Serum is the centrifuged fluid component extracted from either clotted or defibrinated whole blood. Bovine serum comes from blood taken from domestic cattle. Whilst the procedure of making serum may seem to be straightforward, the processing of serum takes place under very tightly controlled conditions. The process has been carefully developed and uses sophisticated facilities and equipment, and is accompanied by extensive testing particularly stringent when processed bovine serum is intended for use in the production of medicinal products.
Bovine serum is a by-product of the meat industry. Bovine blood may be taken at the time of slaughter, from adult cattle, calves, very young calves or (when cows that are slaughtered are subsequently found to be pregnant) from bovine fetuses. It is also obtained from what are called “donor” animals which give blood more than once. Blood is available from bovine fetuses only because a proportion of female animals that are slaughtered for meat for human consumption are found (often unexpectedly) to be pregnant. Bovine serum is categorized according to the age of the animal from which the blood was collected as follows:
– “Fetal bovine serum” comes from unborn foetuses
– “Newborn calf serum” comes from calves less than 20 days old
– “Calf serum” comes from calves aged between 20 days and 12 months
– “Adult bovine serum” comes from cattle older than 12 months
All above sera are collected from animals deemed fit for human consumption.
Fetal Bovine Serum (FBS) comes from the blood drawn from a bovine fetus via a closed system of collection at the slaughterhouse. Fetal Bovine serum is the most widely used serum supplement for the in vitro cell growth factors because of its high content of embryonic growth promoting factors.
There is a wide range of applications for fetal bovine serum. The most important is in the field of biopharmaceuticals and vaccines. It is used in the research, manufacture and control of human and veterinary vaccines and of drugs, many of which are at the cutting edge of drug development. Fetal bovine serum is also used extensively in research. A technique known as “Cell culture” is widely applied in the manufacture of both vaccines and bio-pharmaceuticals in which bovine serum is broadly used.
Maintaining cells in vitro in a healthy condition and over time is a complex task. They will only survive, grow and multiply if they are well fed and provided with an appropriate and protective environment. Complex mixtures of substances (“media”) are used to bathe the cells in order to both feed and protect them. Different cells have different requirements. In many instances the presence of serum in the mixture is essential if the cells are to grow adequately and normally. Bovine serum is the most widely used, because high quality bovine serum is available in sufficient volume and has been found to support cell growth very well indeed.
FBS is collected from the fetuses of pregnant cows, slaughtered in compliance with the OIE (World Animal Health Organization) guidelines and internationally accepted standards of veterinary inspection.
The choice of the FBS supplier is based on Quality, Traceability and Safety along the whole supply chain, endorsed by comprehensive documentation; backed up by audits of the supply chain back to the serum source; and covering several years.
The OIE (World Organization for Animal Health) is an intergovernmental organization created in 1924. In 2011, the OIE totaled 178 Member Countries and Territories. Its missions are:
• To ensure transparency in the global animal disease situation
• To collect, analyze and disseminate veterinary scientific information
• To provide expertise and encourage international solidarity in the control of animal diseases
• To safeguard world trade by publishing health standards for international trade in animals and animal products
• To improve the legal framework and resources of National Veterinary Services Organization
The serum’s source is from a USDA Approved country. This means that serum is produced from blood collected in countries that have been approved by the United States Department of Agriculture (USDA) to export ruminant serum products to the United States. Eligible countries that export fetal bovine serum into the U.S. include: Australia, Canada, Chile, Costa Rica, El Salvador, Guatemala, Honduras, Mexico, New Zealand, Nicaragua, and Panama.
Some cattle viruses can cross the placenta of the cow and infect the calf fetus, thus contaminating FBS and potentially making it unsuitable for use in cell culture. Some of these cattle viruses have a limited distribution and only exist in certain parts of the world. These are viruses of concern when importing FBS from infected countries – See Table of Diseases of Importation Concern for FBS. Other cattle viruses exist in all countries, and regardless of country of origin, the FBS must be tested or treated to assure freedom from these and other viruses (See USDA 9 CFR 113.53 and EMEA-CPMP-BWP-1793-02).
FMD is relevant for regulatory import purposes but not for cell growth. The USA and a few other countries only allow FBS imports from countries free from FMD, WITHOUT vaccination while most other countries also accept FMD-free WITH vaccination. Both types of FMD-free countries are free of FMD outbreaks and circulating FMD viruses, as verified by the OIE and declared equally safe.
The serum’s origin has no influence on cell growth. One batch of FBS may work well for one specific cell line, but not for another. “Serum performance” is specific for each cell line. That is why testing of FBS is widely used when dealing with sensitive cell lines.
Australian FBS prices are higher because Australia is perceived to be a “safer” origin for BSE and cattle viruses. Canada and Australia were the first countries outside the USA where FBS was produced. In the 1980s, BSE cases that occurred in North America became a strong argument in favor of Australian FBS. The point was made that being “isolated”, Australia was necessarily the most secure origin. However, BSE has never been found in young animals, let alone in fetuses, and BSE transmitted by animal feed has been eradicated. The remaining BSE cases are the spontaneous BSE events, which occur in all cattle populations (Stanley B. Prusiner, Nobel Prize 1997). All countries find spontaneous BSE cases if their sanitary surveillance systems are sensitive enough. Additionally, the OIE veterinary authorities have declared all blood and blood product, regardless of country of origin, to be safe in terms of BSE. So, the BSE arguments in favor of Australia were clearly ill founded from the beginning, and have become obsolete. Nevertheless, Australian FBS is still sold as “safer”, at much higher prices than other origins. Paradoxically, Australia is actually among the countries with the most types of viruses of import concern, including Blue Tongue, Akabane, Aino, and Bovine Ephemeral Fever. Like in the tale “The Emperor’s new clothes”, by Danish writer Hans Christian Andersen, those who believe that paying more will assure them a better serum, are being misled.
A huge price difference exists between countries classified as “FMD-Free-without-vaccination” for which demand exceeds supply, and countries listed as “FMD-Free-with-vaccination” where supply historically has exceeded demand. The price difference has been several hundred per cent, whereby serum users in the US have paid billions of USD more than serum users in the EU. Proposals from USDA to harmonize US and EU import rules for FBS relating to FMD (following OIE guidelines), have repeatedly been turned down by the US serum industry. Wrong beliefs about risks associated to BSE have lead some FBS providers to promote the Australian origin as “safer” without any scientific basis, making this origin several times more expensive than any other. The Australia “safer” status is being promoted, despite the virus status of Australia ; and despite the higher risk of misrepresentation associated with such huge price differences. The price differences persist due to longtime marketing efforts promoting certain origins, and regulations limiting trade, even among countries that according to the OIE’s classification have identical veterinary risk status (regarding viruses of import concern for FBS).
FBS Imports into the EU are less restricted than in the USA. A proposal made by USDA in 1994 to apply the same FBS import policies as the EU did not get support from the US FBS industry.
The availability of FBS is diminishing. Meat and calf prices are increasing as consumers in some countries increase the consumption of beef; and as cattle breeding techniques are permanently improving. These combined factors lead to a reduced frequency of pregnant cows at slaughter. The collection of FBS in new countries has, for many years, compensated for the decrease in supply; but now there are no more new producer countries available. The present world supply of FBS is short and will continue decreasing.
The demand for FBS is growing along with the latest research developments, including stem cells, cell therapy, new vaccines and proteomics.
Bovine spongiform encephalopathy (BSE), more commonly known as “mad cow” disease, is a fatal neurodegenerative disease (encephalopathy) in cattle.
According to the OIE (World Animal Health Organization), there is no risk of BSE being transmitted in several products, including: milk, hides and skins, deboned meat, blood and blood by-products, such as fetal bovine serum (OIE Terrestrial Code 11.4 BSE). Most OIE member countries have adopted this position, including the European Union and the United States (USDA). For some time, BSE was an argument used in favor of certain origins. After the OIE has determined that BSE is not transmitted by blood products, these arguments have become obsolete.
FBS is essentially a natural product. All FBS batches are unique, with specific characteristics, different from all other batches.
Traceability is important because it provides a chain of identity of the product from the country and slaughterhouse of origin, to the processing, packaging and labeling facilities ready for sale and final distribution. As you can verify, traceability insures that the product you buy was made respecting regulations at each level. This unbroken chain of information means complete transparency and entire compliance.
OIE’s guidelines for animal welfare are respected in the countries where the FBS is collected (OIE Terrestrial Code 7.5 Slaughter of Animals). Link to the EFSA explanation : EFSA explains animal welfare
The slaughtering of pregnant animals is, in most cases, an unplanned event. The frequency depends on farming techniques. In most cases, the condition of gestation is unknown; especially where animals are produced naturally; in the case of cattle moving freely around, grass fed, heifers and steers together. No cows are killed with the main purpose of harvesting the fetal blood. The blood is collected as a by-product from cattle slaughter operations for the bovine meat. The pregnancy condition is unknown when an animal enters the slaughtering line. The percentage of pregnant cows going to slaughter is very low and decreasing year by year as cattle farming techniques constantly improve. Link to the EFSA explanation : EFSA explains animal welfare
The collection of the blood is done without causing pain to the fetus. The fetus’s life ends through oxygen depletion, generally agreed to be a gentle method of life termination. Cell culture technology can reduce the use of live animals in science. Research is also being done to produce meat by cell culture, which could ultimately lead to the end of breeding animals for food. Link to the EFSA explanation : EFSA explains animal welfare
Given that the death of some pregnant animals is unavoidable, the fetus can be used to serve science, and generate jobs. This contribution benefits research and development and should not be underestimated.
• “Misrepresentation” is when the product is mislabeled in terms of the declared origin, and can be total or partial: “Total” is when FBS from a less expensive origin is sold as if it were from a more expensive origin; “Partial” is when a less expensive origin and a more expensive origin are mixed e.g. in proportion 49-51, and only the more expensive 51%- origin is declared. This generates an illicit profit for seller, at the expense of the serum users; and may cause companies to unknowingly violate import regulations or product master files. The actual research results and end products are unlikely to be seriously affected, but falsified origins violate government, industry and consumer standards of honesty and traceability.
• “Smuggling” is a way of misrepresentation, and can be in the form of importing a product under a false description; directly to a final destination, or via third country.
• “Adulteration” is the most damaging of the criminal activities that may affect serum users! FBS can be adulterated by the addition of water, growth factors and/or serum of other species. Unscrupulous companies in order to enhance performance and/or lower the cost of the product can carry out one or more of these or similar activities. These practices are extremely serious as they affect critical results of life science research, and the purity of final products obtained in biopharmaceuticals, diagnostics, or vaccines. When such cases are detected, victims having used adulterated product must be informed to make it possible to evaluate the damage and take corrective actions.