Gluten in Drug Products and Associated Labeling Recommendations; Draft Guidance for Industry

Administrative draft guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

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DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft
guidance.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., 4 th 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
10903 New Hampshire Ave., Bldg. 71, Room 3128
Silver Spring, MD 20993-0002
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Draft — Not for Implementation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

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Gluten in Drug Products and Associated Labeling	1
Recommendations	2
Guidance for Industry1
3
4
5
This draft guidance, when finalized, will represent the current thinking of the Food and Drug	6
Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not	7
binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the	8
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible	9
for this guidance as listed on the title page.	10
11
12
13
14
I. 	INTRODUCTION	15
16
This guidance is intended to convey to drug manufacturers FDA’s recommendations on how	17
certain drug products should be labeled regarding gluten, a matter of interest to individuals with	18
celiac disease. Some individuals with celiac disease have faced difficulty when trying to	19
determine whether specific drug products contain gluten. Confronted by uncertainty, some	20
patients may forego important medication rather than risk an adverse reaction to gluten. Thus,	21
even if gluten is not present at levels that would harm a typical individual with celiac disease,	22
that individual may be harmed through uncertainty and lack of information.	23
24
Celiac disease (also known as celiac sprue) is an immune-based reaction to dietary gluten that	25
primarily affects the small intestine in susceptible individuals; unmanaged celiac disease can lead	26
to serious health complications. Approximately 1 percent of the U.S. population has celiac	27
disease (Binder 2015). It is characterized by ongoing inflammation of part of the lining of the	28
small intestine that generally heals if foods containing gluten are excluded from the diet and	29
returns if they are reintroduced. At this time, the treatment for celiac disease is adherence to a	30
gluten-free diet.	31
32
FDA’s food labeling regulations define gluten as “proteins that naturally occur in [wheat, barley,	33
and rye or their crossbred hybrids] and that may cause adverse health effects in persons with	34
celiac disease (e.g., prolamins and glutelins)” (21 CFR 101.91(a)). Consistent with this	35
definition, the term gluten in this document refers to certain proteins found in wheat, barley, and	36
rye or their crossbred hybrids that lead to symptoms associated with celiac disease.	37
38
This guidance pertains to human drug products that pass through the small intestine:	39
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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• 	Orally ingested drug products.2	
42
43
• 	Topical drug products applied to or near the lips (e.g., lip sunscreens).3	
44
45
• 	Drug products applied inside the mouth (e.g., cold sore treatments, drugs delivered to or	46
via the oral cavity).	47
48
In this guidance, oral drug product refers to this group of products. Gluten is not believed to	49
harm individuals with celiac disease through routes of exposure other than oral or enteral	50
ingestion.	51
52
This guidance was developed with celiac disease in mind. However, the recommendations in this	53
guidance may be of interest to patients with other conditions that are treated with a gluten-free	54
diet.	55
56
This guidance does not apply to food (including dietary supplements) or products regulated	57
solely as cosmetics.4 In addition, this guidance does not discuss labeling recommendations	58
regarding wheat hypersensitivity.	59
60
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	61
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only	62
as recommendations, unless specific regulatory or statutory requirements are cited. The use of	63
the word should in Agency guidances means that something is suggested or recommended, but	64
not required.	65
66
II. 	DISCUSSION	67
68
A. 	Possible Sources and Amounts of Gluten in Oral Drug Products	69
70
Wheat is not used to a significant extent in the production of drug ingredients, and barley and rye	71
are used either rarely or not at all.	72
73
1. 	Wheat Gluten as an Ingredient	74
75
Wheat gluten itself is never or very rarely added as an inactive ingredient to oral drug products	76
during manufacture.5 As discussed in section II.B of this guidance, any oral drug product that	77
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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contains wheat gluten as an intentionally added ingredient should be labeled to indicate its	78
presence.	79
80
Although the use of wheat gluten as an inactive ingredient in drug products does not generally	81
mean that the product will fail to satisfy applicable requirements for safety, we may question the	82
addition of wheat gluten to certain oral drug products on a case-by-case basis. We would be	83
more likely to question the use of wheat gluten as an ingredient in an oral drug product for which	84
few or no alternative treatments are available. We would also be more likely to question its use	85
as an ingredient in an oral drug product intended for long-term administration or intended to treat	86
comorbidities of celiac disease.	87
88
The level at which wheat gluten would be present in an oral drug product—if added as an	89
ingredient—is directly controlled by the drug manufacturer. In the absence of more detailed	90
information regarding wheat gluten amounts, individuals with celiac disease may choose to	91
avoid oral drug products that are labeled as containing wheat gluten as an ingredient.	92
93
2. 	Wheat Gluten as an Impurity in Ingredients Derived From Wheat	94
95
Apart from its possible addition to oral drug products as an inactive ingredient—something that	96
rarely, if ever, occurs—wheat gluten may be present at low levels as an impurity in ingredients	97
that are derived from wheat, such as wheat starch.	98
99
In this section, we identify drug ingredients and categories of ingredients derived or potentially	100
derived from wheat, and we estimate how much gluten they may contribute to a unit dose of an	101
oral drug product. In general, the quantities we estimate to be present are low and do not exceed	102
the amounts of gluten that could be found in food products labeled gluten-free under FDA’s	103
regulations (21 CFR 101.91). We present this analysis because (1) it has informed our thinking	104
about regulatory options associated with gluten in oral drug products, (2) we would like drug	105
manufacturers to consider the information in this section and review the ingredients they use in	106
their drug products, and (3) if the information or assumptions underlying our analysis are proven	107
incorrect, we would reconsider available regulatory options.	108
109
Drug manufacturers are in the best position to review their specific formulations for oral drug	110
products and to question their ingredient suppliers about ingredients potentially derived from	111
wheat, purification methods, and analytical testing results. We urge manufacturers to consider	112
gluten content when formulating products using ingredients potentially derived from wheat or	113
wheat starch.	114
115
a. 	Wheat flour	116
117
We are aware that some manufacturers have reported the direct addition of wheat flour to oral	118
drug products in the past—but only very rarely. We are not aware of an oral drug product	119
currently being marketed in the United States that contains wheat flour as an ingredient. As	120
discussed in section II.B of this guidance, any oral drug product that contains wheat flour as an	121
intentionally added ingredient should be labeled to indicate its presence.	122
123

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The total protein content of wheat flour is generally 13 percent, with gluten representing part of	124
the total protein.6 The amount of gluten present in an oral drug product to which wheat flour has	125
been added as an ingredient would depend on how much wheat flour is used. Because use of	126
wheat flour in any drug product is so rare, we do not have good information regarding upper,	127
lower, and typical levels that would be present in a drug product. We believe individuals with	128
celiac disease might choose to avoid oral drug products that are labeled as containing wheat flour	129
in the absence of more detailed information about the drug product’s gluten content.	130
131
b. 	Wheat starch	132
133
As with wheat gluten and wheat flour, we believe wheat starch is added to oral drug products as	134
an ingredient only very rarely. Other sources of starch (e.g., corn, potato) are more commonly	135
used in pharmaceutical products. As discussed in section II.B of this guidance, any oral drug	136
product that contains wheat starch as an intentionally added ingredient should be labeled to	137
indicate its presence.	138
139
A monograph for wheat starch in the National Formulary (NF) includes a 0.3 percent limit on	140
total protein but does not include a limit on gluten content.7 The gluten content will be some	141
proportion of the total protein content. Based on published information, we understand the gluten	142
content of wheat starch suitable for use in drug products is variable but is typically in the range	143
of 100 to 500 mg/kg (see, e.g., Kasarda, Dupont, et al. 2008). Based on our review of drug	144
formulation information, we expect wheat starch—in the rare cases in which it is used in oral	145
drug products—to contribute less than 0.1 mg gluten to a unit dose of an oral drug product.	146
147
c. 	Ingredients derived from starch	148
149
Starch is used as a starting material for manufacturing various ingredients added to oral drug	150
products. The starch used for this purpose is often corn or potato starch, not wheat starch.	151
Nevertheless, we recognize that very small amounts of wheat gluten may be present in starch-	152
derived ingredients if wheat starch is used as the starting material.	153
154
Ingredients in this category—potentially derived from wheat starch—include modified starch,	155
pregelatinized starch, and sodium starch glycolate. This category also includes starch	156
hydrolysates (e.g., maltodextrin, dextrates, dextrose, maltose, and sugar alcohols such as sorbitol,	157
xylitol, maltitol, and mannitol) and hydrogenated starch hydrolysates (mixtures of sugar	158
alcohols).	159
160
As with wheat starch, compendial monographs for these ingredients do not include specific	161
limits on gluten content. We have found published reports regarding the gluten content for only a	162
limited number of ingredients derived from wheat starch. In the absence of such specific	163
information, we have made the conservative assumption that wheat-derived modified starches	164
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 Institute’s 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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(e.g., modified starch, pregelatinized starch, sodium starch glycolate), although more highly	165
processed than wheat starch, might contain gluten at the same concentrations at which gluten	166
might be found in wheat starch: 100–500 mg/kg. Based on published literature, we believe that	167
starch hydrolysates and hydrogenated starch hydrolysates derived from wheat may contain up to	168
40 mg/kg gluten (European Food Safety Authority 2007). Based on drug formulation	169
information, we estimate that these ingredients may contribute less than 0.5 mg gluten to a unit	170
dose of an oral drug product.	171
172
d. 	Ingredients produced through fermentation	173
174
Some ingredients, including citric acid and ethanol, may be produced by fermentation, in which	175
microorganisms feed on carbohydrates from plant sources that potentially include wheat. See, for	176
example, 21 CFR 184.1033, which describes the production of food-grade citric acid by various	177
methods, including fermentation. If the fermentation medium includes wheat or wheat-derived	178
ingredients, an ingredient produced by fermentation may—depending on how it is purified—	179
contain small amounts of gluten. Compendial monographs for these ingredients do not include	180
gluten limits.	181
182
In some cases, an ingredient such as ethanol8 may be purified through distillation. It is unlikely	183
that gluten (or any protein) would be present in ethanol purified by distillation using good	184
manufacturing practices, considering the high volatility of ethanol compared with the much	185
lower volatility of a large molecule such as gluten.	186
187
In other cases, the ingredient is highly purified through other means. Anhydrous citric acid, USP,	188
for example, is not less than 99.5 percent pure. We expect the presence of any residual gluten in	189
such ingredients to be very low. Based on drug formulation information we have reviewed, we	190
expect ingredients produced through fermentation to contribute no more than 0.5 mg gluten to a	191
unit dose of an oral drug product.	192
193
As with all of our estimates presented above, there is some uncertainty surrounding the amount	194
of gluten that may be present in drug ingredients produced through fermentation. A more certain	195
estimate would require production information or analytical test results covering multiple	196
batches of the full range of ingredients made by producers around the world. In the absence of	197
such information, we have relied on total protein limits in compendial monographs and published	198
reports covering certain ingredients.	199
200
e. 	Wheat germ oil	201
202
We are aware that wheat germ oil9 may be used as an ingredient in certain products applied	203
topically to the lips or skin, such as lip balms or sunscreen products. If the wheat germ oil is	204
highly refined, it is unlikely to contain detectable amounts of gluten. Even if the oil is not highly	205
8 Alcohol, USP. (USP=United States Pharmacopeia.)
9 Sometimes identified as Triticum vulgare (wheat) germ oil.

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refined, we believe the presence of any gluten in a product applied topically to the lips would be	206
very low, and any oral ingestion of gluten associated with the product would be insignificant.	207
208
3. 	Wheat Gluten as an Adventitious Contaminant	209
210
In theory, wheat gluten that is not associated with a wheat-derived ingredient could be	211
introduced into an oral drug product as an adventitious contaminant (e.g., as a result of contact	212
with gluten during manufacture, processing, transportation, or storage). Although we do not have	213
systematic data in this area, we expect that any gluten present adventitiously in oral drug	214
products would be present only in very small amounts. In all likelihood, the amount of gluten	215
would be below the limits of detection associated with current analytical test methods. It is also	216
likely that the amount of gluten would be well below the levels we have estimated an inactive	217
ingredient, such as wheat starch, could potentially contribute to an oral drug product. Current	218
good manufacturing practice (CGMP) regulations for drug products reflect a basic obligation to	219
prevent contamination of a drug being processed,10 and a violation of the CGMP regulations can	220
result in an enforcement action. FDA would consider taking action if an oral drug product were	221
found to contain significant amounts of gluten as a contaminant.	222
223
B. 	Labeling	224
225
If a drug included an ingredient derived from wheat, barley, or rye, the ingredient would most	226
likely be wheat-derived. The amount of gluten potentially contributed by a wheat-derived	227
ingredient to a unit dose of an oral drug product (unless that ingredient is wheat gluten itself or	228
wheat flour) is expected to be less than 0.5 mg, as a high estimate.11 As discussed in section II.A	229
of this guidance, most oral drug products are not expected to contain ingredients derived from	230
wheat, barley, or rye. The likelihood of them including more than one such ingredient is even	231
less. Thus, it is expected that the amount of gluten potentially present in a unit dose of an oral	232
drug product is less than the amount of gluten that could potentially be found in a single serving	233
of a cookie (30 grams) labeled gluten-free in accordance with FDA’s regulations at 21 CFR	234
101.91 (if all of the criteria of that regulation are satisfied).12 Moreover, the amount of gluten	235
estimated to be potentially present in a unit dose of an oral drug product (less than 0.5 mg) is	236
significantly less than the range at which gluten is estimated to be present in a gluten-free diet (5	237
to 50 mg) (La Vieille, Dubois, et al. 2014; Catassi, Fabiani, et al. 2007).13 This leads FDA to	238
conclude that individuals who respond well to a gluten-free diet are at low risk of experiencing	239
problems as a result of the possible presence of gluten in a drug product. However, we expect	240
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 FDA’s 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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that they might choose to avoid using oral drug products labeled as containing wheat gluten or	241
wheat flour as an ingredient in the absence of more information about the product’s actual gluten	242
content.	243
244
We have also considered the potential impact on those individuals with celiac disease who take	245
multiple oral medications each day. Considering that inactive ingredients are typically derived	246
from sources other than wheat, and that 0.5 mg of gluten per unit dose is a high estimate for	247
gluten in an oral drug product, we expect that an individual taking multiple drug products per	248
day would ingest much less gluten, if any, from drugs than an individual with celiac disease	249
adhering to a gluten-free diet may ingest from food.	250
251
Some celiac patients are more sensitive to gluten than others and do not respond well to a gluten-	252
free diet.14 Patients who are more sensitive to gluten will likely seek to eliminate all sources of	253
ingested gluten, or at least minimize exposure as much as possible. In all probability, these	254
patients are under specialized care and would avoid those rare oral drug products containing	255
added wheat starch in addition to those containing added wheat gluten or wheat flour.	256
Additionally, they or their caregivers would likely reach out to physicians, pharmacists, other	257
health care providers, or drug manufacturers for information about possible inclusion of wheat-	258
derived ingredients in their oral drug products. We encourage drug manufacturers to have	259
accurate information on the sources of their ingredients available so they can respond to	260
questions from the public and health care providers.	261
262
1. 	Ingredient Labeling: Current Regulations and Practice	263
264
As described below, drug ingredients are generally identified in labeling, but substances that are	265
present merely as impurities generally are not.	266
267
a. 	Nonprescription (over-the-counter) oral drug products15	
268
269
Nonprescription drug labels must list “the established name of each inactive ingredient” under	270
the “Inactive ingredients” heading of the Drug Facts label, which appears on the “outside	271
container or wrapper of the retail package, or the immediate container label if there is no outside	272
container or wrapper.”16 This information is visible to consumers at the time of purchase.17	
273
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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b. 	Prescription oral drug products	276
277
Although not currently mandated by FDA’s regulations, manufacturers of prescription oral drug	278
products generally provide a list of inactive ingredients in the DESCRIPTION section of the	279
prescribing information.18	
280
281
Drugs that are licensed biological products (i.e., they are regulated under a biologics license	282
application (BLA)) are subject to additional labeling requirements described in 21 CFR part 610,	283
subpart G. In particular, 21 CFR 610.61 requires identification of certain types of inactive	284
ingredients, including preservatives, “known sensitizing substances,” and “inactive ingredients	285
when a safety factor.”	286
287
We interpret the requirement that inactive ingredients be identified in the labeling of biological	288
products “when a safety factor” as meaning that wheat gluten and wheat flour must be identified	289
by those names if they are present in orally administered biological products.	290
291
2. 	Established Names	292
293
According to section 502(e)(3) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), the	294
term established name means (a) the official name designated pursuant to section 508;19 (b) if	295
there is no such name, the title of a monograph for the ingredient in an official compendium;20 or	296
(c) the “common or usual name” if neither (a) nor (b) applies.	297
298
Consistent with this provision, the established name used in labeling for any wheat-derived	299
ingredient that is the subject of a monograph in an official compendium must be the monograph	300
title, where there is no official name designated pursuant to section 508. For example, wheat	301
starch (not starch) is the established name by which wheat starch must be identified in drug	302
labeling. However, the more highly processed ingredients discussed in section II.A of this	303
guidance (ingredients derived from starch and ingredients produced by fermentation) do not	304
include a botanical source such as wheat in the established name of the ingredient because the	305
titles of their compendial monographs do not include this designation.	306
307
If an ingredient is not recognized in an official compendium and does not have an applicable	308
official name designated pursuant to section 508 of the FD&C Act, then it must be identified in	309
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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labeling by its common or usual name.21 Wheat gluten and wheat flour fall into this category,	310
and we consider wheat gluten and wheat flour to be their appropriate common or usual names.22	
311
312
3. 	Section 502(f) of the FD&C Act	313
314
Section 502(f) of the FD&C Act states that a drug “shall be deemed to be misbranded . . . unless	315
its labeling bears . . . such adequate warnings against use in those pathological conditions . . .	316
where its use may be dangerous to health . . . in such manner and form, as are necessary for the	317
protection of users.”	318
319
We are not aware of any currently marketed oral drug product that contains wheat gluten as an	320
intentionally added inactive ingredient. If such a product exists, we would expect wheat gluten to	321
be included in its labeled list of inactive ingredients. If the labeling fails to disclose wheat gluten	322
as an inactive ingredient, we would consider whether the product is misbranded under section	323
502(f) or other authorities (e.g., 21 CFR 201.66(c)(8)) in the case of a nonprescription oral drug	324
product).	325
326
III. 	RECOMMENDATIONS	327
328
We encourage drug manufacturers to have accurate information about their products’ gluten	329
content available so they can respond to questions from consumers and health care professionals.	330
Manufacturers should pay attention to possible sources of gluten in their products, consider	331
specifications when appropriate, and consider the impact of changes in ingredient sources or	332
formulations on gluten content.	333
334
A. 	Voluntary Statements Regarding Gluten	335
336
1. 	Statements on Labels or in Required Labeling	337
338
We recommend that drug manufacturers that wish to make statements about gluten anywhere on	339
oral drug product labels or in required labeling use the following statement, when it is truthful	340
and substantiated:	341
342
Contains no ingredient made from a gluten-containing grain (wheat, barley,	343
or rye).23	
344
345
We would interpret such a statement to mean that the manufacturer knows that no ingredient in	346
the product was derived directly or indirectly from wheat, barley, or rye or their crossbred	347
hybrids. This would preclude, for example, the use of ingredients derived from wheat starch or	348
from starch of unknown botanical origin. It would also preclude the use of ingredients produced	349
21 See section 502(e)(3) of the FD&C Act.
22 Wheat gluten is the name given to the ingredient in FDA’s 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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through a fermentation process if the fermentation medium is not known to be free of ingredients	350
derived from wheat, barley, or rye or their crossbred hybrids. Substantiation for such a statement	351
is discussed in section III.A.2 of this guidance.	352
353
We encourage use of this recommended labeling statement to provide health care professionals	354
and consumers with consistent, clear, accurate, and readily understood information about the	355
gluten content of the pharmaceutical products they use. Furthermore, this phrase allows easy	356
searching for terms such as gluten and wheat. This recommended labeling statement does not	357
describe a drug as gluten-free because we have not established criteria for gluten-free statements	358
on oral drug products, and it may be difficult to substantiate that a drug product is free of gluten.	359
We are not aware of analytical test methods currently validated to detect or quantify gluten in	360
finished drug products or in drug ingredients at the low levels at which it would generally be	361
expected to be present, if at all. Furthermore, we have not determined whether a gluten-free	362
statement on an oral drug product should refer to an absence of intact gluten or whether such a	363
statement should also require an absence of gluten peptides.	364
365
2. 	Supporting Information	366
367
Firms are responsible for the truthfulness of their gluten-related labeling statements and for	368
ensuring that the information related to their oral drug products supports the use of such	369
statements.24 Firms should also have supporting information available, including information	370
from ingredient suppliers about their processes and raw materials. Indeed, CGMP regulations	371
include recordkeeping requirements encompassing information that may be relevant.25	
372
373
For firms wishing to use the recommended labeling statement, substantiation for such a	374
statement should include a written commitment from ingredient suppliers that, for each	375
ingredient potentially derived from wheat, barley, rye, or their crossbred hybrids or produced	376
through fermentation, these grains are not used in the production of the ingredient.	377
378
For statements other than the recommended labeling statement, the supporting information could	379
vary by product. For example, firms may be able to test individual wheat-derived ingredients for	380
the absence of nitrogen (indicating an absence of all protein, including gluten), or they may be	381
able to provide information demonstrating that the processing of such ingredients removes the	382
gluten. If such ingredient testing is conducted, the manufacturing records26 must include the	383
results of any tests and the conclusions derived from them.27 These records must be readily	384
available to FDA for authorized inspection.28	
385
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
211.184–211.194.
27 See 21 CFR 211.184(b).
28 See 21 CFR 211.180(c).

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B. 	Submission and Adoption	387
388
1. 	Oral Drug Products With New or Pending Applications	389
390
An applicant submitting a new drug application (NDA), abbreviated new drug application	391
(ANDA), or BLA that wishes to use the recommended labeling statement must ensure that its use	392
is consistent with the information in the application related to the oral drug product ingredients.29	
393
We are not asking that applicants submit additional specific information to their applications,	394
such as the supplier agreements referred to above, but applicants should ensure that such	395
information is available. An applicant that wishes to use an alternative statement should propose	396
in the application how it intends to support the alternative statement.	397
398
2. 	Oral Drug Products With Approved Applications	399
400
An NDA, ANDA, or BLA holder with an approved application who seeks to change a product	401
formulation to make a gluten statement should refer to relevant regulations and guidance	402
regarding submission requirements associated with the formulation changes.30	
403
404
An NDA, ANDA, or BLA holder seeking to include the recommended labeling statement who	405
can properly substantiate it without changes to the approved product formulation may revise	406
labeling at any time to do so. The addition of the recommended labeling statement may then be	407
reported in the next annual report, pursuant to 21 CFR 314.70(a)(3) and 601.12(a)(3).31	
408
409
An NDA, ANDA, or BLA holder wishing to use an alternative statement must submit the	410
proposed statement and information that supports its use in a prior approval supplement (PAS).	411
The addition of an alternative statement that communicates something different from or in	412
addition to the absence of ingredients made from gluten-containing grains (wheat, barley, or rye)	413
requires the submission and review of data not already included in the application.32	
414
415
Regarding labeling requirements specific to generic drugs, a firm marketing a product described	416
in an ANDA can include either the recommended labeling statement or an alternative statement	417
addressing gluten—even if the reference listed drug (RLD) for the product described in the	418
ANDA does not include such a statement—as long as the submission provisions described above	419
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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are satisfied and the recommended labeling statement is properly substantiated or the alternative	420
statement is approved. Conversely, if the RLD for a product described in an ANDA includes	421
either the recommended labeling statement or an alternative statement addressing gluten, the	422
product described in the ANDA is not required to include such a statement in its labeling to	423
comply with the same labeling requirement that applies to ANDAs. Although the labeling of a	424
product described in an ANDA and its RLD must generally be the same, an exception is made	425
for differences attributable to the products being produced or distributed by different	426
manufacturers. Such differences may include differences in labeling to reflect permissible	427
differences in the formulation of the drug products (such as permissible differences in inactive	428
ingredients) and labeling revisions made to comply with current FDA labeling guidelines or	429
other guidance. See section 505(j)(2)(A)(v) of the FD&C Act and 21 CFR 314.94(a)(8)(iv).	430
431
3. 	Oral Drug Products With Approved Applications That Already Include a	432
Statement About Gluten Other Than the Recommended Labeling Statement	433
434
We are aware that some marketed oral drug products already include a gluten labeling statement	435
other than the recommended labeling statement described in this guidance. Firms are encouraged	436
to determine whether they will revise their labeling to use the recommended labeling statement	437
or whether they have an adequate basis for the continued use of an alternative statement.	438
439
If a firm chooses to adopt the recommended labeling statement and this action does not require	440
changes in the product formulation (or is not combined with another change that requires	441
submission of a supplement), the firm may submit this labeling change in an annual report to the	442
NDA, ANDA, or BLA (21 CFR 314.70(a)(3), 601.12(a)(3)).	443
444
However, if adopting a gluten labeling statement requires changes in the product formulation (or	445
is combined with other labeling changes that require a PAS), the application holder must submit	446
the change in a PAS.33	
447
448
4. 	Nonapplication Oral Drug Products	449
450
For oral drug products marketed without an application, firms may revise their labeling to adopt	451
the recommended labeling statement if the statement is truthful and substantiated.	452
453
As noted above, if an oral drug product’s labeling already includes a gluten statement, firms are	454
encouraged to review this guidance and determine whether they will revise their labeling to use	455
the recommended labeling statement. If a firm wishes to continue to use a labeling statement	456
other than the recommended labeling statement, the firm is responsible for the truthfulness of	457
such a statement and for ensuring that the information related to the oral drug product supports	458
its use.34	
459
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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C. 	Placement of a Voluntary Gluten Labeling Statement	461
462
1. 	Prescription Oral Drug Products	463
464
When used, a voluntary gluten statement should be included in the DESCRIPTION section of	465
the prescribing information. Specifically, it should appear at the end of the inactive ingredients	466
list. If the oral drug product has associated FDA-approved patient labeling, the statement should	467
also appear in that patient labeling, either at the end of an inactive ingredients list or at the end of	468
the patient labeling, after the name and address of the manufacturer, packer, or distributor. In	469
addition, if a voluntary gluten statement is included on the immediate container label and, if	470
applicable, carton labeling, it should appear on the side or back panel. The statement should not	471
appear on the principal display panel, to avoid interference with the required or recommended	472
information that appears on labels and labeling.35	
473
474
2. 	Nonprescription Oral Drug Products	475
476
Voluntary gluten statements should be visible at the time of purchase and should appear on the	477
immediate container label and carton labeling in a location outside of the Drug Facts label. The	478
statement must not interfere with the required information that appears on labels and labeling.36	
479
480
IV. 	REFERENCES	481
482
Binder, HJ, 2015, Disorders of Absorption. In: D Kasper, A Fauci, S Hauser, D Longo, JL	483
Jameson, J Loscalzo, eds. Harrison’s Principles of Internal Medicine, 19th ed., New York:	484
McGraw-Hill Education.	485
486
Catassi, C, E Fabiani, et al., 2007, A Prospective, Double-Blind, Placebo-Controlled Trial To	487
Establish a Safe Gluten Threshold for Patients With Celiac Disease, Am J Clin Nutr, 85:160–	488
166.	489
490
European Food Safety Authority, 2007, Opinion of the Scientific Panel on Dietetic Products,	491
Nutrition and Allergies on a Request From the Commission Related to a Notification From AAC	492
on Wheat-Based Maltodextrins Pursuant to Article 6, Paragraph 11 of Directive 2000/13/EC,	493
The EFSA Journal, 487:1–7.	494
495
Kasarda, DD, FM Dupont, et al., 2008, Surface-Associated Proteins of Wheat Starch Granules:	496
Suitability of Wheat Starch for Celiac Patients, J Agric Food Chem, 56:10292–10302.	497
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 FDA’s 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
product’s 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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La Vieille, S, S Dubois, et al., 2014, Estimated Levels of Gluten Incidentally Present in a	499
Canadian Gluten-Free Diet, Nutrients, 6:881–896.	500
501
Rubio-Tapia, A, ID Hill, et al., 2013, ACG Clinical Guidelines: Diagnosis and Management of	502
Celiac Disease, Am J Gastroenterol, 108:656–676.	503