GUIDELINES ON USE OF PHARMACEUTICAL-/NON- PHARMACEUTICAL-GRADE SUBSTANCES ON ANIMALS

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1 GUIDELINES ON USE OF PHARMACEUTICAL-/NON- PHARMACEUTICAL-GRADE SUBSTANCES ON ANIMALS A pharmaceutical-grade substance is defined as any active or inactive drug, biologic or reagent, for which a chemical purity standard has been established by a recognized national or regional pharmacopeia (e.g., the U.S. Pharmacopeia (USP), British Pharmacopeia (BP), National Formulary (NF), European Pharmacopoeia (EP), Japanese Pharmacopeia (JP), etc.). These standards are used by manufacturers to help ensure the products are of the appropriate chemical purity and quality, in the appropriate solution or compound, to ensure stability, safety, and efficacy. Whenever possible, pharmaceutical-grade substances must be used for the clinical treatment of animals and to prevent or reduce/eliminate animal pain or distress, even in acute procedures. Non-pharmaceutical grade substances should only be used in clinical treatment 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 nonpharmaceutical-grade substances in clinical treatment. For research purposes, i.e when the compounds are used to accomplish the scientific aims of the study, pharmaceutical-grade substances are preferred, if available, and suitable. If the use of non-pharmaceutical-grade substances is essential for the conduct of science, the goal of the IACUC is to 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. (A) Use of pharmaceutical-grade substances (a) Pharmaceutical-grade substances should be reconstituted according to the product insert. (b) Any excipient used in the formulation such as vehicle, diluent and others not described in the product insert should be of pharmaceutical-grade. Commonly used solvent / vehicle such as normal saline, Phosphate Buffered Saline (PBS) and Dimethyl sulfoxide (DMSO) are available in pharmaceutical-grade. Pharmaceutical-grade substances adulterated by non-pharmaceutical-grade excipients will render the preparation non-pharmaceutical-grade. (c) Reconstitution or formulation should be done under aseptic conditions. Sterilized pipette or pipettor tips should be used in the transfer of reconstitutents or vehicles. (B) Use of non- pharmaceutical- grade substances Date of last IACUC Approval: 17 September 2012 Page 1 of 5

2 The use of non-pharmaceutical-grade compounds in experimental animals will only be acceptable by IACUC in the following situations. Use is compliant with applicable national regulatory guidelines and requirements and the requirements of relevant funding agencies The pharmaceutical-grade compound is not available in the appropriate concentration or formulation or the appropriate vehicle control is unavailable in pharmaceutical-grade. 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 their use is well documented in scientific literature. The method of preparation, labeling (i.e., preparation and use-by dates), administration and storage of formulations is appropriately considered with the aim of maintaining their stability and quality (i.e., to prevent inadvertent co-administration of infectious agents or contaminants). (C) Consideration of factors affecting the health and well-being of animals When (i) non-pharmaceutical-grade substances, (ii) pharmaceutical- grade substances adulterated with non-pharmaceutical-grade excipients, and (iii) pharmaceutical- grade substances not appropriate for the species and route(s) of administration are used, the following factors affecting the health and well-being of animals should be considered and documented in the animal use protocol: 1. Vehicle, diluent and solvent Consideration should be given to formulations using pharmaceutical-grade excipient such as vehicle, diluent and others. When non-pharmaceutical - grade excipient is used, it should be sterile and physiologic. 2. Grade and purity. 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. 3. Sterility Date of last IACUC Approval: 17 September 2012 Page 2 of 5

3 All formulations must be prepared under strict aseptic conditions and/or sterilized prior to use. A 0.22 um filter could be used to filter-sterilize heat sensitive formulations. 4. ph The ph range of the internal environment of animal is very narrow (e.g., limited of 7.4 ± 0.4 in human). Formulation with high or low ph should be adjusted or diluted with a buffer if possible. Formulations of high or low ph given by the intra-muscular or subcutaneous will cause irritation, pain or tissue necrosis. The ph for these routes should be 7.3 to 7.45 or alternative routes such as intra-peritoneal or intra-venous should be considered. The ph of the formulation for IV or IP should be between 4.5 and 8.0. Use of formulation outside this ph range if required, must be administered in small volume. The effect of ph on the solubility of the substance should also be considered as precipitation may occur when mixed with blood, resulting in vascular occlusion, emboli, and thrombosis of local and distant capillary beds. 5. Osmolality The formulation should be isotonic or adjusted if it is not, whenever possible. Non-isotonic formulations may either cause red blood cell crenation or haemolysis when administered via the intravenous route, or may cause localized tissue damage and associated pain upon injection. Non-isotonic formulations should be administered slowly and in small volume. 6. Stability The stability of the formulation should be considered to ensure that the dose is effective and no harmful degradation by-products may compromise the experimental results or the welfare of animals based on available information. Methods of storage, such as dark bottles for light-sensitive compounds, refrigeration or freezing for compounds unstable at room temperature, etc. should be determined. Formulations should be used as soon as possible, or within a week if the shelf-life of the preparation is unknown and depending on the usage of the compound i.e. possible contamination after multiple use from the same vial. Use of fresh preparation should be considered if any unstable compound is included in the formulation. The preparation should be labeled with the name, concentrations, date of preparation and expiry date of the formulation, and should be discarded if changes in color and/or precipitation occur. 7. Pharmacokinetics Information on the pharmacokinetic of the substance should be noted where available. Such information will assists in determination of the dose, route and frequency and efficacy of the substance. 8. Toxicity, pyrogenicity, compatibility and side effects The toxicity, pyrogenicity, compatibility and side effects available in the literature should be reviewed. These factors cause pain and distress to Date of last IACUC Approval: 17 September 2012 Page 3 of 5

4 animals post-administration and measure to be taken to minimize pain and distress should be documented. Distinction should be made between the intended effects and potential side effects. Toxic substances should be used at lowest possible effective doses for the intended effect and at shortest possible humane endpoints. Pyrogens, such as endotoxins, may cause fever when injected into an animal. Purity and sterility of a non-pharmaceuticalgrade substance do not assure that pyrogens are not present. Pyrogenicity is a potential experimental variable that PI should be aware of when using nonpharmaceutical grade drugs. Pyrogens can be avoided by using purified and characterized compounds and diluents in preparation of the final formulation. Substance that is not compatible may cause tissue damage when administered to animals. The above and other side effects in animals should be monitored daily. 9. Pilot Study An efficient way to reduce the negative impacts on laboratory animals is the use of a pilot study. If a novel compound is being tested, a pilot study using a minimum number of animals should be conducted to determine the dose and induced adverse effects. This would in turn help determine humane end point criteria specific to the project. References. The Guide for the Care and Use of Laboratory Animals. NRC. ILAR. Eighth Ed P Administration of Substances to Laboratory Animals: Equipment Considerations, Vehicle Selection, and solute Preparation. Journal of the American Association for Laboratory Animal Science. September 2011, Vol 50, No 5, Administration of Substances to Laboratory Animals: Routes of Administration and Factors to Consider. Journal of the American Association for Laboratory Animal Science. September 2011 Vol 50, No 5 Pages A good practice guide to the administration of substances and removal of blood, including routes and volumes. Karl-Heinz Diehl, Robin Hull, David Morton, Rudolf Pfister, Yvon Rabemampianina, David Smith, Jean-Marc Vidal, Cor Van De Vorstenbosch. J Appl Toxicol , Refining procedures for the administration of substances. Report of the BVAAWF/ FRAME/ RSPCA/ UFAW joint working group on refinement. D.B. Mortom, M. Jennings, A. Beckwell, R. Ewbank, C. Godfrey, B. Holgayte, I. Inglis, R. James, C. Page, I. Sharman, R. Verschoyle, L. Westall and A.B. Wilson. Laboratory Animals 35, 1-41, Office of Laboratory Animal Welfare: Educational Resources Date of last IACUC Approval: 17 September 2012 Page 4 of 5

5 Recognition and Alleviation of pain in Laboratory Animals. Institute of Laboratory Animal Research, National Research council 2009 P 124 AAALAC Frequently Asked Question on the use address non-pharmaceutical-grade compounds. Date of last IACUC Approval: 17 September 2012 Page 5 of 5