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Compounded protamine zinc insulin
A D VA N C E S
PAG E 5
Procedure Samples of PZI insulin were obtained from 112 vials (16 vials of the commercially manufactured product and 8 vials from each of 12 compounding pharmacies) purchased over an 8-month period. Appearance, endotoxin concentration, crystal size, insulin concentration in the supernatant pH, total insulin and zinc concentrations, and species of insulin origin were evaluated. Analysis was performed on samples from 2 vials of each product at 4 time points.
Results
COMPOUNDED PROTAMINE ZINC INSULIN Background Protamine zinc insulin (PZI) is a longacting insulin preparation that is released from the site of injection by the action of proteolytic enzymes that degrade protamine. Zinc inhibits these enzymes and slows the release of insulin. Desired PZI action depends on careful and consistent formulation of the product with 3 critical ingredients: protamine, zinc, and insulin. PZI of bovine and porcine origin was manufactured by an animal health pharmaceutical company for treatment of diabetes in cats until production was discontinued in 2008. Although an FDAapproved human recombinant PZI product is commercially available for use in cats, high cost and intermittent shortages of commercially manufactured PZI have led to alternative products being offered by compounding pharmacies. The United States Pharmacopeia (USP) is an independent organization that sets standards for the pharmaceutical industry and the practice of pharmacy. Whether compounded PZI products consistently meet USP specifications for PZI has not been established.
Objectives To evaluate and compare characteristics of a commercially manufactured PZI obtained from various compounding pharmacies.
All 16 vials of commercially manufactured PZI met USP specifications. Of 96 vials of compounded PZI, 1 contained an endotoxin concentration of more than 32 endotoxin U/ml, 23 had concentrations of insulin in the supernatant of more than 1.0 U/ml, and 45 had pH values less than 7.1 or more than 7.4. All of these values were outside of specifications. Half (52 of 96) vials of compounded PZI did not meet specifications for zinc concentration, and total insulin concentration in 36 vials was less than 90% of the labeled concentration.
Author Conclusion Only 1 of 12 compounded PZI products met all USP specifications in all vials tested. Use of compounded PZI insulin products should be limited to those that consistently meet USP specifications to reduce the risk of serious problems with glycemic control in veterinary patients.
Inclusions Four tables, 13 references.
Editor Annotation PZI is commonly prescribed for use in veterinary patients. Although once used to treat diabetes in human patients, it is no longer widely used, which has resulted in commercially manufactured PZI products leaving the market. Recently, an FDA-approved, commercial PZI product containing recombinant human insulin has returned to the veterinary market. With the market comings and goings of PZI, consistent demand has supported a market for compounded PZI, supplied by a variety of compounding pharmacies. In this study, Scott-Moncrieff et al. compared the commercial PZI product and PZI prepared by various compound-
PAG E 6
A D VA N C E S
ing pharmacies to standards for PZI set by the USP. Detailed analysis of the pharmacologic properties of 116 vials of compounded and commercially manufactured PZI products was performed by a quality control laboratory able to perform analysis using USP and cGMP (current good manufacturing process) methods. The study results were dramatic. All 16 vials of the commercially manufactured PZI met USP standards, but compounded PZI products varied from USP standards in almost every vial tested. Some of the variability discovered among compounded products (for example, vials labeled as containing 40 units of insulin/ml actually ranged from approximately 24 to 42 U/ml) would be expected to negatively impact diabetic regulation of patients. An additional concern is that the data indicates that compounded PZI products are inconsistent. Not only did most products deviate from at least 1 of the USP standards, the magnitude of the deviation was found to vary, sometimes greatly, from vial to vial from the same compounder. In fact, just 1 of the compounded PZI products satisfied USP standards for every vial tested (8 vials of PZI were tested from each compounding supplier). Veterinarians who prescribe compounded PZI should review this interesting study. The study results raise great concern about the consistency and reliability of compounded PZI products. Inconsistencies in the insulin product could lead to unpredictable effects on glycemia and introduce a significant source of variability to complicate diabetes control. (TS) Scott-Moncrieff JCR, Moore GE, Coe J, et al. Characteristics of commercially manufactured and compounded protamine zinc insulin. J Am Vet Med Assoc 2012;240:600-605.
PAG E 5
Procedure Samples of PZI insulin were obtained from 112 vials (16 vials of the commercially manufactured product and 8 vials from each of 12 compounding pharmacies) purchased over an 8-month period. Appearance, endotoxin concentration, crystal size, insulin concentration in the supernatant pH, total insulin and zinc concentrations, and species of insulin origin were evaluated. Analysis was performed on samples from 2 vials of each product at 4 time points.
Results
COMPOUNDED PROTAMINE ZINC INSULIN Background Protamine zinc insulin (PZI) is a longacting insulin preparation that is released from the site of injection by the action of proteolytic enzymes that degrade protamine. Zinc inhibits these enzymes and slows the release of insulin. Desired PZI action depends on careful and consistent formulation of the product with 3 critical ingredients: protamine, zinc, and insulin. PZI of bovine and porcine origin was manufactured by an animal health pharmaceutical company for treatment of diabetes in cats until production was discontinued in 2008. Although an FDAapproved human recombinant PZI product is commercially available for use in cats, high cost and intermittent shortages of commercially manufactured PZI have led to alternative products being offered by compounding pharmacies. The United States Pharmacopeia (USP) is an independent organization that sets standards for the pharmaceutical industry and the practice of pharmacy. Whether compounded PZI products consistently meet USP specifications for PZI has not been established.
Objectives To evaluate and compare characteristics of a commercially manufactured PZI obtained from various compounding pharmacies.
All 16 vials of commercially manufactured PZI met USP specifications. Of 96 vials of compounded PZI, 1 contained an endotoxin concentration of more than 32 endotoxin U/ml, 23 had concentrations of insulin in the supernatant of more than 1.0 U/ml, and 45 had pH values less than 7.1 or more than 7.4. All of these values were outside of specifications. Half (52 of 96) vials of compounded PZI did not meet specifications for zinc concentration, and total insulin concentration in 36 vials was less than 90% of the labeled concentration.
Author Conclusion Only 1 of 12 compounded PZI products met all USP specifications in all vials tested. Use of compounded PZI insulin products should be limited to those that consistently meet USP specifications to reduce the risk of serious problems with glycemic control in veterinary patients.
Inclusions Four tables, 13 references.
Editor Annotation PZI is commonly prescribed for use in veterinary patients. Although once used to treat diabetes in human patients, it is no longer widely used, which has resulted in commercially manufactured PZI products leaving the market. Recently, an FDA-approved, commercial PZI product containing recombinant human insulin has returned to the veterinary market. With the market comings and goings of PZI, consistent demand has supported a market for compounded PZI, supplied by a variety of compounding pharmacies. In this study, Scott-Moncrieff et al. compared the commercial PZI product and PZI prepared by various compound-
PAG E 6
A D VA N C E S
ing pharmacies to standards for PZI set by the USP. Detailed analysis of the pharmacologic properties of 116 vials of compounded and commercially manufactured PZI products was performed by a quality control laboratory able to perform analysis using USP and cGMP (current good manufacturing process) methods. The study results were dramatic. All 16 vials of the commercially manufactured PZI met USP standards, but compounded PZI products varied from USP standards in almost every vial tested. Some of the variability discovered among compounded products (for example, vials labeled as containing 40 units of insulin/ml actually ranged from approximately 24 to 42 U/ml) would be expected to negatively impact diabetic regulation of patients. An additional concern is that the data indicates that compounded PZI products are inconsistent. Not only did most products deviate from at least 1 of the USP standards, the magnitude of the deviation was found to vary, sometimes greatly, from vial to vial from the same compounder. In fact, just 1 of the compounded PZI products satisfied USP standards for every vial tested (8 vials of PZI were tested from each compounding supplier). Veterinarians who prescribe compounded PZI should review this interesting study. The study results raise great concern about the consistency and reliability of compounded PZI products. Inconsistencies in the insulin product could lead to unpredictable effects on glycemia and introduce a significant source of variability to complicate diabetes control. (TS) Scott-Moncrieff JCR, Moore GE, Coe J, et al. Characteristics of commercially manufactured and compounded protamine zinc insulin. J Am Vet Med Assoc 2012;240:600-605.