaluation, reduction, and acceptance of different risks in the supply chain,” Zylberberg said. “For instance, animal-derived materials are generally considered to be high risk. Neutralizing potential pathogens by irradiation or nanofiltration or replacing these materials with xeno-free alternatives (where feasible) are attractive risk-mitigation steps. Human-derived products can also present challenges, which is why shifting towards virus inactivated raw materials can effectively mitigate risk while still enabling the use of critical materials like Human AB Serum and Human Fibronectin.”
Other challenges cell and gene therapy developers face while sourcing materials have to do with time to market, according to Nandu Deorkar, vice-president of R&D for Biopharma Production at Avantor.
“The demand for reducing the time that a therapy reaches the market is pushing manufacturers to implement lab-scale processes and the research-use-only grade of materials used within them into commercialization levels that are neither efficient nor effective,” Deorkar explains. “Unlike in monoclonal antibody manufacturing, materials in use for cell and gene therapies are required in smaller scales. Many of the materials available today are for research-use only and need to be adapted to meet current good manufacturing practices (cGMP) as well as other regulatory standards (e.g., non-animal derived sources).”
Zylberberg notes that demand for materials continues to grow. “More than 50 percent of biomanufacturers expect to experience moderate to severe capacity constraints at commercial scale by 20251,” he says. “Pressure on the supply base is likely to grow, with more than 1,000 regenerative clinical trials underway globally2.”
He adds that suppliers need to grow to support this demand. “The cell and gene therapy supply chain has expanded considerably in the last few years, but must continue to grow, consolidate, and standardize to support the industry moving forward,” Zylberberg says. “Building greater cGMP-compliant ancillary material manufacturing capacity and supporting developers and regulators with robust Drug Master Files will be important in ensuring that ancillary materials are suitable for clinical and commercial manufacturing use.”
Deorkar suggests partnerships between raw materials suppliers and biopharma manufacturers are beneficial in terms of improving workflow and enhancing materials sourcing activities.
“Raw materials suppliers can partner with biopharma manufacturers to help them gain efficiency in raw materials management for their cell and gene operations in several areas, with customized packaging being a large area of opportunity,” he says. “Additionally, the requirement for biological activity to be retained in cell and gene therapies limits the use of harsh purification methods. This adds a special sensitivity that potentially harmful or adventitious agents cannot be introduced through the raw material supply chain. This is another area that benefits from partnership between manufacturers and their suppliers of raw materials: understanding the requirements for cGMP materials and implementing them early in the therapy development and manufacturing process.”
Using smaller package sizes improves efficiency and reduces risks, says Deorkar. “Packaging materials in smaller, single-use bags is not only more effective from the standpoint of helping to eliminate material waste and remove process steps, allowing for immediate use in operations, but [these packages] are also nimbler to transport between facilities that may be undertaking different steps of the scale-up process for a therapeutic,” Deorkar says. “Ready-to-use solutions, like buffers in single-use packaging configurations, can also help with streamlining operations, eliminating extra process steps such as opening/closing/reopening containers under hoods and sub-dividing from bulk containers.”
Lakelin adds that software platforms can benefit organizations by reducing supply chain risks. “For autologous therapies, do not underestimate the advantages of using cellular orchestration platforms,” Lakelin says. “These software solutions have been designed specifically to manage all aspects of starting material collection and movement. A good orchestration system will minimize risk in the supply chain whilst maximizing efficiency, [aid] coordination of collection centers with manufacturing centers, and ensure utilization of manufacturing assets whilst permitting starting material donation only when it can be used.”
Securing materials from more than one main source, referred to as parallel sourcing, is often used to lessen risks during emergencies, such as the ongoing COVID-19 pandemic. While Zylberberg recognizes that parallel sourcing can add expense, he says it is necessary.
“Qualifying secondary suppliers is costly and time-consuming. It requires that quality assurance, purchasing, manufacturing, and planning teams collaborate to identify suitable alternate sources of critical inputs to production,” he said. “However, it is vital, especially during these times, to ensure that these activities have been properly executed. The time and effort placed on secondary supplier qualification up front will be rewarded with the availability of options if and when bottlenecks present themselves.”
“Beyond identifying suitable alternatives, biomanufacturers need to properly assess their options, audit their facilities, and qualify them per their quality management systems,” Zylberberg says. “It is incumbent upon biomanufacturers to adopt and implement a risk-based approach to sourcing that recognizes the exceptional circumstances we find ourselves in [during the pandemic] and mitigates potential issues accordingly.”