advanced and characterized vaccines, human papilloma virus (HPV) vaccine, a

virus like particle (VLP) vaccine, has a mean size diameter of 40 nm, as compared

to an immunoglobin (IgG) with a size of about 10 nm. HPV vaccine manufacturing

requires an extensive post-production disassembly/reassembly reprocessing of the

capsid structural proteins to achieve a high level of purity of VLPs within a narrow

distribution size range.

As detailed in the virology section (Chapter 2), viruses have different structures

and properties and analytical methods to monitor their production as vaccines are

often under-developed. The potency of the vaccine product that might involve an

adjuvant in the final formulation is determined by its interaction with the immune

system which is incompletely understood (Chapter 3), contributing to the com-

plexity of viral vaccines design and manufacturing. Viral vaccine production pro-

cesses are characterized by 1) a lack of platform technologies requiring multiple cell

types, mostly operated in adherent cell culture mode; 2) different virus/cell inter-

actions; 3) different scales for production contributing to further complexity in the

bioprocessing and biomanufacturing of viral vaccines. This is particularly empha-

sized when compared to the well-established process for manufacturing monoclonal

antibodies using a CHO platform in the broad context of biomanufacturing of

biologics.

Manufacturing and releasing a cell-culture produced viral vaccines is lengthy and

complex (Figure 1.5). The current good manufacturing process (cGMP) requires

establishing and extensively documenting a master cell bank and a master virus seed

bank derived from the virus isolates according to regulatory guidelines [19].

In short, the manufacturing process is initiated by cell amplification from a

working cell bank, derived from the master cell bank. The cell culture process

stream will depend on the cell substrate type that would grow in adherent or sus-

pension cell cultures and would determine the mode of operation and type and scale

of the bioreactor for production. In the case of adherent cell lines such as Vero cells,

supports such as T-Flasks, roller-bottles, cell factories, or packed-bed bioreactors

are required to sustain cell growth. To mitigate surface limitation to produce large

quantities of vaccines as is the case for polio vaccines, microcarrier technology as a

support might be used to facilitate the scalability up to 3,000 L operational volume.

Cell cultures in suspension are generally more amenable to streamlined scale-up to

larger volumes up to 10,000 L. As it has been the trend for production of biologics

such as recombinant proteins and monoclonal antibodies, single-use equipment is

deployed more and more frequently as a rapid response to surge manufacturing of

viral vaccines [20].

USP

DSP

Formulation

Delivery

Cell bank

Storage

Transport

Virus bank

FIGURE 1.5 Typical scheme on cell-based vaccine manufacturing.

Viral vaccines

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