UNDERSTANDING THE BIOLOGY OF THE PRODUCTION ORGANISM

In contrast to small molecules, the production of biopharmaceuticals is a process–within–a–process, with the cultivation process supporting the metabolic production process within the cell. In order to develop a detailed process understanding, one must understand the biology of the organism and its environment. In short, what is required is a systems biology approach, with a focus on building a solid understanding regarding the biology of the cells themselves. Ultimately, the cells are the primary production vehicles, and by following PAT guidelines and QbD principles, one can develop a clear understanding of the biology of the cells and control of the overall bioprocess. By identifying both genomic and metabolic factors that play into the production of therapeutic biologics, process engineers can identify CPPs and characterize the impact that each of the variable CPPs (i.e., media conditions, fermentation conditions, pH, temperature, dissolved oxygen content) has on titers and quality. Process engineers can identify how well these variables can be controlled, and subsequently establish the criticality of these variables within the overall bioprocess. By understanding these CPPs and their importance in the overall bioprocess (e.g., effects on product yield, quality, and process stability), process engineers can rapidly and effectively improve production titers and process robustness. We took the approach of initially focusing on the biology of the production cells. By focusing on the genetic changes associated with the overall bioprocess, one develops a very clear understanding of how changes in CPPs influence production yields and overall product quality. Once manufacturers understand the intricacies of the overall bioprocess, one can consider bioprocess flexibility.

For existing processes and products already in revenue–generating production, the cost of one change, even if it results in significant increases in yield and stability, can often be too high to be recuperated within the product lifecycle. Process changes, even if they could be made technically, are rarely made because of the costs associated with requalification and validation of the overall process. Bioprocess flexibility in the recent past has been associated with increased safety risks, primarily due to our lack of understanding of the actual biology of the production cells and how it affects process quality and stability. Flexible manufacturing, implemented with a systems–biology understanding, fits well within FDA's current QbD initiative and allows for ongoing process improvement. We believe NGG is a key tool for the acquisition and rational use of this understanding. In a flexible manufacturing environment, once a design space has been defined, using NGG and other tools, manufacturers will have the flexibility to make process changes within that design space with no prior approval from FDA regulators. Manufacturers that adopt this approach will be able to regularly improve their performance and efficiencies, while maintaining higher stability and quality control, and while also reducing the costs of recertification.