extensive testing protocols for identifying adventitious agents are not applied because

those protocols are only used with cell banks. Nevertheless, European Pharmacopeia

and CBER guidance amongst others, define strict testing programs for CEF-based

vaccines to demonstrate that the appropriate safety criteria are satisfied (see also

Section 4.3).

Diploid cell lines were developed in the 1960s, based on their capacity to withstand

storage in a cell bank (see Section 4.2.2.1). These cells have a finite in vitro life span,

are euploid (diploid) through the life span, and are structurally identical to those cells

in the species from which they were derived. They also display contact inhibition and

senescence. Diploid cell lines used for marketed human vaccines have been derived

from human tissue. One advantage arising from the use of these cell lines is that any

potential residual proteins are of human origin and therefore not susceptible to trig-

gering an immune reaction. One disadvantage is the finite life span.

A continuous cell line is a cell line with an apparently unlimited capacity for

population doubling [5]. The life span is indefinite allowing good cell amplification

to large scale. However, many continuous cell lines display genetic aberrations

manifested by aneuploidy. Therefore, the genetic stability needs to be well char-

acterized: certain mutations could lead to tumor or oncogene activation [6]. The

features of these cell lines led to define specific regulatory considerations.

4.2.2

TECHNICAL CONSIDERATIONS

This paragraph addresses the technical considerations to start development or

manufacturing of a vaccine that requires cell lines for virus propagation or for

TABLE 4.3

Types of cells used in the manufacture of marketed vaccines

Cell-type category

Cell line

Vaccine against

Primary cells

CEFs (Chicken Embryo Fibroblasts)

Measles, mumps, rabies, tick-borne

encephalitis

Diploid cell lines

MRC-5

Measles, mumps, rubella

Hepatitis A, poliomyelitis, rabies

Varicella

WI-38

Rubella, adenoviruses

Continuous cell

lines

Vero

Poliomyelitis (inactivated)

Rotavirus, pandemic and seasonal flu,

Japanese encephalitis, rabies, smallpox

CHO (Chinese Hamster Ovary) ^∗

Zoster-shingles

MDCK

Influenza

Hi-5 with BEVS (Baculovirus

Expression Vector System) ^∗

HPV (human papilloma virus)

Note

∗ Recombinant systems

Cell lines for vaccine production

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