United States: Current Trends In The FDA's Enforcement Of GMP Requirements

Last Updated: March 18 2013
Article by Jonathan Berman

Drugs and devices are "adulterated," as that term is used in the Food, Drug, and Cosmetic Act, if the drugs and devices are contaminated, impure, or diluted; deliver too much or too little of the active ingredient; or do not conform to mandatory specifications. A product can also be deemed "adulterated"—even in the absence of any such defects—if the manner in which the product was manufactured did not conform to the "Good Manufacturing Practice" or "Quality System" regulations (collectively known as the GMP regulations). Manufacturers therefore must not only avoid product defects but must also proactively undertake thorough measures designed to prevent defects. To enforce the adulteration, GMP, and other laws, the Food and Drug Administration ("FDA") conducts thousands of establishment inspections each year, issues thousands of "FDA-Form 483" observations alleging the adulteration of medical products, and issues hundreds of Warning Letters.

An analysis of recent Warning Letters and inspectional observation data reveals that, more than ever, most allegedly "adulterated" products work as intended and conform to all release specifications. Most Warning Letters, including most of those that focus on GMP issues, are not reactions to product failures. Rather, the bulk of the warnings reflect instead the FDA's increasing focus on the processes and procedures that are intended to prevent defects. For manufacturers, this means that there is no substitute for thoroughness and diligence, and that the process of manufacturing is as important as the results.

Although this Commentary focuses on medical products, food providers should note that enforcement of food GMP regulations is moving in the same direction. The FDA currently examines whether food processors—particularly processors of higher risk foods—are taking proactive steps to avoid contamination. Further, the FDA has recently released extensive proposed changes to the food GMP regulations. The new regulations, when finalized, will require almost all food processors to adopt stringent preventive controls.

Trends in Inspection Observations

If an FDA inspector notes any regulatory violations during an establishment inspection, the FDA will issue an "FDA-Form 483." This form sets out the inspector's observations. Although the FDA does not publish most 483s,1 the FDA does publish extensive summary statistics. This data set shows that the FDA cites inadequacies in the procedures for avoiding product defects far more often than actual product failures or responses to product failures.

This trend is most pronounced in the 483s issued to device manufacturers. The four most common observations are: failure to establish procedures for corrective and preventive action; failure to establish procedures for handling complaints; failure to develop, maintain, or implement adverse event reporting procedures; and failure to establish procedures to determine whether incoming materials and services conform to specifications. In all, 15 of the 25 most commonly cited violations involve a lack of established procedures (which could mean either that the written procedures are lacking or that a firm's employees fail to follow them). To be sure, the FDA also cites device manufacturers for inadequate documentation, failure to validate processes and designs, not investigating product failures, and other violations. But the FDA's emphasis on written procedures is striking.

The observations relating to drug facilities are more heterogeneous. Failure to establish written procedures is a persistent issue, and four of the seven most common violations fall into this category. Other common observations include: the responsibilities of the quality control unit are either not written or are not fully followed, the manufacturer failed to fully investigate out-of-specification batches (including both released and rejected batches), and laboratory controls are not validated.

For biologic facilities,2 the FDA cites inadequate procedures three times as often as any other observation. Failure to investigate out-of-specification products is the second most common violation, and the next four each relate to inadequate documentation.

Warning Letters, and How to Avoid Them

A Warning Letter, although technically informal, signals that the FDA is prepared to begin a court proceeding unless violations are quickly corrected. Most Warning Letters demand that the recipient set out, within 15 working days, "specific steps [the] firm has taken to correct the noted violations, as well as an explanation of how [the] firm plans to prevent these violations, or similar violations, from occurring again." Warning Letters are public. After only a short delay, and with minimal redactions, the FDA posts all Warning Letters to its web site—and from there it is often not long before the letters come to the attention of the media, investors, and plaintiffs' lawyers.

A review of recent Warning Letters shows that there is no simple method for avoiding them. Rather, manufacturers should commit themselves to the hard work of bringing their processes into compliance before the FDA arrives. It is also crucial to provide a thorough response if an inspection reveals GMP issues, and to give serious attention to complaints from patients and medical practitioners.

Releasing a contaminated or out-of-specification product into the marketplace increases the likelihood of an inspection and often results in a Warning Letter. A handful of Warning Letters directly cite such problems as grounds for issuing the Letter. More frequently, the FDA will cite the underlying GMP violation, noting the eventual product defect as an example of the importance of maintaining or following appropriate procedures.

It is more common still for the FDA to issue a Warning Letter on GMP issues where there is no known problem with the released products, and there have been no complaints. As the FDA wrote in one Warning Letter, "the lack of current customer complaints alone is neither a verification of a robust quality system nor that you have appropriate process controls in place." Indeed, only a minority of recent Warning Letters indicate that the finished product failed to perform or is known to be out of specification. Even in the absence of an actual product defect, the FDA is unwilling to tolerate unreliable processes that could result in defects.

Since Warning Letters, at least those that focus on GMP issues, are seldom issued immediately following an inspection, a firm can take steps to prevent a bad inspection from developing into a Warning Letter. In almost every instance, the FDA first provides its criticisms through 483 observations and in-person meetings, and solicits the firm's responses. While the FDA can and does issue Warning Letters regardless of the response, more commonly the FDA does not issue one unless the FDA perceives both a serious GMP issue and a failure to respond properly.

Providing a thorough response to the 483 is critical. Most GMP-related Warning Letters note that the manufacturer did respond, but conclude that the response is inadequate. The FDA typically demands an investigation of the cause of the observed GMP violations, a proposed solution, implementation of the solution (including retraining relevant employees), an investigation into released lots that may have been affected, and documentation demonstrating all actions were completed.

Another recurring cause of Warning Letters is poor handling of complaints. Manufacturers are required to collect complaints, evaluate them, and report certain adverse events to the FDA. The FDA has issued numerous Warning Letters to companies that do not implement (or do not have) written complaint handling procedures. This issue is more common with small or foreign companies that may not be fully conversant with FDA requirements. A problem that trips up large and small companies alike, however, is a failure to properly investigate complaints. If complaints indicate that a product is defective or dangerous, the FDA will expect an investigation that determines the root cause of the observed problems and leads to corrective actions.

Of course, many Warning Letters do not relate, or at least do not primarily relate, to GMP problems. Some letters are aimed at companies that make no apparent effort to comply with their regulatory obligations. Some of these companies may not believe that their products are subject to regulation. Others know but do not appear to care. Warning Letters to these companies indicate that everything is amiss: no registration, no product approvals, no written procedures, no adverse event reporting, etc. Established companies are unlikely to receive such letters.

The FDA issues other letters in response to allegedly impermissible advertising claims. The FDA sometimes issues "cyber" Warning Letters without an establishment inspection, relying solely on company web sites or other marketing materials. Some recipients of advertising-focused letters are fly-by-night operations that make extravagant claims about dubious products. But the FDA (and in particular the Office of Prescription Drug Promotion) also warns legitimate companies that, the FDA believes, make claims that outstrip their product approvals, or cross the blurry lines separating dietary supplements or cosmetics from drugs.

Viewing the body of recent Warning Letters as a whole, there is no one GMP regulation, nor even a discrete set of regulations, that can be said to command the FDA's focus. Rather, the FDA will scrutinize the entire manufacturing process.

Current and Future Enforcement of Food GMPs

When the FDA inspects food facilities, the most common negative observation, by a considerable margin, is that the facility did not adequately control pests. Other insanitary conditions likewise draw inspection observations and Warning Letters. But the FDA also focuses on failures to take proactive steps to maintain sanitary conditions. For example, design flaws hindering the cleaning of a facility are cited (slightly) more often than actual failures to maintain a facility in a sanitary condition. Many fisheries, which are subject to stringent "HACCP" regulations3 in addition to the general GMP requirements, receive warnings for failing to take mandatory proactive steps. Eight of the 15 regulations most cited in 483s to food establishments pertain only to fisheries. These regulations mandate establishing a plan for sufficient monitoring of sanitation conditions, implementing the plan, recordkeeping, and verification of various aspects of the HACCP plan.

The FDA's focus on preventive steps will only increase when the Food Safety Modernization Act ("FSMA") is fully implemented. The FDA views this 2011 law as a "sweeping reform" that will "ensure the U.S. food supply is safe by shifting the focus from responding to contamination to preventing it."

Among many other provisions, FSMA requires most food manufacturers to implement "hazard analysis and risk-based preventive controls" similar to the HACCP obligations that currently apply to only a subset of the industry. On January 4, 2013, the FDA released draft regulations that will implement this mandate and will overhaul and modernize the GMP regulations pertaining to environmental pathogens, food allergens, mandatory employee training, and sanitation of food contact surfaces. These regulations are not binding at present, nor are they in their final form. But when they go into effect, the FDA's focus on preventive steps will be redoubled.


There are no quick fixes for avoiding 483 observations and Warning Letters. Product failures may encourage the FDA to increase the frequency of inspection of a facility. But avoiding product failures will not prevent inspections, and even without product failures, the FDA will demand full compliance with GMP requirements.

1.Form 483s are public; the FDA posts selected 483s to the FDA web site, and generally 483s can be obtained from the FDA through FOIA (Freedom of Information Act) requests. But the FDA does not post the vast majority of the 483s.

2.In this dataset, "biologic" facilities are largely facilities that handle blood products.

3.Hazard Analysis Critical Control Points. The HACCP regulations pertaining to processors of fish or fishery products are collected at 21 C.F.R. Part 123.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

To print this article, all you need is to be registered on Mondaq.com.

Click to Login as an existing user or Register so you can print this article.

Jonathan Berman
Similar Articles
Relevancy Powered by MondaqAI
Akin Gump Strauss Hauer & Feld LLP
Strasburger & Price, L.L.P.
In association with
Related Topics
Similar Articles
Relevancy Powered by MondaqAI
Akin Gump Strauss Hauer & Feld LLP
Strasburger & Price, L.L.P.
Related Articles
Up-coming Events Search
Font Size:
Mondaq on Twitter
Register for Access and our Free Biweekly Alert for
This service is completely free. Access 250,000 archived articles from 100+ countries and get a personalised email twice a week covering developments (and yes, our lawyers like to think you’ve read our Disclaimer).
Email Address
Company Name
Confirm Password
Mondaq Topics -- Select your Interests
 Law Performance
 Law Practice
 Media & IT
 Real Estate
 Wealth Mgt
Asia Pacific
European Union
Latin America
Middle East
United States
Worldwide Updates
Registration (you must scroll down to set your data preferences)

Mondaq Ltd requires you to register and provide information that personally identifies you, including your content preferences, for three primary purposes (full details of Mondaq’s use of your personal data can be found in our Privacy and Cookies Notice):

  • To allow you to personalize the Mondaq websites you are visiting to show content ("Content") relevant to your interests.
  • To enable features such as password reminder, news alerts, email a colleague, and linking from Mondaq (and its affiliate sites) to your website.
  • To produce demographic feedback for our content providers ("Contributors") who contribute Content for free for your use.

Mondaq hopes that our registered users will support us in maintaining our free to view business model by consenting to our use of your personal data as described below.

Mondaq has a "free to view" business model. Our services are paid for by Contributors in exchange for Mondaq providing them with access to information about who accesses their content. Once personal data is transferred to our Contributors they become a data controller of this personal data. They use it to measure the response that their articles are receiving, as a form of market research. They may also use it to provide Mondaq users with information about their products and services.

Details of each Contributor to which your personal data will be transferred is clearly stated within the Content that you access. For full details of how this Contributor will use your personal data, you should review the Contributor’s own Privacy Notice.

Please indicate your preference below:

Yes, I am happy to support Mondaq in maintaining its free to view business model by agreeing to allow Mondaq to share my personal data with Contributors whose Content I access
No, I do not want Mondaq to share my personal data with Contributors

Also please let us know whether you are happy to receive communications promoting products and services offered by Mondaq:

Yes, I am happy to received promotional communications from Mondaq
No, please do not send me promotional communications from Mondaq
Terms & Conditions

Mondaq.com (the Website) is owned and managed by Mondaq Ltd (Mondaq). Mondaq grants you a non-exclusive, revocable licence to access the Website and associated services, such as the Mondaq News Alerts (Services), subject to and in consideration of your compliance with the following terms and conditions of use (Terms). Your use of the Website and/or Services constitutes your agreement to the Terms. Mondaq may terminate your use of the Website and Services if you are in breach of these Terms or if Mondaq decides to terminate the licence granted hereunder for any reason whatsoever.

Use of www.mondaq.com

To Use Mondaq.com you must be: eighteen (18) years old or over; legally capable of entering into binding contracts; and not in any way prohibited by the applicable law to enter into these Terms in the jurisdiction which you are currently located.

You may use the Website as an unregistered user, however, you are required to register as a user if you wish to read the full text of the Content or to receive the Services.

You may not modify, publish, transmit, transfer or sell, reproduce, create derivative works from, distribute, perform, link, display, or in any way exploit any of the Content, in whole or in part, except as expressly permitted in these Terms or with the prior written consent of Mondaq. You may not use electronic or other means to extract details or information from the Content. Nor shall you extract information about users or Contributors in order to offer them any services or products.

In your use of the Website and/or Services you shall: comply with all applicable laws, regulations, directives and legislations which apply to your Use of the Website and/or Services in whatever country you are physically located including without limitation any and all consumer law, export control laws and regulations; provide to us true, correct and accurate information and promptly inform us in the event that any information that you have provided to us changes or becomes inaccurate; notify Mondaq immediately of any circumstances where you have reason to believe that any Intellectual Property Rights or any other rights of any third party may have been infringed; co-operate with reasonable security or other checks or requests for information made by Mondaq from time to time; and at all times be fully liable for the breach of any of these Terms by a third party using your login details to access the Website and/or Services

however, you shall not: do anything likely to impair, interfere with or damage or cause harm or distress to any persons, or the network; do anything that will infringe any Intellectual Property Rights or other rights of Mondaq or any third party; or use the Website, Services and/or Content otherwise than in accordance with these Terms; use any trade marks or service marks of Mondaq or the Contributors, or do anything which may be seen to take unfair advantage of the reputation and goodwill of Mondaq or the Contributors, or the Website, Services and/or Content.

Mondaq reserves the right, in its sole discretion, to take any action that it deems necessary and appropriate in the event it considers that there is a breach or threatened breach of the Terms.

Mondaq’s Rights and Obligations

Unless otherwise expressly set out to the contrary, nothing in these Terms shall serve to transfer from Mondaq to you, any Intellectual Property Rights owned by and/or licensed to Mondaq and all rights, title and interest in and to such Intellectual Property Rights will remain exclusively with Mondaq and/or its licensors.

Mondaq shall use its reasonable endeavours to make the Website and Services available to you at all times, but we cannot guarantee an uninterrupted and fault free service.

Mondaq reserves the right to make changes to the services and/or the Website or part thereof, from time to time, and we may add, remove, modify and/or vary any elements of features and functionalities of the Website or the services.

Mondaq also reserves the right from time to time to monitor your Use of the Website and/or services.


The Content is general information only. It is not intended to constitute legal advice or seek to be the complete and comprehensive statement of the law, nor is it intended to address your specific requirements or provide advice on which reliance should be placed. Mondaq and/or its Contributors and other suppliers make no representations about the suitability of the information contained in the Content for any purpose. All Content provided "as is" without warranty of any kind. Mondaq and/or its Contributors and other suppliers hereby exclude and disclaim all representations, warranties or guarantees with regard to the Content, including all implied warranties and conditions of merchantability, fitness for a particular purpose, title and non-infringement. To the maximum extent permitted by law, Mondaq expressly excludes all representations, warranties, obligations, and liabilities arising out of or in connection with all Content. In no event shall Mondaq and/or its respective suppliers be liable for any special, indirect or consequential damages or any damages whatsoever resulting from loss of use, data or profits, whether in an action of contract, negligence or other tortious action, arising out of or in connection with the use of the Content or performance of Mondaq’s Services.


Mondaq may alter or amend these Terms by amending them on the Website. By continuing to Use the Services and/or the Website after such amendment, you will be deemed to have accepted any amendment to these Terms.

These Terms shall be governed by and construed in accordance with the laws of England and Wales and you irrevocably submit to the exclusive jurisdiction of the courts of England and Wales to settle any dispute which may arise out of or in connection with these Terms. If you live outside the United Kingdom, English law shall apply only to the extent that English law shall not deprive you of any legal protection accorded in accordance with the law of the place where you are habitually resident ("Local Law"). In the event English law deprives you of any legal protection which is accorded to you under Local Law, then these terms shall be governed by Local Law and any dispute or claim arising out of or in connection with these Terms shall be subject to the non-exclusive jurisdiction of the courts where you are habitually resident.

You may print and keep a copy of these Terms, which form the entire agreement between you and Mondaq and supersede any other communications or advertising in respect of the Service and/or the Website.

No delay in exercising or non-exercise by you and/or Mondaq of any of its rights under or in connection with these Terms shall operate as a waiver or release of each of your or Mondaq’s right. Rather, any such waiver or release must be specifically granted in writing signed by the party granting it.

If any part of these Terms is held unenforceable, that part shall be enforced to the maximum extent permissible so as to give effect to the intent of the parties, and the Terms shall continue in full force and effect.

Mondaq shall not incur any liability to you on account of any loss or damage resulting from any delay or failure to perform all or any part of these Terms if such delay or failure is caused, in whole or in part, by events, occurrences, or causes beyond the control of Mondaq. Such events, occurrences or causes will include, without limitation, acts of God, strikes, lockouts, server and network failure, riots, acts of war, earthquakes, fire and explosions.

By clicking Register you state you have read and agree to our Terms and Conditions