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  • Guidelines on Diluting, Mixing and Compounding Sterile Pharmaceuticals
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Last Updated 28 June 2013

  1. Definitions

    1. Pharmaceutical Grade: A drug, biologic, or reagent that is approved by the Food and Drug Administration (FDA) or for which a chemical purity standard has been established by the United States Pharmacopeia-National Formulary (USP-NF), or British Pharmacopeia (BP). For chemicals, a certificate of analysis is usually available upon request.
    2. Non-pharmaceutical Grade: These chemicals do not meet or exceed requirements of USP/NF/BP and may have higher levels of impurities that can introduce unwanted variables or toxic effects.
    3. Diluent: An agent that dilutes or renders an active compound less potent or irritant. Example – 0.9% sterile saline or sterile water.
    4. Dose: The quantity to be administered at one time, as a specified amount of medication.
    5. Dosage Forms: The physical form of a dose of medication (e.g., tablet, capsule or injection).
    6. Route of Administration: The body system through which the drug is delivered. Examples include oral, intravenous, subcutaneous, intraperitoneal, etc. Medications are formulated for particular routes and can have decreased efficacy or be toxic if given by another route. The approved routes indicated by the manufacture MUST be used, unless it is stated otherwise in an UCUCA approved protocol. Example: Oral tablets cannot be injected.
    7. Parenteral: Medications that are administered through any route other than the gastrointestinal tract (oral or rectal). Includes intravenous, intraperitoneal, subcutaneous, intradermal, intramuscular, etc.
    8. UCUCA Approved Protocol: The method of administration to be performed, the intervals between substance administration, and the maximum volume to be given MUST be listed in the approved protocol specific to each study. Please refer to UCUCA's policy "Use of Expired Medical Materials and Non-pharmaceutical Grade Compounds" and Guidelines on Administration of Substances to Laboratory Animals.
  2. Pharmaceutical Calculations

    1. Diluting Pharmaceutical Grade Parenteral Medications

      Formula


      • Volume of undiluted drug needed X Undiluted drug concentration = Final total volume X Desired final drug concentration
      1. After volume of undiluted drug needed is calculated a sterile diluent should be added to reach the final volume desired. Only sterile diluents should be used (e.g., sterile normal saline)
      2. EXAMPLE: Ketamine undiluted concentration = 100mg/mL; Ketamine desired final concentration = 10mg/mL; Final volume desired = 10mL. Plug into formula: (volume of undiluted ketamine needed) X (100mg/mL) = (10mL) X (10mg/mL). Volume of undiluted ketamine needed = 1mL, mix with 9mL of sterile saline in a sterile vial to get 10mL of 10mg/mL ketamine
    2. IV Fluid Preparations
      1. After volume of undiluted drug needed is calculated, this volume should be removed from the fluid bag prior to adding the additive. Thus the final volume will be the starting volume of the fluid bag.
      2. EXAMPLE: Dextrose starting concentration = 50% (0.5g/mL); Dextrose desired final concentration = 5% solution in LRS (0.05g/mL); Final volume desired = 1000mL of a 5% dextrose solution. Plug into formula: (volume of 50% dextrose needed) X (0.5g/mL) = (1000mL) X (0.05g/mL). Volume of 50% dextrose needed = 100mL of 50% dextrose, remove 100mL of LRS from 1000mL bag prior to adding 100mL 50% dextrose.
      3. NOTE: This method will give you a generalized concentration of medication in suspension, do not use if precise drug dosing is needed.
    3. Beyond Use Date
      1. Sterile fluids (with no drugs added after opening) that intended to be accessed multiple times to obtain small volumes for administration and drug mixing can be used for 30 days beyond initial opening if containers are kept refrigerated and accessed in an aseptic manner.
      2. Sterile fluids that have had drugs or substances added after opening and intended to be accessed multiple times to obtain small volumes for administration and drug mixing can be used for 7 days beyond initial opening if containers are kept refrigerated and accessed in an aseptic manner.
      3. Sterile fluids used directly in patients to provide IV fluid support during surgery or treatment of illness must be replaced every 24 hours.
      4. Beyond use dates for compounded sterile preparations may vary (<7 or >30 days) depending upon known manufacturer or published stability, compatibility, or sterility data.
      5. **Dilution of any FDA approved medication will shorten its stability. If proper sterile technique is followed for dilution or fluid preparation the beyond use date should be set according to manufacturer preparation data or no greater than 7 days after dilution if manufacturer or published data is nonexistent.
    4. Combining Two or More Medications

      Formula


      (volume of drug A needed) X (starting concentration of drug A) = (final total volume of mixture desired) X (desired final concentration of drug A) + (volume of drug B needed) X (starting concentration of drug B) = (final total volume of mixture desired) X (desired final concentration of drug B)

      1. Use the formula above to determine the volume of drug A, B, C, etc needed to reach the desired final concentration of drug A, B, C, etc. Once each drug volume is calculated they should be added, then a sterile diluent should be added to reach the final volume desired. Only sterile diluents should be used (e.g., sterile normal saline).
      2. NOTE: Some medications cannot be mixed, please make sure that drugs are compatible prior to mixing.
      3. EXAMPLE:
        1. Ketamine (drug A): Ketamine starting concentration – 100mg/mL; Ketamine desired final concentration = 8.8mg/mL; Final total volume of mixture desired = 25mL. Plug into formula: (volume of drug A needed) X (100mg/mL) = (8.8mg/mL) X (25mL). Volume of Ketamine needed for mixture = 2.2mL
        2. Xylazine (drug B): Xylazine starting concentration – 100mg/mL; Xylazine desired final concentration = 1.0mg/mL; Final total volume of mixture desired = 25mL. Plug into formula: (volume of drug A needed) X (100mg/mL) = (1.0mg/mL) X (25mL). Volume of Xylazine needed for mixture = 0.25mL
        3. Ketamine 8.8mg/mL and Xylazine 1.0mg/mL (Total Volume = 25 ml) : Mix 2.2mL of 100mg/mL Ketamine + 0.25mL 100mg/mL Xylazine + 22.55mL of sterile dilutent.
        4. 0.2mL of this Ketamine-Xylazine mixture would deliver a dose 1.76mg of Ketamine and 0.2mg of Xylazine.
        5. Compounded doses should be calculated to the animal's weight prior to administration and MUST be listed in an approved UCUCA protocol.
  3. Sterile Preparation of Non-pharmaceutical Powders for Parenteral Administration

    1. All preparation should be performed under a clean laminar flow hood. Some powders may require a fume-hood or BSC due to potential human risk and exposure. Contact OSEH for more information.
    2. Only sterile diluents should be used (e.g., sterile normal saline or phosphate buffered saline).
    3. Top of vial or injection port of fluid bags should be swabbed with 70% isopropyl alcohol prior to puncture with needle.
    4. Combine the measured amount of powder and sterile diluent necessary to achieve desired concentration, as directed by manufacture, USP monograph, or experiment, and mix.
    5. All solutions intended for parenteral use must be sterile and balanced. The following guidelines should be used.
      1. Filtering: Filter though a 0.2µ filter
      2. pH Testing: The pH should be between 6.8-7.2. If the compound is intended to be administered intravenously through a central vein (jugular, femoral, etc) the pH range can be 3-9.
      3. Osmolarity Testing: The final solution should be isotonic, with an osmolarity around 300 mOsm.
      4. Culture (optional): For further conformation of sterility, the final solution can be cultured for bacterial growth. You can have this performed by ULAM's Animal Diagnostic Lab (936-3395).
      5. Endotoxin testing can be performed by commercial laboratories or with test assay materials.
    6. If compounding medications are NOT in the specified range or if particulates are visible in the final solution, they should NOT be injected.
    7. The final product should be sterilely transferred to a sterile vial within a laminar flow hood.
  4. Other

    1. Prior to removal or transfer of any medication from a vial, swab rubber port of the vial with alcohol and allow to dry completely.
    2. Labeling: If a drug is removed from its original packaging a label MUST be placed on the new container. Please list the name of the drug, the concentration of the drug and the beyond use date..
    3. Commercial instruments are available for measuring pH and osmolality.
    4. Questions? Please contact the ULAM veterinary staff at 743-936-1696 or ulam-vets@med.umich.edu.
    5. This document can also be found on the ULAM and UCUCA websites.
  5. References

    1. Blood DC, Studdert VP. 1999. Saunders comprehensive veterinary dictionary. London ; New York: WB Saunders.
    2. Lake T. 2003. Dosage calculations for veterinary nurses and technicians. Edinburgh ; New York: Butterworth-Heinemann.
    3. Matthews, K. and Taylor, D., Assessment of Sterility in Fluid Bags Maintained For Chronic Use; J. American Association for Laboratory Animal Science, Vol. 50, No. 5, Pages 708-712, September 2001.
    4. Plumb DC. 2005. Plumb's veterinary drug handbook. Stockholm, Wis. Ames, Iowa: PharmaVet ; Distributed by Blackwell Pub.
    5. Office for Animal Care and Use, NIH. Updated February 19, 2009. (http://oacu.od.nih.gov/)
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