Responding to FDA compliance observations

Responding to FDA compliance observations

By Richard Prince

You have just had your close-out meeting with the FDA investigator. You have been told both verbally and in writing that some compliance concerns have been identified by the agency. How should your firm respond?

The Food and Drug Administration (FDA) issues a Form 483 to a firm when it believes there is evidence of deficient good manufacturing practices (GMPs). Successfully reacting to written agency concerns requires, firstly, a proper understanding of the underlying issues and, secondly, knowing how to draft the proper response.

After the close-out meeting, you should be ready to provide an initial response. Previously, plant management would have been expected to be issuing daily updates detailing the inspection status and emerging issues to top management. Management and a cadre of subject-matter experts would then be expected to mobilize in drafting the company`s written response. The firm`s written response should be submitted within 10 days for Form 483 observations. Strive to implement the appropriate corrective actions within 30 days. The corrective actions should be supported by analysis of the underlying problem(s).

On occasion, some firms exacerbate their problems when offering their responses to the FDA. Responses are occasionally defensive in nature, even argumentative. Even if the inspection process or the style of the inspection was conducted in a manner that the company felt was somewhat adversarial, it does not behoove the firm to carry any residual frustration or anger into its response. If the firm does not agree with the finding, it should clearly and politely state that it does not agree and, most importantly, offer the scientific rationale why it believes that the FDA position is unwarranted. Without a sufficient rationale, such as prevailing industry norm, (company practice represents better science, or FDA 483 point is at variance with other published FDA guidance), there is only one appropriate response to the FDA observation: accept it and commit to promptly fixing the problem. Thus, the firm`s written response should be respectful, science-based and actionable.

In responding to an FDA observation or compliance point, firms sometimes focus on the specific observation as opposed to additionally addressing the larger underlying system that governs the particular area that generated the deficient practice. Let`s say, for example, that the GMP deficiency dealt with a piece of production equipment that had not undergone any type of cleaning validation. FDA would expect the firm to not merely state that the cleaning process for a piece of equipment will be correspondingly validated, but it would prefer to be told that the overall cleaning validation system was reexamined to assure that all other pieces of appropriate production equipment are or were scheduled for some type of cleaning validation. Additionally, it would be prudent to evaluate the validation master plan to determine if cleaning validation was an element of the overall validation program. Further, the possible product impact of a non-validated piece of production equipment, from a cleaning perspective, ought to be appropriately investigated. The response would therefore focus on the specific item of concern, but also shed light on the relative robustness of the associated quality systems such as validation, change control and training. This type of detailed response will indicate to the FDA that the company has identified or is in the process of identifying the root cause of the deficiency and has implemented the necessary corrective actions to hopefully prevent a recurrence of the deficient practice.

If the FDA, for example, observed that a beaker containing a hazardous material was improperly stored in a QC laboratory, it would be insufficient to merely respond that the beaker was subsequently moved to the proper location within a hood. It would be better to say that the firm took a look at its general housekeeping practices in the laboratory and reexamined personnel training records in an attempt to understand what may have caused the bad practice to occur. Perhaps, that more systematic probe may actually result in the firm upgrading its procedure on laboratory housekeeping by requiring refresher training. Thus, the firm`s response to a given FDA observation should directly answer the agency concern, as well as address the possible impact of the observation on an associated quality system.

Always be honest in your dealings with the FDA or any other regulatory authority. Telling the truth helps to reinforce management`s credibility with the agency. If anyone in your company ever advocates that the truth, or a full accounting of the facts, should be shielded from the FDA, speak up and make an ethical stand if you believe you are in command of the facts. Having pioneered and promulgated the concept of GMPs, the FDA is the original subject-matter expert when it comes to GMP compliance. If the written response to the original Form 483 is seen as deficient by an FDA compliance officer, the firm will very likely be inspected again with the possible risk of a warning letter.

Richard Prince, Ph.D., is president of Richard Prince Associates Inc. (Short Hills, NJ), a compliance and technical based consultancy, and an officer of Microgen, a provider of quality disinfectant-cleaner products. He can be reached at (973) 564-8565, fax aat (973) 564-8731 or e-mail: [email protected].


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