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Non-Pharmaceutical Grade Compounds

Number: IACUC-GUID-007 

Responsible Office: Office of Research and Creative Scholarship (ORCS) 

Applies to: Principal Investigators Conducting Animal Research 

1. Purpose 

Investigators are expected to use pharmaceutical-grade compounds (PGC) in animals when available. Whenever possible, pharmaceutical grade substances must be used for compounds selected for medical treatment or to prevent or reduce animal pain or distress. The use of non-pharmaceutical grade substances may be necessary to meet the scientific goals of a project or when pharmaceutical grade substances are not available. This is consistent with the regulatory requirements and the expectations of the public that research animals will be provided with adequate veterinary care. 

The Guide states, “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. In such instances, consideration should be given to the grade, purity, sterility, pH, pyrogenicity, osmolality, stability, site and route of administration, formulation, compatibility, and pharmacokinetics of the chemical or substance, etc. be administered, as well as animal welfare and scientific issues relating to its use.”  

The Guidance presented here is intended to help investigators understand their responsibilities and comply with federal law when non-pharmaceutical-grade compounds (non-PGCs) are necessary to complete their research objectives. The requirements below also apply to a pharmaceutical-grade product modified by the investigator (i.e., diluted, combined, etc.):  

For all agents administered to animals, the following must be considered in the order presented for pharmaceuticals and reagents of all kinds before use: 

1. Is this an FDA-approved veterinary or human pharmaceutical compound? 
2. Is this an FDA-approved veterinary or human pharmaceutical compound used to compound a needed dosage or form? 
3. Are there US Pharmacopeia–National Formulary (USP-NF), British Pharmacopeia (BP), or other pharmacopeia-recognized PGCs used in a needed dosage form? 
4. Are you using analytical grade bulk chemical [>95% pure by weight of the active chemical] (USP-NF <797> Pharmaceutical Compounding-sterile preparations) used to compound a needed dosage form (requires justification)?
5. If using other grades and sources of compounds, you must provide justification.  

2. Guidance for Investigators: 

Sufficient information must be provided in an Animal Use Protocol (AUP) for all substances administered to an animal for the UM Institutional Animal Care and Use Committee (UM IACUC) to effectively evaluate the safety of the agent. Information to include:  

1. Source of purchase (e.g., Sigma Chemical, Fisher Scientific, Millipore, etc.)
2. Indicate the form of the parent chemical (e.g., suspension, emulsion, dry powder, liquid, tablet, capsule, etc.) 
3. If you are purchasing the substance from a medical supply company, a drug wholesale supply, or directly from the manufacturer, and the substance is supplied as a product intended for use in medical or veterinary patients, then the substance is likely “pharmaceutical grade.” In most cases, bulk reagents purchased from chemical supply companies, or the substance is designated for use in research only, that substance is most likely NOT pharmaceutical grade. If you are unsure, consult the Attending Veterinarian (AV) for advice.  
4. Justification must address why you need to use this compound and why a pharmaceutical grade product could not be used. Cost savings alone is not an adequate justification for the use of a non-PGC when a PGC alternative exists and is available. Examples of acceptable scientific justifications for the use of non-PGCs include: 
   1. A PGC is not available; this includes new investigational compounds. 
   2. A PGC is not available in the appropriate concentration or formulation, or the appropriate vehicle control is unavailable.  
   3. A PGC is available but does not meet the non-toxic vehicle requirements for the specified route of administration.  
   4. The non-PGC is required to generate data that are part of an ongoing study or to generate data that are comparable to previous work. 
5. Will the compound be altered in any way before being given to the animal (diluted, dissolved, mixed with food or flavoring, etc.)? If the compound will be diluted, mixed with another substance, suspended, dissolved, or mixed into the animal’s drinking water or food, or otherwise altered, please describe how the compound will be altered, the solvent/vehicle to be used, and final concentration. If the drug will be administered directly to the animal, as supplied by the manufacturer for that purpose, then nothing needs to be specified. Diluents, excipients (An excipient is a substance formulated alongside the active ingredient of a medication that is used to enhance the active ingredient's therapeutic properties; to facilitate drug absorption; to reduce viscosity; to enhance solubility; to improve long-term stabilization; or to add bulk to solid formulations that have small amounts of potent active ingredients), or vehicles administered to animals in biomedical research should be pharmaceutical grade, if available. Products administered orally, which are not pharmaceutical grade, should be food-grade. 
6. Provide the pH and tonicity of the final product to be administered if the product will deviate from neutral pH or isotonic, or does not use a buffered and/or isotonic diluent or vehicle. 
7. Any compounds delivered by parenteral injections must be sterile. It is not necessary to sterilize medications that will be delivered orally or topically unless required by scientific study design. 
   1. If the compound cannot be sterilized, scientific justification as to why the material cannot be sterilized and describe what techniques will be used to ensure the final product is free of unwanted pathogens, pyrogens (such as endotoxin), or contaminants that might impact animal welfare.  
   2. Good aseptic technique in the preparation of all administered compounds is critical. In addition, storage conditions and expiration/use by date are also very important to protecting the integrity, purity, sterility, and stability of the compounds being administered and should be described in the AUP. 
   3. There are several acceptable methods for sterilization, but the two most commonly used are autoclaving and filter sterilization. Aseptic technique is again critical as there are limits to what sterilization can remove. 
      • Autoclaving uses moist heat and pressure to sterilize components. Care must be taken when autoclaving liquids to ensure that the final concentration is appropriate and that an unacceptable amount of water has not boiled off. The compound must also be heat-stable so that it is not destroyed by autoclaving. 
      • Filter sterilization involves passing the final solution through a 0.22-micron pore or smaller filter into a sterile container.  
8. Do these considerations apply to the vehicle/diluent/excipient as well? The guidelines pertain to all components, both active and inactive, contained in the preparation to be administered. Therefore, the vehicle used to facilitate administration of a compound is as important a consideration as the active compound in the preparation. 
9. Veterinary and human drugs that are reconstituted in a manner not in accord with the product insert are considered non-PGCs.  

3. Guidance for the IACUC on the Use of Non-PGCs in Animal Research: 

Where the use of non-PGCs may be essential for the conduct of science, the goal of the IACUC should 

consider the health and well-being of the animals while aiding the researcher in minimizing potentially confounding experimental variables and maximizing reproducibility of the research.  

Additional considerations include: 

1. Consider the purpose for which a particular compound is being given: 
   1. When compounds are used for the clinical treatment of animals or to prevent or reduce/eliminate animal pain or distress, PGCs must be used whenever possible. 
   2. When compounds are used to accomplish the scientific aims of the study, PGCs are preferred if available and suitable.  
2. Consider the justification for any non-pharmaceutical-grade compounds to be used: 
   1. The use of non-PGCs in laboratory animals must be described and justified in an approved Animal Use Protocol (AUP) and/or covered by an IACUC-approved policy. 

Examples of acceptable scientific justification for the use of non-PGCs include: 

1. No equivalent veterinary or human drug is available for experimental use.  
   • If this is the case, the highest grade equivalent chemical reagent should be used and formulated aseptically, with a non-toxic vehicle as appropriate for the route of administration.  
2. Although an equivalent veterinary or human drug is available for experimental use, the analytical or chemical grade reagent may be required to replicate methods from previous studies.  
3. Although an equivalent veterinary or human drug is available, dilution, concentration, or change in formulation is required.  
4. If the formulation as provided must be diluted, altered by addition, or otherwise changed, there may be no additional advantage to be gained by using the USP formulation. 
   1. In this situation, use of the highest-grade reagent may have the advantage of single-stage formulation and result in purity that is equal to or higher than the human or veterinary drug.  
5. The available human or veterinary drug does not meet the non-toxic vehicle requirements for the specified route of administration.  
6. Additional considerations for the use of drugs/chemicals/reagents in animals: 
   1. Whether the chemical properties of the compound are appropriate for the study and the route of administration (e.g., purity, grade, sterility, stability in and out of solution, solution vehicle properties, pH, osmolality, pyrogenicity, and compatibility of the solvent and other compounds of the final preparation). 
7. The method of preparation, labels (preparation and use-by dates), administration, and storage of formulation should be appropriately considered with the aim of maintaining their stability and quality.  
8. Use must be compliant with applicable national or regional regulatory guidelines and requirements of relevant funding agencies.  
9. The potential side-effects and adverse reactions should also be evaluated along with how animals will be monitored to detect these events and what, if any, treatments may be required.  
10. Considerations for non-survival studies: although the potential animal welfare consequences of complications are less evident in non-survival studies, the scientific issues remain the same as in survival studies and therefore apply to non-survival studies. 
11. The use of Non-PGC euthanasia agents must meet the same standards as for use in any other application.  
12. All of the above considerations apply to the vehicle/diluent/excipient. The guidelines pertain to all components, both active and inactive, contained in the preparation to be administered. 
13. Veterinary and human drugs that are reconstituted in a manner not in accord with the product insert are considered non-PGCs.  

4. References: 

1. U.S. Department of Agriculture, Animal and Plant Health Inspection Service, Animal Care, Animal Care Policy Manual, Policy #3 Veterinary Care, March 14, 2014. 
2. AAALAC Frequently Asked Questions: C. Institutional Responsibilities 9. Non-Pharmaceutical-Grade Compounds 
3. OLAW FAQ- Non-Pharmaceutical-Grade Substances 
4. Transcript of OLAW On-line Seminar broadcast on March 1, 2012 - Use of Non-Pharmaceutical-Grade 
5. Chemicals and Other Substances in Research with Animals 
6. Transcript of OLAW On-line Seminar broadcast on June 4, 2015 - Regulatory Considerations for Using Pharmaceutical Products in Research Involving Laboratory Animals 
7. OLAW Frequently Asked Questions – PHS Policy on Humane Care and Use of Laboratory Animals, F. Animal Use and Management, 4. May investigators use non-pharmaceutical-grade substances in animals? 
8. USP-NF Online. General Notices and Requirements. https://online.uspnf.com (accessed 03-05-2021). 
9. National Research Council, Guide for the care and use of Laboratory Animals. 8th edition. Institute for Laboratory Animal Research, The National Academies Press, Washington, DC, 2011. page 31. 
10. USP-NF Online. USP-NF <797> Pharmaceutical Compounding-sterile preparations. https://online.uspnf.com (accessed 03-05-2021). 
11. Turner, P., et. al. (2011) Administration of Substances to Laboratory Animals: Routes of Administration and Factors to Consider. Lab. Animal Sci. 50:600-613 
12. Turner P.V., Brabb T., Pekow C., Vasbinder M.A., (2011) Administration of Substances to Laboratory Animals: Routes of Administration and Factors to Consider. Journal of the American Association of Laboratory Animal Science, Vol. 50, No. 5, pages 600-613. 
13. Turner P.V., Pekow C., Vasbinder M.A., Brabb T. (2011) Administration of Substances to Laboratory Animals: Equipment Considerations, Vehicle Selection, and Solute Preparation. Journal of the American Association of Laboratory Animal Science, Vol. 50, No. 5, pages 614–627 

5. Review and Approval and Version History 

Review and approval version history for this policy

Version	Date	Description of Changes	Approved By
1.0	May 19, 2025	Initial creation and Adoption	IACUC Committee