United States: Programs & Policies

US Pharmacopeia

Last updated: December 6, 2007

The US Pharmacopeia (USP) is a nongovernmental organization founded in 1820 to establish and disseminate public standards for the quality of all pharmaceuticals, biologics, dietary supplements, and other health care products manufactured and sold in the US Federal law requires that all prescription and over-the-counter drugs marketed in the US meet USP standards, where they exist. In the context of regulatory toxicology, USP standards prescribe animal use to test for impurities or contaminants in serial batches of drugs, biologics, and/or biological products and to assess the toxic potential of plastics or leachable components of implanted medical devices.

Animal-Based Standards

USP standards prescribing animal use include the following:

  • Rabbit Pyrogen Test (USP )to detect fever-producing contaminants in injectable drugs and other medicinal products.
  • Limulus Amoebocyte Lysate Test (USP)using blood from horseshoe crabs to detect bacterial endotoxin contamination in injectable drugs and other medicinal products.
  • General Safety Test (USP )to evaluate systemic toxicity of transfusion and infusion assembly extracts; test samples are injected into mice, who are observed over a 48-hour period for survival and overt toxicity.
  • Biologics Safety Test (USP )for lot validation of licensed biological products. At least two mice and two guinea pigs are injected intraperitoneally with a test dose of the product and monitored over seven days. The test requirements are met if the animals survive the test period, do not exhibit toxic responses, and show no weight loss.
  • Mouse Systemic Injection Test (USP )to provide direct assessment of adverse systemic effects. Groups of five mice are injected intravenously or intraperitoneally with each of several test or negative control extracts and observed for three days.
  • Rabbit Intracutaneous Reactivity Test (USP )to determine the irritant effect of toxic leachable substances present in extracts of test materials. Groups of two rabbits are injected subcutaneously with each of four test (ten sites) or control (five sites) extracts and scored daily for three days post-treatment.
  • Rabbit Intramuscular Implantation Test for 1 to 52 weeks (USP )to provide a direct assessment of the acute or long-term tissue response to the toxic effects of leachable substances from candidate biomaterials. The length of the implant period is determined by the end-use of the material. USP procedure requires that two rabbits be implanted with at least four strips of test material and two strips of negative control plastic into the paravertebral muscles. Macroscopic evaluation of tissue response to implants of the test material are compared to the corresponding negative control sites.
  • In Vivo Biological Reactivity Tests for Plastics (USP) to evaluate the biological response to plastics for use in medical devices, implants, containers, and base materials following systemic injection, intracutaneous reactivity, and/or muscle implantation.
Alternative Policies & Actions

USP does not have a clear position in regard to the 3Rs. However, its adoption of the Limulus Amebocyte Lysate (LAL) test for detection of endotoxic pyrogens as a partial replacement to the Rabbit Pyrogen Test suggests an openness to consider validated alternatives where available.