In a recent article on key improvements for improving the quality of biopharmaceutical manufacturing, the author, "The Dish" states:
While I agree that eliminating animal-derived sources will improve the process, this claim is rather spurious.
Let's go through this one claim at a time:
This is certainly true... there is always a risk, albeit small. Peptones and other animal-derived media components are heat-inactivated. Automation engineers code recipes into the PLC or DCS to make certain this happens. After the animal-derived media components are added during cell culture media preparation, the entire media is virally-inactivated with a process similar to pasteurization. Whatever risks were there are significantly diminished before the bioreactor is even batched.
In the case of antibody manufacture, the Protein A chromatography is the step that binds the antibody and throws everything else away. To present the risks of viruses or prions in the final product as a risk - given the viral barriers and purification capabilities of modern biotechnology - is extremely irresponsible.
What about this claim?
Is it true that we fully understand the components of animal-derived ingredients? I'm not aware that this is true. Perennially, miniferm experiments confirm that cultures that use animal-derived sources produce higher titers than "veggie" media or fully-defined media.
There's that je ne sai quoi in animal-derived media that the cells seem to like. Some think it is the shear-reduction capabilities; others think it is some magic ingredient that we have yet to fully characterize, but these process R&D managers aren't stupid. If your process titers are low, and using animal-derived media can increase titers so that you can commercially manufacture the API... you use animal-derived media. It's that simple.
All this said, The Dish is correct about eliminating animal-derived media components... but for the wrong reasons.
Elimination of undefined media sources will reduce process variability because you've eliminated a potentially huge source of variability. I've seen titers swing 300% from year to year with no change in the manufacturing formula, no change in manufacturing execution, no change in anything but the lots of ingredients that we get. Using defined media will simply eliminate the lingering question of, "Is it the peptone lot?"
On top of that, variability reduction increases process capability. Even if using fully-defined media loses out 25% yield to the best performing undefined media, you gain from the predictability of your process.
Now, you can schedule campaigns with greater confidence. You can manage the supply chain. You can be assure that there will be fewer disturbances to your manufacturing process... you can keep less inventory... and you can ultimately save in costs.
Variability reduction is the reason you want to eliminate animal-derived media components... not risk of viral or prion contamination.
Process R&D managers that "get it" understand that optimizing titer must be balanced with optimizing process capability.
Many problems with respect to contamination are a result of problems with raw materials and too often these raw materials are sourced from animals. Animal-derived products always carry a risk of contamination from adventitious agents, such as viruses and prions. Not only are animal sourced products a safety risk, but also they simply are no longer necessary ingredients in manufacturing.
While I agree that eliminating animal-derived sources will improve the process, this claim is rather spurious.
Let's go through this one claim at a time:
Animal-derived products always carry a risk of contamination from adventitious agents, such as viruses and prions.
This is certainly true... there is always a risk, albeit small. Peptones and other animal-derived media components are heat-inactivated. Automation engineers code recipes into the PLC or DCS to make certain this happens. After the animal-derived media components are added during cell culture media preparation, the entire media is virally-inactivated with a process similar to pasteurization. Whatever risks were there are significantly diminished before the bioreactor is even batched.
In the case of antibody manufacture, the Protein A chromatography is the step that binds the antibody and throws everything else away. To present the risks of viruses or prions in the final product as a risk - given the viral barriers and purification capabilities of modern biotechnology - is extremely irresponsible.
What about this claim?
Not only are animal sourced products a safety risk, but also they simply are no longer necessary ingredients in manufacturing.
Is it true that we fully understand the components of animal-derived ingredients? I'm not aware that this is true. Perennially, miniferm experiments confirm that cultures that use animal-derived sources produce higher titers than "veggie" media or fully-defined media.
There's that je ne sai quoi in animal-derived media that the cells seem to like. Some think it is the shear-reduction capabilities; others think it is some magic ingredient that we have yet to fully characterize, but these process R&D managers aren't stupid. If your process titers are low, and using animal-derived media can increase titers so that you can commercially manufacture the API... you use animal-derived media. It's that simple.
All this said, The Dish is correct about eliminating animal-derived media components... but for the wrong reasons.
Elimination of undefined media sources will reduce process variability because you've eliminated a potentially huge source of variability. I've seen titers swing 300% from year to year with no change in the manufacturing formula, no change in manufacturing execution, no change in anything but the lots of ingredients that we get. Using defined media will simply eliminate the lingering question of, "Is it the peptone lot?"
On top of that, variability reduction increases process capability. Even if using fully-defined media loses out 25% yield to the best performing undefined media, you gain from the predictability of your process.
Now, you can schedule campaigns with greater confidence. You can manage the supply chain. You can be assure that there will be fewer disturbances to your manufacturing process... you can keep less inventory... and you can ultimately save in costs.
Variability reduction is the reason you want to eliminate animal-derived media components... not risk of viral or prion contamination.
Process R&D managers that "get it" understand that optimizing titer must be balanced with optimizing process capability.
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