Manufacturing contamination risks presented by the different pathogenic agents can include the following: Vegetative Bacteria Vegetative bacteria are actively growing and reproducing bacteria. If there are no steps in the manufacturing process to kill vegetative bacteria, they can proliferate and accumulate during drug ingredient processing. Toxin-Producing Microorganisms Several genera and species of microorganisms are capable of producing toxins.

Microbial toxins can be divided into two general groups: exotoxins and endotoxins. An exotoxin is a soluble protein excreted by a microorganism, including bacteria, fungi, algae, and protozoa. Exotoxins can include heat-stable toxins that remain active at temperatures as high as 100°C or heat-labile toxins that are readily inactivated by heat treatment. Exotoxins, especially heat-stable exotoxins, can remain in the ingredient throughout the manufacturing process and adversely affect patient health. An endotoxin is a component of the outer membrane of a Gram-negative bacterium. Unlike exotoxins, endotoxins are only released when the organisms are disrupted or destroyed. Endotoxins are heat- and chemical-resistant and, if injected, may induce reactions including febrile effect, hypotension, and shock. Spore-Forming Bacteria Spore-forming bacteria can be difficult to eliminate from the manufacturing environment because the spores may be extremely resistant to heat, freezing, extreme pH, desiccation, and chemicals. Spore-forming bacteria can produce exotoxins and can remain dormant without nutrients for extended periods.

Spores can be resistant to harsh manufacturing processes that will kill vegetative bacteria. When dormant spores are reintroduced into an acceptable germination environment they can become active reproductive vegetative cells. Once spores germinate and begin reproducing as vegetative cells, production of exotoxins can occur in a short period of time. Fungi/Molds Molds are a subset of fungi that reproduce by releasing spores into the air which, if they land on a moist nutrient source or animal tissue, can germinate. Some species of molds produce toxic byproducts called mycotoxins. Mycotoxins can accumulate in animal tissues, rendering the affected organs/tissues unfit for use as a source of starting material for the production of animal-derived drug ingredients. It is important to prevent molds from growing in drug ingredients and when feasible and valuable remove all molds that may contaminate such ingredients. Yeasts, another type of fungi, can also be pathogenic or cause spoilage of an ingredient.

Viruses Although a virus can only multiply within its host, the inadvertent use of material from virus-infected animals or contact of the drug ingredient with virus-contaminated surfaces can transmit viral particles to patients. Virus survival rates differ based on virus type and variables associated with surface materials that become contaminated. On hard, nonporous surfaces, some virus species can survive and remain transmissible for days or weeks. The probability of an animal virus contaminating an animal-derived ingredient will depend on the viral load of the raw material (e.g., tissue, glands, blood) and the viral clearance capability of the drug ingredient manufacturing process. Both of these factors should be considered when assessing the risk of viral contamination of the ingredient. Internal Animal Parasites Transmission of internal parasites occurs from host to host through the consumption of contaminated food or water.

Parasites live and reproduce within the tissues and organs of infected hosts and are often excreted in feces. Government inspectors are trained to look for internal parasites and prevent unhealthy animals from entering the food supply. Animals deemed fit for food consumption are inspected and certified as healthy. Prions Protection from prion contamination includes obtaining bovine meat and meat by-products from animals not infected with bovine spongiform encephalopathy and protecting against contamination of the product with high-risk tissues, especially the brain and spinal cord tissue.

Drug manufacturers importing bovine material into the United States should be familiar with and adhere to all import eligibility requirements and government regulations pertaining to food and drugs. It is important that farms, slaughterhouses, and renderers observe government regulations prohibiting the use of unhealthy animals in the food supply. Animals deemed fit for food consumption are normally inspected and certified as healthy in many countries.