Preparation, storage, and beyond-use dates of anesthetics and analgesics for animal use

Policy

The use of compounded (mixed or diluted) drugs in live animals must follow strict aseptic technique during preparation and storage of the drug mixtures or dilutions. Mixed drugs must be stored according to manufacturer guidelines and used within the expiration date of each of the drug components and within the beyond-use date of the mixture as described in this policy.

In general, beyond-use dates (e.g., after broaching primary container) and storage of drugs (e.g., at specific temperatures, protected from light) should follow manufacturer guidelines. In cases where such guidance does not exist (e.g., mixing of specific drug cocktails), this policy sets a maximum beyond-use date of six months after mixing for compound drugs. This policy also sets extended beyond-use dates (longer than manufacturer recommendations) for select drugs where published performance standard studies have demonstrated extended maintenance of sterility and strength/efficacy.

Background

Compounded drugs may change in efficacy and stability once mixed or diluted. Some drugs come with manufacturer guidelines for beyond-use dates, which is defined as the date after which a drug must not be used. The date is a set number of days after the drug vial is first punctured or the date a drug is mixed or diluted. The beyond-use-date should never exceed the printed expiration date for the drug.

Procedures

Preparation

1. Gather supplies:
   • Alcohol swabs
   • Sterile empty injection vial(s)
   • Appropriately sized sterile syringe and corresponding needle
   • Sterile diluent (sterile saline or sterile water) if needed for dilution or mixture
   • Drug components
2. Calculate and verify the dilution or mixture amounts of each drug component.
3. Use the alcohol swab and clean the tops of all vials to be used.
4. Using a sterile needle and syringe, extract the first drug to be mixed and inject that into the sterile empty injection vial. Repeat using a new needle and syringe for each remaining component of the cocktail.
5. Properly label the aliquot, dilution, or mixed cocktail with all of the following:
   • Drug components and their respective new concentrations
   • Mix date
   • Beyond-use date (see below)

Setting a Beyond-use Date

1. Beyond-use dates must not exceed the printed expiration date of any of the mixture components (this includes sterile saline).
2. Stock aliquots maintain the manufacturer expiration date printed on the bottle unless the manufacturer indicates a beyond-use date based on a number of days after puncture of the vial (e.g., carprofen, maropitant). Performance standard literature may be used to set appropriate beyond-use dates, as follows:
   • Stock carprofen may be maintained for up to six months when refrigerated, stored in glass vials, and protected from light (Xu et al., 2021).
3. Dilutions or cocktail mixtures have a beyond-use date of six months from the mix date unless any component expires sooner. Performance standard literature may be used to set appropriate beyond-use dates, as follows:
   • Diluted carprofen may be maintained for up to six months when refrigerated, stored in glass vials, and protected from light (Xu et al., 2021).
   • Ketamine-acepromazine-xylazine may be maintained for up to six months when protected from light and stored in glass vials (Taylor et al., 2009).
   • Diluted buprenorphine may be maintained for six months when protected from light and stored in glass vials (DenHerder et al., 2017).

Storage

1. Products must be stored appropriately per manufacturer guidelines or conditions cited in performance standard literature (e.g., refrigeration, protection from light, storage in a glass container, etc) to maintain appropriate expiration and beyond-use dates.
2. Products should be visually examined for changes before use; color change, homogeneity, or precipitation indicate the product may no longer be safe for use even if it has not expired.

Note: Additional record-keeping and documentation may be required for controlled drugs (CFR Title 21, Chapter II), please contact the Controlled Substance Program for more information.

References

• CFR, Title 21, Food and Drugs, Chapter II, Drug Enforcement Administration, Department of Justice

• Xu, Jiajie J., Renner, Deanna M., & Lester, Patrick A. (2021). Strength and sterility of stock and diluted carprofen over time. Journal of the American Association for Laboratory Animal Science, 60(4), 470-474. doi: 10.30802/AALAS-JAALAS-20-000102.

• Taylor, Brett J., Orr, Steven A., Chapman, Jennifer L., & Fisher, Diana E. (2009). Beyond-use dating of extemporaneously compounded ketamine, acepromazine, and xylazine: Safety, stability, and efficacy over time. Journal of the American Association for Laboratory Animal Science, 48(6), 718-726.

• DenHerder, Johnathan M., Reed, Ralph L., Sargent, Jennifer L., Bobe, Gerd, Stevens, Jan F., & Diggs, Helen E. (2017). Effects of time and storage conditions on the chemical and microbiologic stability of diluted buprenorphine for injection. Journal of the American Association for Laboratory Animal Science, 56(4), 457-461.