section_path: Production
section_name: Production
paragraph_text: Production
  
  Vaccine production is fundamentally different from other kinds of manufacturing – including regular pharmaceutical manufacturing – in that vaccines are intended to be administered to millions of people of whom the vast majority are perfectly healthy. This fact drives an extraordinarily rigorous production process with strict compliance requirements that go far beyond what is required of other products.
  
  Depending upon the antigen, it can cost anywhere from US$50 to $500 million to build a vaccine production facility, which requires highly specialized equipment, clean rooms, and containment rooms. There is a global scarcity of personnel with the right combination of skills, expertise, knowledge, competence and personality to staff vaccine production lines. With the notable exceptions of Brazil, China, and India, many developing countries' educational systems are unable to provide enough qualified candidates, and vaccine makers based in such countries must hire expatriate personnel to keep production going.
  
  Vaccine production has several stages. First, the antigen itself is generated. Viruses are grown either on primary cells such as chicken eggs (e.g., for influenza) or on continuous cell lines such as cultured human cells (e.g., for hepatitis A). Bacteria are grown in bioreactors (e.g., Haemophilus influenzae type b). Likewise, a recombinant protein derived from the viruses or bacteria can be generated in yeast, bacteria, or cell cultures.
  
  After the antigen is generated, it is isolated from the cells used to generate it. A virus may need to be inactivated, possibly with no further purification required. Recombinant proteins need many operations involving ultrafiltration and column chromatography. Finally, the vaccine is formulated by adding adjuvant, stabilizers, and preservatives as needed. The adjuvant enhances the immune response to the antigen, stabilizers increase the storage life, and preservatives allow the use of multidose vials. Combination vaccines are harder to develop and produce, because of potential incompatibilities and interactions among the antigens and other ingredients involved.
  
  The final stage in vaccine manufacture before distribution is fill and finish, which is the process of filling vials with vaccines and packaging them for distribution. Although this is a conceptually simple part of the vaccine manufacture process, it is often a bottleneck in the process of distributing and administering vaccines.
  
  Vaccine production techniques are evolving. Cultured mammalian cells are expected to become increasingly important, compared to conventional options such as chicken eggs, due to greater productivity and low incidence of problems with contamination. Recombination technology that produces genetically detoxified vaccines is expected to grow in popularity for the production of bacterial vaccines that use toxoids. Combination vaccines are expected to reduce the quantities of antigens they contain, and thereby decrease undesirable interactions, by using pathogen-associated molecular patterns.