Monoclonal antibodies (mAbs) are used extensively in the diagnostics industry, where their superior selectivity and binding greatly increases the robustness of such tests.
In contrast to the manufacturing of therapeutic mAbs, where a single product is made in large batches, the diagnostic industry tends towards multiple products made in small-volume batches. This can create the perception that a scaled-up R&D process will be suitable for commercial production, both from a quality and economic standpoint. However, typically, this is not the case.
In this SelectScience webinar, Dr. Paul Beckett, Technical Applications Consultant at Merck KGaA Darmstadt Germany, explores the key considerations for scaleup and provides insights into large-scale production technologies.
Read on for highlights from the live Q&A session or register to watch the webinar at a time that suits you.
PB: One of the parameters you can alter is the amount of meters squared that you can install in the system. The impact of increasing this is that you just need to match it with the rest of the normalized parameters. If I was to go from 5-meters squared to 20-meters squared, the actual flow rate you need to apply to that will be four times higher. However, on paper, this is normalized to liters per minute, per meter squared. Therefore, that would be six liters per minute, per meter squared, and the actual flow rate, the volumetric flow rate, will be four times higher. Now, that becomes an issue when we start running into pump issues. Larger-scale devices have a much more limited pump window. You’ve got to be careful because all the numbers stay the same, but the actual flows, the actual engineering constraints, change substantially.
In the case of the TFF system, we can increase the number of meters squared inside the system, as long as the rest of the system can keep up with it.
Can you explain the safety factor considerations and how you would implement these?
PB: This depends on where in the process you are. In the case of TFF, when you do your process development, you will find the minimum time that you need to do a particular process. For example, when you do the process development, you may work out that you need 15-meter squared of membrane to do this in four hours. Now, you could just use 50-meter squared of membrane for that, and do it in four hours, but that gives you no safety factor whatsoever. This means that if there was something different about that process, some of the feed was inconsistent or there's a temperature change, it's not going to take four hours anymore. This could have all sorts of problems for the scheduling, and potentially with things like final filtration. It could even be a validation and regulatory issue where time is critical to the specification.
To mitigate this, what we do is we work out what is called an A-min, so that is a minimum area that we need to achieve that. Then we add the safety factor on top of that. Now, in the case of TFF, for final formulation, that safety factor is typically 20%, as a rule of thumb . We don't go much bigger than that, because, again, it affects process time and gets expensive to add a lot of membrane, which you don't necessarily need. What is critical is that minimum area that you use needs to be clarified and it needs to be done on a worst-case feedstock to know if everything else goes wrong, what is the absolute minimum error you need to do to get this process to be within specification. When you've got that, you then add the safety factor on top of that purely as assurance.
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