Issue link: https://www.e-digitaleditions.com/i/1067339
sumers have become accustomed to this label terminology, it should help alleviate possible confusion to use this term as the proposed statement for drug products. CFSAN's current position, as described in the Codex Alimentarius standard 118-1979 [3], is that the concentration of gluten in food must not exceed 20 mg/kg (20 ppm) for products to be labeled glu- ten-free. The related regulation, 21 CFR 101.91, which the FDA's small entity compliance guide notes as being binding and having the full force and effect of the law, also defines "gluten-free." IPEC-Americas members are con- cerned that, if acceptable gluten lim- its are not established or if gluten limits are "open ended" or require labeling such as "free from," this could lead to unnecessary reformula- tions of drug products that currently meet the same requirements as glu- ten-free food products. This would not provide any significant benefit to patients but would cause significant increases in drug costs. IPEC-Americas recommended that the FDA replace the current sug- gested statement to require labeling a drug only when the presence of glu- ten is above a defined "gluten-free" (<20 ppm) threshold. Since the final concentration of gluten depends on the ingredients, their level of use in the formulation, and any processing that may impact the final level, label- ing statements should be established on a case-by-case basis. The FDA is not aware of vali- dated analytical test methods to detect quantities of gluten in fin- ished drug products. IPEC-Americas members recommended that the commercially available enzyme- l i n k e d i m m u n o s o r b e n t a s s a y (R5-ELISA), which is the current validated gold standard for gluten testing in foods, should be explored for use in pharmaceutical products. The FDA Threshold Working Group reviewed available data from various gluten challenge studies to establish a threshold for gluten [4]. The FDA CFSAN set a 20-ppm threshold based on the lowest con- very little gluten, if any, expected to be present in the ingredient or the drug product. Very few, if any, oral drug products contain ingredi- ents derived from barley or rye." Based on this information, IPEC- Americas recommended that any l a b e l i n g s t a t e m e n t s h o u l d b e addressed between the FDA and the drug product manufacturer during development and approval of the package insert and package label. This approach would only be required if ingredients may be present that con- tain gluten above a scientifically established level that would impact people with celiac disease. The CDER "Medications and Gluten" webpage also contains information concerning expected gluten levels in drug products [2]: "The vast majority of oral drug products either contain no gluten or vir tually no glute n. In the ver y rare cases where glute n may be present, we estimate based on drug formulation information that wheat starch and other ingredients derived from wheat would contribute no more than 0.5 mg gluten to a unit dose of an oral drug product. This amount is less than may be found in a single 30-gram serving of food labeled glute n-free according to FDA's regulations." Consumers should be familiar with the phrase "gluten-free" based on its permitted use on food prod- ucts, including dietary supplements, which are regulated by the FDA's Center for Food Safety and Applied Nutrition (CFSAN). The FDA issued its Final Rule for Food Labeling: "Gluten-Free Labeling of Foods" on August 5, 2013, defining the term "gluten-free" for the food industry (21 CFR 101.91(a)). Because con- centration of gluten that can be con- sistently detected in foods using valid scientific analytical methods. As patients are likely to consume a sig- nificantly smaller amount of medica- tion than food, the risk of exposure to gluten from the daily intake of medication is even lower. Gluten content in drug products must be individually assessed In a recent article, Shah et al. (2017) [5] proposed that: "…all existing drug products may also be made gluten-free by replacing certain excipients, if any, that may contain gluten with alter- native gluten-free excipients." The article does not specifically state what is intended by "gluten-free excipients" and if this would preclude the use of all excipients derived from wheat, even when the gluten content is less than 20 ppm. This could impact a number of drug formulations. Refor- mulating existing approved drug products is extremely expensive, not to mention the associated changes in labeling, GMP risk assessments, pro- cessing, sanitation, prior approval sup- plements (PASs), requalification, and documentation. Avoiding the use of excipients derived from wheat that contain less than 20 ppm of gluten is not necessary to minimize risks for celiac patients. Such unnecessary and non-value-added reformulation would also potentially increase the burden on the FDA since reformulation to remove an excipient and replace it with an entirely different excipient would typically require a PAS filing. Several statements and conclu- sions made in the Shah et al. article are misleading or factually incorrect. Readers may incorrectly assume that gluten in pharmaceuticals is a signifi- cant risk to patient safety and that many medications contain gluten, neither of which are the case. Tablets & Capsules January 2019 43