Adventitious agents

Appendices This section is most likely to contain additional data associated with biological-based products. It should contain information as regards the facilities and equipment used for the manufacture of biotech products. Assessment of the risk of contamination from adventitious agents such as transmissible spongiform encephalopathy agents (TSEs), bacteria, mycoplasma, fungi or viruses should also be provided. Additional information on novel excipients that have not been used before should also be included in this section. 

Part II Composition, Method of Preparation, Controls of Starting Materials, Control Tests on Intermediate Products, Control Tests on the Finished Product, Stability and Other Information (Placebos, Comparator Products, Adventitious Agents, etc.)... 

Cell Line One needs to know the origin, source, and history of the cells. Records must be kept for the cultivation of cells, medium used, genetic manipulation, selection criteria, isolation methods, identification, characteristics, and tests for endogenous and adventitious agents. 

Characterization and Testing of Cell Banks Test for adventitious agents, endogenous agents, and molecular contaminants (toxins, antibiotics) to confirm identity, purity, and suitability for manufacturing use... 

Examples of characterization testing of CHO MCB include sterility, mycoplasma, identity, retrovirus, adventitious agents, and bovine and porcine virus. 

Changes in the vims or adventitious agent removal or inactivation methods. This is applicable to any material where such procedures are necessary, including drug substance, drag product, reagents, and excipients. 

In this context, testing for adventitious agents is not considered to include tests that are found in an official compendium (e.g., USP <61 >). 

Prior to phase I clinical trials, process steps and assays that relate to safety should be validated. For example, sterility assays and sterilization processes must be validated. Cell lines should be qualified prior to any clinical trials, including testing for adventitious agents and identifying and quantifying indigenous virus. Virus clearance steps should be validated, and removal of any potentially toxic or otherwise harmful agents should be validated [41,42],... 

Adventitious agents (in vitro and in vivo). These assays are designed to detect the presence of infectious viral agents of human or animal origin (serum, trypsin). 

Removal or inactivation of adventitious agents (update from phase 1/ phase 2, where applicable)... 

Another factor to be taken into account when using animal serum is the potential risk for human health, due to the possible presence of adventitious agents, such as virus and proteins as prions. In addition, serum can contain contaminants such as bacteria, fungi, and mycoplasmas (small bacteria without cellular walls), which can negatively affect cell culture. 

If porcine trypsin is used in the passage of cells, it should be free from adventitious agents, including porcine parvovirus. The manufacturers of biological products must provide information about the source(s) and controls of any material derived from ovine or bovine species. 

The major concerns with vaccine production are firstly, is the virus harmless and secondly is the vaccine free of adventitious agents. If the vaccine is produced from a virulent virus it is essential that the virus is completely inactivated before vaccine distribution. If attenuated strains are used the stability of the attenuation must be monitored. In both cases cell cultures are used in tests. 

Characterize adventitious agents and impurities for each raw material... 

The production of proteins is associated with risks of either introducing substances with adverse effects, or failing to achieve total removal of impurity, or both. Potential contamination with adventitious agents is actually one of the main concerns for the product safety of biopharmaceuticals. This situation is extendible to antibodies, whether they are monoclonal or polyclonal, since they are isolated from various biological liquids (see Section III), which are themselves considered as potential sources of risk. 

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