Economic conditions are driving a greater demand for improvements in productivity, cost management, and outsourcing. Technology also continues to advance and change the biomanufacturing environment. This was documented in the recently released 2010 7th Annual Report and Survey of Biopharmaceutical Manufacturing with input provided by 327 biomanufacturers globally. “Productivity improvements” is the #1 area where companies have been focusing on resources this year. The survey also documents an evolutionary change in the basic approaches and technologies used for upstream bioprocessing. While in recent years, the industry has largely been dominated by fed batch (or batch fed) bioprocessing, with fermentation performed in a bioreactor containing the same medium until ready for harvest, the BioPlan survey shows a definite shift towards greater acceptance and use of perfusion bioprocessing…
Tag: <span>upstream processing</span>
Batch processing has long been the predominant bioprocessing paradigm, both up- and downstream. Bioprocessing fluids are processed incrementally, piped as a bolus or transferred via vessels from one process and piece of equipment to the next. This continues to work well, including a number of technological advances resulting in improvements that continue to make bioprocessing more efficient. Upstream and overall process yields are essentially doubling about every five years, with this largely driven by improved cell lines, expression systems and genetic engineering, culture media, and equipment. Among the technologies now gaining increasing adoption and market share for biopharmaceutical manufacture is continuous (bio) processing, with perfusion currently the leading technology, in terms of adoption. The use of incremental, one-step-at-a-time, classic batch processing in biopharmaceutical manufacture is different than most other major products manufacturing and high-tech industries, where processing is generally more continuous. In this context, the move toward more continuous processing in manufacturing is a common characteristic of industries starting to reach maturity. Continuous processing is exemplified by assembly lines, and petroleum refining with processing involving a rather continuous flow of the material being manufactured from one unit operation to the next. Continuous processing generally follows and eventually replaces incremental manufacturing…
The ability to scale a cell culture effectively and efficiently, from lab to manufacturing, is critical to maximizing productivity whilst minimizing the risk of run failures and delays that can cost millions of dollars per month. The task of scaling well, however, is still considered to be a challenge by many upstream scientists, and this can be an exercise in trial and error. Traditionally, scaling has most often been performed using arithmetic in a spreadsheet and/or simple “back of an envelope” calculations. For some, it may even come in the form of support from a team of data scientists using advanced analytical software. This dependency on what some consider to be complex mathematics or statistics has resulted in the common consideration of using just one scaling parameter at a time, one scale at a time.
However, it is difficult to determine easily or optimally, from the start, whether a process successfully transfers across scales based on only one process parameter, at one scale. In this article, we describe the benefits of using a risk-based approach to scaling, and the development of a software scaling tool known as BioPAT® Process Insights for predictive scale conversion across different bioreactor scales. BioPAT Process Insights can be used to consider multiple parameters and across multiple scales simultaneously, from the start of a scaling workflow. We briefly describe how it was used in a proof-of-concept scale-up study to allow a faster, more cost-effective process transfer from 250 mL to 2000 L. In summary, using BioPAT Process Insights, in conjunction with a bioreactor range that has comparable geometry and physical similarities across scales, has the potential to help biopharma manufacturing facilities reach 2000 L production-scale volumes with fewer process transfer steps, saving both time and money during scale-up of biologics and vaccines.
A perfusion approach at N-1, where cells stay in the exponential growth phase throughout the entire culture duration, is becoming more common as a strategy for process intensification. This is because the higher cell densities it generates allows manufacturers to skip seed stages and reduce process transfer time through multiple bioreactor sizes, thus providing more cost-effective biologics production in smaller facilities. However, this N-1 perfusion approach requires optimization. In this article, we describe the development and proof-of-concept studies with single-use rocking motion perfusion bioreactors in which we have achieved a ten-fold increase in viable cell count in N-1 seed stage, compared to the fed-batch control process, in just 6–8 days. We also mention in detail how we inoculated a 50 L bioreactor production run using this intensified seed train and show comparable growth kinetics and yield with a control process, also at 50 L scale. Using this intensification approach in the future will help our manufacturing facility, the Biopharma Division of Intas Pharmaceuticals Ltd., reach 4000 L production-scale volumes with fewer process transfer steps, and without changing the feeding strategy or production bioreactors of our biologics’ portfolio.