The MVS and WVS are prepared from either the MCB or WCB, depending on the

preference of the manufacturer. Some manufacturers derive an inoculum from WVS

to manage seed capacity. Viral seeds are also tested to document consistency of the

biological product across passages.

4.2.2.3

Technology Evolution

Several factors have shaped the evolution of cell-culture technology.

Viral safety associated with the selection of a cell line is a key element that will

be discussed extensively in the next paragraph (see Section 4.3). In association with

this topic, the raw materials required to prepare cell banks contribute to the safety of

the cell line. This will also be reviewed.

The yield and cost-efficiency of the upstream processes are key aspects for

consideration in the manufacture of vaccines, especially as many vaccines are re-

commended for universal or mass vaccination programs. To develop cost-efficient

upstream processes, certain cells, including CHO and many continuous cell lines,

have been developed or selected to be amenable for suspension (non-adherent)

culturing. The shift to suspension allows high-cell density culturing and hence high

yields. By contrast, some cell lines, such as MRC-5 and Vero cells, are adherent in

culture, and hence usually display low to medium yields. For the manufacture of

live-attenuated vaccines, a low virus yield may not be an issue because the content

of a vaccine dose is low. For inactivated viral vaccines and recombinant products,

high yields and hence high cell-culture densities are preferred.

To achieve high cell-culture densities, bioreactors are preferred over stationary

technologies, such as cell factories. Several bioreactor technologies have been de-

veloped. Since 2000, the technologies have evolved from stainless-steel bioreactors to

disposable bioreactors. Disposable bioreactors provide agility to GMP operations and

can contribute to cost efficiency. Disposable bioreactors are also useful for estab-

lishing cell banks. The bioreactor technologies will be further discussed in Chapter 6.

4.3

VIRAL SAFETY

The risk of virus contamination in a manufacturing facility is low, but when it

occurs, the impact is severe [8]. In a recent review published by the Consortium on

Adventitious Agent Contamination in BioManufacturing (CAACB), 26 virus con-

taminations were reported over the past 36 years [9].

4.3.1

RISK AND IMPACTS

The risks resulting from a viral contamination can be positioned at different levels:

•

Risk to vaccine recipients from direct inoculation (safety risk when pa-

thogenic for human)

• Risk to product quality

• Risk to other products in the facility

• Risk to product availability for vaccine recipients

Cell lines for vaccine production

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