•

Risk identification is a systematic use of information to identify ad-

ventitious viruses that can be potentially introduced at each step of the

vaccine manufacturing process and derived from animal-derived raw

materials.

• Risk analysis is the estimation of the risk associated with the identified

viruses. This analysis can consist of interrogating biological information

about the identified potential viral contaminants and the mitigation pro-

cesses to deal with starting materials and raw materials. The result of such

analysis can lead to the exclusion of some viruses from the risk.

•

Risk evaluation is mainly based on an FMEA (failure mode effect ana-

lysis), which evaluates potential extraneous agents that might represent a

potential risk for the vaccine. The risk evaluation takes into consideration

three categories of criteria: occurrence (O), detectability (D), and severity

(S). The composite risk score of each potential contaminant is calculated as

the product of its three individual component ratings: O/D/S. This com-

posite risk is called a risk priority number (RPN), which is used to cate-

gorize the risks.

• Risk control includes decision making to reduce the risk to a low or

medium level. Decision makers have to put in place some action to mi-

tigate the severity and the occurrence of the risk.

• Risk acceptance can be a formal decision to accept the residual risk based

on an extensive justification.

The risk is globally controlled by the three approaches described in ICH, FDA, and

EMEA regulatory guidance:

1. selecting and testing cell lines and other raw materials, including media

components, for the absence of undesirable viruses which may be in-

fectious and/or pathogenic for humans

2. assessing the capacity of the production processes to clear infectious viruses

3. testing the product at appropriate steps of production for absence of

contaminating infectious viruses

A few months after the PCV1/Rotarix contamination alert in 2010, licensed vaccine

manufacturers received a letter from CBER requesting information about the risk

assessment and implementation of additional adventitious agent testing methods for

viral vaccines and/or combination vaccines containing viral antigens.

4.3.6

REGULATORY CONSIDERATIONS

The development of viral-risk assessment is increasingly mentioned in regulatory

guidance as a prerequisite in the definition of a testing program.

With the 9th edition of the European Pharmacopoeia [19], two key chapters for

vaccines were fundamentally revised (§5.2.3 and §2.6.16) in terms of viral-risk

assessment and one new chapter (§5.2.14) was created with the new concept of in

vivo test substitution.

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Bioprocessing of Viral Vaccines