Cell Culture Media

To assess current trends in cell culture media, BioPharm International turned to Bretta Erskine, manager of upstream technology and collaborations, EMD Millipore; and Bruce M. Lehr, director of development, SAFC Biosciences (a business segment of SAFC).

Q: How has the trend toward high cell density cell culture operations affected user requirements for media or feeds?
Erskine: The feeds and the media have both become more concentrated. In the case of the feeds, concentrating the media means removing the salts and insoluble components and adding them back in the right ratios for proper culture conditions.
Lehr: Most customers still run fed batch systems-preferably as chemically defined as possible and certainly animal component free (excluding legacy processes). Most run with leaner base media formulations and then add feeds throughout the course of the bioreactor run to support high cell densities. More feed usage and use of concentrated feeds are seen with higher density culture.

Q: Today, most companies desire to be animal-component–free. Are there any drawbacks to ACF media?
Erskine: I have found some similar drawbacks in that consistency from lot-to-lot (which does not appear to be vendor specific) is still an issue with a chemically defined medium. The more defined the medium you use, the more sensitive your process can be to variations in the medium.
Lehr: Animal-component–free is not equivalent to chemically defined. You can still have undefined components like plant hydrolysates or yeastolates that can introduce significant variability. Even in a chemically defined system, you need to make sure you have a fairly robust, optimized formula. If the concentration of some key components is too close to the edge of the effective range (plateau) then you can still have significant variability-this effect can be exacerbated by adding hydrolysates with their undefined nature. This "formulation variability" is different than variability of individual components like you might see with serum, serum proteins, or hydrolysates-but it is still variability and can be subtle.

Q: How far back do most users now want to trace the origins of raw materials, including animal-component–free certifications?
Erskine: I have always relied on media vendors for assurance of animal-component–free materials. However, I have seen cases where customers want to trace the materials very far back. For example, there is an anti-foam that Invitrogen sells that uses tallow somewhere very far upstream in their process. The Europeans won't touch the stuff, so they buy the animal-free (tallow-free) version. Invitrogen, therefore, sells two version of anti-foam and can charge a premium for the animal-free version.
Lehr: As far back into the supply chain as you can go. We need to do due diligence with all the vendors in the chain-look at their suppliers, raw materials, processes, quality systems, perform vendor audits, etc., and be able to represent as much of that as possible to our pharma and biopharma customers. For example, we now perform audit services of suppliers in the Asia-Pacific region especially for our customers on a contract basis.

Q: What percentage of your sales now comes from chemically defined media? Is this continuing to grow?
Erskine: I would say the majority of sales comes from non-chemically defined media. This is largely because of companies with legacy processes. However, movement toward chemically defined media is indeed continuing to grow.
Lehr: Most customers now wish to try to use chemically defined media in their new processes under development with the idea that they will cut performance variability and eliminate animal-derived pathogen risk. We have several customers in commercial production with chemically defined systems and at all other phases of clinical development. Yes, it is a trend that will continue to expand.

Q: Has the recent growth in vaccines created or increased user demand for different types of fermentation media?
Lehr: I infer from this question that you mean bacterial or yeast fermentation versus mammalian cells. We've seen increased use of both mammalian cell culture and other prokaryotic systems for vaccine production. In a couple of instances, we've been asked by major vaccine manufacturers to help them develop animal component free, chemically defined media for bacterial fermentation and have been able to do so. There are clearly companies using these systems in addition to mammalian cell culture.