Intensify your cell culture processes, in order to keep pace with today’s industry and regulatory expectations
An increased focus on precision medicines and orphan drugs over traditional blockbuster products means today’s manufacturing facilities and process development capabilities must be equipped to manage the growing diversity across the bioprocessing landscape. This includes greater efficiency and quicker time to market using continuous manufacturing for multiproduct production. The importance of reducing development timelines has always been a goal for drug manufacturers, but the need to establish a rapid response strategy for emergency circumstances intensified greatly with the COVID-19 outbreak. Using an approach like continuous manufacturing would not only improve speed to market, which is more important now than ever, but it would also help with the ongoing effort to cut development and manufacturing costs.
In 2019, the FDA issued a draft guidance entitled “Quality Considerations for Continuous Manufacturing,” in an effort to expand upon its previous guidance on the topic as well as encourage companies to switch from batch manufacturing to continuous. The agency recognizes continuous manufacturing as one of the most important tools for modernizing the pharmaceutical industry. The key enabler for intensified processes are continuous manufacturing techniques, e.g. perfusion, which can, which can maximize product output, minimize a manufacturing footprint, and reduce capital expenses. So, how can you intensify your cell culture processes, in order to keep pace with today’s industry and regulatory expectations?
The impact of cell culture media and raw materials on product titer and quality
While monoclonal antibodies (mAbs) continue to be the major modality of biopharmaceuticals, the pipeline is also filling with other new modalities, such as vaccines, cell and gene therapies, and even novel variants of mAbs. The implementation of new approaches to accelerate manufacturing of today’s diverse molecules must be matched by equal efforts to also speed up the process development timeline. However, as companies focus on scaleup and optimization, it is crucial to understand the impact cell culture medias and feed supplements have on cell productivity, yield and product quality.
The formulation of cell culture media can be optimized to modulate the process of product quality attributes, but it must be noted that the raw material impurities and manufacturing process of the media might influence product quality attributes. The design and optimization of a media and feed supplement platform is a task that requires specialized equipment and knowledge, and it is very often a one-off exercise for a project. If your manufacturing strategy involves multiple or global sites, you should know what types of raw material characterization are essential to reducing your process variability and whether your raw material will be subject to scrutiny by regulators (locally as well as globally, if applicable). Oftentimes, it is beneficial to collaborate with a media development service organization that offers a high level of transparency with their raw material characterization. This ensures there is a supply chain and capabilities in place that can handle the intrinsic variations that can exist with ingoing components and their impact on product quality.
Another consideration that affects your decision-making during process development is the level of titer you can achieve, as this is directly proportionate to the number of batches you need to run and, thereby, the production costs. With a lower titer process, there will likely be a need for large bioreactors, in order to make enough material. Higher titers, however, means a smaller bioreactor, reducing capital expenses and other costs. This also opens up the option of implementing single-use technology, which offers several benefits, such as reduced cleaning requirements, smaller manufacturing footprint, and quicker product changeover. Once you determine the needs of your cell culture process, you must also identify the most optimal platform technology for quickly and safely developing your product.
How do you select the most optimal platform technology for your product?
Process scalability is a key consideration for process development. When you develop your process at a small scale, you should do so with production scale and equipment capabilities in mind. The design should be as simple as possible. There are multiple process and engineering parameters that can be used for a process scale up, especially cell culture. Typically, these parameters could be volumetric power input, the impeller tip speed, as well as the energy dissipation rate or the mixing time. While there are many options for you to use, there is, unfortunately, no such thing as a perfect parameter.
A good understanding of your cell line is beneficial for selecting the scale-up strategy. For example, is it sensitive to shear force? Does it have a high demand of oxygen? Digital tools for process scale up, such as computational fluid dynamics and process simulation, can also help you understand the bioreactor physics as well as cell behavior. When selecting the most optimal process platform, let experience, available capabilities, and material supply situation guide. Are there specific requirements like product instability that push you towards perfusion setup? If so, then a continuous upstream process will be the best option. If the answer is not a clear yes, then you must understand the yearly amount of product to be produced and try to calculate what is a relevant production scale. Would a 1,000- to 2,000-liter bioreactor easily produce what you need? If so, then SUT is the best fit.
Implementing process intensification at your facility
There are several application areas where you can implement process intensification. For example, an intensified seed train can stage in the seed or seed the production bioreactor at higher cell densities. Banking your cells in higher volumes and higher cell densities can reduce the number of days in the subsequent expansion train and may allow you to inoculate directly to your N-2 or N-1 bioreactor. Perfusion could also be applied in the N-1 step to inoculate your production bioreactor at significantly higher cell densities. This would cut out the cell expansion in the production bioreactor as well as decrease the time in the production bioreactor by four to five days. In order to run the process intensification, you may need a more sophisticated control software to go along with it.
There are many benefits associated with optimizing process development, but it can sometimes be difficult to convince other teams, such as manufacturing and management, to change the way they approach it. This could be due to aversity to change or concerns about how regulators would react to the implementation of different strategies. When discussing the options available with the stakeholders within your company, demonstrate how these techniques could increase productivity in your plant and what effect that has on efficiency and economy. Then, illustrate a roadmap for implementation, including risk assessment strategies that might help identify issues before they occur. Once you can help them understand the impact these changes could have on the overall success of the business, you can design a plan to implement these changes, preparing you for the challenges ― and successes ― related to today’s emerging therapies.