Media Management in Upstream Process Intensification
First used in the chemical process industry, process intensification (PI) describes a manufacturing philosophy that aims to maximize the output of production.
This article is posted on our Science Snippets Blog.
Intensifying production means different things to different organizations. Typical outcomes include:
- increasing product yields
- speeding-up drug development
- reducing manufacturing costs
- increasing operational flexibility
The principles of PI can be implemented in any process, modality, or application, but upstream cell culture is one of the key areas in which biopharmaceutical manufacturers can effectively implement intensification strategies.
Upstream Manufacturing - Process Intensification Strategies
The standard cell culture technique used across the biopharmaceutical industry is fed-batch culture. In fed-batch processes, cells are cultured in a bioreactor, and protein harvest happens only at the end of the fed-batch. Feed media is added gradually to replenish nutrients and growth factors during the process.
Broadly, there are three alternatives to this approach that intensify the production process:
N-1 perfusion high inoculum fed-batch - A method of seed train intensification in which the production bioreactor is seeded with a higher number of cells. It reduces the time needed to reach the desired cell densities for production or delivers a higher titer within the same time scale as standard fed-batch culture.
Concentrated fed-batch - Media is continuously refreshed by adding it to the perfusion bioreactor. Spent media passes through and goes to waste. Cells and the protein product are recirculated and returned to the bioreactor. The protein is harvested only at the end of the culture process.
Dynamic perfusion - Media is circulated through a growing culture, supplying nutrients, removing waste, and harvesting the product in a single operation. The entire medium volume is exchanged daily while retaining the cells and minimizing waste, increasing cell density, longevity, and protein production.
Selecting an Intensification Strategy
The nature of facility operations and features of the production process are key to selecting the best PI strategy for your facility. However, many aspects of manufacturing will be affected by intensification scenarios, including the media and buffer requirements. As outlined in our recent eBook, some PI strategies require significantly larger volumes of media throughout the production process, influencing all steps of the media journey, from preparation to disposal.
While media management might seem like a simple hurdle to overcome, it actually has significant implications for media preparation, facility design, process scheduling, storage and duration of storage, footprint, and mitigating the risk of quality issues.
Often, there is the perception that the difficulties and increased expenditure associated with media management in process intensification can be barriers to its adoption.
The Value of Conceptual Design
To successfully incorporate PI into a new or existing facility, manufacturers must consider each possibility in the context of the production process. They must also examine the capabilities, capital expenditure, product, and other factors that affect how effectively and seamlessly they can integrate it into their manufacturing facility.
One tool to support the decision-making process and help assess the feasibility of intensification scenarios is conceptual design tools, for example, the Process4Success® platform from Sartorius.
These technologies take the existing parameters and goals of the facility and model potential scenarios at different scales. Users can play around with the settings to see how they might best incorporate PI into their facility.
Starting with the scaled-up process, conceptual design tools reverse-engineer the production process to fit the facility, allowing manufacturers to select the best strategies for their operations. Our ebook demonstrates how a conceptual design approach can support the design and creation of new strategies for media management when intensifying production in existing and new facilities.
Intensification in New and Existing Facilities
The task of introducing intensification scenarios is quite different for new and established facilities.
Existing facilities likely have limits on how much of the current infrastructure can be changed. For example, room layouts and existing instrumentation might be fixed, and they might be at maximum storage capacity, restricting their options for implementing PI, especially where the media demand is significantly higher.
Some PI strategies are simpler to implement into existing processes than others. Implementing dynamic perfusion and concentrated fed-batch processes might require significant changes to the facility layout and equipment needs. The media consumption is also significantly higher (950 and 1,400% for dynamic perfusion and concentrated fed-batch, respectively).
In contrast, seed-train intensification (N-1 perfusion) is likely the most suitable scenario for existing facilities. It requires minimal changes to the process, only a 50% increase in media consumption, and still delivers a productivity increase of around 60%.
When starting from scratch, there is more choice of which elements of intensification to incorporate, as manufacturers do not have to compromise on the existing infrastructure. Their decision will likely depend on the facility operations, budget, expertise, and throughput.
To maximize the opportunity for intensified bioprocessing, manufacturers should consider how they might adopt PI into their facilities during early development. This way, layout, logistics, storage, and scheduling can all be considered during the design and creation of the new facility.
Concentrated fed-batch production is ideal for biologics with a higher throughput demand, and offers a two-fold increase in output. However, media consumption is much higher, with significant media preparation, storage, and scheduling implications.
Dynamic perfusion is ideal for low throughput or difficult-to-express molecules. It is particularly suited for rapid development in next-generation facilities, offering a 45% reduction in footprint, but is also associated with a large increase in media consumption.
The significant changes in media requirements for both concentrated fed-batch production and dynamic perfusion must be carefully considered in the context of the facility operations. Conceptual design tools can help ensure these strategies are both feasible and beneficial in your facility.
Making the Most of Intensification
A robust supply of well-formulated media is essential for the performance of any cell line during upstream manufacturing. To maximize product yield, intensification scenarios will have to be carefully considered in the media journey, including preparation, scheduling, and waste management.
PI results in a higher volumetric demand of liquid media from preparation, hold, consumption, and disposal. If the manufacturing strategy and facility are not well-designed, biotechs might end up with increased expenditure with reduced productivity. This is in contrast to what PI is supposed to offer.
Discover more about how bioprocess intensification impacts the media journey and how best to implement PI in our eBook.
Featured eBook: Intensifying Upstream Processing - Implications for Media Management
This ebook provides the tools and information needed to consider process intensification (PI) options while evaluating the implications of media management. This comprehensive overview of the media journey and how increased volumes associated with PI can be effectively managed is followed by an exploration of the feasibility of different PI scenarios in both new and existing facilities.