FDA Warning Letters About Food Products: How to Avoid or Respond to Citations

FDA Warning Letters About Food Products

How to Avoid or Respond to Citations

Joy L. Frestedt

Alimentix, The Minnesota Diet Research Center, United States

Table of Contents

Cover image

Title page

Copyright

Acknowledgments

Chapter 1. History of FDA, Food Regulations, and Warning Letters to Food Companies

1.1. Food and Drug Administration History

1.2. Food Regulations

1.3. Guidance Documents for Food Companies

1.4. Food and Drug Administration Enforcement Activities

1.5. Warning Letter Process

1.6. Food Warning Letter Examples (Domestic)

1.7. Warning Letter Examples (International)

1.8. Publications

1.9. Conclusions

1.10. Questions to Test Understanding

Chapter 2. Introduction to Quality Systems

2.1. Good Manufacturing Practices and Quality System Controls

2.2. Regulations and Guidance Documents

2.3. Quality System Warning Letter Examples

2.4. Publications

2.5. Conclusions

2.6. Questions to Test Understanding

Chapter 3. Hazard Analysis and Critical Control Points

3.1. Hazard Analysis and Critical Control Points Principles

3.2. Developing a HACCP Plan

3.3. Regulations and Guidance Documents

3.4. What Is HARPC?

3.5. Warning Letter Examples

3.6. Publications

3.7. Conclusions

3.8. Questions to Test Understanding

Chapter 4. Imports/Exports

4.1. Food Import/Export Regulations

4.2. Importing Food Into the United States

4.3. Exporting Food Out of the United States

4.4. Food and Drug Administration Import and Export Guidance Documents

4.5. Warning Letter Examples

4.6. Publications

4.7. Conclusions

4.8. Questions to Test Understanding

Chapter 5. Food Contact Substances

5.1. Food Additives, Color Additives, and Food Contact Substances

5.2. Food Contact Substance (FCS) Regulations

5.3. Food Contact Substance Guidance Documents

5.4. Warning Letter Examples

5.5. Publications

5.6. Conclusions

5.7. Questions to Test Understanding

Chapter 6. Clinical Trials for Foods and Dietary Supplements

6.1. Clinical Trial Regulations

6.2. Regulations

6.3. Guidance Documents

6.4. Warning Letter Examples

6.5. Publications

6.6. Conclusions

6.7. Questions to Test Understanding

Chapter 7. Food Safety Modernization Act (FSMA)

7.1. Food Safety Modernization Act Requirements

7.2. Regulations and Guidance Documents

7.3. Warning Letter Examples

7.4. Publications

7.5. Conclusions

7.6. Questions to Test Understanding

Chapter 8. Future Trends and Directions

8.1. Restructuring the Food and Drug Administration and Changes in Administration

8.2. Increasing Final Rules and Guidance Documents

8.3. Program Alignment and Increasing Oversight of Food Safety

8.4. Focus on Transparency

8.5. Metrics and Food Safety Recalls

8.6. Trends in Food Marketing Terms: Natural, Dietary Fiber, and Added Sugars

8.7. Sugar-Sweetened Beverage Tax

8.8. Food Safety Concerns

8.9. Warning Letter Trends

8.10. Publications

8.11. Conclusions

8.12. Questions to Test Understanding

Appendices

Index

Copyright

Academic Press is an imprint of Elsevier

125 London Wall, London EC2Y 5AS, United Kingdom

525 B Street, Suite 1800, San Diego, CA 92101-4495, United States

50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States

The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom

Copyright © 2017 Elsevier Inc. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices

Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.

Practitioners and researchers may always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.

To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

Library of Congress Cataloging-in-Publication Data

A catalog record for this book is available from the Library of Congress

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library

ISBN: 978-0-12-805470-3

For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Andre Gerhard Wolff

Acquisition Editor: Nancy Maragioglio

Editorial Project Manager: Billie Jean Fernandez

Production Project Manager: Poulouse Joseph

Designer: Greg Harris

Typeset by TNQ Books and Journals

Acknowledgments

Many thanks to the editors and publishers at Elsevier who have contributed to this book and also to Kaitlin Cady, Dr. Lindsay Young, and Leslie Kruk for their assistance in the development of certain parts of individual chapters within this book.

Chapter 1

History of FDA, Food Regulations, and Warning Letters to Food Companies

Abstract

Regulating food is an important function to ensure the health of a population. Removal of contaminated/adulterated food and foods promoted with unscrupulous advertising (e.g., misbranded food) is helpful to ensure food products are safe when they are marketed for human consumption. This chapter reviews some food regulatory history and numerous guidance documents and describes how Warning Letters are used to encourage voluntary compliance with food regulations in the United States (US) including foods produced in the US and foods imported into the US from foreign countries. Several authors have published information on the use of Warning Letters to address food safety issues, and this chapter concludes with some questions to assist the reader in reviewing of some main concepts covered in this chapter.

Keywords

Code of Federal Regulations; Drug and Cosmetic Act; Food; Food and Drug Administration; Food safety; Guidance documents; Warning Letters

Outline

1.1 Food and Drug Administration History

1.2 Food Regulations

1.3 Guidance Documents for Food Companies

1.4 Food and Drug Administration Enforcement Activities

1.5 Warning Letter Process

1.6 Food Warning Letter Examples (Domestic)

1.6.1 Warning Letters About Dietary Supplements Containing Ephedra

1.6.2 Warning Letters About Weight Loss Products

1.6.3 Warning Letters About Front-of-Package Nutrition Labeling

1.6.4 Warning Letters About Caffeinated Alcoholic Beverages

1.7 Warning Letter Examples (International)

1.8 Publications

1.9 Conclusions

1.10 Questions to Test Understanding

References

1.1. Food and Drug Administration History

The United States (US) Food and Drug Administration (FDA) reports many milestones in the nearly 200-year history of the FDA (2013) and a few of these milestones are listed and discussed below:

• 1837, US Patent Office recommended a national agency to encourage agriculture

• 1839, US Congress appropriated $1000 to gather statistics

• 1846, publication about adulteration of foods by Dr. Lewis Calib Beck

• 1848, US Congress appropriated $1000 to chemically analyze foods in US Patent Office

• 1849, Dr. Beck published Report on the Breadstuffs of the United States

• 1862, US Congress created US Department of Agriculture (USDA)

• 1890, USDA includes a Division of Chemistry

• 1901, Division of Chemistry became the Bureau of Chemistry

• 1927, Bureau of Chemistry became Food, Drug and Insecticide Administration (FDIA)

• 1930, FDIA became the Food and Drug Administration (FDA)

• 1940, FDA moved from USDA to Federal Security Agency

• 1953, FDA moved to Department of Health, Education, and Welfare

• 1979, Department of Health, Education, and Welfare became the Department of Health and Human Services (DHHS)

Food safety was largely the responsibility of state and local regulators; however, the FDA began regulating foods and drugs after the 1906 Pure Food and Drugs Act, which prohibits adulterated or misbranded foods or drugs in interstate commerce. This law was debated for nearly 25  years as industry and consumer complaints grew and created the federal food and drug inspector role. Back then, as now, inspectors worked to convince food and drug manufacturers to improve operations or face court cases to prevent poisoning or consumer fraud. Over time, law enforcement became more uniform, and precedents resulting from earlier court decisions created a faster process.

The Food Drug and Cosmetic Act (FDCA) was passed in 1938 as FDA staff were deployed to collect all Elixir Sulfanilamide from stores and homes across the country. The FDA could only charge the company with misbranding even though the liquid product had resulted in more than 100 deaths, mostly in children, because the product contained a solvent similar to antifreeze. From this point forward, the FDA required manufacturers to show safety data for a new drug before any marketing or interstate commerce would be legal in the US. The FDA began carrying out seizures of dangerous drug products and they began gathering data about spray residues, food poisonings, and problems with sanitation.

The 1962 Kefauver–Harris drug amendments added the ability for FDA to enforce current good manufacturing practices (cGMPs) and to review efficacy claims after the lack of drug safety testing resulted in babies born with birth defects when pregnant women consumed thalidomide. From this point forward, the FDA required any claims about new drug efficacy to be shown through credible scientific evidence in adequate and well-designed clinical trials, and each drug would need to be approved by the FDA before the drug could be marketed in the US.

1.2. Food Regulations

In 1899, a new law authorized the Secretary of Agriculture to inspect imported foods and, in 1907, field laboratories were set up in New York, Philadelphia, Boston, Chicago, New Orleans, and San Francisco. Ten years later, in 1917, three districts were set up: Eastern, Central, and Western US (FDA, 2010a).

The 1906 Pure Food and Drugs Act prohibited misbranded/adulterated foods, drinks, and drugs as well as color additives in foods to conceal inferiority or poisons in interstate commerce. Although no premarket approval system was in place, the government could act to remove injurious products from the market. At the same time, the 1906 Meat Inspection Act provided continuous inspection of all red meats in US interstate distribution. This law came after unsanitary conditions in meat packing plants were widely publicized in The Jungle by Upton Sinclair. Also, in 1907, the Food Inspection Decision (FID) 76 listed seven colors approved for use in food, and subsequent FIDs led to voluntary certification and more approved colors for foods (FDA, 2009a).

In 1912, the Sherley Amendment prohibited false therapeutic claims (FDA, 2009b), in 1913 the Gould Amendment required contents to be marked on the outside of food packages, and in 1924 the Supreme Court ruled against deceptive labeling on food; however, in 1938 the FDCA was required before the FDA had the authority to issue food standards for identity, quality, and container fill details (FDA, 2009a).

Food preservatives were studied prior to the FDCA, and a group called the Poison Squad actually consumed foods containing measured amounts of chemical preservatives (FDA, 2009a). These experiments led to recommendations to use chemical preservatives only when necessary, to require the food producer to be responsible for the safety of the foods they produce, and to inform consumers about the ingredients in the foods on the food label. The FDCA required food labels to bear the common/usual name of the food (rather than deceptive distinctive names) and required colors to be listed/approved in the Color Certification Program before any use in foods, drugs, or cosmetics (e.g., this included batch certification for colors made from coal tar). During this same time frame, the US Public Health Service proposed the 1934 Restaurant Sanitation Regulations, which later became the Food Code guiding retail establishments, food service providers, and vending services to keep food safe.

Between 1939 and 1957, additional food standards were issued for tomatoes, jams, jellies, flour, cereals, milk, chocolate, cheese, juices, and eggs (FDA, 2009a). The Food Additives Amendment of 1958 requires manufacturers to establish the safety of any new food additive before marketing (i.e., FDA approval of the new food additive is required before marketing and the Delaney Clause prohibits approval of any cancer-causing food additive). An exclusion to FDA approval of a new food additive is allowed for any food substance generally recognized as safe (GRAS) by qualified experts, and the first list of nearly 200 GRAS substances was published by the FDA in 1958.

The Color Additive Amendments of 1960 require manufacturers to establish the safety of color additives before use in foods, drugs cosmetics, or medical devices. Only about half of the original 200 color additives originally listed by the FDA in 1960 are listed in 2016 as having sufficient scientific data to support their safety (FDA, 2009a).

The Fair Packaging and Labeling Act of 1966 Act allowed the FDA to enforce honest and informative labeling for foods, drugs, cosmetics, and medical devices in interstate commerce (FDA, 2009a).

A chloride deficiency syndrome was identified in 1979 among 130 infants and was associated with two chloride-deficient infant soy formulas (FDA, 2009a). Chloride is an essential nutrient for infant growth and development, and the absence of this nutrient in these infant formulas led to the Infant Formula Act of 1980, which requires manufacturers to have quality control procedures for batch testing to evaluate required nutrients, stability testing to establish product shelf life, container coding to identify each batch, and record keeping to be maintained for FDA inspection.

The FDA Center for Food Safety and Applied Nutrition (CFSAN) was formed in 1984 and is responsible for the safety of most foods in the US today (except meat, poultry, and certain egg products, which are regulated by the USDA). The 1990 Nutrition Labeling and Education Act requires Significant Scientific Agreement for any health claim showing a relationship between a food and a reduced risk of disease (e.g., calcium in dairy products reduces the risk of osteoporosis; soluble fibers in fruits, vegetables, and grains reduce the risk of coronary heart disease). In addition, the Nutrition Facts Panel of 1993 requires standardized terms such as low fat and light. In addition, basic per-serving nutrition information must include clear and reliable serving sizes and amounts of calories, fat, sodium, protein, vitamins, etc.

Since 1992, the FDA has published guidelines and evaluates genetically engineered foods to ensure safety. The first genetically engineered whole food to enter the US market in 1994 was a tomato. The USDA regulates the impact of these plants on the agricultural environment, and the Environmental Protection Agency (EPA) ensures the pesticides introduced into plants are safe for human and animal consumption (FDA, 2009a).

In 1997, the Food Safety Initiative was proposed in the Food Safety From Farm to Table report where the Hazard Analysis and Critical Control Point (HACCP) process was highlighted as a means to improve food safety (FDA, 2009a). The FDA introduced the Seafood HACCP in 1995, followed by the meat and poultry processing HACCP in 1998, and the Juice HACCP in 2001, which became effective in 1997, 2003, and 2004, respectively. Prior to this time, processors relied on general sanitation, GMP, and testing to ensure compliance with regulations. The HACCP system adds a proactive hazard analysis (to identify hazards that might cause food to be unsafe to eat) with targeted critical control points (established and monitored in each food processor situation) and good record keeping (clearly documenting efforts to identify and minimize risks including risks to basic requirements of general sanitation, GMP, and product testing). In addition, a national fingerprinting database of bacterial deoxyribonucleic acid (DNA) was created to evaluate common infection sources and to speed up determinations when an outbreak occurs. FoodNet websites [Foodborne Diseases Activity Surveillance Network, supported by FDA, Centers for Disease Control and Prevention (CDC), and USDA] create a networking tool for detecting, responding to, and preventing foodborne illness.

The 1994 Dietary Supplement Health and Education Act (DSHEA) created a special regulatory category for dietary supplements and ingredients with specific labeling and FDA notifications. DSHEA specifically requires dietary supplements to be regulated like foods as opposed to drugs (FDA, 2009a). Dietary supplements do not require FDA review or approval for safety or effectiveness prior to US marketing. Dietary supplement manufacturers are required to submit a premarket notice to the FDA with appropriate safety evidence for any dietary ingredients/supplements if they were NOT on the market before DSHEA and they are not GRAS. Structure–function claims were allowed for dietary supplements as defined in an FDA rule in 2000, and cGMP requirements were put into place for dietary supplements in 2003 to help prevent adulteration and misbranding (i.e., mistakes with ingredients, contaminants, labeling, and packaging). Preapproval is not required for GRAS, dietary supplement, and conventional foods; however, the FDA will take action against unsafe products. For example, in 2004, the FDA banned ephedra from dietary supplements because of concerns about cardiovascular effects.

US terrorist attacks on 11SEP2001 led the FDA to assess US food supply vulnerabilities, to establish the Food Emergency Response Network (including laboratories ready to respond to a food security emergency) and to release four new regulations under the Public Health Security and Bioterrorism Preparedness and Response Act of 2002: (1) food facilities must register with the FDA, (2) they must receive prior notice of imported food shipments before food arrives in the US, (3) they must keep records of their food sources and recipients, and (4) the FDA may detain any food for up to 30  days when credible evidence suggests the food poses a threat of serious adverse health consequences or death to humans or animals (FDA, 2009a).

In 2003, the CFSAN Adverse Event Reporting System was launched to track and monitor adverse events in foods and dietary supplements and the FDA works to rapidly identify and control foodborne disease outbreaks (FDA, 2009a). Also in 2003, the FDA announced trans-fat content (associated with heart disease) must be included in the Nutrition Facts Panel, and in 2004 the Food Allergen Labeling and Consumer Protection Act requires protein source labeling for any major food allergen ingredients in a food (e.g., peanuts; soybeans; cow’s milk; eggs; fish; crustacean shellfish, such as shrimp and crabs; tree nuts; and wheat).

Nutrition and labeling regulations have greatly expanded over the years including the more recent Food Safety Modernization Act (FSMA) of 2011, which is changing the way food safety is managed by the FDA.

1.3. Guidance Documents for Food Companies

As documented in the FDA’s Food Guidance Documents website (FDA, 2017a), an increasing number of food guidance documents are published regularly and recently added documents are listed (FDA, 2017a). The number of documents in the FDA’s searchable database for guidance documents is constantly in flux with documents appearing and being removed from the database regularly. For instance, during preparation of this book, a search of the FDA guidance document database identified 3441 total entries with 406 documents containing food and 178 containing CFSAN terms. Two months later, the identical search identified 3390 total guidance documents with 408 food and 180 CFSAN documents, and 5.5  months later, the same search identified 3461 total documents with 432 related to food and 193 to CFSAN. Dozens of documents are being issued or changed each year and this fluctuation in availability and speed of guidance document change makes regulatory work challenging as individual regulatory staff struggle to stay current on rapidly changing FDA guidance documents.

Not only does the number of guidance documents change, but the content of individual guidance documents also changes over time as guidance documents are withdrawn or superseded by newer versions of the old documents. For example, the following food guidance documents were introduced to represent FDA’s current thinking at the time of this publication. Legislative changes and FDA priorities are reflected in the released guidance topics during this time.

• Food Safety (FSMA): Draft Guidance for Industry: Control of Listeria monocytogenes in Ready-To-Eat Foods (January 2017)

• Labeling & Nutrition: Draft Guidance for Industry: Questions and Answers on the Nutrition and Supplement Facts Labels Related to the Compliance Date, Added Sugars, and Declaration of Quantitative Amounts of Vitamins and Minerals (January 2017)

• Labeling & Nutrition: Draft Guidance for Industry: Reference Amounts Customarily Consumed: List of Products for Each Product Category (January 2017)

• Food Defense (Registration): Draft Guidance for Industry: Questions and Answers Regarding Food Facility Registration (Seventh Edition)—Revised (December 2016)

• Food Safety (FSMA): Third-Party Certification Body Accreditation for Food Safety Audits: Model Accreditation Standards (December 2016)

• Infant Formula: Draft Guidance for Industry: Preparation of Food Contact Notifications for Food Contact Substances in Contact with Infant Formula and/or Human Milk (December 2016)

• Juice: Draft Guidance for Industry: Fruit Juice and Vegetable Juice as Color Additives in Food (December 2016)

• Food Safety (FSMA): FDA’s Voluntary Qualified Importer Program (November 2016)

• Acidified and Low-Acid Canned Foods: Submitting Form FDA 2541 (Food Canning Establishment Registration) and Forms FDA 2541d, FDA 2541e, FDA 2541f, and FDA 2541g (Food Process Filing Forms) to FDA in Electronic or Paper Format (November 2016)

• Labeling & Nutrition: Draft Guidance for Industry: Scientific Evaluation of the Evidence on the Beneficial Physiological Effects of Isolated or Synthetic Nondigestible Carbohydrates Submitted as a Citizen Petition (21 CFR 10.30) (November 2016)

• Food Safety (FSMA): Draft Guidance for Industry: Questions and Answers Regarding Food Facility Registration (Seventh Edition) (November 2016)

• Food Safety (FSMA): FDA’s Voluntary Qualified Importer Program (November 2016)

• Food Additives: Frequently Asked Questions about GRAS (October 2016)

• Food Safety (FSMA): What You Need to Know About the FDA Regulation: Current Good Manufacturing Practice, Hazard Analysis, and Risk-Based Preventive Controls for Human Food; Small Entity Compliance Guide (October 2016)

• Food Safety (FSMA): Draft Guidance for Industry: Describing a Hazard That Needs Control in Documents Accompanying the Food, as Required by Four Rules Implementing FSMA (October 2016)

• Food Defense (Registration): Necessity of the Use of Food Product Categories in Food Facility Registrations and Updates to Food Product Categories (2016 Edition) (September 2016)

• Infant Formula: Labeling of Infant Formula (September 2016)

• Infant Formula: Draft Guidance for Industry: Substantiation for Structure/Function Claims Made in Infant Formula Labels and Labeling (September 2016)

• Labeling & Nutrition: Use of the Term Healthy in the Labeling of Human Food Products (September 2016)

• Dietary Supplements: Draft Guidance: New Dietary Ingredient Notifications and Related Issues (August 2016)

• Food Safety (FSMA): Draft Guidance for Industry: Hazard Analysis and Risk-Based Preventive Controls for Human Food (August 2016)

• Food Safety (FSMA): Draft Guidance for Industry: Classification of Activities as Harvesting, Packing, Holding, or Manufacturing/Processing for Farms and Facilities (August 2016)

• Labeling & Nutrition: Draft Guidance for Industry: Calorie Labeling of Articles of Food in Vending Machines (August 2016)

• Labeling & Nutrition: Calorie Labeling of Articles of Food in Vending Machines; Small Entity Compliance Guide (August 2016)

• Labeling & Nutrition: FDA’s Policy on Declaring Small Amounts of Nutrients and Dietary Ingredients on Nutrition Labels (July 2016)

• Food Defense (Prior Notice): Prior Notice of Imported Food Questions and Answers (Edition 3) (June 2016)

• Food Ingredients and Packaging: Draft Guidance for Industry: Voluntary Sodium Reduction Goals: Target Mean and Upper Bound Concentrations for Sodium in Commercially Processed, Packaged, and Prepared Foods (June 2016)

• Labeling & Nutrition: Ingredients Declared as Evaporated Cane Juice (May 2016)

• Food Safety (FSMA): Draft Guidance for Industry: Qualified Facility Attestation Using Form FDA 3942a (for Human Food) or Form FDA 3942b (for Animal Food) (May 2016)

• Medical Foods: Frequently Asked Questions About Medical Foods; Second Edition (May 2016)

• Labeling & Nutrition: A Labeling Guide for Restaurants and Retail Establishments Selling Away-From-Home Foods—Part II (Menu Labeling Requirements in Accordance with 21 CFR 101.11) (April 2016)

• Metals: Draft Guidance for Industry: Inorganic Arsenic in Rice Cereals for Infants: Action Level (April 2016)

• Infant Formula: Exempt Infant Formula Production: Current Good Manufacturing Practices (CGMPs), Quality Control Procedures, Conduct of Audits, and Records and Reports (April 2016)

• Chemical Contaminants: Acrylamide in Foods (March 2016)

• Labeling & Nutrition: Nutrient Content Claims; Alpha-Linolenic Acid, Eicosapentaenoic Acid, and Docosahexaenoic Acid Omega-3 Fatty Acids; Small Entity Compliance Guide (February 2016)

For comparison, a couple of earlier guidance documents included the following when genetically engineered foods were a political priority:

• Food Labeling: Draft Guidance for Industry: Voluntary Labeling Indicating Whether Food Has or Has Not Been Derived From Genetically Engineered Atlantic Salmon (November 2015)

• Food Labeling: Voluntary Labeling Indicating Whether Foods Have or Have Not Been Derived from Genetically Engineered Plants (November 2015)

When browsing the guidance documents by Topic for Food, a total of 235 guidance documents were reviewed and a clear trend for rapidly increasing guidance documents is obvious (Fig. 1.1).

Figure 1.1  Number of food guidance documents by year (as of 15JAN2017).

Twenty years ago, the FDA issued zero to one guidance document each year (1993–97); however, the FDA has increased the number of guidance documents more than 30-fold during these 20  years. The spike of 24 guidance documents issued in 2009 is related to updates in food labeling including health claims made in food labeling (n  =  7), microbial safety in plant products and produce (5), chemicals found in bottle water (3), safety reporting for dietary supplements including liquid dietary supplements and beverages (3), seafood certifications (2), and color additives, food additives, food defense, and food registry information (1 each, 4) guidance documents. For comparison, 31 guidance documents were issued in 2016 and these were related to food defense (10), labeling (9), infant formula (4), chemical (3), submission/consultation (2), and medical food, canned food, dietary supplement (1 each, 3) guidance documents. Keeping up with new regulations and guidance is an increasingly difficult task.

Note the number of FDA guidance documents available in the FDA guidance document database decreased over six weeks from 31MAR2016 (n  =  3441) to 14MAY2016 (n  =  3390) while new documents were constantly being added. This decrease is not easily explained by withdrawn or superseded documents because these are also being listed in the database (even though most of these withdrawn/superseded documents are no longer available to read). The reason for this overall decrease and the increasing numbers of withdrawn and superseded documents is not clear (but may be related to poorly controlled quality review and accounting processes for guidance document management at the FDA). These types of issues may render this database and the ability to find needed documents somewhat unreliable. Also the rationale for guidance development appears to be in reaction to external events, entirely consistent with the historical development of the FDA, but this process could be improved by a more risk-based approach to guidance development (e.g., develop guidance for the highest-risk items first and ensure those risks are carefully and completely covered before moving on to other lower-level risks).

Figure 1.2  Food guidance documents (n   =   236) by type (1993–2016; as of 15JAN2017).

Note: Allergens (n  =  5) includes one labeling guidance not included in labeling, dietary supplements (n  =  15) includes one labeling guidance not included in labeling, and seafood/fish (n  =  10) does not include one about labeling GMO salmon, which is counted in labeling, not fish.

An analysis of the 235 food guidance documents listed by the FDA at the time of this book’s preparation allowed a grouping of these guidance documents by topic areas and indicated food defense, labeling, and chemical additives topics were the most common types of guidance documents generated by the FDA (Fig. 1.2).

Because the FDA Guidance Documents change often and navigating the FDA database to find the applicable guidance document is difficult, Appendix 1 lists the year and title for each guidance referenced in this chapter. This table shows how the superseded and withdrawn documents are sometimes traced to the next available document and sometimes are not traced to the replacement document. Also, the table illustrates the rather arbitrary types of guidance documents issued, from a single guidance about lead-free pottery and the Proper Identification of Ornamental and Decorative Ceramicware to the 10 guidance documents on Juice HACCP and pathogen reduction. Obviously, finding the right guidance may be difficult and can become a shot in the dark by searching for a specific guidance by name and finding only tangentially related guidance documents in the FDA guidance database.

1.4. Food and Drug Administration Enforcement Activities

Any of the regulations can be the source of a Warning Letter if the FDA inspects a facility and finds the company is not in compliance with the regulations. Guidance documents are designed to help companies avoid Warning Letters. For example, 10 guidance documents were listed for seafood manufacturers (Table 1.1), which may be helpful to avoid a Warning Letter about seafood processing, export, hazard controls, etc.

Table 1.1

Guidance Documents Applicable to Seafood Manufacturing

Guidance documents are intended to convey the current FDA thinking on particular topics, and these guidance documents are not legally binding; however, they provide a good strategy for compliance and documentation.

The FDA uses many different methods to secure voluntary compliance with US laws and regulations including the following:

• Issuing guidance documents and providing education and public meetings

• Establishment inspections and EIRs (Establishment Inspection Reports)

• Import monitoring (they may deny entry into the US)

• Adverse event and complaints monitoring (they analyze MedWatch and other reports)

• Notifications (they evaluate submissions)

• New dietary ingredient

• Food additive

• Color additive

• Food contacting substances

• Infant formula

• Sample collection and analysis (they report problematic findings)

• Research, focus groups, advisory boards (they conduct studies and convene groups)

• laboratory studies, e.g., to detect pathogens/contaminants, evaluate virulence

• health effects, e.g., to understand the impact of dietary factors, pathogens

• food processing research, e.g., to understand food composition, allergenicity

• cosmetic ingredient research, e.g., to determine skin penetration and health effect

• Memo of understanding (they issue memoranda to partnering groups)

• Academic partnerships (they establish Centers of Excellence to protect the food supply)

• State agreements (they partner with state governments to conduct inspections)

• International organization education (they work to harmonize safety standards)

This last bullet is important because the FDA has greatly increased efforts outside the US because of international treaties and increasing amounts of food moving into the US from locations around the world.

As reported in the FDA website CFSAN—What We Do (2017), the FDA also partners with other federal and local agencies to monitor the US food supply including the US Department of Commerce’s National Marine Fisheries Service, CDC, US Department of Treasury’s US Customs and Border Protection, Federal Trade Commission (FTC), Department of Transportation (DoT), Consumer Product Safety Commission (CPSC), EPA, and the US Department of Justice (DoJ) (FDA, 2016a). Of note, the state regulates food made and sold entirely within the state while the FDA regulates food moving between states.

1.5. Warning Letter Process

A Warning Letter can be issued for a multitude of reasons, and it is just one of the many tools used by the FDA to secure voluntary compliance with the US laws and regulations. US laws are codified in the US Code of Federal Regulations (CFR), and when an FDA inspector finds an individual or company has violated the US laws and regulations, he/she may issue a Warning Letter to notify the person or company of the violation. The process begins when the FDA determines a particular organization or person will be inspected. The FDA uses an FDA Form 482: Notice of Inspection and follows up the inspection with an FDA Form 483 only if significant unresolved violations of the FDCA are reported by the inspector at the end of the inspection. The FDA Form 483 is considered along with the written Establishment Inspection Report, any evidence collected during the inspection, and any responses provided by the individual or company.

Persons receiving an FDA Form 483 are encouraged to reply within 15  days by writing to the FDA and explaining how all of the identified issues will be resolved.

The FDA maintains the Inspection Classification Database Search (FDA, 2016b) where individuals can search to see if a company or individual was issued an FDA Form 483. This database indicates the location and date of the inspection, the area to be inspected, and if the inspection resulted in No Action Indicated, Voluntary Action Indicated, or Official Action Indicated. In addition, inspection observations and citations are available in annual datasets and summaries. Failure to correct violations identified by the FDA may lead to a Warning Letter and further enforcement activities including recall, seizure, injunction, administrative detention, civil monetary penalties, and criminal prosecution to achieve correction.

The Warning Letter is designed to identify the violation (such as poor manufacturing practices, lack of claim support for a product, or incorrect uses promoted for a product) and make clear how the person or company can correct the problem. The Warning Letter will define the time frame for a response and the FDA will follow up to ensure the company has employed adequate corrections to the problems identified. When replying to a Warning Letter, the most important part is to ensure the problem will not recur and to provide clear and complete information about how the immediate correction and future prevention activities will be rolled out to ensure success. Including specific pieces of data with the reply will be most helpful.

1.6. Food Warning Letter Examples (Domestic)

The FDA Inspections, Compliance, Enforcement, and Criminal Investigations website (FDA, 2016c) reviews Criminal Investigations and provides Compliance Manuals and Inspection References for FDA inspectors as they complete their daily activities. The searchable FDA Warning Letters database provides data back to 2005 (FDA, 2017b) and older data are archived elsewhere [e.g., Warning Letters and Notice of Violation Letters to Pharmaceutical Companies back to 1998 (FDA, 2015a) and Office of Scientific Investigations Warning Letters back to 1997 (FDA, 2015b)]. Even though the Freedom of Information Act was amended in 1996 to require electronic reading room access to public information (FDA, 2016d), older Warning Letters back to 1996 are difficult to find on the current FDA websites, and food-related Warning Letters, in particular, take many forms and are often related directly to FDA-specific initiatives.

1.6.1. Warning Letters About Dietary Supplements Containing Ephedra

The FDA issued a safety alert about ephedra and other botanical dietary supplements in 1994 (FDA, 2014a), and the FDA sent Warning Letters to 61 companies making dietary supplements with ephedra in 2003 because these products were found to present an unreasonable risk of illness or injury (FDA, 2014b). The reported reactions ranged from mild adverse events (e.g., nervousness, dizziness, tremor, alternations in blood pressure or heart rate, headache, gastrointestinal distress) to chest pain, myocardial infarction, hepatitis, stroke, seizures, psychosis, and death (FDA, 2014a).

The FDA issued a ban on ephedra in dietary supplements in 2004 and seized more than 2.1M Vitera-XT capsules from Asia MedLabs Inc. in Houston, TX. A search of the FDA Warning Letter database for the term ephedra identified six Warning Letters issued between 2005 and 2016 (Table 1.2).

The Warning Letter to Total Body Nutrition identified an unapproved ingredient (methylsynephrine) in products named Ephedra Free Tummy Tuck and Ephedra Free Shredder. The Warning Letter to Journey Health USA notes their dietary supplement containing ephedra must be removed from the market. The Warning Letter to Chaotic Labz, Inc. indicates the label must list the part of the plant from which the ephedra extract is derived in the Malice in Wonderland product. The Ephedra—Ephedra sinica Herbal Dietary Supplement by Heron Botanicals, Inc. is allegedly misbranded because the labels fail to list the name and place of business of the manufacturer, packer, or distributor in accordance with 21 CFR 101.5.

Table 1.2

Ephedra Warning Letters 15MAY2016

CFSAN, Center for Food Safety and Applied Nutrition.

The Warning Letter to Life Enhancement Products, Inc. indicates the Starters’ Traditional Chinese Ephedra Herbal Tea contained Ma Huang, also known as ephedra, which is an unsafe food additive according to the FDA. The Warning Letter stated: In assessing the GRAS status of Ma Huang for use in a beverage product such as Starters’ Traditional Chinese Ephedra Herbal Tea, FDA considered the criteria described above. FDA’s final rule prohibiting the sale of dietary supplements containing ephedrine alkaloids’ describes the serious cardiovascular risks associated with ephedrine alkaloids. Although the rule applies only to dietary supplements, ephedrine alkaloids in conventional foods, such as herbal teas, have the same physiological activity and therefore present the same types of cardiovascular risks… FDA determined this product was adulterated and misbranded.

In addition, the Warning Letter to Great American Products, Inc. identified products being promoted with claims not supported by competent and reliable scientific evidence including ephedra free. These products are misbranded because the website claims lack substantiation and are false or misleading. These Warning Letters suggest a wide variety of topics are reviewed by the FDA during an inspection of a food facility even when the focus of the inspection is on a particular product component such as ephedra.

1.6.2. Warning Letters About Weight Loss Products

Weight loss products were the center of attention in 2004, when the FDA issued Warning or Advisory Letters to dietary supplement distributors with unsubstantiated weight loss claims. These Warning Letters included a description of an FTC report, which identified eight weight loss claims considered false for nonprescription weight loss products:

• "Consumers who use the advertised product can lose 2  pounds or more per week (over 4 or more weeks) without reducing caloric intake and/or increasing their physical activity.

• Consumers who use the advertised product can lose substantial weight while still enjoying unlimited amounts of high calorie foods.

• The advertised product will cause permanent weight loss (even when the user stops using the product).

• The advertised product will cause substantial weight loss through the blockage of absorption of fat or calories.

• Consumers who use the advertised product (without medical supervision) can safely lose >3  pounds per week for a period of >4  weeks.

• Users can lose substantial weight through the use of the advertised product that is worn on the body or rubbed into the skin.

• The advertised product will cause substantial weight loss for all users.

• Consumers who use the advertised product can lose weight only from those parts of the body where they wish to lose weight."

Some of the products cited are no longer on the market and some of the companies are no longer in business while other companies modified their marketing materials and continue to produce the weight loss products cited in these Warning Letters.

The Warning Letters database was searched for the term weight loss to see if additional Warning Letter activities related to weight loss claims were ongoing and 99 Warning Letters were found (Fig. 1.3).

The FDA issues about eight Warning Letters each year to food and dietary supplement manufacturers regarding weight loss products including big companies as well as many, much smaller companies.

1.6.3. Warning Letters About Front-of-Package Nutrition Labeling

For example, in 2009, the FDA Commissioner, Dr. Margaret Hamburg encouraged food companies to review labeling practices to ensure front-of-package nutrition labeling will help consumers choose healthy diets. In line with this initiative, 17 Warning Letters and 1 untitled letter were issued for 24 food products reportedly in violation of the FDCA, which clearly requires labels to be truthful and not misleading (Appendix 2). The requirement for calorie and nutrient content of food was considered important in light of diet-related diseases and obesity in the US. This initiative was designed to encourage food manufacturers to improve their labeling and included