Characteristics of Commercially Manufactured and Compounded PZI Insulin

Characteristics of Commercially Manufactured and Compounded Protamine Zinc Insulin

By J. C. Scott-Moncrieff, G. E. Moore, J. Coe, R. Lynn, W. Gwin, R. Petzold

Journal of the American Veterinary Medical Association 2012; 240: 600-605.

Background
Protamine zinc insulin is a long-acting insulin preparation commonly used for treatment of diabetes mellitus in cats (1-3) and, less commonly, in dogs (4). This insulin is combined with protamine (a protein extracted from salmon) and zinc to delay the absorption of injected PZI insulin and thus prolong its duration of effect (5). Therefore, for PZI insulin to work as expected, the insulin must be properly and carefully formulated with its 3 critical ingredients: protamine, zinc, and insulin (6).

Currently, an FDA-approved human recombinant PZI product (ProZinc, Boehringer Ingelheim Vetmedica, Inc) is commercially available for use in cats and has been reported to result in clinical responses comparable to those achieved with PZI of bovine and porcine origin (2,3). Because of the high cost of commercially manufactured PZI, alternative products have been made available to veterinarians by compounding pharmacies.

The purpose of this study by Scott-Moncrieff et al (7) was to evaluate the quality and consistency of several compounded PZI products and compare them to the commercially manufactured PZI insulin. Moreover, this study was designed to determine if compounded PZI would be as reliable as the commercially manufactured PZI product.

Objective
To evaluate and compare characteristics of a commercially manufactured protamine zinc insulin (PZI) product and PZI products obtained from various compounding pharmacies.

Design of study and 
sample collection
This was an evaluation study looking at 112 vials of PZI (16 vials of the commercially manufactured, FDA-approved PZI product and 96 vials obtained from 12 compounding pharmacies) purchased over an 8-month period.

Procedures
Validated methods were used to analyze 2 vials of each product at 4 time points. Appearance, endotoxin concentration, crystal size, insulin concentration in the supernatant, pH, total insulin and zinc concentrations, and species of insulin origin were evaluated.

Results
All 16 vials of commercially manufactured PZI met United States Pharmacopeia (USP) specifications. Of 96 vials of compounded PZI, 1 (1%) contained a concentration of endotoxin > 32 endotoxin U/mL, 23 (24%) had concentrations of insulin in the supernatant > 1.0 U/mL, and 45 (47%) had pH values below 7.1 or above 7.4; all of these values were outside of specifications.

Several vials of compounded PZI (52/96 or 54%) did not meet specifications for zinc concentration, and total insulin concentration in 36 (38%) of the vials was less than 90% of the labeled concentration.

Conclusions and clinical relevance
Only 1 of 12 compounded PZI products met all USP specifications in all vials tested. Use of compounded PZI insulin products could potentially lead to serious problems with glycemic control in veterinary patients.

My Bottom Line:

Protamine zinc insulin is a complex protein, requiring special expertise to manufacture. The long duration of PZI is attributable to the complexing of insulin with zinc and protamine in precise proportions to form a precipitate, which is released slowly from the subcutaneous tissues after injection (5,6).
It is easy to imagine why a compounding pharmacy may not be able to manufacture PZI insulin, especially insulin that is safe to use and consistent in concentration, onset of action, and duration of the insulin effect. To be honest, I find it more amazed that a compounding pharmacy could produce an insulin product that worked at all!

However, in this study by Scott-Moncrieff (7), a number problems were identified in compounded PZI preparations, included the following:

• Lack of an expiration date or lot number on the vial
• Lack of identification of the species of origin (bovine, porcine, or human)
• High endotoxin concentration
• pH below or above the recommended range
• Low total insulin concentration
• Zinc concentrations below or above acceptable limits
• Variability in insulin concentration among vials from a single compounding pharmacy
• Variability in insulin concentration among different compounding pharmacies that had the same labeled concentration
• Unacceptably high concentrations of insulin in the supernatant.

This study was not designed to identify the clinical consequences of these problems with the use of compounded PZI insulin in cats. However, such deficiencies would likely contribute to poor glycemic control in cats treated with compounded PZI. Other problems that may be seen would include changes in the onset and duration of insulin action, hypoglycemia due to inadvertent insulin overdosage, or fever due to endotoxin.

Based on the results of this study (7), it is clear that compounded PZI insulin cannot be recommended. Regulating diabetic animals is difficult enough without having to deal with variations in insulin quality and potency every time we buy a new bottle.  I believe that it’s best to use a FDA-approved insulin preparation that has external quality control standards applied to it.

 Remember, a bad insulin is almost worse than no insulin at all.

References:

1. Nelson RW, Lynn RC, Wagner-Mann CC, et al. Efficacy of protamine zinc insulin for treatment of diabetes mellitus in cats. Journal of the American Veterinary Medical Association 2001;218:38–42.
2. Nelson RW, Henley K, Cole C, et al. Field safety and efficacy of protamine zinc recombinant human insulin for treatment of diabetes mellitus in cats. Journal of Veterinary Internal Medicine 2009;23:787–793. 
3. Norsworthy GD, Lynn R, Cole C. Preliminary study of protamine zinc recombinant insulin for treatment of diabetes mellitus in cats. Veterinary Therapeutics 2009;10:24–28. 
4. Maggiore AD, Nelson RW, Dennis J, et al. Efficacy of protamine zinc recombinant human insulin for controlling hyperglycemia in dogs with diabetes mellitus. Journal of Veterinary Internal Medicine 2012;26:109-115.
5. Scott DA, Fisher AM. Studies on insulin with protamine. Journal of Pharmacology and Experimental Therapeutics 1936;58:78–92. 
6. Brange J. Galenics of insulin, the physico-chemical and pharmaceutical aspects of insulin and insulin preparations. New York: Springer-Verlag Inc, 1987.
7. Scott-Moncrieff JC, Moore GE, Coe J, et al. Characteristics of commercially manufactured and compounded protamine zinc insulin. Journal of the American Veterinary Medical Association 2012;240:600-605.