Considerations for US Fetal Bovine Serum Sourcing

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Fetal bovine serum (FBS) is an important supplement in many biopharmaceutical manufacturing workflows, where it provides the various components necessary for successful cell culture. Due to concerns around safety relating to FBS origin, certain regions have typically been considered safer sources than others, resulting in high demand and prices.

However, thanks to extensive work to combat these safety concerns, it is now possible to source safe FBS more widely. In addition, regions such as the United States can offer the benefits of improved availability and competitive prices, making them an appealing alternative source of FBS.

FBS Challenges

FBS is a biological product, derived from blood drawn from bovine fetuses via a closed system of collection at the slaughterhouse. It comprises over 1000 different components, including growth factors, nutrients, and lipids as well as many undefined factors, all of which promote robust cell growth and protect cells from changes in pH and toxic agents. As a result of its low levels of antibodies, FBS is the most widely used serum supplement for the in-vitro culture of eukaryotic cells.

As an animal-derived product, however, the exact composition of FBS is undefined and can vary between batches. Moreover, it can be vulnerable to contamination by viruses and other pathogens, impacting lot-to-lot consistency and safety. While inconsistent composition can have knock-on effects on the performance of processes and product yields, affecting the efficacy and safety of the end product, a larger concern revolves around the presence of microbiological contaminants. For example, certain pathogens that may be found in serum add an additional element of risk because their presence in end products could lead to severe immunological responses in patients (1).

For FBS, there is particular concern around bovine spongiform encephalopathy (BSE) disease, first identified in the United Kingdom in 1986 (2). BSE is a fatal neurodegenerative disease in cattle that is part of a group of transmissible spongiform encephalopathies (TSEs) and is believed to be caused by a prion—an abnormal form of a protein. As the disease is transmissible to humans and other animals, and is untreatable, concerns arose around obtaining FBS from potentially infected cattle. There is currently no way to screen for BSE in live cattle, and no effective way to remove the presence of BSE from animal by-products. As a result, the safe use of FBS in biopharmaceutical manufacturing was thrown into question. In response, many manufacturers attempted to remove the need for serum in their processes.

“Safer” sources of FBS

Moving away from the use of serum altogether is not always feasible or practical, as some cell lines may require serum supplementation, and it can be complex and expensive to change established processes. Therefore, many manufacturers continued to use FBS despite the risks.

Following the emergence of BSE, it became essential to identify safe regions with no BSE risk. As island nations, Australia and New Zealand are more geographically isolated than other regions and have not had any detected cases of BSE. Additionally, a number of viruses that can be found in FBS are not present in the region. Because of this, these two countries became popular sources of FBS and have continued to be viewed as premium suppliers. This reputation has led to high demand for FBS from Australia and New Zealand, resulting in high prices. Compounding this, as a by-product of the meat industry, FBS supply can fluctuate. It can be impacted by climate conditions, such as drought, as well as economic factors, including cattle feed prices and demand for beef. Over recent years, factors such as these have led to low herd sizes in Australia and New Zealand, further driving up prices.

Recently, many countries around the world have taken steps to reduce the risk of BSE. This work has included careful breeding and testing of cattle, as well as stricter regulations around cattle feed. Therefore, multiple regions in the world now have the same negligible BSE risk status as Australia and New Zealand, as certified by the World Organisation for Animal Health (OIE) (2). The US obtained this official classification in 2013, which means that there is no greater risk of BSE in FBS from the US than there is from Australia or New Zealand. While other regions have also achieved this status, many have barriers that may make them less appealing to biopharmaceutical manufacturers. For example, despite their negligible risk of BSE, both Japan and Korea have a higher risk of certain viruses compared to other countries, so FBS from these regions may require more stringent testing. Consequently, the US is emerging as an attractive alternative source of serum.

Virus testing

While many regions have significantly reduced their risk of BSE, this does not eliminate the risk of viral contamination. As viruses can pass through the filtration system used to remove other contaminants, such as bacteria, they can be much more challenging to eliminate. Consequently, it is impossible to ensure that FBS from any source is completely free of any viral contaminants, necessitating strict regulations to minimize and control this risk. The specific regulations are dependent on the viruses present in each area, but typically include in-depth testing and sterilization to prevent the production and distribution of unsafe FBS.

One example of contamination risk mitigation is in preventing the presence of the bovine viral diarrhea (BVD) virus, which occurs in all regions of the world and is of concern to the biopharmaceutical industry. It is possible to test for BVD when sourcing blood for FBS before it is processed into the final product, and precautions can be taken during collection. By coupling these steps with gamma irradiation—a sterilization method that significantly reduces the virus risk in sera—the risk of BVD can be eliminated in FBS.

Most regulatory bodies around the world require serum to be gamma irradiated, as it is an effective way of eliminating the majority of viruses that may be present. However, it is possible that certain viruses may persist, which is why testing in line with general and local regulations is vital to further minimize risk. Specific testing requirements are determined by the governmental regulatory authorities for each region, but generally include virus testing methods in line with Title 9 of the Code of Federal Regulations (3), as well as endotoxin, mycoplasma, and hemoglobin testing. Many suppliers carry out additional tests to meet custom requirements for FBS needed for specific applications. By identifying any batches that do not meet safety requirements, both suppliers and manufacturers can have confidence in the quality of their FBS, regardless of its origin.

Benefits of US FBS

With many regions now classified as having negligible BSE risk, there is no longer a need to source FBS solely from New Zealand and Australia. Furthermore, given that no region is safe from all viruses, all FBS is required to be tested in line with regional regulations. This means that several regions around the world, including the US, are now able to offer FBS that is equally as safe as serum that originates from regions typically regarded as premium sources.

In addition to the comparable safety level, regions such as the US may be able to offer additional benefits surrounding FBS supply. As demand is currently lower, US FBS has better availability compared to Australia and New Zealand and therefore benefits from comparably lower and more stable pricing. This makes it more economical for manufacturers, without any reduction in product quality or safety.

Considerations when sourcing FBS

In addition to considering the origin of FBS, it is also important to consider the supplier. This includes the support it can provide as well as any additional measures it employs to maximize the safety of its sera. Traceability of origin is vital to provide verification of the region from where the FBS came and, therefore, its safety. Serum traceability is regulated by the International Serum Industry Association (ISIA), and this certification helps to provide additional confidence in the origin and integrity of FBS (4).

Manufacturers should look for a supplier that employs robust methods of origin confirmation and is ISIA-certified, in addition to having oversight of the entire FBS production process starting from collection. Beyond this, it can be beneficial to work with suppliers that can conduct a full range of testing to meet the needs of various applications and that can offer technical and regulatory support if required. By carefully considering the source of FBS and working with a transparent supplier that is committed to traceability, biopharmaceutical manufacturers can continue to benefit from the use of FBS in cell culture while minimizing the associated risks.

References

1. C. Challener, BioPharm International 29 (3) 20–24 (2016).

2. OIE, “Bovine Spongiform Encephalopathy,” www.oie.int, accessed April 4, 2022.

3. CFR Title 9, 113 (Government Printing Office, Washington, DC) 713-738.

4. International Serum Industry Association, “ISIA Traceability,” www.serumindustry.org, accessed April 4, 2022.

About the authors

Ton van Raalte is cell culture specialist at Thermo Fisher Scientific. Brian Dalton is senior product manager, Sera, at Thermo Fisher Scientific.

Article details

BioPharm International
Volume 35, Number 6
June 2022
Pages: 22-24

Citation

When referring to this article, please cite it as T. van Raalte and B. Dalton, “Considerations for US Fetal Bovine Serum Sourcing” BioPharm International 35 (6) 22-24 (2022).