Authored by Dr. Kim Baughman, Director of Development, Microbac Laboratories, Inc.

In response to the issue of melamine contamination in pet food, infant formula, and dairy products in 2007 and 2008, the FDA has published a Guidance-for-Industry document titled, Pharmaceutical Components at a Risk for Melamine Contamination. The purpose of the document, dated August 2009, was to alert pharmaceutical manufacturers of the risk of contamination of specific raw materials used in the formulation of pharmaceutical finished products in the U.S. As was the case with the actual contamination episodes, the risk is not necessarily associated with inadvertent contamination, but with deliberate adulteration to manipulate the concentration of nitrogen in the product.

For raw materials with a nitrogen specification, the normal testing protocol is the Total Kjeldahl Nitrogen (TKN) method. This method converts all nitrogen in the sample to ammonia and provides for its distillation and trapping, followed by titrimetric determination of the liberated ammonia. The United States Pharmacopeia (USP) designates this method as <461> or USP 461. Because the method is not specific for any particular compound, any nitrogen-containing compound will respond and will be reflected in the final result. Melamine contains a high level of nitrogen (about 66%), thus the FDA is concerned it could be added to pharmaceuticals products to manipulate the testing data as it was in the cases of pet food and infant formula.

The FDA has published two methods for the determination of melamine in dry protein-containing materials. One method uses gas chromatography with mass spectroscopy (GC/MS or GC/mass spec), and the second uses high-performance liquid chromatography with tandem mass spectrometers (LC/MS/MS or LC/mass spec/mass spec). Each of these methods can be used, in modified form, to detect and determine melamine in pharmaceutical components. Both methods also determine cyanuric acid, which is the major metabolite of melamine.

Melamine is primarily toxic to the kidneys. It causes the formation of cyanuric acid crystals in the kidneys or in the renal tubes which can lead to blockage.

As a guidance document, the publication is a non-binding recommendation for industry. At-risk components were designated based on the use of the TKN method discussed above as a quality control standard for the product. Over 25 components are on the initial list.

Microbac Laboratories Inc. is a full service FDA-inspected cGMP laboratory. We perform the full range of testing discussed above, including the determination of melamine by GC/MS or LC/MS/MS. We also perform USP chemical and microbiological assay testing on pharmaceutical raw materials and finished products.

The FDA document can be viewed at the following link:

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM175984.pdf

For more information, please contact: microbac_info@microbac.com.