Overview of Vaccine Manufacturing

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http://www.fda.gov/cber/bse/over.htm

 

Bovine Spongiform Encephalopathy (BSE)

 

Overview of Vaccine Manufacturing

The common childhood vaccines (www.cdc.gov/nip/recs/child-schedule.pdf) and many

other vaccines, derive from bacteria, yeast, or viruses that are grown in

culture. Bacteria are free-living organisms that are able to grow and reproduce

when placed in a medium containing various nutrients (the culture medium) such

as sugars, salts, or amino acids. Growing bacteria in culture simply refers to

placing a small quantity of bacterial cells into a nutrient medium, and then

allowing the cells to multiply.

 

Viruses, on the other hand, are not free-living organisms, and can reproduce

(multiply) only in cells (they require many of the cellular enzymes and

machinery for reproduction). Human- and animal-derived cell cultures are

commonly used for growing vaccine viruses. The cells that are used as substrates

for viral growth can, like bacterial cells, maintain themselves and grow only in

a medium that contains their needed nutrients. Growing viruses in culture,

therefore, involves adding a small quantity of virus to an existing culture of

cells and letting the virus replicate in these cells. Commonly, the virus will

kill the cell in which it is grown.

 

In order to manufacture vaccines consistently, it is essential to begin the

manufacturing process (the growth of the virus or bacteria) with the exact same

virus or bacterium; moreover, it is essential to start the process with a virus

or bacterium that is pure. This is accomplished through the development and

maintenance of “seed banks.” A seed is the general term that is used to describe

the small amount of bacteria or virus that is added to growth media or cell

cultures to initiate further expansion of the bacterial cells or viruses.

 

Consider, for example, the manufacture of a bacterial vaccine; see Figure 1.

During the period when a new bacterial vaccine is being developed, a small

amount of a pure culture of that vaccine bacterium is grown and frozen away;

this material is termed the “master seed bank.” A small portion of this master

seed bank is then expanded (grown in culture) and frozen away in many small

portions (for example, in a thousand different vials); these small portions are

collectively referred to as the “working seed bank.” The “master” and “working”

cell banks are purified, characterized and shown to be free of known

contaminants prior to using them in production. Each time a batch of the vaccine

is manufactured, the process begins with one of the vials from the working seed

bank. Through the use of “working seed banks” the manufacturing process always

begins with the same material. If the vials of working seed are exhausted,

another small portion of the master bacterial cell bank can be used to

produce a new working seed bank, for example, another thousand vials. Since the

number of batches of vaccine that are produced each year is limited, this

banking system provides a sufficient amount of material to last, in a practical

sense, indefinitely.

 

The viruses that are used in vaccine manufacturing also use a seed lot system.

“Master” and “working” viral seed banks are produced and stored away in a

similar fashion, the difference being that the viruses are propagated in cells

as opposed to a simple nutrient medium. In order to ensure the consistency of

the viral vaccines, “master” and “working” cell banks are also kept in those

instances for which the virus is propagated in cell lines (as opposed to primary

animal cell cultures). When a cell line is developed, a substantial amount is

frozen away as a “master cell bank;” a small portion of the master cell bank is

grown and stored away in many small vials, thus forming the " working cell bank. "

 

The nutrient media that are used to support the growth of bacteria and the cell

cultures in which viruses are grown often contain animal-derived components and,

commonly, bovine-derived (from cows) components. As examples, the cells that are

used to propagate viruses generally require calf serum for their maintenance and

growth and the nutrient broths that are commonly used to grow bacteria contain

beef extracts (e.g., a beef broth).

 

A typical viral vaccine production scheme is outlined in Figure 2. The seed

banking system has been described above. At the start of vaccine production, the

manufacturer thaws a vial of the working cell bank and grows it to large

amounts, whereupon it is infected with a vial of the working seed virus, which

will then grow to large numbers. One vial of the working cell bank and working

seed virus may result in a half million or more doses of vaccine.

 

One of the major difficulties in the manufacture of vaccines arises from the

possibility of introducing adventitious agents into the process. Obviously, if

the seed virus or cells contain a viral agent other than the vaccine virus, it

too may grow. Similarly, and the topic of current concern, if the BSE agent

enters into the vaccine manufacturing process at any point, that agent may be

carried through into the final vaccine formulation. Variant Creutzfeldt-Jakob

disease, as mentioned in other sections of this Web Site, has been attributed

to, among other possibilities, the consumption of products from BSE-infected

cattle.

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