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Responding to 483s and Warning Letters

by David L. Chesney and Anne E. Kelly
December 1998

At the conclusion of an inspection, FDA investigators issue a form FDA-483 which lists the adverse observations made during the inspection. Following review of the 483 and the establishment inspection report (EIR), the FDA District Office may elect to send the inspected company a Warning Letter. Most companies prepare elaborate responses to 483s and Warning Letters. This article presents the views of a two former FDA compliance officials regarding what makes an inspection response letter effective. It also reviews some common problems and pitfalls companies should avoid when writing response letters to the FDA.

Introduction

At the conclusion of an FDA inspection, the inspection team communicates its observations to the inspected company via Form FDA-483 (or simply, "483"). In an April, 1996 article in BioPharm this author described the history and present use of the 4831. In the current article, we will explore how to respond to both 483s and Warning Letters in effective ways, and how to avoid some common pitfalls.

A Comparison of 483s and Warning Letters

First, it is important to understand the distinction between a 483 and a Warning Letter.

FDA will first communicate inspection findings to company officials by presenting the 483 at the conclusion of the inspection. Companies have an opportunity to make an initial response during an exit discussion. Subsequently, most companies elect to send a formal written response. Although the law does not require any response at all, such responses are common practice and failing to respond would be seen as unusual by the FDA. Hence, a written response should always be prepared (unless legal counsel advises against it).

Upon returning to the FDA District Office, the inspection team writes an Establishment Inspection Report (EIR) which elaborates and expands on the inspection observations and links the observations to the evidence collected to support them. The EIR is reviewed, and if the conditions it describes are serious enough in the minds of the reviewing officials, a Warning Letter may follow.

A Warning Letter differs from a 483 in several important respects. A 483 represents the observations of the inspection team (or lone investigator, if such is the case). A Warning Letter indicates that higher level FDA officials have reviewed the inspection findings and have concluded that the findings warrant further formal notification to the inspected company that FDA believes serious violations may exist.

A Warning Letter has a twofold purpose: (1) To stimulate voluntary corrective action and (2) to establish a background of prior warning should further regulatory action by FDA be needed at a later date. As FDA itself states in its Warning Letter Reference Guide2, "Warning letters should be issued only for violations of "regulatory significance." The threshold for determination of what constitutes "regulatory significance" is that failure to adequately and promptly achieve correction to the warning letter may be expected to result in enforcement action...the warning letter would be appropriate to document prior warning if adequate corrections aren’t made and subsequent enforcement action is warranted, i.e., injunction or prosecution."

FDA also takes the position that a Warning Letter is not a final agency action. This has generally served to ward off judicial review of Warning Letters with the exception of a provision found in certain Warning Letters which states that Federal agencies that procure medical material will be advised that the Warning Letter recipient is an unacceptable supplier. On this topic, FDA’s Warning Letter Guide states "In order to minimize the possibility that a court might consider the Agency’s action to be final and permit an immediate court challenge, FDA officials should not make public statements which state that the Agency has reached a definitive position about the subject of a warning letter." FDA has also toned down the statement about Federal agencies that purchase medical material to read "Federal agencies are advised on the issuance of all warning letters about drugs and devices so that they may take this information into account when considering the award of contracts." Legislative efforts to force judicial review of Warning Letters have thus far failed.

Another key difference between a 483 and a Warning Letter is in the two documents’ accessibility under FOI. Although 483s are theoretically available immediately after they have been issued [see 21 CFR 20.101(a)]3, in practice it is often difficult to obtain them quickly, and one must know the record exists in order to request it. Warning Letters, on the other hand, are published upon issuance and promptly posted on the agency’s internet web site (www.fda.gov).

Both the 483 and the Warning Letter are serious documents which warrant a prompt and thoughtful reply. Companies often tend to rush replies, at the expense of careful consideration of the issues. Many companies believe that a rapid response to a 483 will prevent a Warning Letter. In certain cases this may be true, but a rapid 483 reply is no guarantee that a Warning Letter will not follow. A poorly written 483 response, on the other hand, may very well increase the likelihood of a subsequent Warning Letter.

Responding to an FDA-483

A company’s first look at the 483, and hence, first opportunity to respond comes at the conclusion of the inspection during the exit discussion. The inspection team presents the 483 and provides an opportunity for discussion. Companies should take full advantage of this opportunity to gain an understanding of the issues as FDA sees them, and, where practical, to make commitments about corrective action. The inspection team will take notes of company officials’ statements during the exit discussion and will report those statements in the EIR. However, companies should emphasize that their formal reply will follow in writing within a short period of time after the inspection. A week or two (or longer in some cases) is normally an acceptable response time, provided there are no serious health hazards involved nor any threats of imminent regulatory action, such as seizure or temporary restraining order, by the agency.During the exit discussion, companies should carefully point out any immediate corrective actions taken during the inspection, and ascertain whether the inspection team deemed the actions sufficient to address the concern.

Companies should also feel free to challenge the inspection team to explain the basis of citations. Many companies are unwilling to challenge the inspection team, out of fear of provoking some sort of "retaliatory" response. However, FDA will usually interpret silence as agreement, and if there are serious questions or concerns they should be raised for discussion. In reality, questions and challenges are not uncommon, and do not tend to upset most investigators, as long as the discussion is focused on the issues and not directed personally at the investigator or their competence. FDA’s policy is that if convincing information is presented that nullifies an observation, then the inspection team will delete the item from the FDA-4834.

Following the inspection, a carefully written response to the FDA-483 should be sent promptly, addressed to the District Director, with a courtesy copy to the lead investigator. If a Warning Letter is received, either respond within the time period prescribed (almost always 15 calendar days) or request an extension of time, providing a justification for why more time is needed.

Guidelines for Preparing the Response Letter

Whether responding to an FDA-483 or a Warning Letter, the following general guidelines may be of assistance in composing the response:
Begin with a statement of commitment to comply with applicable laws and regulations. Make it clear that your company understands its obligation under the law and is serious about its intent to follow the law.

Address each item on the FDA-483 or in the Warning Letter individually. For convenience, quote each specific citation verbatim and follow with your reply.

Where there is actual or potential impact on product (for example, excursions in critical process parameters, repeated failures or deviations, unresolved environmental monitoring excursions, etc.) provide an assessment of product impact and the basis for the assessment.

Describe the scope of the corrective action plan. Include a report of the corrective action for each of the specific examples listed in the observation, the steps taken to address any other area which may be subject to the same deficiency, and the measures taken to prevent the reoccurrence of the problem in the future.

Avoid long-winded discussions of background information. Remember, FDA’s main interests are:

  • What is the impact on the product?
  • What are you doing about the specific citation?
  • What was the root cause failure in the implicated quality system and how is that being addressed?
  • How will you prevent reoccurrence?
  • When making root cause determinations in quality systems, always ask "How-Why-What-Who?":
  • How and why did this happen?
  • What could have prevented it?
  • Who was responsible?

The answers to these questions will provide the information you will need to formulate a corrective action plan that will work and will provide a lasting "fix". For example, propose to prevent reoccurrence through directed internal audits until consistent satisfactory performance is documented. (Do not promise to share internal audit findings with the FDA, however. See FDA Compliance Policy Guidance Manual Section 130.300, CPG 7151.02,"FDA Access to Results of Quality Assurance Program Audits and Inspections"5 for information about FDA’s position on this issue.)

Avoiding Common Problems and Pitfalls

Be careful to avoid common pitfalls in your response. Among the most common pitfalls (but by no means the only ones) are these:

Incorrectly ascribing root cause to a lack of training or poor training. There are many roadblocks to compliance. Lack of training or poor training is only one. Ask yourself: Did the problem really arise because people did not know the right thing to do, or did they know what to do and simply not do it? If people did not do the right thing, why not? Was it a lack of resources, lack of supervision and discipline, an unclear Standard Operating Procedure (SOP), lack of clear role definition, or some other cause? Make certain that the issue has been properly assessed before prescribing training or retraining as the corrective action.

Setting unattainable goals. Only commit to what you are sure you can accomplish, and keep time lines and milestones realistic. In many cases, FDA will even agree to extensions of time when original objectives turn out to be unreasonable. If an extension of time is needed, communicate your request to the agency as soon as possible; be absolutely certain the proposed new date is attainable; clearly articulate the reason(s) the extension is needed; and demonstrate that there is no significant risk to the product or the consumer arising from the delay. Finally, set and meet a new date. FDA may lose confidence if there are repeated requests for modifications to corrective action plans or for extensions of time.

Too Much or Too Little Supporting Documentation. FDA will consider documented evidence provided as an attachment to the response. Provide documentation that supports your point, or demonstrates a corrective action was taken, as part of your written response. This may be literature search material, sections of a revised SOP which was not available at the time of the 483 exit discussion, qualification/validation documents, or similar information.

Pertinent documentation that supports your point can be very valuable, but there is such a thing as too much. Do not overwhelm FDA with volumes of supporting information. Keep the documentation succinct and on point. Express a desire to cooperate with FDA by providing anything further that the agency feels it needs upon request, and offer to meet with the agency to clarify the response if a meeting would be deemed useful.

Downplaying the significance of a reported complaint. Some companies attempt to minimize GMP issues by reporting a low incidence of complaints. FDA officials are well aware that not all product defects are reported to the firm by the product users. Also, for certain serious issues, even a single valid complaint can be extremely significant. Therefore, FDA is not likely to be influenced by this type of argument. Time is better spent resolving the GMP system issues suggested by the nature of the complaint.

Minimizing problems by stating that others in the industry do the same things. Even if an assertion of this sort is true, it may be that FDA considers the issue to be an industry wide problem. When faced with this argument, FDA may request a list of others in the industry with the same condition or practice, then follow up with inspections at those sites. A better approach is to deal with the issue on the merits, and avoid references to other firms’ practices.Failing to proofread the response for editorial errors. While this may seem obvious, many responses go through multiple drafts and may contain cut-and-paste errors, imbedded notations or be missing critical information. (Someone that has not been involved in the draft-and-redraft process may make the best proofreader.)

Failing to follow through with verification audits to ensure that corrective actions have been satisfactorily implemented. Many a management official of an FDA-regulated company has been dismayed to learn, during an FDA follow-up inspection, that a promised corrective action was not properly carried out. Leave nothing to chance. A company’s most valuable regulatory asset is its credibility with the FDA. Credibility is built through charting a proper course of action and following it in a manner that ensures that problems do not reoccur. In deciding whether to take regulatory action, FDA looks for repeated patterns of noncompliance. Where they exist, future promises of corrective action are unlikely to be believed, and the risk of further action by the agency is increased.

Summary

A 483 or a Warning Letter from the FDA are never welcome events, but they do not have to be disasters. By focusing communication with the FDA on the factors the agency considers important, developing well thought out corrective action plans, and by following through to make certain actions have been carried out as promised, companies can achieve genuine improvements in quality practice and thus reduce or eliminate the risk of further regulatory action.

References

Chesney, David L., "The FDA-483: Its History and Present Use", BioPharm 9 (4), 30-32 (1996).

Warning Letter Reference Guide, FDA, Office of Regulatory Affairs/Office of Enforcement, October, 1994.

Code of Federal Regulations, Food and Drugs. Title 21, Part 20, FDA FOI Policy, "Public Information," Subpart F, "Availability of Specific Categories of Records," 20.101(a), "Administrative Enforcement Records."

Investigations Operations Manual, FDA, Chapter 5, Section 512.

Compliance Policy Guidance Manual, FDA, Section 130.300, CPG 7151.02,"FDA Access to Results of Quality Assurance Program Audits and Inspections," as revised January, 1996.

Page last updated: 5 March 2009