Vaccines, Blood & Biologics
Bovine Derived Materials Used in Vaccine Manufacturing Questions and Answers
Why are animal products used in the manufacture of vaccines?
Vaccines contain either killed or weakened forms of disease-causing bacteria or viruses, or components of these that stimulate a response by the body's immune system, which then protects against the development of disease. In the late 19th century, microbiologists began to grow bacteria in the laboratory. The early bacteriologists tried to mimic as closely as possible the environment in an infected person's tissues by using solutions containing sugars, salts, and various meat extracts to make "growth media." These kinds of conditions were quite successful in growing bacteria and then viruses in the lab, because these media supplied the many necessary nutrients. Although synthetic media have been developed for growth of many medically important microorganisms, some still require additional nutrients which are easily provided by animal-derived products such as serum and blood. Viral vaccines are produced in living cells, which, similarly, require the addition of complex growth media components, such as fetal calf serum.
Which bovine derived materials are used in vaccine manufacture?
Microorganisms for vaccine manufacture are grown under controlled conditions in media which provide the nutrients necessary for growth. Cow components are often used simply because cows are very large animals, commonly used for food, and thus much material is available. Animal-derived products used in vaccine manufacture can include amino acids, glycerol, detergents, gelatin, enzymes and blood. Cow milk is a source of amino acids, and sugars such as galactose. Cow tallow derivatives used in vaccine manufacture include glycerol. Gelatin and some amino acids come from cow bones. Cow skeletal muscle is used to prepare broths used in certain complex media. Many difficult to grow microorganisms and the cells that are used to propagate viruses require the addition of serum from blood to the growth media.
Do all bovine materials have the same risk of transmitting the BSE agent?
Scientists have found that different bovine tissues contain different amounts of the BSE agent. It is generally believed that the highest amounts of infectivity are found in the brain and spinal cord from animals in the final stages of clinical disease. Some tissues, such as skeletal muscle and milk, have never been shown to have any infectivity. However, the slaughtering and butchering methods used to obtain tissues and prepare materials can affect the amount of infectivity that may be present. Also the production processes used to prepare bovine-derived materials (such as heat sterilization and chemical treatment) may reduce or remove infectivity.
What measures have the FDA taken to ensure that people are not exposed to the BSE agent in vaccines?
It is believed that variant CJD was acquired from eating food products containing the BSE agent. However, FDA wants to minimize any chance that the BSE agent could be introduced into biologic products during manufacture. The Center for Biologics Evaluation and Research (CBER) is responsible for regulation of biologic products, including vaccines. In a 1991 letter to manufacturers CBER expressed concern about bovine sourced material. In December 1993 and May 1996 FDA issued letters advising that bovine derived materials from animals born in or residing in countries where BSE had occurred should not be used to manufacture FDA-regulated products intended for administration to humans. A 1993 Points to Consider document ("Points to Consider in the Characterization of Cell Lines Used for the Production of Biologics") stressed the importance of control of sourcing of bovine materials. On April 19, 2000, CBER issued a letter reminding manufacturers that the USDA list of BSE-countries had been expanded to include not only those countries where BSE was known to exist but also those where BSE may exist (FR, January 6, 1998). CBER strongly recommended "that manufacturers take whatever steps are necessary to assure that materials derived from all species of ruminant animals born, raised or slaughtered in countries where BSE is known to exist, or countries where the USDA has been unable to assure FDA that BSE does not exist, are not used in the manufacture of FDA-regulated products intended for administration to humans." Although Canada and the US have each reported one case of BSE and the USDA has placed Canada on the list of countries with BSE, FDA has not recommended that manufacturers find a new source for bovine derived materials obtained from these countries for use in manufacture of drugs or biological products. The FDA believes that the control measures in place assure the safety of bovine derived materials sourced from these countries and used in manufacture of vaccines.
Are bovine derived materials from North America used in the manufacture of vaccines?
Yes, bovine derived materials from North America, specifically the US and Canada, are used in vaccine manufacture. Since there has been extensive movement of live cows and cow-derived materials between Canada and the US it is difficult to establish that an animal has not been born, raised or slaughtered in Canada. Moreover, control measures, such as the ruminant-to-ruminant feed ban have been similar in the two countries. Therefore, FDA has not recommended that manufacturers using bovine derived material from Canada replace those materials with materials from countries not on the USDA list of countries that have BSE or are at risk of BSE.
How did the FDA discover that some manufacturers are not universally following letters, Points to Consider (PTC) and guidance documents?
During review of new license applications manufacturers are asked to provide detailed descriptions of the manufacturing process and documentation of source country for all materials of animal origin. In 2000, during review of a license application it was determined that some of the material used during manufacture had been obtained from countries which are on the USDA list of countries which either have or may have BSE. This finding prompted an inquiry of all licensed vaccines.
What is FDA doing now to assure that companies follow guidance, letters, and PTC documents?
The Center for Biologics Evaluation and Research (CBER) has asked licensed vaccine manufacturers to evaluate all bovine sourced material used at any stage of manufacture. Manufacturers have been requested to identify all material of animal origin. For materials of bovine origin CBER has asked manufacturers to identify the source country from which the animals originated, the date the material was obtained and the date the material was used in manufacture of vaccine lots. When it is determined that any bovine-derived component used to make the working seeds or during routine production was obtained from a country on the current USDA list of countries (with the exception of Canada) which either have or may have BSE or from an unknown country, the manufacturer has been asked to change the source of such material. CBER inspects vaccine manufacturers on a routine basis to determine whether sourcing and documentation are consistent with current recommendations contained in letters and guidance documents.
Division of Communication and Consumer Affairs
Office of Communication, Outreach and Development
Food and Drug Administration
10903 New Hampshire Avenue
Building 71 Room 3103Silver Spring, MD 20993-0002