How to handle a warning letter: FDA’s new meeting type benefits generic drug companies

The Post-Warning Letter Meeting, a little-noticed meeting type established recently under the Generic Drug User Fee (GDUFA) program, is set to provide new clarity to generic drug facility owners who receive warning letters following a facility inspection and help them to remediate their problems more quickly. But as a new guidance document clarifies, the FDA need to receive certain information from companies to make this meeting type work, and its not in a rush to receive requests, either.

Regulatory background

• A warning letter is a significant occurrence for a company, and in particular if it follows an inspection of a company’s facility. A warning letter represents the FDA’s determination that a manufacturer has “ significantly violated” FDA regulations, including those related to current good manufacturing practices (CGMPs). As the FDA explains, “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 company must correct the problem and provides directions and a timeframe for the company to inform FDA of its plans for correction.”
• The impact of warning letters: Warning letters often correspond with additional regulatory actions, including import alerts, the temporary closure of a manufacturing facility, recalls and more. Warning letters may also preclude a company from having products manufactured at a facility approved by the FDA until the warning letter is satisfactorily resolved, known as a “close-out letter.”
• FDA Warning Letters are often sent to manufacturers of generic drugs. Such products are often made in foreign facilities by staff less experienced with FDA regulatory requirements and at margins which may preclude significant investments in drug quality.
• This impact was apparently enough for the FDA and generic pharmaceuticals industry to include a new meeting type in the most recent iteration of the Generic Drug User Fee program (GDUFA), called a “Post-Warning Letter Meeting.” According to the GDUFA III Commitment Letter – a set of expectations and commitments negotiated between the FDA and industry, and agreed to by Congress – the purpose of this meeting is “to obtain preliminary feedback from FDA on the adequacy and completeness of the facility’s corrective action plans.”

About the Post-Warning Letter Meeting (PWLM)

• According to the commitment letter, to be eligible for a PWLM, the facility must have been inspected and subsequently receive an FDA Form 483 with an Official Action Indicated (OAI, or a finding that action must be taken by the facility). The facility must also have paid a required annual GDUFA facility fee (or be named in a pending application), and the warning letter must be related to CGMP-related problems for a human drug or drug-device combination. The facility must also have submitted to the FDA a “thorough and complete corrective action and preventive action (CAPA) plan that addresses all items cited in the warning letter, and reasonable progress has been made toward remediation.”
• The meeting itself will “generally” take place 6 months after the facility submits “an initial response to the FDA warning letter,” and also requests the meeting with the FDA. It may also take place earlier if requested by the facility and FDA agrees that an earlier meeting “would be beneficial to both parties.” Any information to be discussed at the meeting must be submitted to FDA 60 days in advance of the meeting.
• According to the GDUFA Commitment Letter, FDA can deny a meeting request if it determines that the facility “does not appear to be ready for a meeting as evidenced by an incomplete CAPA plan,” or if the facility isn’t making adequate progress to remediate the issues found during the inspection. FDA may also defer a meeting if it believes a re-inspection is the most appropriate next step, and companies may re-submit a meeting request 3 months after they are rejected. These actions will be explained, briefly, to the sponsor by the FDA.
• Meetings may take place in almost any form – face-to-face, over video conference or teleconference. However, the meeting form is at the discretion of the FDA.
• The FDA has also set certain performance criteria around these meetings. Next year, in FY2024, the FDA aims to response to 50% of Post-Warning Letter Meetings within 30 days of the initial request. In FY2025, that will increase to a goal of 70%, and in FY2026-2027, it will increase to 80%.
• Importantly, a commitment to meet with a facility is not a commitment by the FDA to take no further action. According to the letter, acceptance of a meeting request “Does not preclude FDA from taking any regulatory actions necessary, including a follow-up inspection at any time.” In addition, the advice given at the meeting “is not binding on the agency.”

FDA’s new guidance on PWLMs

• Buried within the GDUFA commitment letter was a requirement that the FDA “issue guidance regarding the Post-Warning Letter Meeting process, including recommendations on items facilities should submit as part of a meeting request.” Unlike most commitments, this one was not associated with a specific timeline (i.e., for FDA to publish it in draft or final form by a specific date).
• That draft guidance document, Post-Warning Letter Meetings Under GDUFA, has just been published. The document itself is relatively brief at just 14 pages, of which most of the first half of the document is simply a history of the GDUFA program and repeating, verbatim, the elements of the plan previously included within the GDUFA commitment letter. However, there are some additional details worth noting, including:
• FDA wants requests for PWLMs to be submitted electronically, and include “the [Corrective and Preventive Action] CAPA plan and any supplementary information that demonstrates that actions in progress are intended to assure systemic remediation of deficient practices at the facility. The meeting package should contain sufficient detail to meet the intended meeting objectives,” and should also “clearly indicate” the purpose of the meeting and allow FDA to “assess the potential utility of the meeting.”
• FDA’s bar for a useful meeting appears to be that of “reasonably progress toward remediation.” Because of this, FDA says it does not plan to accept requests that are received within 15 days of the issuance of the Warning Letter. Requests for a PWLM should therefore be separate from the Warning Letter response letter.
• Who can submit a PWLM request? Only a limited number of entities, according to the FDA’s guidance. The agency only intends to accept a request “from the facility, parent company, or authorized legal representative.” It will not accept requests from third parties, including customers of the facility, unless they are “the same legal entity.”
• What should the meeting request package include? According to the FDA, “Preparing the meeting package should help the facility focus on describing its principal areas of interest. The meeting package should show that the facility has made reasonable progress towards systemic remediation of the deviations and/or violations cited in the warning letter.” The guidance suggests that facilities should focus on providing information that is sufficiently specific to inform discussion about the proposed discussion topics. For example, a request may “include discussion of remediation activities for all deviations identified during the inspection, whether or not those issues were included in the warning letter,” FDA wrote.
• Further, the guidance advises that the request address each deviation or violation within the warning letter, along with a “description of the root cause analysis and a retrospective evaluation of the impact of each deficiency on product quality and other systems” both at the affected facility, and other similar facilities under the company’s control. “The meeting package should include a reference to each warning letter response and supporting documentation,” FDA added. The guidance also includes a request to include a section containing a summary of all Corrective and Preventive Actions (CAPA), a status report and questions “that can be reasonably discussed within the scheduled meeting time.” The use of a table format is encouraged to organize information within the request package.
• The meeting request package should also include other basic information, including the establishment name, address, FDA Establishment Identification number, warning letter number, people attending the meeting, requested meeting dates, and a proposed agenda, among other items of interest to FDA (see the guidance for the full list).

Analysis

• The FDA’s new draft guidance is largely what we expected coming out of the GDUFA III Commitment Letter. Due to the nature of the negotiations that create the letter, the FDA is generally “locked in” to what the program must look like. As a result, most of the new details from this guidance are related to what the FDA wants to see in the documents it receives – the area where the Commitment Letter was arguably least prescriptive.
• It’s worth noting that the FDA has already been promoting these meeting types with generic drug companies in receipt of a Warning Letter. For example, in a letter dated July 28, 2023 to Intas Pharmaceuticals, a footnote in the letter advised the company that the company’s facility “may be eligible for a Post-Warning Letter Meeting to obtain preliminary feedback from FDA on the adequacy and completeness of your corrective action plans.” That language is contained in other recent letters as well, and according to AgencyIQ’s analysis began to appear in December 2022. Only 11 letters sent by the FDA to date have mentioned them, however.
• But as the guidance makes clear, the FDA’s understanding of “preliminary feedback” may be quite different than that of some companies. This meeting type is not meant to be a meeting to talk about the warning letter and argue about it; rather, it’s for companies who are already engaged in remediation efforts for several weeks to request the FDA provide additional feedback, which would then be obtained months later. That’s an important distinction: This meeting type is not meant to facilitate rapid feedback, but it is meant to help ensure that a company doesn’t receive multiple warning letters for the same facility, doesn’t find it difficult to obtain a final close-out letter (which can sometimes take years), and that such issues are solved in such a way that similar issues at other facilities controlled by the same company don’t result in additional warning letters.
• It’s also worth noting that some discussions about warning letter close-outs are naturally going to take longer than others. FDA’s letter contains a footnote referencing a line which states that regulators want to see “timeframes for CAPAs, including interim actions.” As FDA notes, some actions will take such a long time to complete – such as building a new facility with improved capabilities to provide “durable solutions” – that the company might instead need to talk about interim solutions. FDA would find these discussions acceptable, and even “preferable if FDA determines that quality and compliance will clearly benefit.”
• We also wonder if the scope of this meeting type might change over time. For example, there’s no mention of drug shortages in this guidance, or even the role that FDA warning letters play in occasionally contributing to them. Would the FDA consider accelerating these meetings as part of its drug shortage remediation efforts? Given that the FDA mentioned the PWLM request as an option to Intas Pharmaceuticals, whose warning letter was linked to a subsequent facility shutdown and shortages of some cancer drugs, we expect that this issue might come up in industry comments on this draft guidance. Comments are due to FDA by November 6, 2023.

To contact the author of this analysis, please email Alec Gaffney ( agaffney@agencyiq.com)

Key Documents and Dates

• Post-Warning Letter Meetings Under GDUFA
• Federal Register notice
• Comments due November 6, 2023