You have the form FDA-483 after your inspection, and you have taken a global, systematic approach to your response. Lots of hard work in the correction and prevention of items mentioned on the 483 remain, but no big surprises hopefully. Well, for at least three firms in the past 2 ½ years that hasn’t exactly been the case. It is one thing for FDA to deem your response to the form 483 unsatisfactory and issue a warning letter but quite another to include an item that was not on the form 483. Three warning letters, two from 2012 and one from 2015, identify deficiencies that were specifically not identified in the form 483. That having been said, it’s impossible to know whether these items were:
- mentioned as potential serious concerns during the inspection orate the close out meeting
- if the investigators asked the firm to respond even though the item was not listed on the form-483 and the firm chose not to do so or
- additional review by the district office resulted in the additional item in the warning letter to stress the seriousness of the practice in question
Whatever the reason, while this remains unusual it isn’t simply a one-off event when it appears in three warning letters. It stresses the importance of paying close attention to investigators concerns during the inspection itself and clarifying issues and expectations during the close out meeting.
A comprehensive GXP Regulatory Intelligence program will be able to identify these rare events. Even though I work primarily in the pharmaceutical GMP area of Regulatory Intelligence, I skim most all published warning letters. Sometimes it’s possible to discern new approaches and possible trends by reading warning letters issued to firms in the other areas that FDA regulates. That is certainly true in the three examples presented below. I provide the name of the firm, date of the warning letter, link to the warning letter on the FDA website and the specific deficiency identified in the warning letter.
- Hospira, Costa Rica, Aug 22, 2012 warning letter
- Failure to identify the actions needed to correct and prevent recurrence of nonconforming product and other quality problems, as required by 21 CFR 820.100(a)(3).
For example, your firm initiated a recall in February 2011 due to a failure of audible alarms on Plum branded infusion pumps. A corrective action was initiated with the supplier, (b) (4), to correct defective components on the piezoelectric assembly. The original piezo alarm, Hospira part number 830-03329-005, was redesigned with new specifications and provided a new part number (830-03329-006) effective November 11, 2011. In March of 2012, your firm received multiple complaints of no audible alarms on Plum devices after the supplier corrective action was initiated.
Your firm did not respond specifically to this citation because it was not listed on the FDA 483 issued to your firm
- Memorial Hospital of South Bend, IN IRB, September 21, 2012 warning letter
- The IRB failed to prepare, maintain, and follow required written procedures governing the functions and operations of the IRB [21 CFR 56.108(b) and21 CFR 56.115(a) (6)].
In order to fulfill the requirements of the IRB regulations, each IRB must prepare, maintain, and follow written procedures describing IRB functions and operations specified in the regulations.
The IRB’s “Policy and Procedures Manual” does not include all the required written procedures. Specifically, the IRB does not have procedures to ensure prompt reporting to the IRB, appropriate institutional officials, and the FDA of:
- unanticipated problems involving risks to human subjects or others;
- any instance of serious or continuing noncompliance with these regulations or the requirements or determinations of the IRB; and
- any suspension or termination of IRB approval.
We note that the Form FDA 483 did not include an observation related to the lack of procedures for the reporting of any suspension or termination of IRB approval, and therefore this issue was not addressed in your corrective action plan. However, we acknowledge the IRB’s corrective action plan that promises prompt notification to FDA and the president of the institution, and revisions to the written procedures, for the reporting of (1) serious or continuing noncompliance with FDA regulations, and (2) unanticipated problems involving risks to human subjects or others. The IRB’s response is inadequate because it does not include a copy of the revised written procedures.
Please submit a copy of your written procedures, or any draft procedures in development, and a timeline for the implementation of any new procedures. In addition, please provide a description of any training provided to IRB staff on the new procedures and a list of attendees, or a projected timeline of planned training.
- XZeal Technologies, February 20, 2015 warning letter
- Although not listed on the FDA Form 483, further review by Compliance revealed a failure to establish and maintain procedures for quality audits and conduct such audits to assure that the quality system is in compliance with the established quality system requirements and to determine the effectiveness of the quality system, as required by 21 CFR 820.22. For example, you confirmed to the FDA investigator that your firm has not conducted internal audits at defined yearly intervals, as prescribed in your quality audit procedure, Internal Auditory, PR0-02.01, Ver. 00.
In conclusion, a comprehensive GMP Regulatory Intelligence Program considers enforcement actions taken against all product types that are regulated by FDA. Lots to read, yes, but simply skimming the warning letters issued to firms outside your primary area of interest may provide clues and suggestions as to where and how FDA is implementing enforcement actions.