FDA Warning Letter
Encyclopedia
The United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...

 Food and Drug Adminstration 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
Federal Food, Drug, and Cosmetic Act
The United States Federal Food, Drug, and Cosmetic Act , is a set of laws passed by Congress in 1938 giving authority to the U.S. Food and Drug Administration to oversee the safety of food, drugs, and cosmetics. A principal author of this law was Royal S. Copeland, a three-term U.S. Senator from...

 (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
Regulatory compliance
In general, compliance means conforming to a rule, such as a specification, policy, standard or law. Regulatory compliance describes the goal that corporations or public agencies aspire to in their efforts to ensure that personnel are aware of and take steps to comply with relevant laws and...

 with the Act.


While violations are generally determined through the FDA's own inspections, they can also be issued based upon evidence obtained by state personnel 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
Lawsuit
A lawsuit or "suit in law" is a civil action brought in a court of law in which a plaintiff, a party who claims to have incurred loss as a result of a defendant's actions, demands a legal or equitable remedy. The defendant is required to respond to the plaintiff's complaint...

.

The FDA expects that most individuals, firms, and government
Government
Government refers to the legislators, administrators, and arbitrators in the administrative bureaucracy who control a state at a given time, and to the system of government by which they are organized...

 establishments will voluntarily comply
Voluntary compliance
Voluntary compliance is one of possible ways of practicing corporate social responsibility.Voluntary compliance is seen as an alternative to the state-imposed regulations on company's behavior...

 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
Notice
Notice is the legal concept in which a party is made aware of a legal process affecting their rights, obligations or duties. There are several types of notice: public notice , actual notice, constructive notice, and implied notice....

."

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
Form FDA 483
The U.S. Food and Drug Administration is authorized to perform inspections under the Federal Food, Drug, and Cosmetic Act, SEC. 704 "Factory Inspection". Form FDA 483, “Inspectional Observations,” is a form used by the FDA to document and communicate concerns discovered during these inspections...

 that supports the alleged violations, the Establishment Inspection Report (EIR), and any written response by the firm.

Delivery

Warning Letters should be sent to ensure overnight delivery and receipt of delivery (e.g., return receipt
Return receipt
A return receipt is a postal service document confirming the arrival of a message or parcel at its intended destination. Internationally, the service is known as avis de réception , but in some English-speaking countries, acknowledgement of receipt or advice of receipt is used.-Email:As applied to...

 requested, FedEx
FedEx
FedEx Corporation , originally known as FDX Corporation, is a logistics services company, based in the United States with headquarters in Memphis, Tennessee...

) should be documented. The mode of delivery will be stated upon the Warning Letter.

Addressees

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.

Inspection details

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
Form FDA 483
The U.S. Food and Drug Administration is authorized to perform inspections under the Federal Food, Drug, and Cosmetic Act, SEC. 704 "Factory Inspection". Form FDA 483, “Inspectional Observations,” is a form used by the FDA to document and communicate concerns discovered during these inspections...

, the Warning Letter will cite regulatory references for each violation.

Promised corrections

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

Response request

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.

Warning statement

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.

Impact

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.

Additional impact for device manufacturers

There will be a statement in device Warning Letters (except those issued to IRB
Institutional review board
An institutional review board , also known as an independent ethics committee or ethical review board , is a committee that has been formally designated to approve, monitor, and review biomedical and behavioral research involving humans with the aim to protect the rights and welfare of the...

s, 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."

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."

Instructions for the response

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

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

Issuer

The entity issuing the Warning Letter will be identified, whether 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 will be in closing paragraphs as follows (bold type indicates optional/alternative language to be used as appropriate):

"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.]"

Avoiding a Warning Letter

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:
  • "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.

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 (ANDA
ANDA
An Abbreviated New Drug Application is an application for a U.S. generic drug approval for an existing licensed medication or approved drug....

s, NDAs
New drug application
The New Drug Application is the vehicle in the United States through which drug sponsors formally propose that the Food and Drug Administration approve a new pharmaceutical for sale and marketing...

, BLA
Biologic License Application
As defined by the US FDA, a Biologic License Application is: Biological products are approved for marketing under the provisions of the Public Health Service Act. The Act requires a firm who manufactures a biologic for sale in interstate commerce to hold a license for the product...

s) 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."

Center review

Warning letters with the following violations are required to be reviewed by their respective FDA Center (e.g. CDER):
  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
    Advertising
    Advertising is a form of communication used to persuade an audience to take some action with respect to products, ideas, or services. Most commonly, the desired result is to drive consumer behavior with respect to a commercial offering, although political and ideological advertising is also common...

     violations."


CDER requires their review for additional types of violations, which are:
  1. "New drug charges - including unapproved changes in processes or formulations
    Formulations
    Formulation is a term used in various senses in various applications, both the material and the abstract or formal. Its fundamental meaning is the putting together of components in appropriate relationships or structures, according to a formula...

     and recommendations to withhold approvals of applications or supplements
    Supplement (publishing)
    A supplement is a publication that has a role secondary to that of another preceding or concurrent publication.A follow-on publication complements its predecessor, either by bringing it up-to-date , or by otherwise enhancing the predecessor's coverage of a particular topic or subject matter, as in...

    ;
  2. Adverse drug experience
    Adverse drug reaction
    An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

     reporting violations;
  3. Novel and unusual tamper-evident
    Tamper-evident
    Tamper-evident describes a device or process that makes unauthorized access to the protected object easily detected. Seals, markings or other techniques may be tamper indicating.-Tampering:...

     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
CBer
CBER and similar may refer to:* Center for Biologics Evaluation and Research, one of the six main centers of the Food and Drug Administration* Center for Business and Economic Research, Ball State University research center...

 requires their review if these violations are being reported:
  1. "Donor re-entry violations (e.g., HBsAg
    Hbsag
    HBsAg is the surface antigen of the Hepatitis-B-Virus . It indicates current Hepatitis B infection.-Structure and function:The capsid of a virus has different surface proteins from the rest of the virus which act as antigens...

    , 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
    Virus
    A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...

     marker test run deficiencies...;
  6. [Certain] Violations in areas where specific guidance has not been provided...;
  7. Violations relating to HIV
    HIV
    Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...

     and HCV
    Hepatitis C virus
    Hepatitis C virus is a small , enveloped, positive-sense single-stranded RNA virus of the family Flaviviridae...

     lookback; and
  8. Violative inspections of manufacturers of human cell, tissue
    Tissue (biology)
    Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...

    , 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
Center for Veterinary Medicine
The Center for Veterinary Medicine is a branch of the U.S. Food and Drug Administration that regulates the manufacture and distribution of food, food additives, and drugs that will be given to animals. These include animals from which human foods are derived, as well as food additives and drugs...

, and CFSAN
Center for Food Safety and Applied Nutrition
The Center for Food Safety and Applied Nutrition is the branch of the United States Food and Drug Administration that regulates food, dietary supplements, and cosmetics .-Area of regulation:...

.

Lead center

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.

OCC review

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.

Follow up inspections

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.

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. Should violations be observed during a subsequent inspection
Inspection
An inspection is, most generally, an organized examination or formal evaluation exercise. In engineering activities inspection involves the measurements, tests, and gauges applied to certain characteristics in regard to an object or activity...

 or through other means, enforcement action(s) may be taken without further notice. Additional enforcement actions (sequential or concurrent) available to the FDA to achieve correction are product recall
Product recall
A product recall is a request to return to the maker a batch or an entire production run of a product, usually due to the discovery of safety issues. The recall is an effort to limit liability for corporate negligence and to improve or avoid damage to publicity...

, seizure
Search and seizure
Search and seizure is a legal procedure used in many civil law and common law legal systems whereby police or other authorities and their agents, who suspect that a crime has been committed, do a search of a person's property and confiscate any relevant evidence to the crime.Some countries have...

, injunction
Injunction
An injunction is an equitable remedy in the form of a court order that requires a party to do or refrain from doing certain acts. A party that fails to comply with an injunction faces criminal or civil penalties and may have to pay damages or accept sanctions...

, administrative detention
Administrative detention
Administrative detention is arrest and detention of individuals by the state without trial, usually for security reasons. A large number of countries, both democratic and undemocratic, resort to administrative detention as a means to combat terrorism, control illegal immigration, or to protect the...

, civil money penalties
Civil penalty
A civil penalty or civil fine is a term used to describe when a state entity, government agency, or private party seeks monetary relief against an individual as restitution for wrongdoing by the individual. The wrongdoing is typically defined by a codification of legislation, regulations, and decrees...

 and/or prosecution.

Joint Warning Letters

The FDA and the FTC
Federal Trade Commission
The Federal Trade Commission is an independent agency of the United States government, established in 1914 by the Federal Trade Commission Act...

 issued their first joint Warning Letter on October 15, 2009. It was issued to a web site marketing fraudulent supplements.

Cyber Warning Letters

"Cyber" Warning Letters are Warning Letters sent via the Internet
Internet
The Internet is a global system of interconnected computer networks that use the standard Internet protocol suite to serve billions of users worldwide...

 to web sites that offer to sell online prescription drug
Prescription drug
A prescription medication is a licensed medicine that is regulated by legislation to require a medical prescription before it can be obtained. The term is used to distinguish it from over-the-counter drugs which can be obtained without a prescription...

s 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.

Warning Letter alternatives

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:
  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
    Felony
    A felony is a serious crime in the common law countries. The term originates from English common law where felonies were originally crimes which involved the confiscation of a convicted person's land and goods; other crimes were called misdemeanors...

     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:
  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 residue
    Pesticide residue
    Pesticide residue refers to the pesticides that may remain on or in food after they are applied to food crops. The levels of these residues in foods is often stipulated by regulatory bodies in many countries...

    s; or
  4. The product shows short contents, subpotency, or superpotency
    Potency (pharmacology)
    In the field of pharmacology, potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A highly potent drug evokes a larger response at low concentrations, while a drug of lower potency evokes a small response at low concentrations...

    .

Warning Letter close-out letter

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.

Public access to Warning Letters

Warning Letters are made available under the Freedom of Information
Freedom of information
Freedom of information refers to the protection of the right to freedom of expression with regards to the Internet and information technology . Freedom of information may also concern censorship in an information technology context, i.e...

 (FOI) Office. Published letters are redacted
Redaction
Redaction is a form of editing in which multiple source texts are combined and subjected to minor alteration to make them into a single work. Often this is a method of collecting a series of writings on a similar theme and creating a definitive and coherent work...

 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. (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.

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

External links

The source of this article is wikipedia, the free encyclopedia.  The text of this article is licensed under the GFDL.
 
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