Use of Non-Pharmaceutical Grade Compounds in Animals

Type

Policy

Pharmaceutical-grade chemicals, when available, should be used for all animal-related procedures.¹ Use of pharmaceutical-grade chemicals in laboratory animals reduces the potential for extraneous compounds to be introduced that in turn might cause toxic or unwanted side effects.

The use of non-pharmaceutical-grade chemicals or substances should be described and justified in the animal use protocol and be approved by the IACUC.¹

Background

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 product.^1-4 Cost savings or convenience are not adequate justification.^1-4 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 regulations^1-5 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 Act.⁵

Definitions

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 pharmacopeia or formulary. A medical device is defined by the FDA as an instrument, apparatus, implement, implant, in vitro reagent, or another 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 body 6.
Pharmaceutical Grade Compound: A chemical, 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 Pharmacopeia (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. Chemicals, compounds, substances, solutions, or reagents obtained from chemical supply companies and prepared in a research laboratory are non-pharmaceutical grade. Pharmaceutical grade chemicals or substances compounded with other non-pharmaceutical grade chemicals, substances, or diluents, 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.

Guidelines

The use of non-pharmaceutical grade compounds may be acceptable under specific circumstances and must be justified in an IACUC protocol. 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 for injection, sterility, pH, pyrogenicity, osmolality, 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 needed.^7-10 Expired drug containers should be clearly labeled “EXPIRED – DO NOT USE” and be separated from other in-date drugs that are still in use.

Responsibilities

Principal Investigator

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 following state and federal guidelines.

Institutional Animal Care and Use Committee

The IACUC is responsible for the 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.

ACP-Ag Program

ACP-Ag veterinarians can assist investigators with the use of anesthetics and analgesics and other drugs in approved protocols. ACP-Ag also provides consulting and training to investigators regarding drug use.

ACP-Lab Program

ACP-Lab provides consultation and provides training to investigators and their staff members regarding drugs for anesthesia, analgesia, and euthanasia in their IACUC-approved protocols. Researchers who need to use controlled substances in their research must obtain their own State of Illinois9 and US DEA⁷ controlled substances licenses

Exceptions

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 in the document linked below. 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: https://animalcare.illinois.edu/sites/default/files/recipe_for_sodium_pentobarbital.pdf

References

NIH Office of Animal Care and Use, Guidelines for the Use of Non-pharmaceutical Grade Compounds in Laboratory Animals (Last revised 2016) https://oacu.oir.nih.gov/sites/default/files/...guidelines/pharmaceutical_compounds.pdf
NIH OLAW FAQ F.4. May investigators use non-pharmaceutical grade compounds in animals? (https://grants.nih.gov/grants/olaw/faqs.htm#f4)
NIH OLAW FAQ F.5. May investigators use expired pharmaceuticals, biologics, and supplies in animals? (https://grants.nih.gov/grants/olaw/faqs.htm#f5)
OLAW webinar on non-pharmaceutical grade drugs. (https://grants.nih.gov/grants/olaw/120301_seminar_transcript.pdf)
AWA [Animal Welfare Act], 9 CFR Subchapter A,Washington DC, Office of the Federal Register (https://www.govinfo.gov/content/pkg/CFR-2016-title9-vol1/xml/CFR-2016-title9-vol1-chapI-subchapA.xml)
FDA Regulatory Information (https://www.fda.gov/drugs/informationondrugs/ucm079436.htm)
Federal Registration site for DEA Controlled Drugs. (https://www.deadiversion.usdoj.gov/drugreg/index.html)
Disposal of Controlled Drugs (Federal). (https://www.deadiversion.usdoj.gov/21cfr_reports/surrend/index.html)
State of Illinois main controlled drugs page. (http://www.idfpr.com/profs/ContSub.asp)
Disposal of controlled drugs (DRS website) (https://www.drs.illinois.edu/SafetyLibrary/DEAControlledSubstancesGuide)