FDA Warning Letter

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The United States Food and Drug Administration (FDA) defines a 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 (the 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.[1]

While violations are generally determined through the FDA's own inspections, they can also be issued based upon evidence obtained by state personnel[2] A Warning Letter is considered by the agency to be informal and advisory. While it communicates the agency's position on a matter it does not commit the FDA to taking enforcement action. For these reasons the FDA does not consider Warning Letters to be final actions on which it can be sued.[3]

The FDA expects that most individuals, firms, and government establishments will voluntarily comply with the law. When departures are observed the FDA gives an 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 serves to establish "prior notice."[3]

The agency has a computer application called the Compliance Management System (CMS, or MARC-CMS).) that is used for electronically submitting Warning Letter recommendations from district offices to FDA Centers. All recommendations by the district offices must use the CMS for submitting the proposed Warning Letter, the Form FDA 483 that supports the alleged violations, the Establishment Inspection Report (EIR), and any written response by the firm.[3]

Warning Letter content[edit]

The elements listed below are common to Warning Letters:[3]

Title[edit]

The Warning Letter will have the words "WARNING LETTER" at the top.[3]

Delivery[edit]

Warning Letters should be sent to ensure overnight delivery and receipt of delivery (e.g., return receipt requested, FedEx) should be documented. The mode of delivery will be stated upon the Warning Letter

Addressees[edit]

The Warning Letter should be addressed to the highest known official in the firm that includes the facility that was inspected, and a copy should be sent to the highest known official at the specific facility that was inspected. If a separate response from other officials is expected by the FDA, they may be included as addressees. Districts will routinely provide copies of Warning Letters to appropriate state agencies. Suitable notations (e.g., cc, or copy sent to) should be used in the letter and identify each person by name, title, and, if appropriate, address.[3]

Inspection details[edit]

The dates of the inspection and a description of the violative condition, practice, or product in brief but sufficient detail to provide the respondent the opportunity to take appropriate corrective actions. Include citation of the section of the law and, where applicable, the regulation violated. Unlike the Form FDA 483, the Warning Letter will cite regulatory references for each violation.[3]

Promised corrections[edit]

The Warning Letter should acknowledge corrections promised during the inspection or provided to the district in a written response.[3]

Response request[edit]

The Warning Letter will request corrections and a written response within a specific period after receipt of the letter, usually fifteen (15) working days. At the district's discretion, the recipient may be offered an opportunity to discuss the letter with district officials or, when appropriate, with center officials.[3]

Warning statement[edit]

There will be a warning statement that failure to achieve prompt correction may result in enforcement action without further notice. While examples of such actions may be could be included, there will not be any commitment that enforcement action will be taken.[3]

Impact[edit]

For drug Warning Letters (except those issued to IRBs, clinical investigators, sponsors, and monitors involved in clinical trials), there will be a statement regarding the implications for the award of federal contracts. If cGMP violations are cited, a statement regarding the potential impact on requests for approval of export certificates and drug applications.[3]

Additional impact for device manufacturers[edit]

There will be a statement in device Warning Letters (except those issued to IRBs, clinical investigators, sponsors, and monitors involved in clinical trials) that, "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."[3]

And for device Warning Letters that include cGMP violations:

"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."[3]

Instructions for the response[edit]

Instructions, as appropriate, will be provided stating that the response include:[3]

  1. "each step that has been or will be taken to completely correct the current violations and to prevent similar violations;
  2. the time within which correction will be completed;
  3. any reason the corrective action has not been completed within the response time; and,
  4. any documentation necessary to show that correction has been achieved."

Identification of the response recipient[edit]

The Warning Letter will specify a designated district or center official to whom the response should be addressed.[3]

Issuer[edit]

The entity issuing the Warning Letter will be identified, whether the district director, division director, or higher agency official.[3]

Standardized closing text[edit]

For drug Warning Letters, the information in the above sections 1.6-1.8 and 1.10 will be in closing paragraphs as follows (bold type indicates optional/alternative language to be used as appropriate):[3]

"The violations cited in this letter are not intended to be an all-inclusive statement of violations that exist [at your facility/in connection with your product(s)]. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence or the occurrence of other violations. It is your responsibility to assure that [you/your firm] comply[ies] with all requirements of federal law and FDA regulations.

"You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice, including, without limitation, seizure and injunction. Other federal agencies may take this Warning Letter into account when considering the award of contracts. [If cGMP VIOLATIONS ARE CITED: Additionally, FDA may withhold approval of requests for export certificates, or approval of pending new drug applications listing your facility as a [supplier or manufacturer] until the above violations are corrected. A reinspection may be necessary.]

"Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct violations. Include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the time within which you will complete the correction. [If you no longer manufacture or market ____, your response should so indicate, including the reasons that, and the date on which, you ceased production.]"[3]

Avoiding a Warning Letter[edit]

Ongoing or promised corrective actions generally do not prevent receiving a Warning Letter, although a written promise to take prompt corrective action, in the right context, can result in a decision to not issue a Warning Letter. The potentially influencing factors are:[3]

  • "The firm's compliance history, e.g., a history of serious violations, or failure to prevent the recurrence of violations;
  • "The nature of the violation, e.g., a violation that the firm was aware of (was evident or discovered) but failed to correct;
  • "The risk associated with the product and the impact of the violations on such risk;
  • "The overall adequacy of the firm's corrective action and whether the corrective action addresses the specific violations, related violations, related products or facilities, and contains provisions for monitoring and review to ensure effectiveness and prevent recurrence;
  • "Whether documentation of the corrective action was provided to enable the agency to undertake an informed evaluation;
  • "Whether the timeframe for the corrective action is appropriate and whether actual progress has been made in accordance with the timeframe; and,
  • "Whether the corrective action taken ensures sustained compliance with the law or regulations. In the case of Warning Letters being considered for products offered for sale through internet web sites, corrective action to remove claims or inactivate the website is easily reversible, and should be carefully considered, along with the other factors above, in determining whether or not to issue a Warning Letter. Warning Letters for, or involving, internet web sites should be issued in as close proximity as possible to the time when the claims were last observed, and reference to the date on which the claims were observed should be included in the letter."

Also, a Warning Letter usually will not be issued if the agency finds that corrective actions are implemented, adequate, and that the violations that would have supported the Warning Letter have been corrected.[3]

District offices will not recommend the use of a Warning Letter as a follow-up to a preapproval inspection (PAI) for pending drug or device applications (ANDAs, NDAs, BLAs) if no other FDA-regulated products are marketed by the firm. However, if other FDA-regulated products are marketed by the firm and the issue(s) affect marketed products, or the inspection has extended to marketed products that are included on the FDA 483, then a Warning Letter may be issued. These should 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."[3]

Center review[edit]

Warning letters with the following violations are required to be reviewed by their respective FDA Center (e.g., CDER):[3]

  1. "All labeling violations - except where specific guidance has been provided, e.g., Compliance Programs, Compliance Policy Guides, and Drug Health Fraud Bulletins;
  2. Computer application and software violations;
  3. Bioresearch Monitoring Program violations; and
  4. Product advertising violations."

CDER requires their review for additional types of violations, which are:[3]

  1. "New drug charges - including unapproved changes in processes or formulations and recommendations to withhold approvals of applications or supplements;
  2. Adverse drug experience reporting violations;
  3. Novel and unusual tamper-evident packaging violations;
  4. Prescription Drug Marketing Act violations;
  5. Investigational drug use violations;
  6. CGMP charges involving active pharmaceutical ingredients and other drug component manufacturing deficiencies;
  7. CGMP charges involving all dosage forms, including medical gases;
  8. CGMP charges involving inspections of facilities for therapeutic biologic products regulated by CDER; and
  9. Pharmacy compounding issues."

CBER requires their review if these violations are being reported:[3]

  1. "Donor re-entry violations (e.g., HBsAg, anti-HIV-1);
  2. [Certain] Violations relating to drug CGMP...;
  3. Violative inspections of federal government agencies;
  4. Violative inspections of Team Biologics (Core Team) facilities for biologic products regulated by CBER;
  5. [Certain] Viral marker test run deficiencies...;
  6. [Certain] Violations in areas where specific guidance has not been provided...;
  7. Violations relating to HIV and HCV lookback; and
  8. Violative inspections of manufacturers of human cell, tissue, and cellular and tissue-based products (HCT/Ps)."

Refer to the FDA's Regulatory Procedures Manual, section 4-1 - "WARNING LETTERS" for details on the above criteria, and for additional criteria pertaining to these Centers: CDRH, CVM, and CFSAN.[3]

Lead center[edit]

When the issues in a Warning Letter require review by more than one center, a "lead center" is designated. The lead center is responsible for communication with the other involved center(s), the district, and the FDA's Office of Chief Counsel (OCC). 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.[3]

OCC review[edit]

Deputy Secretary of the Department of Health and Human Services directed on November 29, 2001, that the FDA submits all Warning Letters to the OCC prior to their issuance so that they can be reviewed 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 can presume concurrence and may send the Warning Letter out without additional input from the OCC.[1]

Follow up inspections[edit]

For a CBER Warning Letter, a follow-up inspection will be scheduled to occur approximately 30 days after the response to the Warning Letter is received to determine the adequacy of the reported corrective actions. If corrective action has not been made or the firm has failed to respond, the district will consider suitable follow-up.[3]

During any subsequent inspection, FDA investigators are expected to verify overall completeness and effectiveness of corrective actions. The timing of a subsequent investigation may be expedited or routine, as determined by the issuing office.[3] Should violations be observed during a subsequent inspection or through other means, enforcement action(s) may be taken without further notice.[4] Additional enforcement actions (sequential or concurrent) available to the FDA to achieve correction are product recall, seizure, injunction, administrative detention, civil money penalties and/or prosecution.[3]

Special types of Warning Letters[edit]

Joint Warning Letters[edit]

The FDA and the Federal Trade Commission issued their first joint Warning Letter on October 15, 2009. It was issued to a web site marketing fraudulent supplements.[5]

Cyber Warning Letters[edit]

"Cyber" Warning Letters are Warning Letters sent via the Internet to web sites that offer to sell 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. [6]

Warning Letter alternatives[edit]

As there is no legal requirement for the FDA to warn individuals or firms that they or their products are in violation of the law before taking enforcement action, a Warning Letter is not a required prerequisite to taking 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:[3]

  1. The violation reflects a pattern of conduct of a substantially similar nature during which time the individual and/or firm has been notified of violation;
  2. The violation is intentional or flagrant;
  3. The violation presents a reasonable possibility of injury or death;
  4. The violations are intentional and willful acts that once having occurred cannot be retracted. Also, such a felony violation does not require prior notice. Therefore, Title 18 U.S.C. 1001 violations are not suitable for inclusion in Warning Letters; and,
  5. When adequate notice has been given by other means and the violations have not been corrected, or are continuing.

In certain situations, the agency may also take other actions as an alternative to, or concurrently with, the issuance of a Warning Letter. For example:[3]

  1. The product is adulterated under Section 402(a)(3) or 402(a)(4) of the Act;
  2. There is a violation of cGMP;
  3. The product contains illegal pesticide residues; or
  4. The product shows short contents, subpotency, or superpotency.

Warning Letter close-out letter[edit]

After the FDA has completed an evaluation of corrective actions via follow-up inspection, it may issue a Warning Letter close-out letter ("close-out letter"). This procedure applies to Warning Letters issued on or after September 1, 2009.[4]

Public access to Warning Letters[edit]

Warning Letters are made available under the Freedom of Information (FOI) Office. Published letters are redacted or edited to remove confidential information. Redacted copies will not include "bcc" information, or the "credit page" related to drafting sequence, etc.

It is important to third parties reading Warning Letters to understand that matters described in FDA Warning Letters may have been subject to subsequent interaction between FDA and the recipient of the letter that may have changed the regulatory status of the issues discussed in the letter.[6] (See the "External links" section below for electronic access to Warning Letters.)

The Freedom of Information Act (FOIA) requires publicly accessible "electronic reading rooms" with agency FOIA response materials and other information to be routinely available to the public, with electronic search and indexing features.[7]

The FDA Public Reading Room can be visited in person at 5600 Fishers Lane, Rockville, Maryland.[7]

External links[edit]

References[edit]