Use of Non-pharmaceutical-grade Compounds in Live Vertebrate Animals

Standard

Investigators are expected by regulatory authorities to use pharmaceutical grade compounds whenever possible.  The use of pharmaceutical grade substances in animals ensures that the substances administered meet established documentable standards of purity and composition, and this helps ensure animal health and welfare, as well as the validity of experimental results.

Non-pharmaceutical-grade chemical compounds should only be used in live vertebrate animals after specific review and approval by the IACUC for reasons such as scientific necessity or non-availability of an acceptable veterinary or human pharmaceutical-grade product. Cost savings alone is not an adequate justification for using non-pharmaceutical-grade compounds in live vertebrate animals.

When selecting substances for use in animals the following order of choice should be applied:

Pharmaceutical Grade

1. FDA-approved veterinary or human pharmaceutical substances
2. FDA-approved veterinary or human pharmaceutical substances used to compound a needed dosage form
3. USP/NF or BP pharmaceutical grade substance used in a needed dosage form (also includes compounded products from any source)

Non-Pharmaceutical Grade

4. Analytical grade bulk chemical used to compound a needed dosage form (requires justification)
5. Other grades and sources of substances (requires justification)

Non-Pharmaceutical Compound Use Categorization

Clinical Use

Compounds used for the clinical treatment of animals and to prevent or reduce/eliminate animal pain or distress. Investigators are expected to use pharmaceutical-grade medications whenever they are available, even in acute procedures.

Research Use

Compounds used to accomplish the scientific aims of the study. If available, and suitable, pharmaceutical-grade compounds are preferred; but when non-pharmaceutical-grade preparations are used, The IACUC will expect investigators to consider the following factors and include the rationale in their IACUC application:

• Use must be compliant with applicable national or regional regulatory guidelines and requirements and the requirements of relevant funding agencies;;
• A scientific justification is provided in the application;
• The pharmaceutical-grade compound is not available in the appropriate concentration or formulation or the appropriate vehicle control is unavailable;
• The compound is required to generate data that are part of an ongoing study or that are comparable to previous work;
• The chemical properties of the compound are appropriate for the study and the route of administration (e.g., the purity, grade, stability in and out of solution, solution vehicle properties, pH, osmolality, and compatibility of the solvent and other components of final preparation). In some cases the reagent-grade of the compound may be as or more pure than the pharmaceutical-grade; and
• The method of preparation, labeling (i.e., preparation and use-by dates), administration and storage of formulations should be appropriately considered with the aim of maintaining their stability and quality (i.e., to prevent inadvertent co-administration of infectious agents or contaminants).

Dilutions and Combinations

Oftentimes administering anesthetics, analgesics, or other drugs to very large or very small animals may necessitate dilution or adulteration of drugs that will cause them to be classified as non-pharmaceutical grade compounds. The NC State IACUC recognizes that such compounds may be preferable in certain circumstances and approves the use of the following agents without scientific justification for routine anesthesia, analgesia, or euthanasia:

• Anesthetic cocktails utilizing pharmaceutical grade compounds such as:
  • Tiletamine/ketamine/xylazine combination for large swine
  • Rodent “cocktails” that contain mixtures of ketamine, xylazine/dexmedetomidine, and/or acepromazine
  • Other cocktail combinations that are considered standard veterinary practice and listed as a combination on your approved IACUC protocol.
  • Cocktail combinations consistent with standard veterinary care used for veterinary care procedures
• Dilution of the analgesics such as:
  • Carprofen, buprenorphine, and meloxicam or other analgesics with USP-grade saline or water prior to administration to small rodents
  • Dilution of sodium pentobarbital euthanasia solutions with USP-grade saline or water prior to administration to small rodents
  • Other dilutions consistent with standard veterinary care

In all of the above instances the adulteration of such substances must be performed aseptically and in accordance with appropriate dosages as dictated by standard of care.  Scientific justification is not required if the diluted or adulterated pharmaceutical is pharmaceutical grade. If any component of the adulterated or diluted product is not pharmaceutical grade, scientific justification is necessary for use of that product.

Once adulterated, expiration date must be clearly indicated and must account for stability in the altered conditions. As a rule of thumb, the adulterated drug must not be used beyond 30 days of initial dilution/mixture/or adulteration. Before using a diluted drug, visually inspect it for signs of degradation such as discoloration, precipitation, or cloudiness and if its integrity appears compromised, it should not be utilized in live animals.  Additional details are described in the Use and Expiration of Medical Materials Standard.

References

• Approved Animal Drug Products (Green Book)
• Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book)
• Guide for the Care and Use of Laboratory Animals: Eighth Edition
• OLAW FAQs: May Investigators Use Non-pharmaceutical Grade Substances in Animals

Updated and Approved February 20th, 2025