Responding to a Warning Letter

Part 2 of 2 on what to do when the FDA sends you a letter

By Shamik Pandit

In Part 1 of this article (see Contract Pharma April 2008), we discussed various parts of an FDA warning letter. In this section we will discuss how to respond to one. But before we jump into the specifics, we need to look at some of the factors that may have led to the warning letter. In itself, a warning letter should not be a complete surprise to the company. Such events are usually perpetuated by systemic issues within the company; however, it may seem to some, that the company was caught unaware. Typical ‘root causes’ that lead up to a warning letter are often of organizational origin, specifically with the implementation of the Quality System and the company’s senior management involvement.

A business is perpetually dealing with business constraints and conflicting priorities. There is always this rush to fill the order for this big customer, or to meet that set of performance goals for this quarter, be they financial or otherwise. Pharmaceutical and medical device companies are no exception; the day-to-day tasks and the management of tactical issues often distract even the most competent individuals within a company. Once you add a weak Quality System to poor management, the results are disastrous. A Warning Letter does not necessarily predict disaster. But if it is not responded to effectively, things can go downhill pretty quick.

So how does a company respond to a warning letter?

1. Know Where You Stand

Risk management begins with identification of the scope of the risks. One way to know where you stand is to get a good grip on all the systemic issues identified by the warning letter. Does the FDA seem concerned about imminent public health risks from your product? Is the agency concerned with multiple systems or is the letter pointing to a single system? Does the warning letter hint at issues of organizational competence in terms of specific department, personnel or practices? Is the it hinting at an even more serious regarding about ethical behaviors or practices? This knowledge about the hierarchy and the scope of the risks facing your company is extremely important, since these can be very different issues. In the order of importance, the following risk dimensions are of concern to most regulatory bodies:

• Imminent risks to public health
• Lack of management involvement at the company
• Evidence of potentially unethical practices or gross negligence of compliance requirements
• Lack of knowledge (compliance requirements) and know-how (technical competence)
• Lack of communication and escalation channels within
• and between departments
• Lack of processes and practices for an effective quality system
• Lack of staffing and other organizational resources
• Conflicting organizational priorities

The first step is therefore to identify a team of professionals both within and without your organization. While the internal team of experts can provide a very good inside-out look at your company’s state of Quality systems (they know where all the bodies are buried), the external experts can identify the legendary ‘elephant in the room’ that your company has either chosen to avoid or has somehow adjusted to. Get this exercise completed within the first week of the receipt of the warning letter.

2. Develop a Corrective Action Plan

A Corrective Action plan should include the following:

• Acknowledgment and identification of the issues highlighted by the warning letter.
• A full explanation of issues that you might have a different opinion on, along with specific evidence to support your position, e.g. expert opinions, or additional documentation that was not available at the time of the FDA visit.
• A management commitment to correct the issues adequately, systematically and in a timely manner.
• A list of actions already taken, e.g. initiation of a product correction or recall, organizational restructuring, hiring or termination decisions that have been implemented, procedure and practices that has been immediately suspended or revised as a stopgap measure, retention of any external consultants along with their expertise, experience and purpose of assisting the company, any additional exceptional measures taken to ensure prompt communication, and management involvement.
• A prioritized list of activities and actions planned in the near future by the company, along with reasonable and practical timeline.
• A commitment to provide periodic updates to the FDA about the corrective action plan.
• A request for meeting with the FDA if the company needs to clarify or submit additional information.
• A request for response from the FDA about the Corrective Action Plan.
• A list of specific contact personnel at the company site, along with phone numbers. This should be limited to one or two individuals who have ready access to senior management.

These activities should be conducted during the second week.

3. Implement Corrective Action Plan

While it may be tempting to wait for FDA’s response to your response, do not wait any longer to implement the Corrective Action plan. If FDA finds your response inadequate or requests additional information or evidence, you can always revise your plan.

4. Monitor Progress

What looks great on paper may not always pan out as originally planned. Your organization will go through serious challenges in implementing the plan, if it is still expected to perform all the regular tasks at full strength. You must make some choices in terms of what the company will choose not to do. Resource budgeting may require you to hire more people or to cut down operational activities. This is especially crucial, where your company is in contract for supplying to customers at a certain rate. You may need to renegotiate your supply agreement so that the pressure on your people is reduced, and they can focus on the Corrective Action plan. Expect your team to meet regularly and provide you with feedback on any issues that are hindering the implementation of the plan. Show up at these meetings in support and to identify any potential ‘political’ issues. Reorganize the team if personal and departmental agendas are hijacking the overall intent of the plan. Retain an external support (expert consultant or coach) to help the team through complex issues.

5. Provide Updates to the FDA

As important milestones are reached or missed, or if the Corrective Action plan has been modified since the original response, let the FDA know what’s going on. Limit your updates to the highlights and add any evidence, e.g. new SOPs developed, new protocols implemented, or new responsibilities assigned. Reiterate your commitment to address all the warning letter’s concerns.

6. Verify

When all the commitments are completed and the Corrective Action plan is implemented, hold another review of the implemented systems with the help of both internal and external experts. Choose people who were not involved with implementing the plan, to ensure objectivity. If there are serious gaps, inform the FDA of any additional corrective action planned. If the plan is implemented effectively, provide one final communication to the FDA with an itemized list of all the corrective actions and the supporting binder(s) of evidence. Commit to continuously monitoring the effectiveness of the Corrective Action plan for an additional period through internal assessments. Here is a sample response to the FDA Warning Letter:

Dear FDA,

We are in receipt of your communication dated — on —–. We take your communication very seriously and commit ourselves to address your concerns adequately and expeditiously. We will take all the necessary measures to ensure our customers’ well-being and safety. Enclosed please find an attachment that addresses your concerns on an individual and on a systematic basis.

We agree that a sound Quality System is the result of effective management commitment, dedicated employees, and sound processes and practices.

To that end we have retained _____, a reputable consulting firm, to assess our Quality System in greater detail and to help ensure that our Corrective Action plan will address all systemic issues effectively. We have attached a qualification profile for your review.

We have already taken the following immediate corrective actions to remediate potential urgent concerns as follows:

[Describe here in brief these corrective actions.]

Additionally, we have chartered a Management Action plan staffed with expert individuals to develop long-term corrective actions. This plan is attached for your review. You will find that we have prioritized our next set of actions based on the risk assessment of your concerns. The plan includes the specifics of our actions along with targeted timelines. We will closely monitor the implementation of this plan and will provide you with updates on our progress on a monthly basis along with evidence of implementation. Should we change any of our commitments, we will provide you with our reasons and supporting documentation.

We also intend to monitor the effectiveness of our corrective action plan on a long-term basis.

We believe that this comprehensive Corrective Action plan will successfully rectify all deficiencies described by your communication and will make our company even stronger and more effective in meeting GMP compliance.

We would like to request a review of our plan and invite your feedback as to its adequacy. We also remain available for any phone consultations or personal visit to your offices should that be necessary.

Feel free to contact Mr. _____ at ______, if there are any concerns with our response.

Sincerely,

President

Shamik (Sam) Pandit is an FDA coach at GMP Scientific, Inc., a Newtown, PA-based consultancy for the FDA-regulated industry.