Use of Non-Pharmaceutical grade Chemicals and Substances in Mammals

PURPOSE: 

The use of pharmaceutical-grade substances in laboratory animals ensures that the substances administered meet established documentable standards of purity and composition. This in turn helps ensure research animal health and welfare, as well as the validity of experimental results. The use of lower grade substances/compounds with undefined or higher levels of impurities or poorly formulated non-commercial preparations can introduce unwanted experimental variables or even toxic effects, and so should be avoided if at all possible. Although pharmaceutical grade substances should be used in experimental animals whenever possible, the use of non-pharmaceutical-grade substances in experimental animals is an acceptable practice under certain circumstances. The NIH Office of Laboratory Animal Welfare (OLAW) and the United States Department of Agriculture (USDA) both have determined that the use of non-pharmaceutical-grade substances should be based on (1) scientific necessity, (2) non-availability of an acceptable veterinary or human pharmaceutical-grade compound, and (3) specific review and approval by the institutional IACUC. Cost savings alone is not considered an adequate justification for the use of non-pharmaceutical-grade substances in laboratory animals. It is important to understand that this guideline pertains 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 of a consideration as the active compound in the preparation.

REFERENCE: 

Guide for the Care and Use of Laboratory Animals, 8th edition, page 31 

 

POLICY:

The policy is consistent with the guidance from the NIH/ILAR Guide for the Care and Use of Animals, the corresponding Position Statement from AAALAC - International, and the NIH/Office of Laboratory Animal Welfare’s Position Statement. 

When selecting compounds the following order of choice should be applied:

  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 sources such as compounding pharmacies); 
  4. Analytical grade bulk chemical used to compound a needed dosage form (requires justification); 
  5. Other grades and sources of substances (requires justification); For new investigational drugs the grade and formulation is not optional, but the investigator and IACUC can verify health and safety issues described above.


For a majority of common substances used in laboratory animal research, pharmaceutical grade (USP or NF grade) substances are available and should be used. Examples of common substances that are available in USP or NF grades include:

  • Saline 
  • DMSO 
  • Corn oil 
  • Tamoxifen 
  • Tetracycline 


When a non-pharmaceutical grade substance is proposed: When developing and reviewing a proposal to use non-pharmaceutical grade substances, the investigator and IACUC should consider animal welfare and scientific issues related to the use of the substances, including potential for contamination, safety, efficacy, and the inadvertent introduction of confounding research variables. For all non-pharmaceutical grade substances used in animals, the IACUC shall consider the grade/purity being proposed, the formulation of the final product, and issues such as sterility, pyrogenicity, stability, pH, osmolality, site/route of administration, pharmacokinetics, physiological compatibility, and quality control. The use of non-pharmaceutical-grade compounds in laboratory animals shall be clearly delineated and justified in the protocol document and/or covered by an IACUC policy developed for their use. 

Osmolality: Normal plasma has an osmolality in the range of 285-295 mOsm/kg (osmolarity range of 300-310 mOsm/L) and intravenously administered compounds should generally be formulated to a range matching this osmolality as closely as possible. Agents with an osmolality greater than 600mOsm/kg cause red blood cell crenation upon intravenous injection while agents less than 150 mOsm/kg will cause hemolysis, both of which are associated with pain and physiologic disturbances. Solutions with an osmolality less than 450 mOsm/kg are generally well tolerated by intravenous
infusion. Agents with widely non-physiologic osmolality administered via other routes (IM, SC, IP) may result in localized tissue damage and associated pain upon injection. As the volume of injected compound increases the potential for tissue damage and pain due to non-physiologic osmolality also increases dramatically. Osmolarilty/osmolality calculators are available on the internet to assist in calculating predicted drug osmolality/osmolarity (http://www.rxkinetics.com/iv_osmolarity.html).

pH: Plasma pH is tightly regulated normally between 7.35 and 7.45. The administration of compounds with widely variant pH values may impact the overall normal physiologic acid-base balance and result in pain and distress upon injection. Acidic (<4) and alkaline (>11) solutions should be avoided and if required, should be administered in small overall volumes. Solutions compounded within a pH range of 6.5 to 8.0 are generally well tolerated in continuous intravenous infusions while solutions in the pH range of 5-9 can be tolerated for a shorter duration.

Sterility and Pyrogenicity: Parenteral (IV, SC, IM, IP) administered compounds should be sterile and pyrogen-free. Sterility can be accomplished by steam autoclaving, dry heat sterilization, irradiation, sterile filtration, etc. dependent upon the compound and the diluent used. Pyrogens can be avoided by using purified and characterized compounds and diluents in preparation of the final drug. 

Examples for use of Non-Pharmaceutical-Grade Substances: It would be reasonable for the IACUC to review and potentially approve the use of non-pharmaceutical-grade substances in the following situations:

  • If no equivalent veterinary or human drug is available for experimental use, then the highest-grade equivalent chemical reagent should be used and formulated aseptically and with a non-toxic vehicle as appropriate for the route of administration. 
  • Although an equivalent veterinary or human drug is available for experimental use, the chemical-grade reagent is required to replicate methods from previous studies because results are directly compared to those of replicated studies. 
  • Although an equivalent veterinary or human drug is available, dilution or change in formulation is required. 
    • If adulteration by dilution, addition, or other change in formulation is required, there may be no additional advantage to be gained by using the USP formulation. 
    • Use of the highest-grade reagent may have the advantage of single-stage formulation and also result in purity that is equal to or higher than the human or veterinary drug. 
    • Professional judgment should be used to determine the appropriate test material and to ensure use of an agent with the least likelihood for causing adverse effects. 
  • The available human or veterinary drug is not concentrated enough to meet experimental requirements. 
  • The available human or veterinary drug does not meet the non-toxic vehicle requirements for the specified route of injection. 

 

 

Policy Adoption Date: 12/13/2012

Reference Minutes: 12/13/2012