GRAS Notifications to FDA – a Review of Ingredients with Intended Use In

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GRAS Ingredients for Use in Medical Foods

GRAS Ingredients for Use in Medical Foods:

An Overview of FDA Regulation

Ginny Bank, Cheryl Dicks, MS, RAC

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GRAS Ingredients for Use in Medical Foods

Contents

Introduction ...... 3

FDA Medical Food Regulation Overview ...... 4

GRAS Notifications to FDA – A Review of Ingredients with Intended Use in

Medical Foods ...... 6

Ready to seek GRAS status for your medical food ingredient? ...... 11

Regulatory Services Include: ...... 11

Uncover greater market opportunities for your ingredient ...... 12

Contact GRAS Associates today ...... 12

Appendix A – Summary of GRAS Notifications Submitted to FDA for

Ingredients Intended for Use in Medical Foods ...... 13

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GRAS Ingredients for Use in Medical Foods

Introduction

The medical food arena is a growing specialty product category that presents food and dietary supplement manufactures with interesting business opportunities for market expansion of an ingredient or final product. The Business Insights: The Emerging Market for Medical Foods Nutraceuticals World report states that the U.S. has seen over 100 new medical foods enter the marketplace since 2009. Medical foods marketing does, however, present regulatory challenges within the “gray zone” of regulation and guidance for medical foods as overseen by the Food and Drug Administration (FDA).

In this article, you will learn:

 What products/ingredients are classified as medical foods  How medical foods differ from conventional foods, dietary supplements and specialty foods  Specific regulatory requirements for medical foods as overseen by the FDA  What you need to do to ensure your medical food complies with the regulations  The benefits of Generally Recognized as Safe (GRAS) regulatory filings for medical food ingredients  Which ingredients have already achieved GRAS status in marketplace  Common reasons for FDA warning letters for medical foods  How to avoid getting an FDA warning letter

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GRAS Ingredients for Use in Medical Foods

FDA Medical Food Regulation Overview

A medical food, is defined in section 5(b)(3) of the 1988 Orphan Drug Act (ODA) (21 U.S.C. 360ee(b)(3)). This category is defined as “a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.”

The Agency, in 1996, published solicited comments on their advance notice of proposed rulemaking (ANPRM) for this broad category of “foods.” The ANPRM was removed in 2004 and revised as a question and answer guidance document in 2007. In 2013, FDA published a revised version of its 2007 draft guidance for medical foods, Draft Guidance for Industry: Frequently Asked Questions About Medical Foods; Second Edition. This was recently followed up with the Final Guidance on Frequently Asked Questions About Medical Foods. This revised guidance reflects FDA’s viewpoint that the statutory definition of medical foods is to be narrowly constrained to the types of products that fit within this category of food and to distinguish them from “specialty foods,” outlining the criteria. According to the final guidance, a medical food:

 Provides distinctive nutritional requirements, not met by alteration to normal diet;  Can be foods intended for persons not able to ingest foods in certain physical forms; i.e., partial or exclusive oral intake or enteral tube feeding;  Is an integral part of the patent's clinical management under medical supervision;  Is intended for the "specific dietary management" of a disease or condition;

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GRAS Ingredients for Use in Medical Foods

 Is a food that is processed or specially formulated and not in its “natural” state.

Furthermore, according to the FDA’s Compliance Program for Medical Foods, medical foods are classified into the following categories:

a) Nutritionally complete formulas; b) Nutritionally incomplete formulas, including individual "modular" type products that may be mixed with other products before use (e.g., protein, carbohydrate, or fat modulars); c) Formulas for metabolic (genetic) disorders in patients over 12 months of age; or d) Oral rehydration products.

There is much confusion around what type of food or dietary ingredient qualifies as a medical food. It is important note that medical food are NOT foods used in their “natural state” or dietary supplements simply recommended by a physician as part of an overall diet to manage the symptoms or reduce the risk of a disease or condition, and all foods fed to sick patients are not medical foods. Medical foods are foods that are specially formulated and processed for a patient who is seriously ill or who requires use of the product as a major component of a disease or condition’s specific dietary management and cannot be achieved by changes to a normal diet. In addition, medical foods must also comply with all applicable requirements for the manufacture of foods. Ingredients used in medical foods must be approved food additives or a food additive that is the subject of an exemption for investigational use (21 U.S.C. 321 and 348), if the ingredients are not Generally Recognized as Safe (GRAS).

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GRAS Ingredients for Use in Medical Foods

GRAS Notifications to FDA – A Review of Ingredients with Intended Use in Medical Foods

In an attempt to gain insight on defining the “gray zone” of medical food regulation as well as a better understanding of FDA’s viewpoint in the regulation of this category of foods which allows for permissible health and disease claims, a review of GRAS notifications to FDA, identifying medical foods as one of the food uses, is warranted. The review investigated whether the GRAS notification treated the intended use of the ingredient in medical foods differently than its use in conventional foods.

A number of companies have notified FDA of GRAS determinations for ingredients with an intended use in medical foods (A summary of these ingredients is supplied in Appendix A). The majority of the ingredients were found to be sources of specific nutrients such as dietary sources of carotenoids, making up the largest number of medical food use determinations (GRN 110 and 140), minerals, fatty acids and fiber. Two submissions were for ingredients with a functional effect in the final product (e.g., sugar substitutes) and two fit neither category.

Some GRAS notifications to the FDA were amended after receiving a GRN number to include medical foods as observed with the notification of tomato extract (GRN 156) and tomato pulp powder (GRN 163); specifically determining the use of these ingredients in medical foods to be GRAS. In these amendments, the notifier states that “because there is no specific deficiency, disease, syndrome or symptom arising from an absence of lycopene, the addition of lycopene, in and by itself, cannot render a food a ‘medical food’ simply as the result of its addition to the food. In this GRAS notification, tomato extract of lycopene is to be added to foods already determined to be medical foods.” The amendments also include a very detailed definition of a medical food and a detailed evaluation of the dietary

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GRAS Ingredients for Use in Medical Foods

exposure for patients who will consume lycopene from a medical food in addition to conventional foods and dietary supplements containing lycopene. In addition, the amendments state that since medical foods are administered under supervision of a physician, it is therefore unlikely that there would be an overconsumption of lycopene. Both of the amendments received “No Questions” responses from FDA.

The use of palm oil-derivedcarotenoids (GRN 320) included medical foods in the intended uses noting a specific medical food use is for the treatment of erythropoietic protoporphyria. FDA responded with a “No Questions” letter. The medical food use of selenium (GRN 260) received a “No Questions” response from FDA, for use to “facilitate avoidance of selenium deficiency to this essential micronutrient.” The notification assumes that the medical foods uses would replace 20 servings per day of traditional foods and further noted that the medical food use is to be under the supervision of a physician, intake of the ingredient would be monitored to ensure safe use. GRN 260 received a “No Questions” response from FDA.

A second notification for selenium (GRN 353) also considers the use of medical foods as a supplement to the typical diet (when the medical food is not the sole source of the diet), but notes that since medical foods are administered under supervision of a physician, it is “likely that the physician is cognizant of the need for adequate amounts of selenium and the possible overdosing of selenium and therefore, will advise the patient to avoid other dietary sources rich in selenium.” In addition, the submission includes a detailed definition and categories of medical foods, as well as medical conditions for which medical foods are used (renal disease, hypermetabolic states, and malabsorption). While the notifier did not specifically state that the use of the ingredient would be used in medical foods to treat these conditions, it is certainly inferred. GRN 353 received a “No Questions” response from FDA.

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GRAS Ingredients for Use in Medical Foods

It was observed that while some GRAS notifications definitively outlined the intended use of the subject of the notification in medical foods, others do not.

GRAS notifications for dietary sources of DHA and EPA, including krill oil (GRN 242 and GRN 371), phosphatidylserine from fish (GRN 279), and phosphatidylserine from krill (GRN 311), pointedly separated medical food uses from the other food categories both by a much higher use rate and a brief definition of the Orphan Drug Act. All received “No Questions” responses from FDA.

On the contrary, GRAS notification for dietary fiber provided very little detail about their use in medical foods or differentiation between the intended uses in medical foods compared to conventional foods, some only differentiating (GRN 407) its intended use as a medical food only by pointing out that use in medical food is monitored by the health care provider and by estimating the use rate of medical foods based on the number of average servings of a medical food used. The notifiers did, however, point out that medical foods were not included in exposure estimates and a brief definition of a medical food is included. All received a “No Questions” response from FDA.

On the other hand, GRN 477 (long-chain inulin) provides a very detailed intended use description for medical foods. Unlike the other three fiber sources, the intended uses for long-chain inulin do not include conventional foods, only medical foods, and infant and toddler formulas. This submission notes that medical foods are used under physical supervision as supplemental or sole source of nutrition for those “who are unable to ingest sufficient nutrition from conventional foods.” Medical food use includes nutritionally incomplete oral products, nutritionally complete oral products, tube feedings, and pediatric nutritionals. Each of these categories is described in detail with examples of conditions in which the medical food addresses. This notification received a “No Questions” response from FDA.

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GRAS Ingredients for Use in Medical Foods

In every Response Letter from FDA to the notifier (with the exception of those GRNs that were withdrawn), a detailed definition of a medical food as per the ODA was included. In addition, the FDA states clearly that their response to the notice

“does not address the question of whether any particular food product that contains (the ingredient name) would be a medical food within the meaning of section 5(b) of the Orphan Drug Act, and thus would be except from the requirements for nutritional labeling, nutrient content claims, and health claims.”

FDA makes no other reference to medical foods in any of the responses.

A review of FDA Warning Letters using the term “medical foods” returned 10 letters sent between 2006 and 2013. The reason for most of these warning letters appears to be a result of companies attempting to market products that are clearly dietary supplements as medical foods. In each letter, FDA informs the manufacturer that their product is misbranded “because these products are intended to support diseases or conditions that do not have distinct requirements for certain nutrients, these products do not meet the statutory definition or regulatory criterion for medical foods set forth in 21 CFR 101.9(j)(8)(ii).” In addition, FDA also informs the manufacturer that since they are making disease claims, their products are also considered “New Unapproved Drugs.” Prompt action to correct the violations is requested.

It is clear that it would be difficult for any ingredient that is not a well- recognized nutrient to get through the notification process unless it has very specific use for a condition as defined in the Orphan Drug Act and meeting the criteria FDA has laid out in the revised guidance.

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GRAS Ingredients for Use in Medical Foods

While some notifications supplied very little detail on the use of the ingredient in medical foods, most included some simple elements to ensure FDA that the notifier is aware that the use of the ingredient in medical foods requires meeting certain requirements. We recommend that the following elements should be included in any FDA GRAS notification for use in medical foods:

1) Detailed definition of medical foods as per the Orphan Drug Act. 2) Estimated dietary exposure is calculated separately for medical foods. This provides additional evidence that the manufacturer perceives the use of the ingredient in medical foods as either a replacement of conventional foods servings and/or for use by only a small population of individuals (e.g., those with genetic disorders). 3) Awareness that medical foods require physician supervision, which helps eliminate concerns of exceeding maximum use levels. 4) A statement that the intended use of the ingredient in medical foods will follow all applicable regulations; 5) In cases in which a deficiency of the nutrient ingredient causes no specific disease or syndrome, a statement that the use of the ingredient in medical foods will be used only in foods already determined to be medical foods.

It is also important to have on hand substantial clinical support to demonstrate the efficacy and nutrient requirement of the medical food use through the “gold standard” of clinical trials (double-blind, randomized trials), that address nutrient deficiency and effect on targeted disease. This information should be part of a comprehensive product development plan, mapping a synergistic strategy between market placement and regulatory compliance for your medical food.

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GRAS Ingredients for Use in Medical Foods

Ready to seek GRAS status for your medical food ingredient?

GRAS Associates have extensive experience in medical food compliance, as well as the submission of GRAS notifications to the FDA.

With a 90% GRAS notification success rate—15% higher than the current industry average—the experienced GRAS Associates team will guide you through the regulatory review process to ensure your medical food is compliant with FDA requirements before going to market.

The GRAS Associates team is comprised of highly skilled toxicologists, biochemists and regulatory scientists with extensive experience helping clients overcome their most challenging regulatory hurdles.

Regulatory Services Include:

 New Dietary Ingredient Notifications (NDIN)  Regulatory Compliance and Product Development Consulting  Medical Foods Compliance  Animal Food and Feed  Food and Color Additive Petitions  Food Contact Notifications  Technical Writing  Literature Surveillance  Research & Product Testing  cGMP Compliance

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GRAS Ingredients for Use in Medical Foods

Uncover greater market opportunities for your ingredient

Contact GRAS Associates today

Email: [email protected] Phone: 1-239-444-1724

GRAS Associates, LLC 27499 Riverview Center Blvd., Suite 212 Bonita Springs, FL, USA 34134

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GRAS Ingredients for Use in Medical Foods

Appendix A – Summary of GRAS Notifications Submitted to FDA for Ingredients Intended for Use in Medical Foods

Date of FDA Ingredient GRN Manufacturer Intended Uses Closure response Ingredient in baked goods and baking mixes, soy milk, beverages and beverage powders, frozen dairy desserts and mixes, processed fruit and vegetable products, egg products and egg Lutein Esters 110 1/21/03 Cognis No questions substitutes, breakfast cereals (ready-to-eat and hot), fats and oils, hard candy, fruit snacks, and dairy products, and in medical foods intended as the sole item of the diet. Ingredient in baked goods and baking mixes, beverages and beverage bases, breakfast cereals, chewing gum, dairy product analogs, egg products, fats and oils, frozen dairy desserts and mixes, Crystalline Lutein 140 6/14/04 Kemin gravies and sauces, hard candy, infant and toddler No questions foods (other than infant formula), milk products, processed fruits and fruit juices, soft candy, soups and soup mixes, and in medical foods intended as the sole item of the diet.

GRAS Ingredients for Use in Medical Foods

Date of FDA Ingredient GRN Manufacturer Intended Uses Closure response Ingredients in baked goods, breakfast cereals, cheeses, condiments and relishes, confections, dairy product analogs, frozen dairy desserts, gelatins, puddings and fillings, grain products, Tomato gravies and sauces, jams and jellies, meat No Lycopene 156 2/7/05 LycoRed products, milk products, processed vegetables questions Extract and vegetable juices, snack foods, soft candies, soups and soup mixes.

Medical foods (additional correspondence 9/15/10) Ingredient in foods and beverages and in medical Notifier foods. requested FDA to Lactoferrin 162 2/7/08 Ingredient in oral rehydration solutions that are cease purified from medical foods intended for short-term evaluation rice Ventria consumption by children less than five years of

Biosciences age. Notifier

requested

FDA to Resubmission 235 3/12/10 cease evaluation

GRAS Ingredients for Use in Medical Foods

Date of FDA Ingredient GRN Manufacturer Intended Uses Closure response Ingredient in baked goods, ground meat products, meat analogs (vegetable protein-based), dairy Tomato Pulp products, soups and sauces. No 163 8/8/05 LycoRed Powder questions Beverages and medical foods (additional correspondence 1/26/07 and 9/15/10) Ingredient in foods and beverages and in medical Notifier foods. requested FDA to Lysozyme 174 2/7/08 cease purified from evaluation rice Ventria

Biosciences Ingredient in term infant formulas, pre-term infant Notifier

formulas, and fortifiers and in oral rehydration requested

solutions that are medical foods intended for FDA to Resubmission 191 3/31/10 short-term consumption by children up to three cease years of age. evaluation

GRAS Ingredients for Use in Medical Foods

Date of Ingredient GRN Manufacturer Intended Uses FDA response Closure 241 Ingredient in baked products, non-alcoholic 4/9/08 beverages, breakfast cereals, grain products and

pastas, milk products, processed fruits/fruit juices, Notifier High Selenium processed vegetables/vegetable juices, commercial requested FDA Yeast soups and soup mixes, and medical foods as a Cypress to cease source of selenium. Systems evaluation

Resubmitted No questions

3/9/09 260 Direct food ingredient in breakfast cereals, cheese, Neptune Krill Oil 242 10/14/08 beverages, fruit juices, frozen dairy desserts, milk No questions Technologies products, and medical foods. Sweetener in baked products, beverages (non- alcoholic), breakfast cereals, coffee and tea, confections and frostings, dairy product analogs, fats rebaudioside and oils, frozen dairy desserts, fruit and water ices, A purified from milk (whole and skim), milk products, processed the leaves of 278 7/20/09 Blue California No questions fruits and fruit juices, processed vegetables and Stevia vegetable juices, snack foods, soft candy, sugar rebaudiana substitutes, sweet sauces, toppings and syrups, meal replacement food products, and medical foods as well as used as a table top sweetener.

GRAS Ingredients for Use in Medical Foods

Date of Ingredient GRN Manufacturer Intended Uses FDA response Closure Ingredient in breakfast cereals, dairy product analogs, grain products and pastas, milk products, Phosphatidyl- and processed fruits and fruit juices, and as an serine from 279 7/25/09 Enzymotec No questions ingredient of medical foods. fish

(higher levels in medical foods) Ingredient in breakfast cereals, dairy product Krill-based analogs, grain products and pastas, milk products, phosphatidyl- 311 6/15/10 Enzymotec and processed fruits and fruit juices at a use level, No questions serine and as an ingredient in medical foods (higher levels in medical foods). In various food categories, excluding meat and Palm Oil- Malaysian poultry products, at the use levels listed in Table 1, derived 320 9/3/10 No questions Palm Oil Board and in medical foods at a level of 180 milligrams carotenoids (mg) β-carotene per day. Ingredient in yogurts, breads, instant cereals, breakfast and granola-type bars, soups, beverages, pastas, crackers, salty snacks, pretzels, and popcorn High Selenium 353 3/1/11 Alltech at levels of 5 to 60 milligrams per kilogram (mg/kg), No questions Yeast and in medical foods such that the daily intake will not exceed 19.2 mg per day (mg/day).

GRAS Ingredients for Use in Medical Foods

Date of FDA Ingredient GRN Manufacturer Intended Uses Closure response Ingredient in non-alcoholic beverages, breakfast cereals, cheeses, frozen dairy No Krill Oil 371 Aker Biomarine desserts, whole and skim milk, processed questions fruit and fruit juices, and medical foods. Variety of food categories including medical No D-psicose 400 6/18/12 Chelljedang foods (different use rate). questions (amendment to GRN 328) Ingredient to provide dietary fiber or to provide thickening or a stabilizing effect in Polysaccharide yogurts, milk shakes and fruit smoothie-type complex of konjac drinks, frozen yogurt, ice cream bars, No glucomannan, 407 4/10/12 Inovo Biologic puddings, white and whole wheat breads, questions sodium alginate cookies, breakfast bars, granola-type bars, and xanthan gum noodles, whole wheat cereals, meatless lasagna and macaroni/cheese, fruit juices, fruit juice bars, cereal beverages, and medical foods. Beta glucans from Garuda Source of fiber in a variety of foods and No 437 1/27/13 oat bran International medical foods. questions

GRAS Ingredients for Use in Medical Foods

Date of FDA Ingredient GRN Manufacturer Intended Uses Closure response Bulking agent in beers and ales, ingredient in breakfast bars, cereal bars, cheese, chewing gums, custards, flavored and soy Shangdong milk, gelatin desserts and salads, medical Xylooligosac- Longlive foods, milk and milk products, isotonic No 438 8/23/13 charides Biotechnology beverages, milk desserts, ready-to-drink questions Co. milk-based meal replacements, power bars, puddings, protein bars, processed fruits, juice drinks and punch, ready-to-eat cereals, sports drinks, and yogurt. Ingredient in exempt and non-exempt infant formulas for term infants at a maximum level of 0.8 grams (g) per liter (L) of formula, toddler formulas for children ages 12-35 No Long Chain Inulin 477 4/4/14 Danone months of age at a maximum level of 1.2 questions g/L of formula, and medical foods at maximum levels of up to 3.125 g per 1000 kilocalories (kcal).

GRAS Ingredients for Use in Medical Foods