The design and development of the optimal production process is a big challenge – and it’s rare that upscaling runs smoothly. The growing demand of monoclonal antibodies (mAbs) requires efforts to increase production capacities and product titers. Experience shows that an ideal up-scaling process tends to rely on the field of hydrodynamics and process engineering; numerous indicators and values are needed to develop the right strategy. Many parameters, such as mixing time and the volumetric mass transfer coefficient (kLa), however, cannot be transferred in a linear manner, so successful up-scaling always involves compromises.
Mistakes made at the early planning stage can have a high impact later on. Insufficient agitator performance or inappropriate gassing rate and feeding strategy are common barriers that can affect productivity and cause product losses. Start ups, in particular, tend not to have the extra cash required to fix problems – but even large companies don’t want to spend time and money fixing a process that should have been done right first time.
In recent years, I’ve been involved in workshops that aim to raise awareness of issues that need to be addressed in planning procedures. Process flow, functional specifications, architectural conditions or critical quality aspects need to be evaluated while considering all standards and regulations. It always fascinates me to see how companies are often completely unaware of the common, potential bottlenecks in their process steps and how these will affect their scale up! In my view, plant engineers need to be able to influence the planning process at a much earlier stage. Even at the preclinical stage, processes should be analyzed with a view to industrial-scale production and the conceptualization of a pilot plant. Right now, the whole industry is talking about fast-track projects, but these will only work out if plans are made in cooperation with those who build the plant. How can plant engineers give operational guarantees if they don’t have the opportunity to influence the planning process?
The more precisely a process can be investigated and characterized at the early stages, the greater the chances of a smooth scale up. Today, there are plenty of tools that can be used to get a good view of what is happening during the process. For example, determination of concentration and temperature gradients via computational fluid dynamics (CFD) studies is a useful analysis tool for the prediction of process parameters. A precise determination of the kLa-value is a meaningful PAT tool as well, as it gives a comprehensive picture of what’s going on inside the bioreactor. The kLa-value is also a suitable scaling indicator at the early stage: it allows for the calculation of oxygen uptake rate, as well as the estimation of the oxygen transfer rate via stoichiometric correlations in advance. Oxygen uptake and transfer rates represent a sound basis for the bioreactor and agitator design, and support the development of reliable scale-down models, where production conditions in commercial scale are simulated. The process optimization within the design space needs to be executed for each specific production system. As soon as any parameter changes, whether that be the expression system, media components or feed strategy, the performance indicators must be determined again to avoid product loss later on.
Investing in the right tools and expertise early on will pay dividends down the line. As well as optimizing the process, good engineers are also able to optimize the facility, through space-saving designs (easy to evaluate with 3D models) that offer easy access for maintenance and optimized interfaces between skids. A well thought out solution path along the entire planning process offers four key advantages: increased process safety, maximized productivity, reduced costs and shorter time to market.
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