Addressing Challenges in Production of Cell Therapies
Efforts to advance promising cell therapies through the final stages of clinical research and on to commercialization often face challenges in both the design and execution of effective processing and manufacturing systems. From the earliest stages of clinical research, the systems used to produce cell therapies must offer essential qualities in terms of efficiency, scalability and risk reduction. They must also often include unique capabilities that can monitor, identify and address challenges in production from cell collection through processing and administration to patients.
As the challenges in production of cell therapies have grown more complex, new technologies have been developed that can improve performance in key areas including monitoring and coordination of the production process. For example, at Aastrom Biosciences we have advanced ixmyelocel-T, our autologous, expanded multicellular therapy, to a phase 2b clinical trial for the treatment of advanced heart failure due to ischemic dilated cardiomyopathy. At every stage in this development effort, we have maintained a constant focus on our production process. We have supported production with a range of advanced web-based applications and software programs that provide support in key areas including monitoring, quality control and training for clinical research staff. We have also incorporated technologies that have allowed us to reduce the number of manufacturing steps to mitigate risk and drive efficiency.
Protecting cell samples
The focus on optimizing production protocols and technology begins as soon as a cell sample arrives at Aastrom. The Autolotrack software designed by Aastrom assigns a lot number to the cell sample and creates a production schedule that can be edited by the R&D team. We then institute a range of carefully planned and controlled procedural processing and handling steps that are designed to reduce the risk of cell damage, cross-contamination or improper labeling. With an autologous therapy, any problems in these areas could slow down or derail the product development process.
For autologous cell therapy development, the use of a closed-system technology offers many advantages. At Aastrom, each cell sample is processed in a single-use, sterile disposable bioreactor cassette. The unit uniformly distributes the cells over the culture surface for optimal growth. Each cassette also has an electronic memory device that identifies the cell product, instructs instruments through all phases of the production process, and continually records the cassette status and collects data. Data about each cassette is organized and tracked by Autolotrack software.
All instruments used in the Aastrom manufacturing system continually update status. When a cassette is inserted into the incubator unit or when power is restored after an interruption, the device knows exactly how far the sample has advanced in the production process. This fully automated process also helps reduce the risk of operator errors. The system can be easily reconfigured to support modified processing and handling needs for new products and can be readily scaled up to expand production capacity.
Typically, cells harvested from a cell culture are not suitable for direct patient administration. The cells need to first undergo several steps to remove process residuals, achieve an appropriate product volume and formulate the therapy for delivery. These steps can be time consuming and significantly increase the risk of error, contamination and excessive holding times as well as cell loss and decreased viability. In the case of a complex mixture of cell types, as in ixmyelocel-T, this process can also cause a shift in the cell profile.
Traditional approaches to cell harvesting can produce cells mixed with residual culture reagents that need to be washed away in an additional processing step before a therapy can be finalized for administration to the patient. The Aastrom automation system is designed to drain away the culture medium and rinse the cells within the bioreactor before they are harvested. This helps us to eliminate two cell transfer steps and also leads to a lower rate of cell loss and cell damage. The company’s closed system methodology is also used to reduce product volume and introduce storage excipients so that the therapy is in a form suitable for administration.
Efficiency and cost savings
Companies can drive down costs in cell therapy manufacturing through the appropriate application of a range of advanced capabilities in computerization, automation and process integration together with an effort to simplify or eliminate manufacturing steps where possible. At Aastrom, the use of a specially engineered technology to integrate cell washing and harvesting is one example. Implementing automated procedures in cell sampling or quality control can also reduce labor and processing times while improving consistency. Advances in technology are also supporting new options to increase volume and improve efficiency, which are essential considerations as development programs advance to late stage research and teams prepare for commercialization. A key to success is to continually identify and assess viable advances in technology that can be applied to any phase of production of cell therapies and to be prepared to incorporate such advances at the earliest opportunity to continually improve performance and reduce risk.