6-4.3.3 Endogenous and Adventitious Agents Detection:

1. Choice of host animal:

Many animal species have been proposed to develop as hosts for production of therapeutic products. The lack of experience with many of these hosts raises potential safety concerns about adventitious agents are considered on a case-by-case basis by the FDA. Adventitious agents are defined as micro-organisms which are unintentionally introduced to the manufacturing process of a biological product. There is a possibility that adventitious agents or chemical contaminants could enter into the host animals and be concentrated in the product by the purification procedure without signaling their presence. Zoonotic diseases (diseases caused by infectious agents that can be transmitted from vertebrate animals to humans and vice-versa) should be taken care of extremely. Therefore, health monitoring of the livestock is necessary, although not sufficient alone to guarantee absence of these contaminants.  The rigor of infection control in the animal host and validation of elimination of adventitious agents from the product will depend on several factors like:

1. The intended use of the product;
2. The tissue from which the product is derived;
3. The method by which product is collected;
4. The purification process;
5. Animal husbandry practices used during production of the founder and production animals.

2. Source tissue:

Currently therapeutic products are produced in transgenic animals by utilizing systems in which the product will be isolated from bodily fluids (milk, blood, or urine) where significant batch-to-batch variation in both microbiological and virological loads may arise in unpurified products. The extent of such variability should be documented for each product. The downstream manufacturing procedures should have full capability for providing a safe and consistent product.