622518 research-article2015
JFM0010.1177/1098612X15622518Journal of Feline Medicine and SurgeryLetter to the Editor
Letter to the Editor
How to (properly) determine the beyond-use date and stability of a compounded formulation for pets Dear Editors, In the December 2015 issue of the Journal of Feline Medicine and Surgery (JFMS), the article on ‘Beyond-use date determination of buprenorphine buccal solution using a stability-indicating high-performance liquid chromatographic assay’, by LM Kirk and SD Brown, provided detailed methods for determining the beyond-use date (BUD) and stability of a buprenorphine formulation compounded for transmucosal oral absorption in cats.1 Veterinary compounded products are often marketed and sold by compounding pharmacies with assurances that they have performed stability testing and determined the BUD (often erroneously referred to as the ‘expiration date’). However, as the paper by Kirk and Brown illustrates so well, these determinations are difficult to perform. Some pharmacies may claim that the formulation has maintained stability for the time listed on the label. However, if they have performed any tests, it is more likely that they tested the strength of the compounded formulations. But strength and stability are not the same.2 Stabilityindicating tests are rigorous and should be developed using robust methodology. First, the investigator must develop a suitable analytical method, which was well described in Kirk and Brown’s paper. Then, the investigators must expose the formulation to various tests to examine the stability, such as subjecting the formulation to changes in pH, temperature, light and oxidation. These tests are described in the United States Pharmacopeia (USP) General Chapter on Pharmaceutical Compounding.3 The paper by Kirk and Brown contains details on tests that, admittedly, most feline practitioners will never perform in their practice. But the importance of this publication in JFMS is its demonstration of how difficult it is to perform these tests. Therefore, when practitioners see claims on a website, displayed in a brochure or in a convention exhibit hall, they will hopefully be prompted not simply to take these at face value. Pharmaceutical compounding for veterinary patients is about to undergo more scrutiny. On 18 May 2015, the Center for Veterinary Medicine of the US Food and Drug Administration released a draft ‘Guidance for Industry (GFI) #230, Compounding Animal Drugs from Bulk Drug Substances’.4 The Guidance, still to be finalized, outlines specific conditions under which the agency generally would not take action against state-licensed
Journal of Feline Medicine and Surgery 2016, Vol. 18(4) 1–2 © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1098612X15622518 jfms.com
pharmacies, veterinarians and facilities registered as outsourcing facilities when drugs are compounded for animals from bulk drug substances. This would include making formulations for cats, such as the one that is the subject of the article by Kirk and Brown. Among the conditions that must be met is a requirement that the drug is compounded in accordance with the compounding chapters published by the USP,3 which includes BUD. One important standard for compounded preparations is that the final strength of the finished preparation is not less than 90% and not more than 110% of the nominal and labeled quantity of active ingredient per unit weight or volume. That was the standard applied within the Kirk and Brown study. Generally, the BUD for a nonaqueous solid compounded dosage form should not be later than 25% of the time remaining until the expiration date of the shortest-dated ingredient or 6 months, whichever is shorter. For water-containing formulations, such as the buprenorphine formulation that was the subject of the JFMS study, the BUD should not be more than 14 days when stored at cold temperatures, unless there is supporting valid scientific data that applies to the specific compounded formulation. The Kirk and Brown paper provided evidence that a 90 day BUD could be applied to this formulation. Veterinarians should be concerned that the compounded formulations they prescribe maintain strength and effectiveness throughout the period indicated by BUD labeling from the compounding pharmacy. In addition to the questions regarding the efficacy of transmucosal buprenorphine,5,6 the quality of the formulation also should be a concern. Kirk and Brown are to be commended for providing an example that should be used by compounding pharmacies and hospital pharmacies that dispense compounded formulations for pets. It is also an illustration to veterinarians prescribing these formulations of the rigor that is necessary for a properly conducted study. Therefore, when a compounding pharmacy advertises that they ‘used USP standards’, or when they apply a BUD that is outside the USP limits, veterinarians can be skeptical and ask appropriate questions learned from reading this paper. Mark G Papich North Carolina State University, College of Veterinary Medicine, Raleigh, North Carolina, USA
Downloaded from jfm.sagepub.com at TRENT UNIV on December 12, 2015
Journal of Feline Medicine and Surgery 18(4)
2 The authors respond: We are grateful for the high praise from Dr Papich and the opportunity to discuss analytical method development, beyond-use date (BUD) determination and formulation stability in the broader applicable context of veterinary medicine. The objectives of our research were to validate a stability-indicating analytical method by meeting established quality standards, and utilize this method to determine the long-term stability of a veterinary buprenorphine formulation. It is an unexpected outcome to have this project endorsed as an example that should be used by those entities dispensing compounded formulations for pets. Additionally, in our background research of the primary literature, we discovered a dearth of information relating to the published methods for veterinary compounded formulations. Those equipped to develop and validate such analytical methods have a responsibility to contribute to the published literature and establish evidence-based beyond-use dates for commonly used compounded veterinary formulations. It is our hope that more researchers similarly utilize quality standards from the Food and Drug Administration Guidance, the United States Pharmacopeia General Chapters, and such like. Once again, we appreciate the additional discussion of our research and the illumination of the complexities of how to properly determine
the beyond-use date and stability of a compounded formulation. Stacy Brown and Loren Kirk Bill Gatton College of Pharmacy, East Tennessee State University USA References 1 Kirk LM and Brown SD. Beyond-use date determination of buprenorphine buccal solution using a stability-indicating high-performance liquid chromatographic assay. J Feline Med Surg 2015; 17: 1035–1040. 2 Kupiec TC, Skinner R and Lanier L. Stability versus potency testing: the madness is in the method. Int J Pharm Compd 2008; 12: 50–53. 3 USP 38, NF 33. Pharmaceutical compounding. In: The United States Pharmacopeia and The National Formulary. United States Pharmacopeial Convention Inc, Rockville Maryland, 2015. 4 US Food and Drug Administration. FDA releases draft guidance on animal drug compounding from bulk drug substances. http://www.fda.gov/NewsEvents/Newsroom/ Press Announcements/ucm447159.htm. (2015, accessed November 4, 2015). 5 Hedges AR, Pypendop BH, Shilo-Benjamini Y, et al. Pharmacokinetics of buprenorphine following intravenous and buccal administration in cats, and effects on thermal threshold. J Vet Pharmacol Ther 2013; 37: 252–259. 6 Steagall PVM, Monteiro-Steagall BP and Taylor PM. A review of the studies using buprenorphine in cats. J Vet Intern Med 2014: 28: 762–770.
Downloaded from jfm.sagepub.com at TRENT UNIV on December 12, 2015
JFM0010.1177/1098612X15622518Journal of Feline Medicine and SurgeryLetter to the Editor
Letter to the Editor
How to (properly) determine the beyond-use date and stability of a compounded formulation for pets Dear Editors, In the December 2015 issue of the Journal of Feline Medicine and Surgery (JFMS), the article on ‘Beyond-use date determination of buprenorphine buccal solution using a stability-indicating high-performance liquid chromatographic assay’, by LM Kirk and SD Brown, provided detailed methods for determining the beyond-use date (BUD) and stability of a buprenorphine formulation compounded for transmucosal oral absorption in cats.1 Veterinary compounded products are often marketed and sold by compounding pharmacies with assurances that they have performed stability testing and determined the BUD (often erroneously referred to as the ‘expiration date’). However, as the paper by Kirk and Brown illustrates so well, these determinations are difficult to perform. Some pharmacies may claim that the formulation has maintained stability for the time listed on the label. However, if they have performed any tests, it is more likely that they tested the strength of the compounded formulations. But strength and stability are not the same.2 Stabilityindicating tests are rigorous and should be developed using robust methodology. First, the investigator must develop a suitable analytical method, which was well described in Kirk and Brown’s paper. Then, the investigators must expose the formulation to various tests to examine the stability, such as subjecting the formulation to changes in pH, temperature, light and oxidation. These tests are described in the United States Pharmacopeia (USP) General Chapter on Pharmaceutical Compounding.3 The paper by Kirk and Brown contains details on tests that, admittedly, most feline practitioners will never perform in their practice. But the importance of this publication in JFMS is its demonstration of how difficult it is to perform these tests. Therefore, when practitioners see claims on a website, displayed in a brochure or in a convention exhibit hall, they will hopefully be prompted not simply to take these at face value. Pharmaceutical compounding for veterinary patients is about to undergo more scrutiny. On 18 May 2015, the Center for Veterinary Medicine of the US Food and Drug Administration released a draft ‘Guidance for Industry (GFI) #230, Compounding Animal Drugs from Bulk Drug Substances’.4 The Guidance, still to be finalized, outlines specific conditions under which the agency generally would not take action against state-licensed
Journal of Feline Medicine and Surgery 2016, Vol. 18(4) 1–2 © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1098612X15622518 jfms.com
pharmacies, veterinarians and facilities registered as outsourcing facilities when drugs are compounded for animals from bulk drug substances. This would include making formulations for cats, such as the one that is the subject of the article by Kirk and Brown. Among the conditions that must be met is a requirement that the drug is compounded in accordance with the compounding chapters published by the USP,3 which includes BUD. One important standard for compounded preparations is that the final strength of the finished preparation is not less than 90% and not more than 110% of the nominal and labeled quantity of active ingredient per unit weight or volume. That was the standard applied within the Kirk and Brown study. Generally, the BUD for a nonaqueous solid compounded dosage form should not be later than 25% of the time remaining until the expiration date of the shortest-dated ingredient or 6 months, whichever is shorter. For water-containing formulations, such as the buprenorphine formulation that was the subject of the JFMS study, the BUD should not be more than 14 days when stored at cold temperatures, unless there is supporting valid scientific data that applies to the specific compounded formulation. The Kirk and Brown paper provided evidence that a 90 day BUD could be applied to this formulation. Veterinarians should be concerned that the compounded formulations they prescribe maintain strength and effectiveness throughout the period indicated by BUD labeling from the compounding pharmacy. In addition to the questions regarding the efficacy of transmucosal buprenorphine,5,6 the quality of the formulation also should be a concern. Kirk and Brown are to be commended for providing an example that should be used by compounding pharmacies and hospital pharmacies that dispense compounded formulations for pets. It is also an illustration to veterinarians prescribing these formulations of the rigor that is necessary for a properly conducted study. Therefore, when a compounding pharmacy advertises that they ‘used USP standards’, or when they apply a BUD that is outside the USP limits, veterinarians can be skeptical and ask appropriate questions learned from reading this paper. Mark G Papich North Carolina State University, College of Veterinary Medicine, Raleigh, North Carolina, USA
Downloaded from jfm.sagepub.com at TRENT UNIV on December 12, 2015
Journal of Feline Medicine and Surgery 18(4)
2 The authors respond: We are grateful for the high praise from Dr Papich and the opportunity to discuss analytical method development, beyond-use date (BUD) determination and formulation stability in the broader applicable context of veterinary medicine. The objectives of our research were to validate a stability-indicating analytical method by meeting established quality standards, and utilize this method to determine the long-term stability of a veterinary buprenorphine formulation. It is an unexpected outcome to have this project endorsed as an example that should be used by those entities dispensing compounded formulations for pets. Additionally, in our background research of the primary literature, we discovered a dearth of information relating to the published methods for veterinary compounded formulations. Those equipped to develop and validate such analytical methods have a responsibility to contribute to the published literature and establish evidence-based beyond-use dates for commonly used compounded veterinary formulations. It is our hope that more researchers similarly utilize quality standards from the Food and Drug Administration Guidance, the United States Pharmacopeia General Chapters, and such like. Once again, we appreciate the additional discussion of our research and the illumination of the complexities of how to properly determine
the beyond-use date and stability of a compounded formulation. Stacy Brown and Loren Kirk Bill Gatton College of Pharmacy, East Tennessee State University USA References 1 Kirk LM and Brown SD. Beyond-use date determination of buprenorphine buccal solution using a stability-indicating high-performance liquid chromatographic assay. J Feline Med Surg 2015; 17: 1035–1040. 2 Kupiec TC, Skinner R and Lanier L. Stability versus potency testing: the madness is in the method. Int J Pharm Compd 2008; 12: 50–53. 3 USP 38, NF 33. Pharmaceutical compounding. In: The United States Pharmacopeia and The National Formulary. United States Pharmacopeial Convention Inc, Rockville Maryland, 2015. 4 US Food and Drug Administration. FDA releases draft guidance on animal drug compounding from bulk drug substances. http://www.fda.gov/NewsEvents/Newsroom/ Press Announcements/ucm447159.htm. (2015, accessed November 4, 2015). 5 Hedges AR, Pypendop BH, Shilo-Benjamini Y, et al. Pharmacokinetics of buprenorphine following intravenous and buccal administration in cats, and effects on thermal threshold. J Vet Pharmacol Ther 2013; 37: 252–259. 6 Steagall PVM, Monteiro-Steagall BP and Taylor PM. A review of the studies using buprenorphine in cats. J Vet Intern Med 2014: 28: 762–770.
Downloaded from jfm.sagepub.com at TRENT UNIV on December 12, 2015
