Gluten in Drug Products 
and Associated Labeling 
Recommendations 
Guidance for Industry 
 
 
 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance. Submit electronic comments to https://www.regulations.gov. Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact (CDER) Marci Kiester 301-796-0600, or 
(CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010.  
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
December 2017 
Labeling 
 
   
Gluten in Drug Products 
and Associated Labeling 
Recommendations 
Guidance for Industry 
 
 
Additional copies are available from: 
Office of Communications, Division of Drug Information  
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov  
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
and/or 
Office of Communication, Outreach and Development  
Center for Biologics Evaluation and Research 
 Food and Drug Administration 
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Phone: 800-835-4709 or 240-402-8010 
Email: ocod@fda.hhs.gov 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
 
December 2017 
Labeling 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  DISCUSSION .................................................................................................................... 2 
A.  Possible Sources and Amounts of Gluten in Oral Drug Products ............................................. 2 
1. Wheat Gluten as an Ingredient ........................................................................................................ 2 
2. Wheat Gluten as an Impurity in Ingredients Derived From Wheat ................................................. 3 
3. Wheat Gluten as an Adventitious Contaminant ............................................................................... 6 
B.  Labeling .......................................................................................................................................... 6 
1. Ingredient Labeling: Current Regulations and Practice ................................................................. 7 
2. Established Names ........................................................................................................................... 8 
3. Section 502(f) of the FD&C Act ....................................................................................................... 9 
III.   RECOMMENDATIONS .................................................................................................. 9 
A.  Voluntary Statements Regarding Gluten .................................................................................... 9 
1. Statements on Labels or in Required Labeling ................................................................................ 9 
2. Supporting Information .................................................................................................................. 10 
B.  Submission and Adoption............................................................................................................ 11 
1. Oral Drug Products With New or Pending Applications .............................................................. 11 
2. Oral Drug Products With Approved Applications ......................................................................... 11 
3. Oral Drug Products With Approved Applications That Already Include a Statement About  
Gluten Other Than the Recommended Labeling Statement................................................................ 12 
4. Nonapplication Oral Drug Products ............................................................................................. 12 
C.  Placement of a Voluntary Gluten Labeling Statement ............................................................. 13 
1. Prescription Oral Drug Products .................................................................................................. 13 
2. Nonprescription Oral Drug Products ............................................................................................ 13 
IV.  REFERENCES ................................................................................................................ 13 
  Contains Nonbinding Recommendations  
Draft  Not for Implementation 
1  Gluten in Drug Products and Associated Labeling 
2  Recommendations 
3  Guidance for Industry1 
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not 
8  binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible 
10  for this guidance as listed on the title page.  
11   
12   
13   
14   
15  I.  INTRODUCTION  
16   
17  This guidance is intended to convey to drug manufacturers FDAs recommendations on how 
18  certain drug products should be labeled regarding gluten, a matter of interest to individuals with 
19  celiac disease. Some individuals with celiac disease have faced difficulty when trying to 
20  determine whether specific drug products contain gluten. Confronted by uncertainty, some 
21  patients may forego important medication rather than risk an adverse reaction to gluten. Thus, 
22  even if gluten is not present at levels that would harm a typical individual with celiac disease, 
23  that individual may be harmed through uncertainty and lack of information.  
24   
25  Celiac disease (also known as celiac sprue) is an immune-based reaction to dietary gluten that 
26  primarily affects the small intestine in susceptible individuals; unmanaged celiac disease can lead 
27  to serious health complications. Approximately 1 percent of the U.S. population has celiac 
28  disease (Binder 2015). It is characterized by ongoing inflammation of part of the lining of the 
29  small intestine that generally heals if foods containing gluten are excluded from the diet and 
30  returns if they are reintroduced. At this time, the treatment for celiac disease is adherence to a 
31  gluten-free diet.  
32   
33  FDAs food labeling regulations define gluten as proteins that naturally occur in [wheat, barley, 
34  and rye or their crossbred hybrids] and that may cause adverse health effects in persons with 
35  celiac disease (e.g., prolamins and glutelins) (21 CFR 101.91(a)). Consistent with this 
36  definition, the term gluten in this document refers to certain proteins found in wheat, barley, and 
37  rye or their crossbred hybrids that lead to symptoms associated with celiac disease. 
38    
39  This guidance pertains to human drug products that pass through the small intestine: 
40   
41 
                                                 
1 This guidance has been prepared by the Center for Drug Evaluation and Research in cooperation with the Center 
for Biologics Evaluation and Research at the Food and Drug Administration.  
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42    Orally ingested drug products.2  
43   
44    Topical drug products applied to or near the lips (e.g., lip sunscreens).3  
45   
46    Drug products applied inside the mouth (e.g., cold sore treatments, drugs delivered to or 
47  via the oral cavity). 
48   
49  In this guidance, oral drug product refers to this group of products. Gluten is not believed to 
50  harm individuals with celiac disease through routes of exposure other than oral or enteral 
51  ingestion.  
52   
53  This guidance was developed with celiac disease in mind. However, the recommendations in this 
54  guidance may be of interest to patients with other conditions that are treated with a gluten-free 
55  diet. 
56   
57  This guidance does not apply to food (including dietary supplements) or products regulated 
58  solely as cosmetics.4 In addition, this guidance does not discuss labeling recommendations 
59  regarding wheat hypersensitivity. 
60   
61  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
62  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
63  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
64  the word should in Agency guidances means that something is suggested or recommended, but 
65  not required.  
66   
67  II.  DISCUSSION  
68   
69  A.  Possible Sources and Amounts of Gluten in Oral Drug Products 
70   
71  Wheat is not used to a significant extent in the production of drug ingredients, and barley and rye 
72  are used either rarely or not at all.  
73   
74  1.  Wheat Gluten as an Ingredient 
75   
76  Wheat gluten itself is never or very rarely added as an inactive ingredient to oral drug products 
77  during manufacture.5 As discussed in section II.B of this guidance, any oral drug product that 
                                                 
2 The term drug products includes drugs subject to licensing as biological products.  
3 This includes topical drug products that are also cosmetics, such as lipsticks that are also sunscreens.  
4 For regulations pertaining to gluten-free labeling of foods, see 21 CFR 101.91. 
5 In this guidance, when we say added as an ingredient, we are referring to the intentional and purposeful addition 
of that ingredient. We are not referring to the introduction of wheat gluten, for example, as an unintended 
contaminant or impurity associated with an ingredient. Based on information available to us during our analyses for 
this guidance, we are aware of no oral drug products currently marketed in the United States that contain wheat 
gluten intentionally added as an inactive ingredient. 
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Draft  Not for Implementation 
78  contains wheat gluten as an intentionally added ingredient should be labeled to indicate its 
79  presence.  
80   
81  Although the use of wheat gluten as an inactive ingredient in drug products does not generally 
82  mean that the product will fail to satisfy applicable requirements for safety, we may question the 
83  addition of wheat gluten to certain oral drug products on a case-by-case basis. We would be 
84  more likely to question the use of wheat gluten as an ingredient in an oral drug product for which 
85  few or no alternative treatments are available. We would also be more likely to question its use 
86  as an ingredient in an oral drug product intended for long-term administration or intended to treat 
87  comorbidities of celiac disease.  
88   
89  The level at which wheat gluten would be present in an oral drug productif added as an 
90  ingredientis directly controlled by the drug manufacturer. In the absence of more detailed 
91  information regarding wheat gluten amounts, individuals with celiac disease may choose to 
92  avoid oral drug products that are labeled as containing wheat gluten as an ingredient.  
93   
94  2.  Wheat Gluten as an Impurity in Ingredients Derived From Wheat 
95   
96  Apart from its possible addition to oral drug products as an inactive ingredientsomething that 
97  rarely, if ever, occurswheat gluten may be present at low levels as an impurity in ingredients 
98  that are derived from wheat, such as wheat starch.  
99   
100  In this section, we identify drug ingredients and categories of ingredients derived or potentially 
101  derived from wheat, and we estimate how much gluten they may contribute to a unit dose of an 
102  oral drug product. In general, the quantities we estimate to be present are low and do not exceed 
103  the amounts of gluten that could be found in food products labeled gluten-free under FDAs 
104  regulations (21 CFR 101.91). We present this analysis because (1) it has informed our thinking 
105  about regulatory options associated with gluten in oral drug products, (2) we would like drug 
106  manufacturers to consider the information in this section and review the ingredients they use in 
107  their drug products, and (3) if the information or assumptions underlying our analysis are proven 
108  incorrect, we would reconsider available regulatory options.  
109   
110  Drug manufacturers are in the best position to review their specific formulations for oral drug 
111  products and to question their ingredient suppliers about ingredients potentially derived from 
112  wheat, purification methods, and analytical testing results. We urge manufacturers to consider 
113  gluten content when formulating products using ingredients potentially derived from wheat or 
114  wheat starch.  
115   
116  a.  Wheat flour  
117   
118  We are aware that some manufacturers have reported the direct addition of wheat flour to oral 
119  drug products in the pastbut only very rarely. We are not aware of an oral drug product 
120  currently being marketed in the United States that contains wheat flour as an ingredient. As 
121  discussed in section II.B of this guidance, any oral drug product that contains wheat flour as an 
122  intentionally added ingredient should be labeled to indicate its presence.  
123   
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124  The total protein content of wheat flour is generally 13 percent, with gluten representing part of 
125  the total protein.6 The amount of gluten present in an oral drug product to which wheat flour has 
126  been added as an ingredient would depend on how much wheat flour is used. Because use of 
127  wheat flour in any drug product is so rare, we do not have good information regarding upper, 
128  lower, and typical levels that would be present in a drug product. We believe individuals with 
129  celiac disease might choose to avoid oral drug products that are labeled as containing wheat flour 
130  in the absence of more detailed information about the drug products gluten content.  
131    
132  b.  Wheat starch 
133   
134  As with wheat gluten and wheat flour, we believe wheat starch is added to oral drug products as 
135  an ingredient only very rarely. Other sources of starch (e.g., corn, potato) are more commonly 
136  used in pharmaceutical products. As discussed in section II.B of this guidance, any oral drug 
137  product that contains wheat starch as an intentionally added ingredient should be labeled to 
138  indicate its presence.  
139   
140  A monograph for wheat starch in the National Formulary (NF) includes a 0.3 percent limit on 
141  total protein but does not include a limit on gluten content.7 The gluten content will be some 
142  proportion of the total protein content. Based on published information, we understand the gluten 
143  content of wheat starch suitable for use in drug products is variable but is typically in the range 
144  of 100 to 500 mg/kg (see, e.g., Kasarda, Dupont, et al. 2008). Based on our review of drug 
145  formulation information, we expect wheat starchin the rare cases in which it is used in oral 
146  drug productsto contribute less than 0.1 mg gluten to a unit dose of an oral drug product.  
147   
148  c.  Ingredients derived from starch 
149   
150  Starch is used as a starting material for manufacturing various ingredients added to oral drug 
151  products. The starch used for this purpose is often corn or potato starch, not wheat starch. 
152  Nevertheless, we recognize that very small amounts of wheat gluten may be present in starch-
153  derived ingredients if wheat starch is used as the starting material.  
154   
155  Ingredients in this categorypotentially derived from wheat starchinclude modified starch, 
156  pregelatinized starch, and sodium starch glycolate. This category also includes starch 
157  hydrolysates (e.g., maltodextrin, dextrates, dextrose, maltose, and sugar alcohols such as sorbitol, 
158  xylitol, maltitol, and mannitol) and hydrogenated starch hydrolysates (mixtures of sugar 
159  alcohols).  
160   
161  As with wheat starch, compendial monographs for these ingredients do not include specific 
162  limits on gluten content. We have found published reports regarding the gluten content for only a 
163  limited number of ingredients derived from wheat starch. In the absence of such specific 
164  information, we have made the conservative assumption that wheat-derived modified starches 
                                                 
6 According to the International Starch Institute, the typical value of total protein in wheat flour on a dry matter basis 
is 13 percent. See the Institutes Technical Memorandum on Wheat Starch, available at 
http://www.starch.dk/isi/starch/tm33wheat.asp, accessed August 2017. 
7 NF 35 Monograph: Wheat Starch, current at the time of this publication. 
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165  (e.g., modified starch, pregelatinized starch, sodium starch glycolate), although more highly 
166  processed than wheat starch, might contain gluten at the same concentrations at which gluten 
167  might be found in wheat starch: 100500 mg/kg. Based on published literature, we believe that 
168  starch hydrolysates and hydrogenated starch hydrolysates derived from wheat may contain up to 
169  40 mg/kg gluten (European Food Safety Authority 2007). Based on drug formulation 
170  information, we estimate that these ingredients may contribute less than 0.5 mg gluten to a unit 
171  dose of an oral drug product.  
172   
173  d.  Ingredients produced through fermentation  
174   
175  Some ingredients, including citric acid and ethanol, may be produced by fermentation, in which 
176  microorganisms feed on carbohydrates from plant sources that potentially include wheat. See, for 
177  example, 21 CFR 184.1033, which describes the production of food-grade citric acid by various 
178  methods, including fermentation. If the fermentation medium includes wheat or wheat-derived 
179  ingredients, an ingredient produced by fermentation maydepending on how it is purified
180  contain small amounts of gluten. Compendial monographs for these ingredients do not include 
181  gluten limits. 
182   
183  In some cases, an ingredient such as ethanol8 may be purified through distillation. It is unlikely 
184  that gluten (or any protein) would be present in ethanol purified by distillation using good 
185  manufacturing practices, considering the high volatility of ethanol compared with the much 
186  lower volatility of a large molecule such as gluten. 
187   
188  In other cases, the ingredient is highly purified through other means. Anhydrous citric acid, USP, 
189  for example, is not less than 99.5 percent pure. We expect the presence of any residual gluten in 
190  such ingredients to be very low. Based on drug formulation information we have reviewed, we 
191  expect ingredients produced through fermentation to contribute no more than 0.5 mg gluten to a 
192  unit dose of an oral drug product.  
193   
194  As with all of our estimates presented above, there is some uncertainty surrounding the amount 
195  of gluten that may be present in drug ingredients produced through fermentation. A more certain 
196  estimate would require production information or analytical test results covering multiple 
197  batches of the full range of ingredients made by producers around the world. In the absence of 
198  such information, we have relied on total protein limits in compendial monographs and published 
199  reports covering certain ingredients.  
200   
201  e.  Wheat germ oil   
202   
203  We are aware that wheat germ oil9 may be used as an ingredient in certain products applied 
204  topically to the lips or skin, such as lip balms or sunscreen products. If the wheat germ oil is 
205  highly refined, it is unlikely to contain detectable amounts of gluten. Even if the oil is not highly 
                                                 
8 Alcohol, USP. (USP=United States Pharmacopeia.) 
9 Sometimes identified as Triticum vulgare (wheat) germ oil. 
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206  refined, we believe the presence of any gluten in a product applied topically to the lips would be 
207  very low, and any oral ingestion of gluten associated with the product would be insignificant.  
208   
209  3.  Wheat Gluten as an Adventitious Contaminant 
210   
211  In theory, wheat gluten that is not associated with a wheat-derived ingredient could be 
212  introduced into an oral drug product as an adventitious contaminant (e.g., as a result of contact 
213  with gluten during manufacture, processing, transportation, or storage). Although we do not have 
214  systematic data in this area, we expect that any gluten present adventitiously in oral drug 
215  products would be present only in very small amounts. In all likelihood, the amount of gluten 
216  would be below the limits of detection associated with current analytical test methods. It is also 
217  likely that the amount of gluten would be well below the levels we have estimated an inactive 
218  ingredient, such as wheat starch, could potentially contribute to an oral drug product. Current 
219  good manufacturing practice (CGMP) regulations for drug products reflect a basic obligation to 
220  prevent contamination of a drug being processed,10 and a violation of the CGMP regulations can 
221  result in an enforcement action. FDA would consider taking action if an oral drug product were 
222  found to contain significant amounts of gluten as a contaminant. 
223   
224  B.  Labeling  
225   
226  If a drug included an ingredient derived from wheat, barley, or rye, the ingredient would most 
227  likely be wheat-derived. The amount of gluten potentially contributed by a wheat-derived 
228  ingredient to a unit dose of an oral drug product (unless that ingredient is wheat gluten itself or 
229  wheat flour) is expected to be less than 0.5 mg, as a high estimate.11 As discussed in section II.A 
230  of this guidance, most oral drug products are not expected to contain ingredients derived from 
231  wheat, barley, or rye. The likelihood of them including more than one such ingredient is even 
232  less. Thus, it is expected that the amount of gluten potentially present in a unit dose of an oral 
233  drug product is less than the amount of gluten that could potentially be found in a single serving 
234  of a cookie (30 grams) labeled gluten-free in accordance with FDAs regulations at 21 CFR 
235  101.91 (if all of the criteria of that regulation are satisfied).12 Moreover, the amount of gluten 
236  estimated to be potentially present in a unit dose of an oral drug product (less than 0.5 mg) is 
237  significantly less than the range at which gluten is estimated to be present in a gluten-free diet (5 
238  to 50 mg) (La Vieille, Dubois, et al. 2014; Catassi, Fabiani, et al. 2007).13 This leads FDA to 
239  conclude that individuals who respond well to a gluten-free diet are at low risk of experiencing 
240  problems as a result of the possible presence of gluten in a drug product. However, we expect 
                                                 
10 See generally Current Good Manufacturing Practice for Finished Pharmaceuticals, 21 CFR part 211. 
11 Our estimate is based on assumptions regarding gluten content and ingredient usage that favor a high estimate 
(i.e., we considered high levels of use for each inactive ingredient potentially derived from wheat, and we 
considered the high end of the range at which gluten is reasonably expected to be present in each ingredient). 
12 A 30-gram serving of food, corresponding to a single cookie, for example, could contain up to 0.6 mg gluten 
while bearing a gluten-free statement if the criteria for the definition of gluten-free are satisfied. 30 grams x 20 
ppm=0.6 mg. See reference amounts customarily consumed per eating occasion in FDAs food labeling regulations, 
21 CFR 101.12, Table 2. 
13 We recognize that gluten-free diets may be highly variable, and individuals diagnosed with refractory celiac 
disease may have more restrictive diets. 
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241  that they might choose to avoid using oral drug products labeled as containing wheat gluten or 
242  wheat flour as an ingredient in the absence of more information about the products actual gluten 
243  content.  
244   
245  We have also considered the potential impact on those individuals with celiac disease who take 
246  multiple oral medications each day. Considering that inactive ingredients are typically derived 
247  from sources other than wheat, and that 0.5 mg of gluten per unit dose is a high estimate for 
248  gluten in an oral drug product, we expect that an individual taking multiple drug products per 
249  day would ingest much less gluten, if any, from drugs than an individual with celiac disease 
250  adhering to a gluten-free diet may ingest from food.  
251   
252  Some celiac patients are more sensitive to gluten than others and do not respond well to a gluten-
253  free diet.14 Patients who are more sensitive to gluten will likely seek to eliminate all sources of 
254  ingested gluten, or at least minimize exposure as much as possible. In all probability, these 
255  patients are under specialized care and would avoid those rare oral drug products containing 
256  added wheat starch in addition to those containing added wheat gluten or wheat flour. 
257  Additionally, they or their caregivers would likely reach out to physicians, pharmacists, other 
258  health care providers, or drug manufacturers for information about possible inclusion of wheat-
259  derived ingredients in their oral drug products. We encourage drug manufacturers to have 
260  accurate information on the sources of their ingredients available so they can respond to 
261  questions from the public and health care providers. 
262   
263  1.  Ingredient Labeling: Current Regulations and Practice 
264   
265  As described below, drug ingredients are generally identified in labeling, but substances that are 
266  present merely as impurities generally are not.  
267   
268  a.  Nonprescription (over-the-counter) oral drug products15 
269   
270  Nonprescription drug labels must list the established name of each inactive ingredient under 
271  the Inactive ingredients heading of the Drug Facts label, which appears on the outside 
272  container or wrapper of the retail package, or the immediate container label if there is no outside 
273  container or wrapper.16 This information is visible to consumers at the time of purchase.17 
274   
275 
                                                 
14 See current guidelines for the diagnosis and management of celiac disease, such as those published by the 
American College of Gastroenterology (Rubio-Tapia, Hill, et al. 2013). 
15 The Introduction defines oral drug products for the purposes of this guidance. 
16 See 21 CFR 201.66(c), 201.66(d)(8). 
17 See 21 U.S.C. 321(k), 352(c). 
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276  b.  Prescription oral drug products 
277   
278  Although not currently mandated by FDAs regulations, manufacturers of prescription oral drug 
279  products generally provide a list of inactive ingredients in the DESCRIPTION section of the 
280  prescribing information.18 
281   
282  Drugs that are licensed biological products (i.e., they are regulated under a biologics license 
283  application (BLA)) are subject to additional labeling requirements described in 21 CFR part 610, 
284  subpart G. In particular, 21 CFR 610.61 requires identification of certain types of inactive 
285  ingredients, including preservatives, known sensitizing substances, and inactive ingredients 
286  when a safety factor.  
287   
288  We interpret the requirement that inactive ingredients be identified in the labeling of biological 
289  products when a safety factor as meaning that wheat gluten and wheat flour must be identified 
290  by those names if they are present in orally administered biological products.  
291   
292  2.  Established Names 
293   
294  According to section 502(e)(3) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), the 
295  term established name means (a) the official name designated pursuant to section 508;19 (b) if 
296  there is no such name, the title of a monograph for the ingredient in an official compendium;20 or 
297  (c) the common or usual name if neither (a) nor (b) applies.  
298   
299  Consistent with this provision, the established name used in labeling for any wheat-derived 
300  ingredient that is the subject of a monograph in an official compendium must be the monograph 
301  title, where there is no official name designated pursuant to section 508. For example, wheat 
302  starch (not starch) is the established name by which wheat starch must be identified in drug 
303  labeling. However, the more highly processed ingredients discussed in section II.A of this 
304  guidance (ingredients derived from starch and ingredients produced by fermentation) do not 
305  include a botanical source such as wheat in the established name of the ingredient because the 
306  titles of their compendial monographs do not include this designation.  
307   
308  If an ingredient is not recognized in an official compendium and does not have an applicable 
309  official name designated pursuant to section 508 of the FD&C Act, then it must be identified in 
                                                 
18 See 21 CFR 201.57 and 201.80. Licensed biological products that meet the statutory definition of drugs under 
section 201(g) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) are subject to the labeling requirements of 
part 201 (except as otherwise indicated, e.g., section 201.1(m)) and drug labeling provisions of the FD&C Act, and 
thus also bear labeling in Physician Labeling Rule (PLR) format or non-PLR format. 
19 We do not routinely designate official names for excipients; see 21 CFR 299.4(e). 
20 An official compendium is one cited in the FD&C Act. This includes the USP, NF, and the Homeopathic 
Pharmacopoeia of the United States. See section 201(g) of the FD&C Act.  
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310  labeling by its common or usual name.21 Wheat gluten and wheat flour fall into this category, 
311  and we consider wheat gluten and wheat flour to be their appropriate common or usual names.22 
312   
313  3.  Section 502(f) of the FD&C Act  
314   
315  Section 502(f) of the FD&C Act states that a drug shall be deemed to be misbranded . . . unless 
316  its labeling bears . . . such adequate warnings against use in those pathological conditions . . . 
317  where its use may be dangerous to health . . . in such manner and form, as are necessary for the 
318  protection of users.  
319   
320  We are not aware of any currently marketed oral drug product that contains wheat gluten as an 
321  intentionally added inactive ingredient. If such a product exists, we would expect wheat gluten to 
322  be included in its labeled list of inactive ingredients. If the labeling fails to disclose wheat gluten 
323  as an inactive ingredient, we would consider whether the product is misbranded under section 
324  502(f) or other authorities (e.g., 21 CFR 201.66(c)(8)) in the case of a nonprescription oral drug 
325  product). 
326   
327  III.   RECOMMENDATIONS 
328   
329  We encourage drug manufacturers to have accurate information about their products gluten 
330  content available so they can respond to questions from consumers and health care professionals. 
331  Manufacturers should pay attention to possible sources of gluten in their products, consider 
332  specifications when appropriate, and consider the impact of changes in ingredient sources or 
333  formulations on gluten content.  
334   
335  A.  Voluntary Statements Regarding Gluten 
336   
337  1.  Statements on Labels or in Required Labeling 
338   
339  We recommend that drug manufacturers that wish to make statements about gluten anywhere on 
340  oral drug product labels or in required labeling use the following statement, when it is truthful 
341  and substantiated:  
342   
343  Contains no ingredient made from a gluten-containing grain (wheat, barley, 
344  or rye).23  
345   
346  We would interpret such a statement to mean that the manufacturer knows that no ingredient in 
347  the product was derived directly or indirectly from wheat, barley, or rye or their crossbred 
348  hybrids. This would preclude, for example, the use of ingredients derived from wheat starch or 
349  from starch of unknown botanical origin. It would also preclude the use of ingredients produced 
                                                 
21 See section 502(e)(3) of the FD&C Act. 
22 Wheat gluten is the name given to the ingredient in FDAs GRAS (generally recognized as safe) affirmation 
regulation for wheat gluten (21 CFR 184.1322). See also 21 CFR 137.105, which specifically mentions wheat flour. 
23 For the remainder of this guidance, we use the phrase recommended labeling statement to mean this statement or 
minor variations with equivalent meaning and specificity.  
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350  through a fermentation process if the fermentation medium is not known to be free of ingredients 
351  derived from wheat, barley, or rye or their crossbred hybrids. Substantiation for such a statement 
352  is discussed in section III.A.2 of this guidance. 
353   
354  We encourage use of this recommended labeling statement to provide health care professionals 
355  and consumers with consistent, clear, accurate, and readily understood information about the 
356  gluten content of the pharmaceutical products they use. Furthermore, this phrase allows easy 
357  searching for terms such as gluten and wheat. This recommended labeling statement does not 
358  describe a drug as gluten-free because we have not established criteria for gluten-free statements 
359  on oral drug products, and it may be difficult to substantiate that a drug product is free of gluten. 
360  We are not aware of analytical test methods currently validated to detect or quantify gluten in 
361  finished drug products or in drug ingredients at the low levels at which it would generally be 
362  expected to be present, if at all. Furthermore, we have not determined whether a gluten-free 
363  statement on an oral drug product should refer to an absence of intact gluten or whether such a 
364  statement should also require an absence of gluten peptides.  
365   
366  2.  Supporting Information 
367   
368  Firms are responsible for the truthfulness of their gluten-related labeling statements and for 
369  ensuring that the information related to their oral drug products supports the use of such 
370  statements.24 Firms should also have supporting information available, including information 
371  from ingredient suppliers about their processes and raw materials. Indeed, CGMP regulations 
372  include recordkeeping requirements encompassing information that may be relevant.25  
373   
374  For firms wishing to use the recommended labeling statement, substantiation for such a 
375  statement should include a written commitment from ingredient suppliers that, for each 
376  ingredient potentially derived from wheat, barley, rye, or their crossbred hybrids or produced 
377  through fermentation, these grains are not used in the production of the ingredient. 
378   
379  For statements other than the recommended labeling statement, the supporting information could 
380  vary by product. For example, firms may be able to test individual wheat-derived ingredients for 
381  the absence of nitrogen (indicating an absence of all protein, including gluten), or they may be 
382  able to provide information demonstrating that the processing of such ingredients removes the 
383  gluten. If such ingredient testing is conducted, the manufacturing records26 must include the 
384  results of any tests and the conclusions derived from them.27 These records must be readily 
385  available to FDA for authorized inspection.28  
386   
                                                 
24 See section 502(a) of the FD&C Act (21 U.S.C. 352(a)). 
25 See, e.g., 21 CFR 210.3(b)(3), 211.180(c), 211.184(c), 211.186(b)(9), 211.194(a).  
26 In this guidance, we use manufacturing records as an umbrella term to refer to the records discussed in 21 CFR 
211.184211.194. 
27 See 21 CFR 211.184(b). 
28 See 21 CFR 211.180(c). 
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387  B.  Submission and Adoption  
388   
389  1.  Oral Drug Products With New or Pending Applications 
390   
391  An applicant submitting a new drug application (NDA), abbreviated new drug application 
392  (ANDA), or BLA that wishes to use the recommended labeling statement must ensure that its use 
393  is consistent with the information in the application related to the oral drug product ingredients.29 
394  We are not asking that applicants submit additional specific information to their applications, 
395  such as the supplier agreements referred to above, but applicants should ensure that such 
396  information is available. An applicant that wishes to use an alternative statement should propose 
397  in the application how it intends to support the alternative statement.  
398   
399  2.  Oral Drug Products With Approved Applications 
400   
401  An NDA, ANDA, or BLA holder with an approved application who seeks to change a product 
402  formulation to make a gluten statement should refer to relevant regulations and guidance 
403  regarding submission requirements associated with the formulation changes.30  
404   
405  An NDA, ANDA, or BLA holder seeking to include the recommended labeling statement who 
406  can properly substantiate it without changes to the approved product formulation may revise 
407  labeling at any time to do so. The addition of the recommended labeling statement may then be 
408  reported in the next annual report, pursuant to 21 CFR 314.70(a)(3) and 601.12(a)(3).31 
409   
410  An NDA, ANDA, or BLA holder wishing to use an alternative statement must submit the 
411  proposed statement and information that supports its use in a prior approval supplement (PAS). 
412  The addition of an alternative statement that communicates something different from or in 
413  addition to the absence of ingredients made from gluten-containing grains (wheat, barley, or rye) 
414  requires the submission and review of data not already included in the application.32 
415   
416  Regarding labeling requirements specific to generic drugs, a firm marketing a product described 
417  in an ANDA can include either the recommended labeling statement or an alternative statement 
418  addressing gluteneven if the reference listed drug (RLD) for the product described in the 
419  ANDA does not include such a statementas long as the submission provisions described above 
                                                 
29 See section 502(a) of the FD&C Act (21 U.S.C. 352(a)). 
30 See 21 CFR 314.70(b)(2)(i), 601.12(b)(2)(i) and relevant FDA guidance documents including Changes to an 
Approved NDA or ANDA and the Scale-Up and Post-Approval Changes (SUPAC) documents. We update guidances 
periodically. For the most recent version of a guidance, check the FDA Drugs guidance Web page at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
31 Under 21 CFR 314.70(b)(2)(v)(A) and 601.12(f)(1), a labeling change that does not fall into enumerated 
categories is to be submitted as a prior approval supplement (PAS). However, under 21 CFR 314.70(a)(3) and 
601.12(a)(3), an applicant is required to make a change in accordance with a regulation or guidance that provides for 
a less burdensome notification of the change than a PAS. Pursuant to these regulations, we are providing that 
notification may be made in an annual report when labels or labeling are changed to include the recommended 
labeling statement, without other changes to the product. 
32 See 21 CFR 314.70(b)(2)(v)(A), 601.12(f)(1). 
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420  are satisfied and the recommended labeling statement is properly substantiated or the alternative 
421  statement is approved. Conversely, if the RLD for a product described in an ANDA includes 
422  either the recommended labeling statement or an alternative statement addressing gluten, the 
423  product described in the ANDA is not required to include such a statement in its labeling to 
424  comply with the same labeling requirement that applies to ANDAs. Although the labeling of a 
425  product described in an ANDA and its RLD must generally be the same, an exception is made 
426  for differences attributable to the products being produced or distributed by different 
427  manufacturers. Such differences may include differences in labeling to reflect permissible 
428  differences in the formulation of the drug products (such as permissible differences in inactive 
429  ingredients) and labeling revisions made to comply with current FDA labeling guidelines or 
430  other guidance. See section 505(j)(2)(A)(v) of the FD&C Act and 21 CFR 314.94(a)(8)(iv).  
431   
432  3.  Oral Drug Products With Approved Applications That Already Include a 
433  Statement About Gluten Other Than the Recommended Labeling Statement 
434   
435  We are aware that some marketed oral drug products already include a gluten labeling statement 
436  other than the recommended labeling statement described in this guidance. Firms are encouraged 
437  to determine whether they will revise their labeling to use the recommended labeling statement 
438  or whether they have an adequate basis for the continued use of an alternative statement.  
439   
440  If a firm chooses to adopt the recommended labeling statement and this action does not require 
441  changes in the product formulation (or is not combined with another change that requires 
442  submission of a supplement), the firm may submit this labeling change in an annual report to the 
443  NDA, ANDA, or BLA (21 CFR 314.70(a)(3), 601.12(a)(3)).  
444   
445  However, if adopting a gluten labeling statement requires changes in the product formulation (or 
446  is combined with other labeling changes that require a PAS), the application holder must submit 
447  the change in a PAS.33  
448   
449  4.  Nonapplication Oral Drug Products  
450   
451  For oral drug products marketed without an application, firms may revise their labeling to adopt 
452  the recommended labeling statement if the statement is truthful and substantiated.  
453   
454  As noted above, if an oral drug products labeling already includes a gluten statement, firms are 
455  encouraged to review this guidance and determine whether they will revise their labeling to use 
456  the recommended labeling statement. If a firm wishes to continue to use a labeling statement 
457  other than the recommended labeling statement, the firm is responsible for the truthfulness of 
458  such a statement and for ensuring that the information related to the oral drug product supports 
459  its use.34  
460   
                                                 
33 See 21 CFR 314.70(b)(2)(i), 601.12(b)(2)(i). 
34 See section 502(a) of the FD&C Act (21 U.S.C. 352(a)). 
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461  C.  Placement of a Voluntary Gluten Labeling Statement 
462   
463  1.  Prescription Oral Drug Products 
464    
465  When used, a voluntary gluten statement should be included in the DESCRIPTION section of 
466  the prescribing information. Specifically, it should appear at the end of the inactive ingredients 
467  list. If the oral drug product has associated FDA-approved patient labeling, the statement should 
468  also appear in that patient labeling, either at the end of an inactive ingredients list or at the end of 
469  the patient labeling, after the name and address of the manufacturer, packer, or distributor. In 
470  addition, if a voluntary gluten statement is included on the immediate container label and, if 
471  applicable, carton labeling, it should appear on the side or back panel. The statement should not 
472  appear on the principal display panel, to avoid interference with the required or recommended 
473  information that appears on labels and labeling.35 
474   
475  2.  Nonprescription Oral Drug Products 
476   
477  Voluntary gluten statements should be visible at the time of purchase and should appear on the 
478  immediate container label and carton labeling in a location outside of the Drug Facts label. The 
479  statement must not interfere with the required information that appears on labels and labeling.36  
480   
481  IV.  REFERENCES 
482   
483  Binder, HJ, 2015, Disorders of Absorption. In: D Kasper, A Fauci, S Hauser, D Longo, JL 
484  Jameson, J Loscalzo, eds. Harrisons Principles of Internal Medicine, 19th ed., New York: 
485  McGraw-Hill Education. 
486   
487  Catassi, C, E Fabiani, et al., 2007, A Prospective, Double-Blind, Placebo-Controlled Trial To 
488  Establish a Safe Gluten Threshold for Patients With Celiac Disease, Am J Clin Nutr, 85:160
489  166. 
490   
491  European Food Safety Authority, 2007, Opinion of the Scientific Panel on Dietetic Products, 
492  Nutrition and Allergies on a Request From the Commission Related to a Notification From AAC 
493  on Wheat-Based Maltodextrins Pursuant to Article 6, Paragraph 11 of Directive 2000/13/EC, 
494  The EFSA Journal, 487:17. 
495   
496  Kasarda, DD, FM Dupont, et al., 2008, Surface-Associated Proteins of Wheat Starch Granules: 
497  Suitability of Wheat Starch for Celiac Patients, J Agric Food Chem, 56:1029210302. 
498   
                                                 
35 The prominence, placement, font, and color should be consistent with the concepts described in the draft guidance 
for industry Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication 
Errors. When final, this guidance will represent the FDAs current thinking on this topic. See also section 502(c) of 
the FD&C Act (21 U.S.C. 352(c)) and 21 CFR 201.15, on prominence of required labeling information. 
36 The general labeling requirements in 21 CFR part 201 specify which information must be included on a drug 
products labeling and how the information should be presented, among other things. See also section 502(c) of the 
FD&C Act (21 U.S.C. 352(c)) and 21 CFR 201.15, on prominence of required labeling information. 
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499  La Vieille, S, S Dubois, et al., 2014, Estimated Levels of Gluten Incidentally Present in a 
500  Canadian Gluten-Free Diet, Nutrients, 6:881896. 
501   
502  Rubio-Tapia, A, ID Hill, et al., 2013, ACG Clinical Guidelines: Diagnosis and Management of 
503  Celiac Disease, Am J Gastroenterol, 108:656676. 
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