A Generic Growth Test Method for Improving Quality Control of Disposables in Industrial Cell Culture - Independent data, using several different cell lines and growth media, reported growth inhibition

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A Generic Growth Test Method for Improving Quality Control of Disposables in Industrial Cell Culture
Independent data, using several different cell lines and growth media, reported growth inhibition resulting from the use disposable bags and suggests a method that can be implemented for quality control at disposable-bag vendors.


BioPharm International
Volume 23, Issue 6, pp. 34-41

DISCUSSION

Disposable bags used in cell-culture applications have complex manufacturing processes. Polymeric films in many cases are sourced from secondary vendors where a similarly complex manufacturing environment may exist. Bag assemblers may not have detailed knowledge of film manufacturing methods or the authority to influence them if they wished to. Once bags are assembled, they are typically gamma irradiated, which along with the length of shelf-life post-irradiation, is another potential source of variability between manufacturing lots as well as between vendors' products with respect to this effect on cell growth (2).

The length of media or water warming used for the testing described here is slightly longer than would likely be used in practice. However, the method is useful in uncovering growth inhibition effects and reveals an underlying issue with these products. While industry may not be able to supply vendors with a suitable CHO or NS0 production line to apply this method, the general nature of the effect across multiple CHO lines suggests that a nonproprietary CHO line may be suitable for implementation. However, end-users would likely need some degree of bridging data prior to accepting results generated by a bag vendor using such a CHO cell line. The existence of such bridging data could, in a general sense, also reduce the total in-house effort required at a given end-user to accept bag vendor cell-culture test results in the future.

To date, the mechanisms that result in cell growth impacts by disposable bags are varied and not completely understood. Medium component adsorption has been identified as one mechanism that can inhibit cell growth in a cholesterol-dependant cell line (7). Cell growth impacts resulting from a specific leachable/extractable have been characterized (8, 9). The cell-based assay was able to identify which disposable bags impacted cell growth and eventually led to identification of the specific leachable inhibiting cell growth. The vendor was then able to optimize the film composition to ensure biocompatibility.

It cannot be assumed that these are the only mechanisms that can result in inhibition of cell growth. The use of a cell-based assay like those described here can be used to identify where such impacts exist. Once they have been determined, various factors such as raw materials, leachables and extractables, irradiation, storage, and other factors can be systematically investigated. This investigational approach underpinned by a cell-based assay can lead to the identification of the root cause of cell-growth impacts that can be readily addressed by the vendors once understood. The growth test method described is useful in troubleshooting and can be applied proactively as a harmonized first step in improving quality control of these widely used disposable products for both suppliers and customers.

The problem end-users face is not vendor-specific or fundamentally dependent on the end-users' cell lines or media. The growth test methods described can be applied at bag vendors' own sites. In doing so, vendors may improve the overall understanding and quality control of their disposable products. While some products may not lead to the same observed phenomena, as polymeric film manufacturing or gamma irradiation practices change around them, each vendor could use a test such as this to uncover if those changes have an effect on this particular application. As this issue is still prevalent years after it was first discussed, the authors and the cell culture-engineering community are eager to see the quality-control testing and practices for disposables manufacturers improve.

CONCLUSION

When cell-culture medium or the water used to make it are incubated at operating temperature (37C) in disposable bags prior to use, growth inhibition effects can be observed. These effects are not cell-line, cell-type or cell culture-media specific. The problem is relevant for multiple bag manufacturers. The authors suggest that bag vendors implement the cell-growth test described here as part of their manufacturing quality control and as a means to understand critical film composition attributes and manufacturing controls. The question of what cell lines are best used for this testing remains, but it is believed to be solvable as the effect is observed in multiple CHO lines as well as an NS0 cell line. Having data from such a cell-growth test together with a deeper understanding and control of film composition and manufacture will facilitate adoption and continued use of disposable-bag technology. This knowledge will help ensure robust and predictable performance even through the inevitable changes in bag and bag film manufacturing processes.

ACKNOWLEDGEMENTS

The authors wish to thank Robert Kiss, Masaru Shiratori, Thomas Ryll, Reb Russell, and Richard Schicho for their discussion, review, and comments on this manuscript. Erica Graf and Richard Martel performed cell culture work at Bristol-Myers Squibb Company.

*Brian Horvath is a scientist at Process Technical Development, Late Stage Cell Culture, Genentech, a member of the Roche Group, South San Francisco, CA 94110; Valerie Liu Tsang is senior engineer III and Weimin Lin is a scientist, both at Cell Culture Development, Biogen Idec, RTP, NC 27709; Xiao-Ping Dai is manager at Cell Culture Science, Global Manufacturing and Supply, Bristol-Myers Squibb Company, Bloomsbury, NJ 08804; Kurt Kunas is a principal scientist and Greg Frank is a principal engineer, both at Amgen, Thousand Oaks, CA 91320.

* To whom all correspondence should be addressed,
.


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