The Anatomy of a Warning Letter, Part One: A Primer

This is the first of two articles dealing with the dreaded Food & Drug Administration (FDA) Warning Letter. This first article is an introduction, if you will, to Warning Letters. The second article will contain actual warning letter excerpts with a recommended strategy to respond to FDA in a compliant and effective manner.

What this Article Contains:

  • Understanding What a Warning Letter Is: Introduction and Factoids
  • Contents of a Warning Letter
  • Warning Letter Model: a Sample

Introduction

A Warning Letter is one of FDA’s principal means of achieving timely voluntary compliance with the Food, Drug, and Cosmetic Act (The Act or FD & C Act – The Law).

When the Food and Drug Administration (FDA) finds that a manufacturer has significantly violated FDA regulations, FDA notifies the manufacturer directly. This often comes in the form of a Warning Letter. The letter is emphatic and pointed in nature: the company must correct the problem. In time, FDA then checks to make certain that the company’s corrections are compliant. 

FDA expects that individuals, firms and government establishments will voluntarily comply with the law. When departures are found, FDA gives the organization an opportunity to take voluntary and prompt corrective action before FDA initiates an Enforcement Action (e.g., seizure, injunction to stop continued production or distribution of a violative product, administrative detention, civil money penalties and/or prosecution).

Definitions

Warning Letter. A warning letter is 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 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.

Medical Device. “…an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent or other similar or related article, including any component, part or accessory, which is - (1) recognized in the official National Formulary, or the United States Pharmacopeia, or any supplement to them, (2) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or (3) intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes.”


Warning Letter Factoids

FDA’s position is that Warning Letters are issued only for violations of regulatory significance. Significant violations are those violations that may lead to enforcement action if not promptly and adequately corrected. A Warning Letter is the agency’s principal means of achieving expeditious voluntary compliance with the Federal Food, Drug and Cosmetic Act.

The Warning Letter was developed by the Agency to correct violations of the statutes or regulations.

Responsible officials in positions of authority in regulated firms have a legal duty to implement whatever measures are necessary to ensure that their products, practices, processes or other activities comply with the law. Under the law, such individuals are presumed to be fully aware of their responsibilities.

A Warning Letter is informal and advisory. It communicates the agency’s position on a matter, but does not commit FDA to taking enforcement action. For these reasons, FDA does not consider Warning Letters to be final agency action. Further regulatory and/or legal actions can ensue.

This is important. There are times when issuing a Warning Letter is not appropriate, nor is it timely enough, due to potentially high-risk situations. In these cases, a Warning Letter is not a prerequisite to taking enforcement action. Examples of situations in which FDA will take rapid enforcement action without taking the time (and resources) to issue a Warning Letter:

1. When the violation reflects a history of repeated or continual conduct of a similar or substantially similar nature, during which time the individual and/or firm has been notified of a similar or substantially similar violation

2. When the violation is intentional or flagrant

3. When the violation presents a reasonable possibility of injury or death

4. When the violations are intentional and willful acts

5. When adequate notice has been given by other means and the violations have not been corrected or are continuing  

Warning Letters can be issued at the discretion of the district director without concurrence from the Center for Devices and Radiological Health (CDRH), except in specific program areas that require prior center concurrence.


In determining whether to issue a Warning Letter, district directors and CDRH or other officials with authority to issue should consider whether:

  • Evidence shows that a firm, product and/or individual is in violation of the law or regulations, and that failure to achieve adequate and prompt correction may result in agency consideration of an enforcement action;
  • The violation(s) are determined to be of regulatory significance, and the issuance of a Warning Letter is appropriate and consistent with agency policy, as described in Compliance Policy Guides or elsewhere; and
  • There is a reasonable expectation that the responsible firm and persons will take prompt corrective action. 

When a firm is in the process of correcting the violations or has made a written promise to take prompt corrective action, a district or center will at least consider the following factors when determining whether or not to issue a Warning Letter: 

  • 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 of which the firm was aware (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 noted violations, 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
  • Whether the corrective action taken ensures sustained compliance with the law or regulations

As a general rule, a Warning Letter should not be issued if the agency concludes that a firm’s corrective actions are adequate and that the violations that would have supported the letter have been corrected. As a “heads up,” your company should expect a follow-up inspection.

This is important. Relying on a firm’s completed corrective actions does not preclude consideration of regulatory action, should we later observe that the same or similar violations have not been corrected.

Contents of a Warning Letter

  • Title
  • Delivery
  • Addressees
  • Inspection details
  • Promised corrections
  • Response request
  • Warning statement
  • Impact
  • Instructions for the response
  • Identification of the response recipient
  • Issuer
  • Standardized closing text

Warning Letter Model: a Sample

CERTIFIED MAIL - RETURN RECEIPT REQUESTED
RESPONSIBLE INDIVIDUAL, TITLE
FIRM NAME
FIRM’S COMPLETE ADDRESS

Dear (Addressee),

During an inspection of your firm located in (City, State), on (dates) , our Investigator(s) determined that your firm manufactures (type of device). (Name of device) are devices as defined by Section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act).

The above-stated inspection revealed that these devices are adulterated within the meaning of Section 501(h) of the Act, in that the methods used in, or the facilities or controls used for manufacturing, packing, storage, or installation are not in conformance with the Good Manufacturing Practice (GMP) for Medical Devices Regulation, as specified in Title 21, Code of Federal Regulations (CFR), Part 820, as follows:

1. Failure to conduct…
2. Failure to investigate…For example, there are no records of failure investigations…
3. Failure to implement…
4. Failure to correct…

Additionally, the above stated inspection revealed that your devices are misbranded within the meaning of Section 502(t)(2) of the Act, in that your firm failed to submit information to the Food and Drug Administration as required by the Medical Device Reporting (MDR) Regulation, as specified in 21 CFR Part 803. Specifically, you failed to submit an MDR report to FDA after receiving information which reasonably suggested that one of your commercially distributed devices may have caused or contributed to a death. The February 19, 2011, incident report from the XYZ Medical Center in which a patient standing in a crib fell over, caught his head in a space formed by the crib rail and end post, and died, should have been reported as a death.

This letter is not intended to be an all-inclusive list of deficiencies at your facility. It is your responsibility to ensure adherence to each requirement of the Act and regulations. The specific violations noted in this letter and in the FDA 483 issued at the close-out of the inspection may be symptomatic of serious underlying problems in your firm’s manufacturing and quality assurance systems. You are responsible for investigating and determining the causes of the violations identified by the FDA. If the causes are determined to be systems problems, you shall promptly initiate permanent corrective actions.


Federal agencies are advised of the issuance of all Warning Letters about devices so that they may take this information into account when considering the award of contracts. Additionally, no premarket submissions for devices to which the GMP deficiencies are reasonably related will be cleared until the violations have been corrected. Also, no requests for Certificates for Products for Export will be approved until the violations related to the subject devices have been corrected.

You should take prompt action to correct these deviations. Failure to promptly correct these deviations may result in regulatory action being initiated by the Food and Drug Administration without further notice. These actions include, but are not limited to, seizure, injunction, and/or civil penalties.

Please notify this office in writing within 15 working days of receipt of this letter, of the specific steps you have taken to correct the noted violations, including an explanation of each step being taken to identify and make corrections to any underlying systems problems necessary to assure that similar violations will not recur. If corrective action cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed.

Your response should be sent to (Name), Compliance Officer, Food and Drug Administration, (City, State & Zip Code).

Sincerely yours,

Form FDA 483 Response, a copy 

Conclusion

If a decision is made not to issue a Warning Letter because adequate corrective action has been taken, or because corrective action is being taken or has been promised, an alternate form of communication (e.g., a response letter to the firm’s letter promising corrective action) can be issued to the responsible individuals at the company to supplement the record of the violation(s) and reflect the agency’s decision to rely on the firm’s actions and/or promises. The response letter will commonly indicate that the agency is relying on the firm’s corrections or commitment regarding corrective actions. 


Alternatively, during any subsequent inspection, FDA investigators are expected to verify overall completeness and effectiveness of corrective actions (because of the Warning Letter). 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 or through other means, enforcement actions may be taken without further notice. As was previously mentioned, additional enforcement actions available to FDA to achieve correction are product recall, seizure, injunction, administrative detention, civil money penalties and/or prosecution. 

In the next issue, we will address The Anatomy of a Warning Letter, Part Two: Excerpts and Response Strategies. 
 

REFERENCE

Inspections, Compliance, Enforcement, and Criminal Investigations. More information and most recently-posted Warning Letters. www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm 

John Gagliardi has had success over the past 40 years in the Medical Device and Pharmaceutical industries because of his practical approach to process-orientation and business. He has been actively involved in research and development, quality assurance, training, operations, process architecture, FDA inspections and regulatory affairs. John specializes in building systems in a compliant and business-ready manner. Email John at This email address is being protected from spambots. You need JavaScript enabled to view it..

MidWest Process Innovation, LLC
513-573-0085 (phone)
www.midwestprocessinnovation.com


John GagliardiJohn Gagliardi returns to OMTEC in 2012 with three sessions.

Design Controls: Concept and Feasibility To and Including Commercialization
Wednesday, June 13, 10:00 am - 12:00 pm  

This scenario-driven session will use the design controls traceability matrix as the backbone for discussion and design strategy (just like in real life). Using a simple Class II orthopaedic medical device as an example, attendees will watch the process from concept and feasibility through and including commercialization and post-commercialization processes.

Attendees will participate in planning, approval of design inputs and outputs, a design review template, design change formats, design verification vs. design validation, constructing a Design History File and successfully transferring this design into manufacturing.

Dissection of a Warning Letter
Wednesday, June 13, 3:15 pm - 4:00 pm  

Walk through a warning letter, live. Come prepared with questions to leave with the most thorough understanding of what it is and what happens after one is delivered.

FDA Inspections
Thursday, June 14, 10:00 am - 12:00 pm 

Inspections are not just about compliance. Handling FDA inspections is about preparation, putting the right people in front of the investigator, having a plan of administration and having the presence of mind—allowing you to use people skills to your advantage.

This session is all about preparing for and handling FDA inspections as a contract manufacturer specializing in orthopaedic medical devices and assemblies. John will lead attendees through the steps of FDA inspections, starting from being informed of the inspection through answering FDA 483 observations in a timely manner. This session will enable you to procedurally direct an inspection using your quality management system to its best advantage.