FDA warning letter


An FDA warning letter is an official message from the United States Food and Drug Administration to a manufacturer or other organization that has violated some rule in a federally regulated activity.
The FDA defines an FDA warning letter as:
... a correspondence that notifies regulated industry about violations that FDA has documented during its inspections or investigations. Typically, a Warning Letter notifies a responsible individual or firm that the Agency considers one or more products, practices, processes, or other activities to be in violation of the Federal Food, Drug, and Cosmetic Act, its implementing regulations and other federal statutes. Warning Letters should only be issued for violations of regulatory significance, i.e., those that may actually lead to an enforcement action if the documented violations are not promptly and adequately corrected. A Warning Letter is one of the Agency's principal means of achieving prompt voluntary compliance with the Act.

While the FDA generally determines violations through its own inspections, they can also issue one based on evidence from state personnel. The FDA considers a warning letter informal and advisory. It communicates the agency's position on a matter, but does not commit the FDA to an enforcement action. For that reason, the FDA does not consider a warning letter a final action on which it can be sued.
The FDA expects most individuals, firms, and government establishments to voluntarily comply with the law. When the FDA observes a deviation from acceptable practice, they give the organization an opportunity to take voluntary and prompt corrective action before it initiates an enforcement action. A step in this process, depending on the nature of the violation, is to issue a warning letter, which also establishes prior notice.
The agency has a computer application called the Compliance Management System that district offices use to electronically submit warning letter recommendations to FDA Centers. All district office must use the CMS to submit the warning letter recommendation, the Form FDA 483 that supports the alleged violations, the Establishment Inspection Report, and any written response from the firm.

Contents

The elements listed below are common to warning letters:

Title

The warning letter must have the words "WARNING LETTER" at the top.

Delivery

The warning letter is sent in a way that ensures overnight delivery and receipt is documented. The delivery mode is stated on the Warning Letter.

Addressees

The FDA addresses the warning letter to the highest known official in the firm that owns the inspected facility, and sends a copy to the highest known official at the specific inspected facility. If the FDA expects a separate response from other officials, they may included their addressees. Districts routinely provide copies of warning letters to appropriate state agencies using suitable notations in the letter, and identifying each person by name, title, and, if appropriate, address.

Inspection details

The warning letter includes the inspection dates and a description of the violating condition, practice, or product in brief but sufficient detail to provide the respondent the opportunity to correct the matter. It cites the section of the law and, where applicable, the regulation violated. Unlike the Form FDA 483, the warning letter cites regulatory references for each violation.

Promised corrections

The warning letter acknowledges corrections promised during the inspection, or that the organization provides to the district in a written response.

Response request

The Warning Letter requests corrections and a written response within a specific period after receipt of the letter—usually fifteen working days. The district, at its discretion, may offer the recipient an opportunity to discuss the letter with district officials or, when appropriate, with center officials.

Warning statement

The Warning Letter includes a statement that warns that failure to promptly correct the matter may result in an FDA enforcement action without further notice. It may include examples of such actions, but makes no commitment that the FDA will take these actions.

Impact

A drug warning letter includes a statement of implications for the award of federal contracts. If current good manufacturing practice violations are cited, it adds a statement regarding the potential impact on requests for approval of export certificates and drug applications.

Additional impact for device manufacturers

Device Warning Letters include the notice, "Federal agencies are advised of all Warning Letters about devices so that they may take this information into account when considering the award of contracts."
Warning letters that include cGMP violations include the statement:
Additionally, premarket approval applications for Class III devices to which the Quality System regulation deviations are reasonably related will not be approved until the violations have been corrected. Requests for Certificates to Foreign Governments will not be granted until the violations related to the subject devices have been corrected.

Instructions for the response

The Warning Letter provides instructions, as appropriate, stating that the organization's response must include:

Response recipient identification

The Warning Letter specifies a designated district or center official to whom the organization must address their response.

Issuer

The Warning Letter identifies the entity that issued it—the district director, division director, or higher agency official.

Standardized closing text

For drug Warning Letters, the information in the above sections 1.6-1.8 and 1.10 is in closing paragraphs as follows :

Criteria that prevent issuance of a warning letter

Ongoing or promised corrective actions generally do not prevent the FDA from issuing a warning letter, though a written promise to take prompt corrective action, in the right context, can result in them deciding not to issue one. Potentially influencing factors include:
Also, the agency usually doesn't issue a Warning Letter if they find the organization has implemented actions that corrected the violations that would have supported the Warning Letter.
District offices do not recommend a Warning Letter as a follow-up to a preapproval inspection for pending drug or device applications if the firm markets no other FDA-regulated products. However, if the firm does market other FDA-regulated products and the issue affect marketed products—or the inspection extended to marketed products included on the FDA 483, then they may issue a Warning Letter These include the following statement: "Due to the deficiencies listed on the attached FDA 483 we are recommending to the center that approval of the _____ application be withheld."

Center review

Warning letters with the following violations must be reviewed by their respective FDA Center :
CDER requires their review for additional types of violations, which are:
CBER requires their review if these violations are being reported:
Refer to the FDA's for details on the above criteria, and for additional criteria pertaining to these Centers: CDRH, CVM, and CFSAN.

Lead center

When the issues in a Warning Letter require review by more than one center, the agency designates a lead center. The lead center is responsible for communication with other involved centers, the district, and the FDA's Office of Chief Counsel. The lead center is responsible for bringing the Warning Letter through the review process, including the review and incorporation of comments as appropriate from the other involved entities.

OCC review

Deputy Secretary of the Department of Health and Human Services directed on November 29, 2001, that the FDA submit all Warning Letters to the OCC before they issue them so the OCC can review them for legal sufficiency and consistency with Agency policy. The OCC has 15 working days to complete its review. If the OCC fails to make a timely response to Direct Reference Warning Letters and those issued as a result of foreign inspections, the District or Center may presume concurrence and send the Warning Letter out without additional OCC input.

Follow up inspections

For a CBER warning letter, the agency schedules a follow-up inspection for approximately 30 days after they receive the warning letter response to determine the adequacy of reported corrective actions. If the firm has made no corrective action or has failed to respond, the district considers suitable follow-up.
During subsequent inspection, FDA investigators must verify overall completeness and effectiveness of corrective actions. The timing of a subsequent investigation can be expedited or routine, as determined by the issuing office. Should violations be observed during a subsequent inspection or through other means, enforcement action may be taken without further notice. Additional enforcement actions available to the FDA to achieve correction are product recall, seizure, injunction, administrative detention, civil money penalties or prosecution.

Special types of warning letters

Joint warning letters

The FDA and the Federal Trade Commission issued their first joint Warning Letter on October 15, 2009 to a web site that was marketing fraudulent supplements.

Cyber warning letters

"Cyber" Warning Letters are Warning Letters the FDA sends via the Internet to web sites that offer online prescription drugs that may be illegal. These letters warn that they may be engaged in illegal activities, and informs them of the laws that govern prescription drug sales.

Alternatives to warning letters

There is no legal requirement that the FDA warn individuals or firms that they are violating a law before taking enforcement action, so a warning letter is not a required prerequisite to enforcement action. The FDA further asserts that there are egregious circumstances when issuing a Warning Letter is not appropriate, and it will then take immediate enforcement action. These include:
In certain situations, the agency may take other actions instead of, or concurrent with, a Warning Letter. For example:

Warning letter close-out letter

After the FDA completes an evaluation of corrective actions via a follow-up inspection, it may issue a so-called warning letter close-out letter if the FDA's evaluation shows that the firm has taken corrective action to address the violations contained in the warning letter. This procedure applies to warning letters issued on or after September 1, 2009.

Public access to warning letters

Warning letters are available under the Freedom of Information Office. Published letters are redacted or edited to remove confidential information. Redacted copies do not include "bcc" information, or the "credit page" related to drafting sequence, etc.
It is important that third parties reading Warning Letters understand that matters that FDA Warning Letters describe may have been subject to subsequent interaction between the FDA and the recipient that may have changed the regulatory status of the issues discussed.
The Freedom of Information Act requires that publicly accessible "electronic reading rooms" with agency FOIA response materials and other information be routinely available to the public, with electronic search and indexing features.
Members of the public can visit the FDA Public Reading Room in person at 5600 Fishers Lane, Rockville, Maryland.