MEDIA DEVELOPMENT USING QBD PRINCIPLES
To predict the interaction of media components feeds and supplements and the effect they may have on cell performance, media
and supplement suppliers must work closely with their customers to understand their specific process requirements.
Quality has become increasingly important at all stages of the biomanufacturing process, supported by the implementation of
quality by design (QbD) concepts. With the emphasis on both product and process understanding, QbD is being applied at the
product/process development stage. If these principles are to be applied to the complete biomanufacturing processes, then
it must include raw materials such as media components, which as mentioned are prone to variability and are not directly controlled
by process development scientists.
Availability of detailed information about raw-material quality specifications can vary among suppliers and is often dependant
on customer relationships. Lack of raw material understanding or protection of formulation information can make it difficult
to call some supplements truly defined. Some suppliers work closely with their customers to ensure that all aspects of product
quality meet biomanufacturers' process requirements.
Cell-line specific complex media supplements developed by Sheffield Bio-Sciences are current examples of the supplier acknowledging
the change in media design and listening to customer requirements. Created using innovative media optimization methods, the
supplements are manufactured using proprietary process technology to enhance performance of various biopharmaceutical production
systems. This process allows for the combination of complex and/or chemically defined animal-component free media additives
into a single homogeneous functional supplement.
As an example, The Sheff–CHO system is a series of complete medium supplements optimized for Chinese hamster ovarian (CHO)
cells. The systems contain mixtures of factors known to promote CHO cell growth, cell metabolism and protein production and
have been carefully optimized to give superior recombinant protein yields.
In recent studies, the application of cell line specific supplements such as Sheff–CHO ACF Plus and Sheff–feed both in batch
and fed batch cultures was examined. The addition of Sheff–CHO to commercially available CDM or the basal media Dulbecco's
Modified Eagle Medium (DMEM) was shown to significantly improve CHO cell culture performance when compared with cells grown
in medium alone. Peak viable cell density was seen to be at least 2-fold greater for medium supplemented with Sheff–CHO. This
growth improvement was further enhanced with the addition of the feed (see Figure 6a).The increased growth rate translated
to increased product titer, with a greater than 4-fold increase when the supplement was introduced as a feed (see Figure 6b).
Figure 6: Addition of Sheff–CHO supplements commercially available chemically defined media (CDM) or basal media significantly
improved CHO performance compared with medium alone. Feeding with Sheff–Feed further enhanced both Chinese hamster ovary (CHO)
cell growth and productivity.
In a comparison with competitors' feed systems, the Sheff–feed was seen to outperform with respect to both CHO cell growth
and productivity in either CDM or DMEM (see Figures 7a and 7b). Interestingly, while the competitor feeds had minimal effect
on cell performance in the basal media, DMEM, the Sheff–feed enhanced overall cell performance equivalent to that in CDM.
Figure 7: Comparison of Sheff–Feed against two competitor feeds in either chemically defined media (CDM) or Dulbecco’s Modified
Eagle Medium (DMEM) for Chinese hamster ovary (CHO) cell growth and productivity. Sheff–Feed enhanced CHO cell performance
compared with both competitor feeds.