Guest Column | January 24, 2016

Learning From FDA Warning Letter Trends

By Michael Wienholt, Halloran Consulting Group

We read a lot in the trade press about warning letters issued by FDA to industry, and our clients often ask us if we discern any trends that might indicate particular areas of focus of FDA’s wrath. In this column, we’ll share some of the insights we provide our clients related to this issue. Specifically, we will:

  • Identify important sources of information on FDA enforcement activities;
  • Share observations on trends in FDA Form 483 observations; and
  • Offer advice on implementing a quality management system.

Key Sources Of FDA Information

FDA is responsible for oversight of food, drugs, cosmetics, tobacco, and medical devices, so it issues all sorts of enforcement letters for all kinds of reasons. Our consulting practice focuses on pharma, devices, and biotech, so we rely upon the following FDA websites for the latest information on enforcement letters of interest to us:

  • A comprehensive database of enforcement letters searchable by issuing office is here, and it includes the most recently posted warning letters.
  • Untitled “Letters to Industry” for violations that do not meet the enforcement threshold of a warning letter are published here by the Center for Devices and Radiological Health (CDRH).
  • Warning letters and notices of violations to pharmaceutical companies are published here by the Center for Drug Evaluation and Research (CDER). The page provides links to several Offices within CDER, including the Office of Prescription Drug Promotion and the Office of Manufacturing Quality. These letters are of particular interest to manufacturers of combination products.

Recent Trends In Enforcement Activity

Surveying the FDA warning letter database, we learn that there was a 36 percent decrease in the number of warning letters issued by CDRH in 2014 (108) compared to 2013 (169), with most of these issued to domestic manufacturers. FDA hasn’t published the full data for 2015, but the totals change from year to year, and it is often difficult to discern a meaningful trend based upon data from the previous year.

The best way we have found to take the pulse of FDA enforcement activity is to attend the more informative industry meetings and roundtables, and to speak directly with FDA compliance officers who attend them. In November, we met with a field investigator in the Baltimore District Office who shared insights gleaned from conducting quality systems inspection technique (QSIT) evaluations of device manufacturers.

When we asked about enforcement trends, we were told that the top 10 Form 483 observations that resulted in issuance of a warning letter between January 2014 and April 2015 remained consistent compared with previous years. Again, corrective and preventive action (CAPA) was #1, with complaint handling, purchasing controls, process validation, and medical device reporting (MDR) rounding out the top five. The available data for Q1 of 2015 show that observations against purchasing controls and design change controls are increasing.

How To Stay Out Of Trouble

When industry consistently errs with respect to these compliance issues, it is worth paying attention to the direct advice offered by investigators in the field. So, what is the best advice from our inspector in the Baltimore District regarding CAPA? First, analyze all appropriate data sources for input into the CAPA system, and then perform adequate investigations and root cause analyses.

In our own quality management system auditing work, we consistently find that clients fail to establish the appropriate linkages between their management review, CAPA, complaint handling, and nonconforming materials procedures, such that not all quality data identified in management review procedures are tracked or trended, and there is no statistically valid criteria identified for the threshold level requiring the opening of a CAPA.

Often, we find that employees who lack qualifications by training and experience are performing investigations and risk assessments that prove inadequate, making verification of corrective and preventive actions impossible.

One example illustrates this point. During an FDA inspection of one of our clients, a 483 observation was documented for inadequate complaint investigation, in that the investigation of a customer complaint included only an attempt to obtain a return sample, with no review of the device history file. The client opened a CAPA for this specific citation, and then failed to identify potential quality problems related to the raw materials used in the affected manufacturing lot in the CAPA investigation. Not surprisingly, this led to a repeat observation. 

Regarding production and process controls, FDA emphasizes the need to adequately define acceptance criteria for incoming, in-process, and final inspection, and to link these to purchasing specifications. Often, we find that nonconforming material reports are opened against production lots that lack a problem statement linked to a purchasing specification. The resulting investigations and product dispositions are not supported by appropriate rationales or risk assessments. That is easy pickings for an FDA compliance officer trained in QSIT.

FDA also finds inadequacies in MDR procedures, and its inspectors apparently enjoy a fair amount of entertainment challenging manufacturers to provide hypothetical scenarios for examples of product issues that would be reportable as MDR. A firm that has never filed an MDR will be challenged to demonstrate a complete understanding of the regulation, and often we find that MDR procedures are woefully lacking in addressing the definition of a malfunction that may have caused or contributed to a reportable event.

Some Advice On Quality Management Systems

Finally, FDA inspectors make note of the fact that many manufacturers approach an FDA inspection with the assumption that an ISO certification provides insurance against 483 observations. If you are a medical device manufacturer operating internationally, that is also regulated by FDA. We offer the following advice:

  • Do not rely upon consultants with limited FDA regulatory compliance experience to write your ISO quality management system documents.
  • Strictly define functional roles and responsibilities, and link these to documented job descriptions with specified requirements for education, background, training, and experience to ensure that all activities required by the FDA quality system regulation are correctly and consistently performed. Hire only qualified staff to manage the quality system.
  • Ensure that you have auditors trained and experienced in the FDA quality system regulation conducting your internal audits. Nothing replaces your internal audit program to inform senior management of the true state of compliance with FDA requirements. Consider an independent third party assessment to supplement your internal audit program. No two auditors are alike, and often a fresh set of eyes will identify issues that your internal auditors may have overlooked.

We look forward to hearing your questions and thoughts regarding warning letter trends in the comments section below.

About The Author

Michael Wienholt, a principal consultant at Halloran Consulting Group, joined the company in 2015. Despite his youthful look, he brings more than 25 years of experience in the medical device industry, including 15 years of experience in global regulatory affairs and quality management systems for medical devices and in vitro diagnostics. Michael provides expertise in regulatory strategies and submissions and the design, implementation, and audit of quality management systems.  Clients also benefit from his uncanny ability to weave quotes from movies into conversations in a very appropriate way.

Prior to joining Halloran, Michael was the owner and principal consultant at FDA Consulting LLC where he built a reputation as a go-to person for resolving sticky regulatory situations.  His reputation for doing the right thing preceded him to Halloran as he came highly regarded from industry personnel and FDA contacts.

Prior to that, he was the VP of Regulatory Affairs and Quality Assurance at Accumetrics, Inc., where he was responsible for global regulatory compliance and submissions and served as the Management Representative for quality.  Michael has kindly agreed to man the western outposts of Halloran, toughing it out in San Diego.  

Michael holds a B.S. in Forestry from North Carolina State University. He is Regulatory Affairs Certified (RAC) in both US and EU regulatory requirements by the Regulatory Affairs Professional Society (RAPS). He is also an ANSI-RAB-accredited lead auditor for medical device quality systems.