Quality and Manufacturing System Implications for Cell and Gene Therapy

The life sciences industry is experiencing a surge of advances in gene and cell therapies. The millions of people worldwide struggling with genetic or cellular (e.g., autoimmune) diseases makes these scientific breakthroughs a high priority. Still, companies involved in developing these products face significant challenges with development, navigating regulatory pathways, engaging in clinical trials, and transitioning to commercial manufacturing. Overcoming the obstacles calls for a solid connection between the innovations and the technologies necessary to translate them into useful health care products.

While there are slight differences between gene and cell therapy, many of the challenges are the same. Cell therapies or autologous products are those where cells are taken from an individual patient, treated, or expanded in some way, and then returned to the patient they came from to treat their disease. Whereas for gene therapies or allogeneic products, the source material is donor cells. The same is true for in vivo gene therapy where the genes are modified by a vector such as Adeno-associated virus (AAV) to treat or cure a disease. As the industry continues to grow and evolve, advanced therapies are now being produced in unique settings, including hospitals, translational facilities, and facilities for small-scale manufacturing.

In this article, we will examine some of the unique challenges faced by companies that are responsible for manufacturing and ensuring quality for gene and cell therapy products along with potential solutions to improve these processes by using digital manufacturing execution systems (MES) and quality management systems (QMS).

The specific challenges that exist with respect to manufacturing gene and cell therapies involve unique and complex protocols for trial design, patient recruitment, and planning and coordination. There are also significant challenges with quality, compliance, and manufacturing. Even biomanufacturers with facilities designed for biologic production — that are already compliant with current good manufacturing practices (cGMP) — face obstacles like those described below.

Labor Intensive Production Process

Many cell therapies today are produced one dose at a time, using the patient’s own cells as the starting material, i.e., autologous, in which cells from a specific patient are the foundation for the therapy administered to the same patient. This approach is very labor intensive, failure prone, and extremely difficult to scale with manual, paper-based methods.

Today’s production environments are still reliant on laboratory technicians and manufacturing operators to execute complex, time-sensitive tasks that must be documented, traceable, and auditable. To maintain productivity timelines, these manufacturers need closed-loop MES and a digital QMS that can connect data, documentation, and processes across product development through approval for commercialization. This includes the extended network of donor sites, cell banks, logistics providers, and suppliers. In addition, ensuring that the QMS is integrated with electronic batch record (EBR) systems is critical for right-first-time execution, in-line quality, traceability, review-by-exception, and many other essential tasks.

Traceability

Trying to ensure the stability, progression, and traceability of complex biological therapies during the production cycles is often problematic due to using manual tracking processes (paper-based forms, spreadsheets, etc.). The use of paper or unvalidated spreadsheets to track the product throughout its lifecycle is still common for smaller companies, but these methods are subject to many errors in transcription, accidental deletion, and is not compliant with 21 CFR Part 11 requirements.

Managing the Supply Chain

Managing the complex supply chain for gene and cell therapy products using a paper-based system often leads to missing documents and shipping errors which is very costly and can negatively impact patient access to the products when needed. Due to the short shelf-life of gene and cell therapy products, there is often little time to ship the products and ensure they arrive at the site on time and without shipping delays.

Challenging Analytics

Aseptic processes are required since terminal sterilization is rarely an option. Many required assays are product specific and difficult to develop. Testing is difficult, time consuming, and requires volumes of scarce product.

Conclusion

The transition from the clinical trial of cell therapies to commercial stage production requires companies to establish a highly standardized industrial process. Still, even companies that have successfully secured regulatory approval globally have struggled to anticipate and prepare for the difficult challenges of commercial manufacturing. For many companies, investors want to know early on how the organization will manufacture their products while remaining compliant with regulatory guidelines. Therefore, effective quality management, process development, and scalable production capabilities are critical to the company’s success.

In summary, the gene and cell therapy segment of the life sciences industry is growing exponentially. The pressure is on for stakeholders to apply more modernized approaches and technologies to augment their manufacturing capacity to remain relevant and contribute to this rapidly evolving value chain. Using intelligent manufacturing solutions and quality management systems as early in the process as possible can eliminate the burden of using a paper system to seamlessly integrate the individual’s or donor’s cells from initial harvesting, processing, testing, and shipment to the site for patient use and comply with cGMP.