Pre-slaughter manipulation - Bioactives impact on pharmaceutical and diagnostic productivity

Summary

FBS has traditionally been used as a media supplement for mammalian cell culture as it provides a rich source of growth factors, extracellular matrix proteins, fatty acids, lipoproteins, carrier proteins, antioxidants and buffering capacity. Since the 1980s there has been a growing trend to remove FBS from culture media due to potential contamination with adventitious agents, lot to lot variation, complicated downstream processing, high cost, and regulatory burden. Despite this FBS is used in the manufacture of most biologics produced in mammalian cells approved prior to circa 2000, including six to seven of the current top ten biologics by revenue. FBS will not be removed from these products as a new licence would be required, which, due to the regulatory burden and need for further clinical trials, would be extremely costly. 

To reduce the opportunity for contamination due to FBS the FBS used for biologics manufacture undergoes extensive screening for adventitious agents. In addition FBS sourced from countries with a low risk for BSE are preferred. Australia and New Zealand are recognised as the safest sources of serum available in commercially viable volumes and have been assessed for BSE risk by the European Food Safety Authority (EFSA) as “highly unlikely” (GBR I). Generally for industrial uses FBS is sourced from Australia, New Zealand or the US, despite the fact that the US has had cases of BSE and has been assessed for BSE risk by the European Food Safety
Authority as “likely but not confirmed or confirmed, at a lower level” (GBR 3). In addition on 19 Nov 2007 the US will open its borders with Canada to allow free movement of cattle. Canada is considered to have a higher risk for BSE than the US. This may result in more biologic manufacturers moving away from US sourced serum and provides an opportune time for Australian suppliers to gain market share. 

Feedback from industry regarding interest in an improved FBS for supporting the production of biologics (i.e. through “on farm” manipulation) is that industry is always vigilant regarding issues relating to bioprocess improvement and cost reduction, however the regulatory burden would need to be low. A significant market for FBS, though smaller than the biopharmaceutical market, is the
production of live, attenuated viral (LAV) vaccines. Merck produces a number of LAV vaccines that require FBS-supplemented media; two of these, RotaTeq and Zostavax, are potential blockbusters. Merck currently use US-sourced FBS and calf serum for viral vaccine production. Senior Merck personnel have indicated interest in GBR1-sourced FBS and FBS with improved performance. 

The research market is a substantial consumer of FBS, however, the supply and regulatory concerns of the industrial sector are not shared by the research sector where cost and performance are paramount. As a result this sector is more likely to purchase serum from cheaper sources than Australia, such as Mexico, France, South America, Central America and Canada. While this also means it is easier for researchers to switch to a better product they would need to see substantial benefits to use a more expensive product.
There is very little information available in the literature on the potential impact of variations in the bioactive content of FBS on biologic production. Information is available on the mode of action of many identified bioactives.

Growth factors are probably the most important group. The major growth factors that would be of interest for further investigation are insulin like growth factors (IGFs) and their binding proteins, fibroblast growth factors (FGFs), transforming growth factors
(TGFs), platelet derived growth factor PDGF) and epidermal growth factor (EGF) . In particular bFGF plays an important role in the growth of a number of cell types and could be a lead candidate biomarker for assessing the quality of FBS through on farm manipulation of bioactives.