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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Vaccines

Background on Viral Vaccine Development

What is the standard development and manufacturing process for viral vaccines?

Viral vaccines protect individuals from disease by eliciting an immune response, which will prevent disease if an individual is subsequently infected with a disease-causing strain of the virus.

There are three types of licensed viral vaccines: subunit, killed, and live-attenuated.  Subunit vaccines are purified viral proteins.  Killed and live-attenuated viral vaccines are made from virus purified from a medium into which a viral “seed” has been introduced.  Rotarix and RotaTeq are live-attenuated viral vaccines.

There are a variety of media used in the manufacture of viral vaccines.  These include:

  • Whole animal substrates, such as embryonated eggs
  • Primary cells derived from animal tissue, such as chick embryo fibroblasts
  • Cell lines in culture, such as Vero cells, derived from monkey kidneys

Rotarix was produced in Vero cells.

Live-attenuated viral vaccines are manufactured by purifying whole virus from infected cells.  Because the virus has been attenuated, or weakened, and no longer is able to cause disease, the purified live virus is used as the vaccine.

 

The general production process for a live-attenuated viral vaccine can be divided into four stages:

  • Cell culture preparation – development of cell lines appropriate for manufacturing vaccines for human use
  • Virus inoculation and propagation – addition of the virus to the cell culture and allowing it to replicate
  • Virus harvest – retrieval of the virus from the medium
  • Purification – further processing of the virus for later incorporation into the finished vaccine

Vaccine manufacturers are required to have controls in place to ensure the vaccine product’s identity, potency, quality, and purity.

What steps do manufacturers and FDA take to assess the quality of viral vaccines during the production process?

FDA requires vaccine manufacturers to implement certain manufacturing practices to assure the quality of the viral “seed” which is used to generate large amounts of virus needed for vaccine manufacture, the cell culture medium in which the virus will grow, and any components added in the manufacturing process.

Vaccine manufacturers must conduct a variety of quality assurance tests throughout the manufacturing process, including tests for vaccine sterility and potency.  Samples of each finished vaccine are tested by the manufacturer prior to market release, and FDA may also perform additional testing prior to market release.  The specific types of testing required vary from product to product.

What FDA regulations and guidance apply to the production of vaccines?

The general standards for assuring the quality of vaccines intended to be administered to humans can be found in 21 CFR 610

Vaccine manufacturers are required to implement “current good manufacturing practices,” as described in the Federal Food, Drug, and Cosmetic Act and in 21 CFR 210 and 21 CFR 211.

On March 2, 2010, FDA issued a Final Guidance for Industry entitled “Characterization and Qualification of Cell Substrates and Other Biological Materials Used in the Production of Viral Vaccines for Infectious Disease Indications”.

Has testing for circoviruses such as PCV1 been required as part of vaccine development?

Circoviruses have not been associated with illnesses in humans, and FDA has not required the routine testing of vaccines for these viruses.  Current FDA guidance, released in March 2010, recommends that manufacturers consider testing for these agents.  FDA introduced this recommendation as an additional precaution for vaccines manufactured with animal-based components.  The agency is reviewing the current situation and may update its approach based on additional findings.