Understanding FDA Regulations for the Food, Drug, and Medical Device Industries

The United States Food and Drug Administration (FDA) regulates, but is not limited to, the food, drug, and medical device industries, which are subject to the Federal Food, Drug and Cosmetic Act (FD&C Act or the Act).1 The Act is implemented under Title 21, Code of Federal Regulations (CFR) or 21 CFR Food and Drugs (also known as FDA regulations). FDA enforces the Act including other laws and regulations. It is of paramount importance to abide by the applicable laws and regulations, since FDA enforcement actions are based on the industry’s failure to comply with the Act, including other laws and FDA regulations.

This article focuses on three FDA enforcement actions in accordance with the Act and the FDA regulations. In particular, the authors discuss Form FDA 483s (FDA 483s),2 Warning Letters (Letters),3,4 and injunction5 cases related to Current Good Manufacturing Practices (cGMPs) applicable to the food (including dietary supplements), drug, and medical device industries. In addition, they offer best practices on how to improve the current compliance programs so that industries can avoid objectionable items to be cited in FDA 483s, FDA Warning Letters, and consent decree of permanent injunction, and to respond once FDA 483s are received.

Form FDA 483

According to section 704 of the Act (21 U.S.C. § 374), the FDA is authorized to perform inspections. There are three establishment inspection types:

  • Establishment Inspection—careful, critical, official examination of a facility to determine its compliance with laws administered by FDA
  • Comprehensive Inspection—risk-based routine surveillance
  • Directed Inspection—cause, complaint, Official Action Indicated (OAI) follow-up.

Specifically, section 704(b) of the Act (21 U.S.C. 374(b)) provides: Upon completion of any such inspection of a factory, warehouse, consulting laboratory, or other establishment, and prior to leaving the premises, the officer or employee making the inspection shall give to the owner, operator, or agent in charge a report in writing setting forth any conditions or practices observed by him/her which, in his/her judgment, indicate that any food, drug, device, cosmetic in such establishment (1) consists in whole or in part of any filthy, putrid, or decomposed substance or (2) has been prepared, packed, or held under insanitary conditions whereby it may have become contaminated with filth, or whereby it may have been rendered injurious to health. A copy of such report shall be sent promptly to the Secretary.

FDA 483 is a document used by the FDA to record and communicate issues discovered during the above-mentioned inspections. The FDA 483 notifies the management of a firm at the conclusion of an inspection of objectionable conditions based on the investigator’s judgment. Industry should be well aware of and become somewhat familiar with the FDA manuals that are used to train FDA investigators. These manuals are listed below.

  • Compliance Program Guidance Manual (CPGM) provides instruction to FDA personnel for conducting activities to evaluate industry compliance with the Act and other laws enforced by FDA
  • Investigation Operations Manual (IOM) serves as the primary procedure manual for FDA personnel performing inspections and special investigations
  • Inspection Technical Guides provide FDA personnel with technical background in a specific piece of equipment, or a specific manufacturing or laboratory procedure, etc.

However, please note that “Compliance Programs do not create or confer any rights for or on any person and do not operate to bind FDA or the public. An alternative approach may be used as long as the approach satisfies the requirements of the applicable statutes and regulations.”

FDA Warning Letters

Table 1 – FDA enforcement statistics summary, fiscal year 2013

Warning Letters are issued as part of FDA’s practice to give individuals/firms an opportunity to take voluntary and prompt Corrective Action (CA) before it initiates an Enforcement Action (EA). The purpose of the Letters is to achieve voluntary compliance and to establish prior notice on significant violations that will lead to enforcement action if not promptly and adequately corrected. It is recommended that one choose to respond within 15 working days from receipt of the Warning Letter.

As shown in Table 1, Warning Letters were the second most common FDA enforcement action in 2013 as a representative year in reference to other years. Furthermore, Figure 1 illustrates the exponential increase in the number of Warning Letters over the years. It should be noted that most of the Warning Letters in 2010 were food related. In addition to looking at Warning Letters, FDA 483 can be utilized as a learning tool for the industry to avoid FDA enforcement actions.

Figure 1 – FDA Warning Letters for fiscal years 2008–2013. Increase was due primarily to enforcement by FDA on individuals and firms in the food industry.

Consent decree of permanent injunction (injunction)

Injunction is a civil judicial process initiated to stop or prevent violation of the law. If a firm has a history of violations and has promised correction in the past, but has not made the corrections, the injunction is more likely to succeed. For an injunction action to be credible in the eyes of the U.S. Department of Justice (DOJ), the evidence must be current. Please note that a Warning Letter is not a prerequisite for an injunction.

Three recent injunction cases illustrate the consequence to the business in case of noncompliance:

1) In 2012, a dietary supplement company received the Warning Letter, which listed serious violation of cGMP requirements, including failure to perform at least one appropriate test or examination to verify the identity of a component that is a dietary ingredient prior to use per 21 CFR 111.75(a)(1)(i). Upon the receipt of the Letter, the company failed to implement Corrective Actions. As a result, in 2014, the company agreed to stop production and distribution of its products per a consent decree entered by the court due to its failure to follow cGMP requirements.

2) A cheese distribution company received a Letter and then the DOJ, at the request of the FDA, filed a complaint for a permanent injunction, preventing the distribution of the adulterated cheese products until the company brings its operations into compliance with the law.

3) A case for an injunction in 2008 prohibited the defendants from manufacturing, processing, packing, labeling, holding, or distributing any drug, other than specific over-the-counter drugs that may be legally marketed. The decree required the defendant to remedy the cGMP violations and allowed FDA to order the defendant to shut down the operation in the event of future violations.

cGMPs for the food and dietary supplement industry

The cGMP regulation is outlined in 21 CFR 110 for food and 21 CFR 111 for dietary supplements. GMPs explain the methods, equipment, facilities, and controls for producing processed food. There are seven subparts to the food GMP regulation, ranging from general provisions to specific provisions such as production and process control, equipment, buildings, and facilities.

In 2013, 2386 FDA 483s were issued in the food/dietary supplement industry alone. The top three most frequent observations were based on 21 CFR 110.35(c) Lack of Effective Pest Exclusion, 21 CFR 123.11(b) Sanitation Monitoring, and 21 CFR 110.20(b)(7) Screening. Table 2 lists the laboratory-related FDA 483s issued for food and dietary supplement cGMP, the majority of which is related to laboratory control processes and documentation/written procedures (commonly known as Standard Operating Procedures or SOPs).

Table 2 – Common deficiencies cited in 2013 laboratory-related FDA 483s for food industry

Those in the industry seem to believe that they have read, understood, and implemented the regulatory requirements in their SOPs. Even so, they are frequently cited for failures to establish and maintain adequate procedures and documentation. It should be noted that when it comes to compliance to applicable cGMPs, a firm should establish and maintain procedures in an adequate manner as part of the overarching Quality Management System (QMS). Otherwise, it invites its own risk and danger of noncompliance.

In an attempt to help industry better understand and adequately implement the regulatory requirements, an example of a gap analysis is given in Table 3.

Table 3 – Gap analysis between regulatory requirements and firm’s violations to ensure adequate understanding and interpretation of the applicable regulatory requirements for implementation

cGMPs for the drug industry

The cGMP for drugs is regulated through 21 CFR 210 cGMP in Manufacturing Processing, Packing or Holding of Drugs, and 21 CFR 211 cGMP for Finished Pharmaceuticals.

In 2013, 690 drug-related FDA 483s were issued. Of these 690, top laboratory-related FDA 483s were based on 21 CFR 211.160(b) where “the laboratory controls do not include the establishment of scientifically sound and appropriate [specifications] [standards] [sampling plans] [test procedures] designed to assure that [components] [drug product containers] [closures] [in-process materials] [labeling] [drug products] conform to appropriate standards of identity, strength, quality and purity.” Common deficiencies for the drug industry are shown in Table 4.

Table 4 – Summary of common deficiencies cited in 483s issued to both drug and device industries for the past eight years

cGMPs for the medical device industry

In the device industry, the cGMP for medical devices is better known as Quality System Regulations (QSRs), as incorporated in 21 CFR 820, or Quality Management Systems.

In 2013, a total of 1099 medical device FDA 483s were issued. The most frequent reason for the FDA 483s was due to 21 CFR 820.100(a) for lack of or inadequate procedures.

Industry’s common misconception leading to frequent mistakes

  • Mere understanding/interpretation instead of accurate understanding and adequate interpretation
  • Simple documentation without ensuring adequate documentation
  • Corrective action without using proper tools to identify root cause(s)
  • Lack of or poor awareness
  • Simple oral commitment in lieu of actual commitment
  • Too much focus on the business instead of on long-term investment
  • Temporary compliance versus sustainable compliance
  • No actual continuous improvement mainly due to a mere oral commitment

How to best deal with common mistakes

  • Management commitment
  • Be serious and act seriously
  • Understand, interpret, and implement adequately with improved awareness
  • Continuous improvement—not cost, but long-term investment attitude
  • Do not have an attitude of “it is just a warning (letter)”
  • Implement practical, actionable, and sustainable solutions/strategies in an integrated, thorough (PASS-IT) manner.

Three key elements to achieve compliance in a PASS-IT manner

There are three key elements for the industry to adequately achieve compliance:

  1. Understand and adequately interpret the regulatory requirements as set out in the Act and the FDA regulations
  2. Establish and maintain Standard Operating Procedures
  3. Carry out practical, actionable, and sustainable solutions/strategy in an integrated, thorough (PASS-IT) manner.

Best practices on how to respond to 483s

If a company receives a 483, it is in the best interest of the company to submit a response, although a response is not legally required. A timely response is crucial because it can mitigate the FDA’s decision for further action. By responding on time, the company can build credibility with the FDA and show its commitment to correcting outstanding issues. The response should include the following:

  1. State that you are fully committed to take Corrective Action (CA).
  2. Address each item separately, completely, and in full (or justification if you disagree with the observation).
  3. Provide your complete, realistic plan and implementation of CA (taken and to be taken) with a timeline that includes a systemic, retrospective CA with justification (e.g., why it is not applicable).
  4. Provide documentation (revised SOPs, training records, your method of verification, and/or validation of CA, including correction).
  5. Be sure to provide documented evidence based on “How” (e.g., how you are going to identify root causes and check the effectiveness of CA).

Conclusion

The protection of public health and safety are at the core of FDA’s enforcement of industry’s compliance with laws and regulations. This is manifested in the recent increase in Warning Letters in past years. Thus, more than ever it is the best time to ensure we understand the FDA regulations and laws more comprehensively and implement systems to achieve sustainable compliance. The information provided in this article can be applied to regulatory compliance areas beyond the cGMP compliance issues.

References

  1. Federal Food, Drug and Cosmetic Act.
  2. FDA Investigations Operations Manual (IOM) 5.2.3.1.4.
  3. FDA Regulatory Procedures Manual (Chapter 4: Advisory Actions).
  4. FDA Warning Letter Database.
  5. FDA Regulatory Procedures Manual (Chapter 6: Judicial Actions).

Disclaimer

Opinions and conclusions expressed in this article are those of the authors and not those of their respective employers or of any other third-party organization. The information contained in this article is for general guidance on matters of interest only and does not amount to legal advice in any way. Application of laws and the regulations can vary drastically based on individual facts and surrounding circumstances involved and thus should be handled case by case accordingly. Before making any legal decision, one should consult an attorney if needed.

Yoonhee Beatty, JD, RAC, is International Regulatory Affairs Specialist, Bard Access Systems, Inc., Salt Lake City, UT, U.S.A. David Lim, Ph.D., RAC, ASQ-CQA, is President and CEO, Regulatory Doctor, P.O. Box 148, Riner, VA 24149, U.S.A.; tel.: 800-321-8567; fax: 866-591-5671; e-mail: [email protected]; www.regulatorydoctor.com