Eye on Excipients: Targeting Gluten Sensitivity in Pharmaceuticals

Americans with gluten sensitivities have shown increased concern over the years regarding the presence of gluten in foods. Recently, the possibility of gluten in oral medications has been raised as a concern for gluten-sensitive patients. Gluten proteins found in wheat, barley, and rye are the primary food triggers. The concern is that gluten may be present in medications that contain starches derived from these foods. 

Celiac disease is an autoimmune reaction to gluten that affects the small intestine. For patients with celiac disease, consuming gluten leads to gastrointestinal distress and possibly other serious medical conditions. Individuals with celiac disease must be made aware if drug products contain gluten at potentially harmful levels. 

Approximately 1 percent of the US population has celiac disease (FDA 2017) and, currently, the only treatment is observance of a gluten-free diet. However, from a regulatory and adverse health effect perspective, foods with gluten levels less than 20 parts per million (ppm) are considered to be acceptably “gluten-free.” Most people with celiac disease will vary in their sensitivity to gluten. 

The International Pharmaceutical Excipients Council of the Americas (IPEC-Americas) believes that the risk of gluten presence in pharmaceutical excipients is very low. Also, the risk to celiac patients from their medications is extremely small and exists only if wheat, barley, or rye-based excipients are used. Excipients derived from wheat are typically highly processed in such a way as to effectively remove or reduce gluten to a tolerable level. There is a slight risk that wheat gluten may be present at low levels (<20 ppm) in certain excipients that are derived from wheat. Typically, gluten is present in the starch of wheat, barley, and rye and to a lesser extent in their derivatives. According to the FDA, wheat is usually not used in the production of drug product ingredients, and barley and rye are used either rarely or not at all (FDA 2017). Wheat gluten itself is very rarely added as an inactive ingredient to oral drug products. Please refer to Table 1 for current US FDA Inactive Ingredient Database listings.

FDA releases new gluten labeling guidance

The December 2017 FDA draft Guidance for Industry titled “Gluten in Drug Products and Associated Labeling Recommendations” ¹ explains the FDA’s recommendations on how drug products should be labeled regarding gluten content. The FDA states that the Guidance was developed to address concerns for patients with celiac disease and that its recommendations also apply to patients with other conditions treated with a gluten-free diet. 

The draft Guidance encourages consistency among manufacturers who label their drug products for the presence of gluten. Standardized labeling should improve consumer awareness and minimize confusion about the presence of gluten in drug products. 

The FDA estimated that the quantities of gluten from excipients derived from wheat are low and do not exceed the amounts of gluten that could be found in food products labeled gluten-free. The agency is not aware of an oral drug product currently marketed in the US that contains wheat flour as an ingredient. The FDA suggests that an oral drug product that contains intentionally added wheat flour as an ingredient should be labeled to indicate it. 

Wheat starch is highly processed, which should remove any significant amount of gluten. Wheat gluten may be found in low concentrations (<20 ppm) as an impurity in ingredients found in food such as wheat starch and, to a lesser extent, in constituents derived from wheat starch and ingredients produced through the fermentation of wheat. 

The FDA recognizes a risk that very small amounts of wheat gluten may be present in wheat-starch derived starch derived excipients if wheat starch is used as the starting material. This category also includes modified starch, pregelatinized starch, sodium starch glycolate, starch hydrolysates (e.g., maltodextrin, dextrates, dextrose, maltose, and sugar alcohols such as sorbitol, xylitol, maltitol, and mannitol), which, if derived from wheat, may have been processed to destroy or remove gluten. Starch derivatives are more highly processed than wheat starch, and the FDA indicated that they may contain gluten at the same or lower concentrations than may be found in wheat starch. The FDA discussed specific considerations and estimates for how much gluten may be found as an impurity per unit dose of a drug product made with these ingredients . The majority of these materials used in pharmaceuticals are derived from corn (maize) or potato starches. 

The FDA concluded that individuals who respond well to a gluten-free diet are at low risk of experiencing problems as a result of the possible presence of gluten in a drug product. 

Drug product manufacturers are encouraged to have available accurate information about their drug product’s gluten content, so they can respond to questions from consumers and healthcare professionals. According to the FDA, drug manufacturers that wish to make voluntary statements about gluten on oral drug product labels or in required labeling should use the following statement: “Contains no ingredient made from a gluten-containing grain (wheat, barley, or rye).” Criteria for “gluten-free” labeling statements for oral drug products have not been established by the Center for Drug Evaluation and Research (CDER).

IPEC-Americas Comments on FDA New Guidance 

IPEC-Americas submitted comments to the docket for the December 2017 Guidance and believes that, if drug products formulated with “wheat gluten” as an ingredient exist, they should clearly disclose on the label that “wheat gluten” is an ingredient. With this added labeling requirement, celiac sufferers should have enough information to avoid using a product that may cause an undesirable immune response and use other therapeutically equivalent products instead. The IPEC-Americas comments submitted to the FDA docket included example calculations estimating the daily gluten consumption level from a hypothetical oral drug product based on worst-case scenarios. 

On the CDER “Medications and Gluten” webpage, the FDA provides the following information for the types of ingredients that may contain gluten in oral drug products ²: 

Based on this information, IPECAmericas recommended that any labeling statement should be addressed between the FDA and the drug product manufacturer during development and approval of the package insert and package label. This approach would only be required if ingredients may be present that contain gluten above a scientifically established level that would impact people with celiac disease. The CDER “Medications and Gluten” webpage also contains information concerning expected gluten levels in drug products²: 

“The majority of oral drug products either contain no gluten or virtually no gluten. Based on information available to the Agency, we are aware of no oral drug products currently marketed in the United States that contain wheat gluten or wheat flour intentionally added as an inactive ingredient. We would expect any such product, if it existed, to include wheat gluten or wheat flour in the list of ingredients in its labeling.

“FDA has identified very few oral drugs that contain wheat starch as an ingredient. Starch can also be used as a starting material for manufacturing various ingredients found in oral drugs. Starch used for this purpose is often corn starch or potato starch, not wheat starch. Even if wheat starch were used, either as an ingredient or as a starting material, there would be very little gluten, if any, expected to be present in the ingredient or the drug product. Very few, if any, oral drug products contain ingredients derived from barley or rye.”

Based on this information, IPECAmericas recommended that any labeling statement should be addressed between the FDA and the drug product manufacturer during development and approval of the package insert and package label. This approach would only be required if ingredients may be present that contain gluten above a scientifically established level that would impact people with celiac disease. 

The CDER “Medications and Gluten” webpage also contains information concerning expected gluten levels in drug products²:

“The vast majority of oral drug products either contain no gluten or virtually no gluten. In the very rare cases where gluten may be present, we estimate based on drug formulation information that wheat starch and other ingredients derived from wheat would contribute no more than 0.5 mg gluten to a unit dose of an oral drug product. This amount is less than may be found in a single 30-gram serving of food labeled gluten-free according to FDA’s regulations.”

Consumers should be familiar with the phrase “gluten-free” based on its permitted use on food products, including dietary supplements, which are regulated by the FDA’s Center for Food Safety and Applied Nutrition (CFSAN). The FDA issued its Final Rule for Food Labeling: “Gluten-Free Labeling of Foods” on August 5, 2013, defining the term “gluten-free” for the food industry (21 CFR 101.91(a)). Because concentration sumers have become accustomed to this label terminology, it should help alleviate possible confusion to use this term as the proposed statement for drug products. CFSAN’s current position, as described in the Codex Alimentarius standard 118-1979³, is that the concentration of gluten in food must not exceed 20 mg/kg (20 ppm) for products to be labeled gluten- free.

The related regulation, 21 CFR 101.91, which the FDA’s small entity compliance guide notes as being binding and having the full force and effect of the law, also defines “gluten-free.” IPEC-Americas members are concerned that, if acceptable gluten limits are not established or if gluten limits are “open ended” or require labeling such as “free from,” this could lead to unnecessary reformulations of drug products that currently meet the same requirements as gluten- free food products. This would not provide any significant benefit to patients but would cause significant increases in drug costs. 

IPEC-Americas recommended that the FDA replace the current suggested statement to require labeling a drug only when the presence of gluten is above a defined “gluten-free” (<20 ppm) threshold. Since the final concentration of gluten depends on the ingredients, their level of use in the formulation, and any processing that may impact the final level, labeling statements should be established on a case-by-case basis. 

The FDA is not aware of validated analytical test methods to detect quantities of gluten in finished drug products. IPEC-Americas members recommended that the commercially available enzyme-linked immunosorbent assay (R5-ELISA), which is the current validated gold standard for gluten testing in foods, should be explored for use in pharmaceutical products. 

The FDA Threshold Working Group reviewed available data from various gluten challenge studies to establish a threshold for gluten⁴. The FDA CFSAN set a 20-ppm threshold based on the lowest concentration of gluten that can be consistently detected in foods using valid scientific analytical methods. As patients are likely to consume a significantly smaller amount of medication than food, the risk of exposure to gluten from the daily intake of medication is even lower. 

Gluten Content in Drug Products Must be Individually Assessed 

In a recent article, Shah et al. (2017)⁵ proposed that:

“…all existing drug products may also be made gluten-free by replacing certain excipients, if any, that may contain gluten with alternative gluten-free excipients.”

The article does not specifically state what is intended by “gluten-free excipients” and if this would preclude the use of all excipients derived from wheat, even when the gluten content is less than 20 ppm. This could impact a number of drug formulations. Reformulating existing approved drug products is extremely expensive, not to mention the associated changes in labeling, GMP risk assessments, processing, sanitation, prior approval supplements (PASs), requalification, and documentation. Avoiding the use of excipients derived from wheat that contain less than 20 ppm of gluten is not necessary to minimize risks for celiac patients. Such unnecessary and non-value-added reformulation would also potentially increase the burden on the FDA since reformulation to remove an excipient and replace it with an entirely different excipient would typically require a PAS filing. 

Several statements and conclusions made in the Shah et al. article are misleading or factually incorrect. Readers may incorrectly assume that gluten in pharmaceuticals is a significant risk to patient safety and that many medications contain gluten, neither of which are the case.

Shah et al. state in their article that:

“In our opinion, the formulation of gluten-free drug products will not cause undue burdens or incur significantly higher manufacturing costs to pharmaceutical companies...Any impact of substituting one excipient by another on the cost of manufacturing a drug product may also be very minor, if at all.”

IPEC-America’s opinion is that the impact of substituting one starch-derived excipient for another in an existing approved drug product is not minor and should be treated as a technical grade and specification change. This is a change in the qualitative or quantitative formulation of the drug product and, as such, according to the FDA’s Scale-up and Post-Approval Changes Guidance for Immediate Release Products (SUPAC IR Guidance, 1995)⁶ would require a PAS by all manufacturers. This would require supporting details on chemistry, dissolution, and stability along with either a biowaiver, if applicable, or an in vivo bioequivalence study. 

A starch-related excipient change may have a significant impact on formulation quality, manufacturing, and performance. The filing documentation required depends on the therapeutic range, and Biopharmaceutical Classification System (BCS) classification (solubility and permeability) of the drug substance molecule. Developing the supporting data and documentation requires extensive studies taking several months to complete, which would increase costs for drug product manufacturers and patients. In addition, the reformulated drug product manufacturing process would require revalidation, which could further increase costs. Removing the older formulation from the market to avoid confusion with the new product would also add costs. 

IPEC-Americas proposes that labeling only be based on the presence, not the absence, of gluten at a threshold to be determined, and information is already available within CDER and CFSAN to establish that threshold. IPEC-Americas recommends that the FDA replace the current suggested statement to require labeling a drug only when the presence of gluten is above a defined “gluten-free” threshold. IPEC-Americas recommends using the same limit as is used for foods considered to be gluten-free (<20 ppm).

New IPEC Industry Guides Improve Excipient Controls 

IPEC participated in the development of practical GMPs and good supply chain practices guides to mitigate excipient risks^7,8,9. These industry guides can be used for managing and evaluating cross contamination from a gluten-containing ingredient. 

The various excipient GMPs were updated to bring them in line with the latest thinking on excipient GMP requirements. The quality of excipients is critical to ensure the safety, quality, and efficacy of medicines. Excipients have a wide range of applications and are essential components of the drug product formulation. Characteristics that excipients impart to drug products make the application of appropriate GMP principles essential. 

Excipient cross contamination is controlled by applying appropriate GMP principles during manufacturing. The various excipient GMPs noted above discuss equipment cleaning and related requirements. Evidence of the effectiveness of cleaning procedures is based on studies showing that the procedures achieved predetermined acceptance criteria. Equipment and utensils must be cleaned at appropriate intervals to prevent cross-contamination of the excipient. 

In addition, excipient manufacturers establish a composition profile¹⁰ that identifies the main components of the excipient and determines their normal range of concentration. Acceptable limits are based on a risk assessment using sound science. Manufacturers of wheat-based excipients should conduct product testing and process capability evaluations to certify that the excipient contains less than 20 ppm of gluten. 

Conclusion 

The position of IPEC-Americas is that FDA CDER should be aligned with either the information on the CDER webpage (not more than 0.5 mg/unit dose) or CFSAN (<20 ppm) and define “gluten-free” for excipients. Not having established limits for the term “gluten- free” is confusing and does a disservice to consumers. The FDA should use consistent terminology and limits related to gluten content for both food and drugs. 

Further, IPEC-Americas does not support requiring that all drug products be “gluten-free” or labeled as such. IPEC-Americas recommends that an established gluten level should be defined in guidance and that, when applicable, manufacturers use a labeling statement to reflect potential gluten concentrations above the established level. 

Patients with celiac disease need to know if a drug product contains a gluten risk so they know which products to avoid, but negative Praclabeling such as “gluten-free” is not beneficial to the consumer. It is often taken advantage of by marketing and consumer groups, even when there is no potential for gluten to be present (“gluten-free water” for example). This is likely to create an unattainable, zero-tolerance situation for drug product manufacturers and give consumers the impression that the presence of any gluten is cause for concern, when, in fact, gluten is a health concern only for an extremely small percentage of the population. Furthermore, patients may avoid necessary or beneficial medications due to gluten concerns when there is no significant risk (<20 ppm). 

Drug product manufacturers have access to information regarding the origin of the ingredients used in their formulations, including the presence of gluten-containing ingredients. Most drug product manufacturers obtain this information from their suppliers, usually in the form of statements or questionnaires. IPEC is updating its Excipient Information Package (EIP) Guide¹¹ to incorporate reference to “gluten statement(s)” in an EIP.

IPEC-Americas supports the FDA’s initiative to ensure that drug product manufacturers obtain information regarding the gluten content of the excipients used in their products. When an excipient contains more than a designated level of gluten, the drug product manufacturer should be required to obtain information from the supplier to determine how the presence of gluten may impact the finished drug product’s labeling.

References 

1. FDA Draft Guidance: Gluten in Drug Products and Associated Labeling Recommendations Guidance for Industry, December 2017. 

2. Medications and Gluten: “What types of ingredients that may contain gluten are in oral drug products? https://www.fda.gov/Drugs/Resources ForYou/Consumers/BuyingUsing MedicineSafely/EnsuringSafeUseof Medicine/ucm410373.htm. 

3. CODEX Alimentarius: Standard for Foods for Special Dietary Use for Persons Intolerant to Gluten, CODEX STAN 118-1979. Adopted in 1979. Amendment: 1983 and 2015. Revision: 2008. 

4. FDA Threshold Working Group Approaches to Establish Thresholds for Major Food Allergens and for Gluten in Food: https://www. fda.gov/Food/GuidanceRegulation/ GuidanceDocumentsRegulatory Information/Allergens/ucm106 108.htm. 

5. Ankita V. Shah, Abu T. M. Serajuddin, and Robert A. Mangione. “Making All Medications Gluten Free.” Journal of Pharmaceutical Sciences. 2018. Vol. 107, No. 5. pages 1,263-1,268. 

6. FDA SUPAC-IR “Guidance for Industry: Immediate Release Solid Oral Dosage Forms: Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation.” November 1995. https://www. fda.gov/downloads/drugs/guidances/ ucm070636.pdf. 

7. The International Pharmaceutical Excipient Council & The Pharmaceutical Quality Group The Joint Good Manufacturing Practices Guide for Pharmaceutical Excipients. 2017. https://www. ipec.org/sites/default/files/files/ 20170323%20IPEC-PQG%20 GMP%20Guide_Final.pdf. 

8. NSF/IPEC/ANSI-363. “Good Manufacturing Practices for Pharmaceutical Excipients.” 2016. 9. EXCiPACT. “Certification Standards for Pharmaceutical Excipient Suppliers: Good Manufacturing Practices/Good Distribution Practices.” 2017. https://www.excipact.orgfiles/ EXCiPAT/Downloads/20180123%20EXC%20Standard_Final-webversion.pdf. 

10. “The IPEC Excipient Composition Guide.” 2009. (revision currently in progress). http://ipeceurope. org/UPLOADS/IPECCom positionGuidefinal.pdf. 

11. “IPEC Excipient Information Package Template and User Guide.” 2009. (revision currently in progress). https://ipecamericas.org/sites/ default/files/ExcipientInformation Package2009.pdf. 

Christopher C. DeMerlis is head of CCD Consulting Services; Luke Grocholl, PhD, is a regulatory affairs expert at MilliporeSigma; Jeffrey Pitt is lead toxicologist at DuPont Nutrition & Health; Irwin Silverstein, PhD, is head of IBS Consulting in Quality; Stephen M. Tyler is director of quality assurance at Abbvie; and Priscilla Zawislak is global regulatory affairs advocacy manager at Dow Chemical. IPEC-Americas (571 814 3449, ipec americas.org) develops, implements, and promotes voluntary science and risk-based guidance for excipients while embracing harmonization of drug approvals and pharmacopeial standards. 

IPEC-Americas is dedicated to working closely with regulatory authorities, industry organizations, and scientific bodies (globally) to advance public health on matters relating to the quality, safety, manufacture, distribution, use, and functionality of excipients. Membership is comprised of a unique partnership between makers, suppliers/distributors, and users of drug components. This partnership enables drug manufacturers to work with excipient suppliers to develop and promote guidance that facilitates the qualification, manufacture, and supply of excipients.