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A Suitable Test for L-citrulline: How Validated Test Methods May Impact Public Health

In the U.S., most newborn babies are screened for rare inborn errors of metabolism (IEM)—a group of genetic disorders caused by a defect in a metabolic pathway. Left untreated, these disorders can lead to a host of medical and developmental consequences ranging from intellectual disability to severe cognitive impairment and even death.1

Some of these metabolic errors require the use of amino acids to avoid the buildup of ammonia in the body. L-citrulline is one such amino acid, and it is used for IEM as a medical food, which is regulated by the U.S. Food and Drug Administration (FDA) under the Orphan Drug Act. Medical foods are distinct within the broader category of foods and need to be administered under the supervision of a health care professional, specifically to help manage a disease or condition associated with distinctive nutritional requirements. In addition to being marketed as a medical food for IEM, L-citrulline is marketed as a dietary supplement for other purposes.

Sometimes, the quality control testing done to authenticate ingredients is insufficient to guarantee their quality. That was the case with L-citrulline in 2014.

One of the primary suppliers of the ingredient for use as a medical food voluntarily recalled several batches of the product after the FDA warned that the product being sold had no L-citrulline present. The agency had received adverse event reports associated with L-citrulline and its lack of efficacy for patients, and conducted their own testing of the batches in question.

Despite the fact that a certificate of analysis (CoA) was provided by the supplier positively identifying the product as L-citrulline with an assay value of 99.88 percent, it was found that affected batches actually contained N-acetyl-leucine, another amino acid, with a molecular weight and chemical structure similar to L-citrulline, but not used in the treatment of IEM. The CoA provided did not specify the assay method used to authenticate the ingredient, but it is likely that the assay method used was a non-specific method such as acid-base titration, which would present similar readouts for both amino acids. A discriminating method, such as one based on high-performance liquid chromatography (HPLC), potentially could have averted the mix-up between the amino acids and the resulting adverse events.

Upon learning about the L-citrulline recall, USP recognized the public health need for a scientifically validated test method that differentiated L-citrulline from N-acetyl-leucine, thus offering manufacturers a way to:

• Help ensure compliance with regulatory requirements
• Test ingredients and products in a science-based manner
• Help ensure quality ingredients and products, thus safeguarding their brands and protecting the health of users and patients.

The new USP monograph for L-citrulline is a dietary supplement monograph, and USP is exploring development of a similar L-citrulline monograph for inclusion in the Food Chemicals Codex (FCC), which applies specifically to food ingredients. The new monograph includes an HPLC method that can discriminate L-citrulline from other closely related amino acids, namely N-acetyl-leucine and arginine. USP specifications also include a requirement for not less than 98.0 percent L-citrulline content, and a limit for related compounds at not more than 2.0 percent. Along with the test method, USP has developed a reference standard for L-citrulline, which manufacturers can use to authenticate their ingredients and products.

For more information on USP’s work in developing public standards for dietary supplements, visit: www.usp.org/dietary-supplements/overview.

Reference:

1 Camp KM, Lloyd-Puryear MA, Huntington KL. Nutritional treatment for inborn errors of metabolism: indications, regulations, and availability of medical foods and dietary supplements using phenylketonuria as an example. Mol Genet Metab. 2012 Sep;107(1-2):3-9.

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