Drugs and Chemical Compounds Used in Experimental Animals
Research investigators are required to provide information to the IACUC on any drug or chemical compound administered to research animals as part of their experimental protocol. The information outlined here must be included in an IACUC application.
The name of the drug/chemical, dose, administration method, volume and frequency of administration.
Information on the pharmaceutical or non-pharmaceutical grade of the drug/chemical (see below). Potential responses may include:
- The drug/chemical is an FDA approved product.
- The drug/chemical is a USP purity grade chemical (or higher) obtained from a reputable chemical supplier because no suitable FDA approved product is available.
- Other (such as an experimental drug/chemical generated in a research laboratory) - An explanation must be provided.
A statement describing the potential for toxicity or adverse reactions. Potential responses may include:
- The drug/chemical will be administered at a dose previously reported safe. No adverse effect/toxicity is expected.
- The drug/chemical has specific toxic effects which is related to the intended purpose of use.
- This is an experimental compound of undetermined toxicity. (See note below.)
If toxic effects are expected to result from administration of the drug/chemical, those effects must be described in the IACUC protocol. Examples include:
- DMBA used as part of a carcinogenesis model.
- Streptozotocin used to induce diabetes.
- Phenylhydrazine used to induce anemia.
- Certain antigen-adjuvant preparations that induce an inflammatory reaction at the site of administration.
Note: The safety/potential toxicity of experimental drugs/chemicals must be documented prior to experimental use. This may be documented via a pilot study or by reference to published studies that confirm the drug/chemical's safety when used within the proposed dose range.
Pharmaceutical versus Non-Pharmaceutical Grade
The term 'pharmaceutical grade' refers to drug products approved by the U.S. Federal Drug Administration (FDA). The FDA approves the complete product formulation including active as well as inactive ingredients and specifies the dose and route of administration. Products approved by the FDA are preferred because they have been extensively tested to verify safety, efficacy, drug absorption, metabolism, excretion and duration of action. Based on guidance documents from the U.S. National Institutes of Health Office of Laboratory Animal Welfare the following situations may justify the use of non-pharmaceutical grade drugs/chemicals in research animals.
- The compound is not available as an FDA approved drug product.
- An FDA approved product is available but not in a formulation suitable for its intended application (for example it is available in an oral dose form but not as an injectable)
- An FDA approved product is available but a significant change in formulation would be required for the intended application.
- An FDA approved product is available but contains additional ingredients that may introduce new variables.
- An FDA approved product is available but there is no equivalent vehicle control.
- An FDA approved product is available but a non-FDA approved product must be used to replicate the results of a prior study.
Drugs for Clinical Use in Animals
Pharmaceutical grade drugs must be used for clinical procedures and medical treatment of animals. This includes but is not limited to anesthetics, analgesics, and drugs used for euthanasia.There are a few exceptions commonly encountered in research:
- Avertin (2,2,2-Tribromoethanol) for anesthesia in mice.
- Pentobarbital obtained from a compounding pharmacy due to the high cost of pharmaceutical grade pentobarbital (Nembutal).
- Occasional shortages of pharmaceutical grade drugs may necessitate purchase from compounding pharmacies.
Drugs for Experimental Use in Animals
Drugs and chemical products used for experimental purposes should be pharmaceutical grade if a suitable product is available. Non-pharmaceutical grade drugs/chemicals may be used when a pharmaceutical grade product is not available or when there is a scientifically valid reason.
Preparation and Use of Drugs/Chemical Compounds Administered to Research Animals
The drug formulation must be appropriate for the route of administration and not harmful to the animal. FDA approved drugs must be used as supplied or if dilution is necessary, the vehicle will be of equivalent purity. Non-pharmaceutical grade drugs/chemicals must be prepared with a compatible vehicle of USP purity grade or higher and will be as close as possible to physiological pH and osmolality. Drugs/chemicals intended for administration via injection must be sterile and stored in a sterile injection vial. A 0.2micron filter may be used to sterilize solutions prepared from non-sterile ingredients.
USP (United States Pharmacopeia) is a non-profit organization that establishes standards and specifications for drug, chemical and food ingredient manufacture. Products that carry the USP designation on the label were manufactured according to USP specifications. You will find the USP mark on the label of drug products approved for use in humans. Many drugs approved for use in animals do not carry the USP designation.
Chemical compounds purchased from companies such as Sigma are available in a variety of purity grades. The USP purity grade meets the USP specifications for production of the chemical and is suitable for use in the manufacture of drug and food products. However, USP grade chemicals purchased from a chemical company are not FDA approved drug products.
Storage and Stability of Drugs/Chemical Compounds
FDA approved drug products must be stored according to label instructions and discarded by the last date of the month of the expiration date. Containers/vials must be labeled with the contents and expiration date. When drugs are mixed and/or diluted, the expiration date will be that of the ingredient with the earliest expiration date. However, unless there is information available suggesting longer or shorter storage times are appropriate, the solution should be used within one month of mixing.
Example: There is evidence that mixtures of ketamine and xylazine are stable for up to six months.
Example: Carprofen may be mixed with sterile water but the mixture should not be used for more than one week.
Storage conditions and stability of some drugs may be described in the literature or are available from university maintained SOPs. For example, instructions for the preparation and storage of Avertin (2,2,2-Tribromoethanol) are readily available. We recommend that the final use solution for Avertin be stored refrigerated, in the dark for up to one month.
References:
The Guide for the Care and Use of Laboratory Animals: http://grants.nih.gov/grants/olaw/guide-for-the-care-and-use-of-laboratory-animals.pdf
USDA Animal Care Resources Guide, Policy Number 3: Veterinary Care: http://www.aphis.usda.gov/animal_welfare/downloads/Animal%20Care%20Policy%20Manual.pdf
OLAW Online Seminar: Regulatory Considerations for Using Pharmaceutical Seminal Products in Research Involving Laboratory Animals, June 4, 2015: Seminar Transcript and questions: http://grants.nih.gov/grants/olaw/150604_seminar_transcript.pdf
OLAW Seminar: Use of Non-Pharmaceutical-Grade Chemicals and Other Substances in Research with Animals, March 1, 2012: Transcript: http://grants.nih.gov/grants/olaw/120301_seminar_transcript.pdf
OLAW FAQ: May investigators use non-pharmaceutical grade substances in animals? http://grants.nih.gov/grants/olaw/faqs.htm#662
AAALAC FAQ: Non-Pharmaceutical Grade Compounds: http://aaalac.org/accreditation/faq_landing.cfm#B9
Use of Biohazardous Materials and Biological Products in Research Animals
The use of pathogenic organisms, radioisotopes, carcinogens or other materials that may be hazardous to animals or humans should be clearly indicated on the Animal Care Request (ACR) form. The Institutional Biosafety Committee must approve experimental procedures involving biohazardous material prior to IACUC approval and ACR form submission. The University Isotopes Committee must approve the use of radioisotopes prior to IACUC approval and ACR form submission. Information on working with biohazardous materials within PSU animal facilities may be found on the ARP website.
Biological products are a potential source of microorganisms, especially pathogenic viruses that may infect laboratory animals. All biological products (tumors, blood, serum or other products of animal origin) must be screened for pathogen contamination before introduction into animals. If documentation of testing of the product you wish to use is available, please submit this to ARP with the Animal Care Request form. If no or incomplete documentation is available, appropriate testing must be performed before animal experimentation can begin. Please contact ARP at least 2 weeks prior to starting any animal experimentation to allow time for testing.
Adjuvant Administration
Investigators should consult the scientific literature for alternatives to Freund's complete adjuvant (FCA). If FCA is deemed necessary, then only one injection of FCA may be administered. Freund's incomplete adjuvant (FIA) should be used for subsequent immunizations. Footpad injections are not allowed. Please see the Penn State IACUC Guideline VI for further information.