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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