Warning Letters: Surviving the Storm

by TLM

We’re always asked about warning letters – What are they? Are we going to get shut down? Is this the end of my job?

While some of you may chuckle about these questions – they represent the real fear from a lot of your staff. The term “warning” literally means “a threat or sign of impending danger”; so you can understand why people have real concern with regard to the letter from the government stating “Warning”.

The United States Food and Drug Administration 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.”

What is a Warning Letter?

When the US FDA finds that a firm has significantly violated FDA regulations (e.g. – 21 CFR, Parts 210, 211, 11, 820, etc.), the FDA notifies the firm via a “letter”. The Warning Letter identifies

  • The violation, such as poor manufacturing practices,
  • Problems with claims for what a product can do, or
  • Incorrect directions for use.

The letter also makes clear that the firm must correct the problem and provides directions and a time frame for the company to inform FDA of its plans for correction. FDA then checks to ensure that the company’s corrections are adequate

Understand Your Observations

Your best approach is avoiding the Warning Letter by appropriately responding to the FDA 483. It is essential that the observations be understood and evaluated in the context in which they were given. Personnel involved with the audit should have input into the reasoning behind the issue. Hopefully, the auditor will provide feedback either when the observation was made or on a daily basis. This is an opportunity to understand the point being made. Typically, the last prospect for obtaining feedback directly from an auditor is during the close-out meeting.

The close-out meeting is a review of the observations made by the auditor. For the US FDA, if a Form 483 is issued, the firm will receive it during this close-out. For internal, corporate or external auditors, there is usually a verbal close-out meeting followed shortly thereafter with a formal report.

During the close-out meeting (especially during formal or governmental audits), it is important to have the appropriate personnel in attendance. These people usually represent Quality Assurance, Regulatory Affairs, Operations and a member of senior management. It is important to keep the number of personnel in attendance to a reasonable level. Too many people and the auditor may become uncomfortable. Too few, it may seem that you are not taking the audit seriously.

Decide in advance how you are going to approach the close-out meeting. Will you question every observation and attempt to get them removed – analogous to a “Scorched Earth Policy”? Will you accept every observation even if there are errors present? Who will comment on the observations – everyone? Will people debate or disagree with valid observations? A good approach is typically one that abides by the following outline:

  • The head of quality is the one who hosts the audit and will be the representative during the close-out. That person alone will be the one who questions any observation unless a person hears a point that is blatantly in error. The head of quality can, and often does, ask for assistance from other key representatives of the group.
  • Review each item with the auditor. Understand what they are citing. Don’t guess or speculate – your response could be far off target if this is the case
  • If errors are present, comment on them. Ask for clarification. Auditors are human and make mistakes.
  • If you have already made corrections – decide if you will indicate that fact during the close-out. There is a concern that should be noted on this point – If the firm has a “knee-jerk” reaction and implements corrective actions too quickly, the auditor may be concerned that you are reacting without truly evaluating the systemic nature of the observation. If the points are minor or easily rectified, you could make the comment that actions have already been implemented to correct the problem but be cautious with this approach. Many questions can be raised such as – “How did you get the change control implemented so quickly?”, “Did you train personnel already?”, “Did you evaluate all the systems?” or “That’s not what I meant by the observation”.
  • If there are true points of contention, discuss them but don’t argue directly with the auditor. You should not argue every point or even a large percentage of them. It should be understood that these observations are simply points made during an inspection by an auditor. The firm has an ample amount of time to respond to the issue in a written format, citing examples of compliance, references, guides, testimony, etc.
  • Be cautious in committing to anything during the close-out. The auditor is taking notes and will indicate that the firm “committed” to a particular action or time frame. This is particularly important during a governmental audit and may result in further actions.

There are other means of gaining an understanding of the observations, including, but not limited to, obtaining the EIR (Establishment Inspection Report) or contacting the inspector directly for questions. If, however, things are bad…and you get the Warning Letter…

The Response – Re-establishing Credibility

Once observations are given, particularly critical or major points, the firm has a limited amount of time to respond. 15 days!!! Work to put a time frame around the response in place and adhere to it diligently. This is the firms chance to re-establish credibility with the FDA.

The last thing an auditor or auditor body wants to do is “chase down” a firm for corrective actions or to conduct extensive follow-up – The FDA will NOT do it. Any issues with the response such as lack of clarity or detail will only result in a request for further information, followed by more details, followed by another review, etc. This loss of time in obtaining a conclusion to the audit can result in your firm’s credibility going down the drain fast.

An approach for formulating a response on each observation is recommended as follows:

  1. Evaluate the current state of compliance in light of the audit observation. If possible, indicate what is compliant.
  2. Identify the root cause of the issue as appropriate. Understand how the firm will resolve the issue systemically.
  3. Review prior commitments. Are any issues a repeat observation or a repeat observation for the same type system issue? This is critical to know and understand. If you have made a commitment in the past regarding an observation but the corrective actions were not implemented or did not resolve the issue, the inspecting body will evaluate the current observations in a more critical light. Repeat observations also greatly increase the likelihood of further regulatory actions.
  4. Identify the root cause. This is a fundamental principle in the FDA’s view of systemic audits and is certainly used widely in Europe as a format for inspections.
  5. Relate each observation to the appropriate Quality System. Understand the area of impact of the issue in relation to the functions impacted by that “system”.
  6. Develop a corrective action plan around the entire scope of the issue(s) noted.
  7. Secure the required resources needed to complete the job in the time frame indicated. DO NOT underestimate the forces needed to complete a job within schedule – let alone evaluating the outcome of the work.
  8. Verify that responsibilities are assigned to key people and make them accountable. Assignments given to “departments” or groups of people are almost doomed to failure. Someone has to be in charge, assign work, track and modify the assignment as needed. Just as important, a single key individual, typically the head of quality, will need to be responsible for the overall work.

Note that in the steps just provided, points 1 through 7 are directly related to formulating a response to the observation. It is critical to understand that points 6 and 7 directly relate to the response letter in that these actions determine the time frame in which actions can be accomplished.

Writing the Response

There are some basic rules that can be established regarding writing a response letter. Some or all of these rules may apply depending upon the particular situation of the firm – e.g. lengthy list of observations, serious issues on the warning letter, etc.

Someone in a high level in a Quality group (internal or external) should write the response.

  1. Personnel copied on the response should include high-level management. This shows that management at the firm is aware of the issues and the commitments being made.
  2. Include a cover letter or opening statement. Thank the auditor(s) for being professional, providing insight or other appropriate remarks as warranted. State the site address of the audit and the dates.
  3. Always remember that you are writing the response to the auditors management – governmental auditing bodies do have supervisors and managers. Do not assume that the person reading the report understands the context of the observation or your reply.
  4. Re-state the observation and reference number in the response. Typically, the observation goes directly above the response.
  5. If possible, indicate the related compliant systems. This shows that you are in control and that some operations were functioning within acceptable GMP parameters.
  6. If the action item is going to take some time to implement, state what will be done in the interim to be compliant with GMPs. Don’t simply indicate that actions will be takenin six months to correct the issue in which you are currently out of compliance without addressing what you will do to be compliant from the current date until the corrections are implemented.
  7. If corrective actions have already taken place, indicate the following
  8. Dates implemented
  9. Training performed (copies of training sign-up sheets included)
  10. Copies of Purchase Orders, installation work, etc.
  11. Copies of updated SOPs – indicating what was changed.
  12. Define how enhancements will prevent recurrence of the issue observed. Don’t assume that the reader will understand this fact.
  13. Explain what will be done to expand, enhance or streamline the compliance system.
  14. Don’t forget about training. Allow sufficient time to implement changes to incorporate training that may include proficiency testing.
  15. Describe how the firm will monitor the progress and effectiveness of the corrective actions.
  16. It may be helpful to explain that despite the issues noted, there has never been an issue. It is not advisable to use this response tactic each time but it can be advantageous for critical observations to state something on the order of “…the product has always met predetermined quality parameters…”
  17. Revise, revise, revise. Allow other people not directly involved with the audit to review and comment on the response. They may have insight on response wording that would assist in clarification or strengthening of points.

Format of the Response

When initially formulating a response, a 4-Stage Inspection Response Approach may be helpful to develop perceptive on the format of the response and contribute to a better understanding of what actually needs to be implemented to be compliant. This type of approach includes 1)

restating the observation, 2) Defining Root Cause, 3) Indicating Corrective Actions and 4) Developing a Due Date.

If this approach is completely followed, any corrective actions will be systemic as they should address the root cause(s) defined. This will also aid in the development of due dates as the firm will be more informed as to what actually need to be accomplished.

For more information on this topic please contact:

Compliance Insight, Inc.


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