By: Dr. Nick Hutchinson
Robust biopharmaceutical production processes are required to supply lifesaving drugs to patients. Many biologics in development or on the market are manufactured using large-scale cell culture technology. Large-scale cell cultures must consistently produce product of the required quality and achieve productivities that allow companies to meet their Cost of Goods requirements. Biologics manufacturers can maximize their annual plant throughputs by minimizing unnecessary complexity and therefore avoiding lost batches through contaminations or manual errors.
Scientists working during early stage development must have these objectives in mind when designing cell cultures processes. The enormous financial implications of reaching the market quickly mean that they must achieve their objectives in the shortest possible time.
Here are five tips for accelerating the development of optimized cell culture processes.
1. Consider outsourcing non-core competencies: External suppliers can often perform activities that are not your core competencies more effectively and with less total cost than you would be able in-house. Outsourcing these activities allows you to expedite cell culture development without having to employ additional resource, invest in additional staff training or purchase new equipment. A range of early stage upstream process development services are now available from third-party providers including cell line construction, cell bank creation and product quality assay development. Letting others perform these tasks frees-up available resources and time for development activities that can add additional value to the process you are designing. Plan to manage actively the partners you work with to get maximum benefit out of outsourcing relationships and develop collaboration abilities as a competency in its own right.
2. Understand how your process will fit large-scale bioreactors: Before starting any process development activities, you should discuss with colleagues in operations the capabilities of the intended large-scale equipment and plant. This will avoid any problems with facility fit upon process scale-up. It is easy for development and operations departments to become silos. Good communication is critical for the overall success of the program. In cases where the company will build a new facility for the process, scientists should understand the implications of different bioreactor designs on the performance of the process they develop. Firms can purchase or design production bioreactors with great geometric similarity to those used in pilot or laboratory settings. Use mathematical scaling tools to ensure that cell culture conditions studied at the smallest scales will be achievable at the large-scale.
3. Invest in high-throughput development tools: You can now run large-numbers of bioreactors in parallel using automated high throughput screening tools. This reduces the need to purchase and resource the operation of many individual bench-top bioreactors. Alternatively, it saves considerable time by not having to operate a small number of bench-top bioreactors sequentially. This can save weeks of time during cell culture development. Using high throughput tools minimizes the cell culture media costs incurred by companies during development. Miniaturized bioreactors provide scalable data such as information on which clones will be the most productive and whether the product they produce will have the required quality attributes.
4. Embrace efficient experimental designs: In the past, scientists have regarded multivariate experimental designs during early stage process development as expensive and time-consuming luxuries. In fact, the opposite is true and they should be the most efficient method for gaining process understanding. For example, researchers have developed high titer processes by creating blends of blending basal cell culture media with different compositions and studying the effects with D-optimal experimental designs. Multivariate experimental methods allow you to understand which process parameters exert an effect on product quality attributes. Furthermore, they allow the definition of design spaces for use in QbD-based regulatory submissions and allow you to develop and transfer into production environments robust upstream processes.
5. Plan your knowledge management approach: Early stage process development is only the first step in the overall lifecycle of the process. Biomanufacturers can and should use the data generated during this phase throughout the process lifecycle to inform operational and quality decisions. Techniques such as multivariate data analysis can provide you with great insights into the performance of cell cultures at difference scales or in different facilities. Plan your approach so that you can take advantage of these tools and readily compare the performance of cultures with historical data. By adopting this mind-set during process development, you can gain a deeper understanding of cell culture variation and the factors that underpin it. Having this knowledge will help you spot detect potential issues before they manifest themselves as deviations or even lost batches and require extensive rework to address.
About the author: Nick Hutchinson is a Technical Content Marketing Manager at Sartorius Stedim Biotech.