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.

Conclusion

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.

Authors
Jonathan Berman
 
In association with
Up-coming Events Search
Tools
Print
Font Size:
Translation
Channels
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
Password
Confirm Password
Position
Mondaq Topics -- Select your Interests
 Accounting
 Anti-trust
 Commercial
 Compliance
 Consumer
 Criminal
 Employment
 Energy
 Environment
 Family
 Finance
 Government
 Healthcare
 Immigration
 Insolvency
 Insurance
 International
 IP
 Law Performance
 Law Practice
 Litigation
 Media & IT
 Privacy
 Real Estate
 Strategy
 Tax
 Technology
 Transport
 Wealth Mgt
Regions
Africa
Asia
Asia Pacific
Australasia
Canada
Caribbean
Europe
European Union
Latin America
Middle East
U.K.
United States
Worldwide Updates
Check to state you have read and
agree to our Terms and Conditions

Terms & Conditions and Privacy Statement

Mondaq.com (the Website) is owned and managed by Mondaq Ltd and as a user you are granted a non-exclusive, revocable license to access the Website under its terms and conditions of use. Your use of the Website constitutes your agreement to the following terms and conditions of use. Mondaq Ltd may terminate your use of the Website if you are in breach of these terms and conditions or if Mondaq Ltd decides to terminate your license of use for whatever reason.

Use of www.mondaq.com

You may use the Website but are required to register as a user if you wish to read the full text of the content and articles available (the Content). 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 & conditions or with the prior written consent of Mondaq Ltd. You may not use electronic or other means to extract details or information about Mondaq.com’s content, users or contributors in order to offer them any services or products which compete directly or indirectly with Mondaq Ltd’s services and products.

Disclaimer

Mondaq Ltd and/or its respective suppliers make no representations about the suitability of the information contained in the documents and related graphics published on this server for any purpose. All such documents and related graphics are provided "as is" without warranty of any kind. Mondaq Ltd and/or its respective suppliers hereby disclaim all warranties and conditions with regard to this information, including all implied warranties and conditions of merchantability, fitness for a particular purpose, title and non-infringement. In no event shall Mondaq Ltd 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 or performance of information available from this server.

The documents and related graphics published on this server could include technical inaccuracies or typographical errors. Changes are periodically added to the information herein. Mondaq Ltd and/or its respective suppliers may make improvements and/or changes in the product(s) and/or the program(s) described herein at any time.

Registration

Mondaq Ltd requires you to register and provide information that personally identifies you, including what sort of information you are interested in, for three primary purposes:

  • To allow you to personalize the Mondaq websites you are visiting.
  • To enable features such as password reminder, newsletter alerts, email a colleague, and linking from Mondaq (and its affiliate sites) to your website.
  • To produce demographic feedback for our information providers who provide information free for your use.

Mondaq (and its affiliate sites) do not sell or provide your details to third parties other than information providers. The reason we provide our information providers with this information is so that they can measure the response their articles are receiving and provide you with information about their products and services.

If you do not want us to provide your name and email address you may opt out by clicking here .

If you do not wish to receive any future announcements of products and services offered by Mondaq by clicking here .

Information Collection and Use

We require site users to register with Mondaq (and its affiliate sites) to view the free information on the site. We also collect information from our users at several different points on the websites: this is so that we can customise the sites according to individual usage, provide 'session-aware' functionality, and ensure that content is acquired and developed appropriately. This gives us an overall picture of our user profiles, which in turn shows to our Editorial Contributors the type of person they are reaching by posting articles on Mondaq (and its affiliate sites) – meaning more free content for registered users.

We are only able to provide the material on the Mondaq (and its affiliate sites) site free to site visitors because we can pass on information about the pages that users are viewing and the personal information users provide to us (e.g. email addresses) to reputable contributing firms such as law firms who author those pages. We do not sell or rent information to anyone else other than the authors of those pages, who may change from time to time. Should you wish us not to disclose your details to any of these parties, please tick the box above or tick the box marked "Opt out of Registration Information Disclosure" on the Your Profile page. We and our author organisations may only contact you via email or other means if you allow us to do so. Users can opt out of contact when they register on the site, or send an email to unsubscribe@mondaq.com with “no disclosure” in the subject heading

Mondaq News Alerts

In order to receive Mondaq News Alerts, users have to complete a separate registration form. This is a personalised service where users choose regions and topics of interest and we send it only to those users who have requested it. Users can stop receiving these Alerts by going to the Mondaq News Alerts page and deselecting all interest areas. In the same way users can amend their personal preferences to add or remove subject areas.

Cookies

A cookie is a small text file written to a user’s hard drive that contains an identifying user number. The cookies do not contain any personal information about users. We use the cookie so users do not have to log in every time they use the service and the cookie will automatically expire if you do not visit the Mondaq website (or its affiliate sites) for 12 months. We also use the cookie to personalise a user's experience of the site (for example to show information specific to a user's region). As the Mondaq sites are fully personalised and cookies are essential to its core technology the site will function unpredictably with browsers that do not support cookies - or where cookies are disabled (in these circumstances we advise you to attempt to locate the information you require elsewhere on the web). However if you are concerned about the presence of a Mondaq cookie on your machine you can also choose to expire the cookie immediately (remove it) by selecting the 'Log Off' menu option as the last thing you do when you use the site.

Some of our business partners may use cookies on our site (for example, advertisers). However, we have no access to or control over these cookies and we are not aware of any at present that do so.

Log Files

We use IP addresses to analyse trends, administer the site, track movement, and gather broad demographic information for aggregate use. IP addresses are not linked to personally identifiable information.

Links

This web site contains links to other sites. Please be aware that Mondaq (or its affiliate sites) are not responsible for the privacy practices of such other sites. We encourage our users to be aware when they leave our site and to read the privacy statements of these third party sites. This privacy statement applies solely to information collected by this Web site.

Surveys & Contests

From time-to-time our site requests information from users via surveys or contests. Participation in these surveys or contests is completely voluntary and the user therefore has a choice whether or not to disclose any information requested. Information requested may include contact information (such as name and delivery address), and demographic information (such as postcode, age level). Contact information will be used to notify the winners and award prizes. Survey information will be used for purposes of monitoring or improving the functionality of the site.

Mail-A-Friend

If a user elects to use our referral service for informing a friend about our site, we ask them for the friend’s name and email address. Mondaq stores this information and may contact the friend to invite them to register with Mondaq, but they will not be contacted more than once. The friend may contact Mondaq to request the removal of this information from our database.

Emails

From time to time Mondaq may send you emails promoting Mondaq services including new services. You may opt out of receiving such emails by clicking below.

*** If you do not wish to receive any future announcements of services offered by Mondaq you may opt out by clicking here .

Security

This website takes every reasonable precaution to protect our users’ information. When users submit sensitive information via the website, your information is protected using firewalls and other security technology. If you have any questions about the security at our website, you can send an email to webmaster@mondaq.com.

Correcting/Updating Personal Information

If a user’s personally identifiable information changes (such as postcode), or if a user no longer desires our service, we will endeavour to provide a way to correct, update or remove that user’s personal data provided to us. This can usually be done at the “Your Profile” page or by sending an email to EditorialAdvisor@mondaq.com.

Notification of Changes

If we decide to change our Terms & Conditions or Privacy Policy, we will post those changes on our site so our users are always aware of what information we collect, how we use it, and under what circumstances, if any, we disclose it. If at any point we decide to use personally identifiable information in a manner different from that stated at the time it was collected, we will notify users by way of an email. Users will have a choice as to whether or not we use their information in this different manner. We will use information in accordance with the privacy policy under which the information was collected.

How to contact Mondaq

You can contact us with comments or queries at enquiries@mondaq.com.

If for some reason you believe Mondaq Ltd. has not adhered to these principles, please notify us by e-mail at problems@mondaq.com and we will use commercially reasonable efforts to determine and correct the problem promptly.