Platform processes and effective risk assessments help overcome time and cost challenges.
Successful biomanufacturing processes not only provide the desired product in high yield and purity, they provide consistent results whether implemented in the lab or the production plant. For many monoclonal antibody (mAb) products, processes must consistently perform at scales ranging from hundreds of milliliters to thousands of liters. Lack of scalability can result in significant project delays and added cost due to the need for further optimization. Developing scalable processes from the outset is therefore the most effective approach to ensuring the smooth advancement of mAb projects through development to commercialization.
Balancing time, cost, and knowledge
The main technical challenges faced during the scaling of upstream mAb processes include variations in cell densities, cell viabilities, and product concentration, as well as potential offsets in product quality attributes, according to a spokesperson from Boehringer Ingelheim. These attributes can be impacted by the bioreactor design, process parameters such as temperature and oxygen transfer, media composition, supplement and feed strategies, and numerous other factors. Obtaining process understanding is therefore essential to establishing robust, scalable processes.
“Addressing these scale-up considerations in upstream mAb process development ultimately comes down to the timeline, budget, and priority of the developer,” says Leslie Wolfe, site head and vice-president (VP) of process development at KBI Biopharma. She notes that it is imperative to fully understand what knowledge exists and what is needed as part of the scope to help support effective process design. Because time and cost are often the most important drivers during early phase development, there may be a necessary trade-off in the form of reduced process knowledge and understanding of the design space. “One potential consequence,” observes Lorenz Hasler, VP of global manufacturing, science, and technology at KBI Biopharma, “may be reduced knowledge of key inputs to process design regarding quality attributes and process performance and underestimation of considerations as they relate to commercial manufacturing equipment.”
Benefits of established platform processes
An important consideration for mammalian upstream processes for mAb production, notes Hasler, is that the potentially critical respective key scale-up factors are comparable between processes. “Process knowledge and expertise can therefore be leveraged between processes. Because potential key parameters and equipment limitations can be taken into consideration upfront, potential scale-up issues can be reduced,” he explains. Risk analysis tools, Hasler adds, can then be used to screen and understand other potential process variables specific to the mAb candidate and thereby mitigate potential process risk at scale.
The best approach to ensuring scalability of mAb production is to use a platform process rather than focusing on individual project variations, observes the spokesperson from Boehringer Ingelheim. Taking this approach, it is possible to manage challenges to scalability using standard equipment (bioreactors).
Wolfe agrees that working with an established and scalable platform is key to mitigating the risks associated with scaling up. She notes that such a platform is typically developed through iterative application, which helps in establishing critical process knowledge.
“This knowledge and understanding form the foundation for establishing a process control and monitoring strategy tailored to each unit operation, leading to a potentially robust and reliable scale-up approach,” says Hasler. Platform processes may also speed up development activities because process development, and facility-fit assessments can leverage process knowledge and understanding, he adds. These platforms also help balance the timeline-versus-process-knowledge conundrum for programs with aggressive development timelines.
Relying on platform processes to ensure scalability must be pursued with some caution, however. “Conditions and predictions to perform a process at scale or commercial process for any new drug substance or drug product still need to be demonstrated at laboratory or pilot scale,” Hasler states. Additional information may also be needed to support the requirements of specific mAb-based candidates. When necessary, for instance, Boehringer Ingelheim uses computational fluid dynamics and process modeling, including detailed equipment characterization, to ensure smooth scale-up.
Considerations for upstream processes
To ensure scalability for upstream mAb processes, designing an efficient process complemented with an effective process control approach is critical and should be tackled during early process development, according to Hasler.
For Boehringer Ingelheim, a critical aspect of its scalability approach for mAb processes is the selection of a robust clone during early development. The chosen clone, says the company’s spokesperson, should not only fit the platform, but also exhibit robustness in relation to classical scaling parameters.
Even when a platform process is employed, Hasler recommends generating process knowledge for a specific mAb candidate using design-of-experiment studies, which help in defining the relationships and multivariate interactions between various process parameters and resulting outputs. He notes that it is also crucial to develop compelling analytical methods to support these small-scale studies. Demonstrating scalability of upstream mAb processes at an intermediate scale is beneficial as well, according to Wolfe, as doing so helps to de-risk scale-up to manufacturing.
Finally, Hasler comments that for mAbs with expedited approval designations, the shortened development timelines may lead to a reduced approach to process design and, therefore, reduced process knowledge and understanding. To balance the potentially reduced process development activities, he suggests that a detailed gap identification and subsequent risk evaluation may support potential scale-up considerations and success.
Consistent scale-up through platform approach
Platform processes not only streamline the development of scalable processes, they also make it possible to use a consistent approach to scale-up across all mAb-related projects. That is the case at Boehringer Ingelheim. “We do not test different scale-up strategies for our projects, as our scale-up strategy is not influenced by the specific product being expressed. Whether the product is a standard IgG1 [immunoglobulin G1] antibody or a trispecific molecule, the scale-up strategy generally remains the same,” says the spokesperson from Boehringer Ingelheim.
While general scale-up strategies also apply to more complex or advanced antibody-based therapeutics, Wolfe observes that appropriate risk assessments should be conducted and considered with more complex therapeutic targets to ensure sufficient knowledge is available. “Using this approach ensures the target product quality profile is achieved from the defined process,” she concludes.
About the author
Cynthia A. Challener, PhD, is a contributing editor to BioPharm International®.
Article Details
BioPharm International®
Vol. 37, No. 8
September 2024
Pages: 27–28
Citation
When referring to this article, please cite it as Challener, C.A. Considering Process Scaling for Monoclonal Antibodies During Early Phase Development. BioPharm International 2024 37 (8).
