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Policy: Use of Non-Pharmaceutical Grade Compounds in Animals (IACUC)
Policy: Use of Non-Pharmaceutical Grade Compounds in Animals (IACUC)
This policy establishes the standards for use of non-pharmaceutical grade compounds and medical grade materials in live vertebrate animals. In accordance with standards set forth in the Guide for the Care and Use of Animals, the United States Department of Agriculture (USDA), and the NIH Office of Laboratory Animal Welfare (OLAW) policies, pharmaceutical grade substances should be used, when available, for all live vertebrate animal procedures. The UIUC IACUC may approve the use of non-pharmaceutical grade substances under special circumstances.
Federal regulations indicate non-pharmaceutical-grade chemical compounds may only be used in animals after specific review and approval by the Institutional Animal Care and Use Committee (IACUC) for reasons such as scientific necessity or non-availability of an acceptable veterinary or human pharmaceutical-grade product1-4. Cost savings or convenience are not adequate justification1-4. However, at times, shortages of pharmaceutical grade drugs may lead to excessive cost increases and IACUC may conclude that a non-pharmaceutical drug may be used as an alternative. Federal regulations1-5 also prohibit the use of expired medical materials such as drugs, fluids, or sutures. Such use is not acceptable veterinary practice and does not constitute adequate veterinary care as required by the Animal Welfare Act5.
Drug and Medical Device: The Food and Drug Administration (FDA) defines a drug as a substance (other than food) that is recognized by an official pharmacopoeia or formulary. A medical device is defined by the FDA as an instrument, apparatus, implement, implant, in vitro reagent, or other similar article which is recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them. A drug or medical device is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease or intended to affect any structure or function of the body6.
Pharmaceutical grade compound: A drug, biologic, or reagent which is approved by the FDA or for which a chemical purity standard has been established by US Pharmacopeia (USP)/National Formulary (NF) or British Pharmocopeia (BP). Pharmaceutical and medical materials are usually identified regarding intended use and usually have a manufacturers’ expiration date.
Non-pharmaceutical grade compounds: A chemical not formulated or manufactured for use in human or veterinary medicine. Compounds obtained from chemical supply companies and prepared in a research laboratory are non-pharmaceutical grade. Pharmaceutical grade drugs compounded with another drug compound (pharmaceutical or non-pharmaceutical grade) or diluent, such as saline or distilled water, are considered non-pharmaceutical grade. USP purity grade, analytical standards, analytical grade and reagent grade compounds are all non-pharmaceutical grade compounds.
Pharmaceutical grade drugs and medical grade materials must be used, when available, for all live vertebrate animal procedures, in both survival and non-survival procedures.
The use of non-pharmaceutical grade compounds may be acceptable under specific circumstances and must be justified in an IACUC protocol. In order to obtain IACUC approval for the use of non-pharmaceutical compounds, specific criteria must be met, including:
- Scientific necessity;
- Non-availability of veterinary or human pharmaceutical grade drug;
- Pharmaceutical drug is not available in the required concentration, formulation, or vehicle necessary to achieve the scientific goal.
When using non-pharmaceutical grade compounds, sterility, pyrogenicity, stability, pH, and safety must be considered. Injectable agents must be prepared using sterile containers, diluents, and filtration. Diluents and solvents used for reconstitution should be pharmaceutical grade.
Compounds must be labeled correctly with the following information: name of compound, concentration, date of preparation, initials of preparer and expiration date.
Records and Disposal of Drugs
Holders of Drug Enforcement Agency (DEA) and State of Illinois controlled drug licenses are required to keep detailed records of every use of the controlled drugs, and to follow specific procedures for disposal when the drugs expire or are no longer needed7-10. Expired drug containers should be clearly labeled “EXPIRED – DO NOT USE” and be separated from other in-date drugs that are still in use.
- The principal investigator is responsible for ensuring that only pharmaceutical grade compounds and medical grade materials are administered to animals by project personnel.
- The investigator and project personnel must allow internal and external inspectors access to drugs, materials, and storage areas.
- Expired drugs or medical materials should be discarded according to campus regulations and stored separately and clearly labeled as “Expired – DO NOT USE”. Expired controlled drugs must continue to be kept in a secured lockbox until they are disposed of in accordance with state and federal guidelines.
The IACUC is responsible for implementation and oversight of this policy. The IACUC is responsible for semi-annual inspections of the animal facilities and farms to ensure that no unapproved non-pharmaceutical compounds or expired medical materials are present.
Agricultural Animal Care and Use Program (AACUP):
AACUP veterinarians can assist investigators with the use of anesthetics and analgesics and other drugs in approved protocols. AACUP also provides consulting and training to investigators regarding drug use.
Division of Animal Resources (DAR):
DAR assists investigators with the use of drugs in approved protocols and also provides consulting and training to investigators regarding use of anesthetics and analgesics. DEA regulations and DAR policy require that Principal Investigators obtain their own Federal and State of Illinois controlled substances licenses. For a six months, DAR can provide controlled substances to Principal Investigators, who have applied for but not yet received their controlled drug licenses. While license requests are being processed, DAR is available to provide controlled substances in daily aliquots as described in an IACUC approved animal care and use protocol. Investigators must request the amount of controlled substance needed for the day of upcoming procedures.
Exception for the Use of Non-Pharmaceutical Grade Sodium Pentobarbital for Perfusion/Euthanasia
On March 1, 2012, representatives of OLAW, USDA, and AAALAC International presented a webinar in which they clarified policies regarding non-pharmaceutical grade pentobarbital for use as a euthanasia agent accompanied by perfusion. They acknowledged that the exorbitant cost of pharmaceutical grade Nembutal (sodium pentobarbital) made it logistically unavailable. They also indicated that terminal perfusion not preceded by other experimental procedures could be considered euthanasia, and that non-pharmaceutical grade could be allowed if scientifically justified and approved by the IACUC. They indicated that the IACUC could craft a general policy, rather than reviewing each case.
The University of Illinois IACUC will allow non-pharmaceutical grade sodium pentobarbital to be used for terminal perfusion when the preparation, storage and handling procedures that generally apply to non-pharmaceutical grade drugs are followed. The recipe and instructions for such preparation are presented at the end of this policy. Researchers intending to use non-pharmaceutical pentobarbital in IACUC protocols must clearly state in their IACUC protocol that they have read this policy and they will use the indicated recipe and instructions for use of non-pharmaceutical grade pentobarbital. If any deviations from this exception policy are necessary, investigators must clearly state all exceptions in the IACUC protocol.
Sodium Pentobarbital Recipe
IACUC Approved Recipe for Sodium Pentobarbital
6 grams sodium pentobarbital
10 ml ethanol (95%)
40 ml propylene glycol USP
qs to 100 ml with 0.9% saline
1. Dissolve the pentobarbital powder in the ethanol.
2. Add 25 ml of saline (but only after the pentobarbital is completely dissolved), mix thoroughly.
3. Add 40 ml propylene glycol, mix.
4. Bring to final volume (100 ml) with 0.9% saline.
The pentobarbital concentration in the final solution is 60 mg/ml. Standard dose of 50 mg/kg i.p. in rats.
1. Stock solutions must be protected from light and maintained at 4°C no longer than 6 months.
2. Stock solutions must be passed through a sterile 0.2 micron filter prior to being stored.
3. Stock solutions must be prepared and stored in sterile tubes.
4. Working solutions can be prepared and maintained similar to stock solutions, but can be stored at room temperature for up to 30 days.
5. Transfer of solutions must utilize sterile supplies and techniques (e.g. sterile needles and syringes).
6. All containers must be labeled with material name, concentration, date prepared, storage requirements, expiration date, and the initials of the person making the solution.
7. Use must be recorded similar to other controlled substances.
8. Standard procedures for monitoring plane of anesthesia apply and supplemental dosing is to be given as needed.
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