Barbara Unger, new editor-in-chief of GMP Regulatory Intelligence, has been providing some great insights on this blog. Last week, she shared her perspective about key FDA enforcement trends. Yesterday, she gave us some insights on her previous roles.
What are one or two key ways you’ve seen the FDA change over the last 10 years?
I think the most important change over the past ten years has been the FDA’s shift to become globally active in GMP enforcement as the drug supply chain changes. Some of the countries to which manufacturing is outsourced have differing interpretations of US GMPs and have regulatory authorities that may not be as mature as, for example, the FDA or EMA. The FDA is not the only regulatory authority impacted by this change. As a result we see the FDA collaborating with other regulatory agencies, such as the EMA, so that both may make most effective use of their resources. This also requires the FDA to develop new ways to assess the risks posed by the sites they regulate and focus inspections on those who pose the most significant risk to patient safety.
How do you use 483s in your role?
483s provide an early warning of what investigators are evaluating during inspections. The challenge is that they are only “observations”, rather than confirmed deficiencies in GMP operations. The information in a 483 is also provided without context and that needs to be considered. Sometimes an investigator has a particular area of focus where they are trying to make a point. Now, with all of those caveats, 483s are very useful in identifying the specific instances that were troubling to investigators. My focus is not on finding the specific statement that identifies the regulation in question. I’m interested in the actual activity that the FDA found problematic. And when they include page after page of examples for a single finding statement, I conclude that this is a significant problem area within the company and not just a one off event.
Simply counting the number of 483 items doesn’t give an accurate perspective on the firm’s GMP status. The FDA might identify a single item that could be expensive and time consuming to remediate, or they could identify 4 or 5 that could be addressed fairly quickly. A 21-page 483, however, strongly suggests that the investigators are trying to make a point and the firm may have a broad range of activities that need remediation. Also, if the 483 was issued to a company who received multiple warning letters within the past few years, it suggests a global problem that the firm has likely not addressed in an effective manner. In this case, I will generally re-read the warning letters and other 483s issued to the company, even if issued to different sites.
Bottom line, 483s are important pieces of the puzzle when trying to understand the GMP enforcement environment but should be considered within the incomplete context of the examples, scope, and other actions that may have been taken against the firm in question. Avoid over interpreting, but don’t ignore them either. They are a key piece of the puzzle.
Do you think FDA 483s have become more or less important over time? Why?
I think 483s remain important and how the firm addresses them has become more important. Years ago, companies and the FDA would have multiple rounds of communication about responses to a 483 before either the FDA agreed to the firm’s corrective actions or the FDA progressed to a warning letter. An announcement in the Federal Register on August 11, 2009 changed that time frame. Now a firm has 15 business days to respond and that response will be considered when deciding whether or not to take additional compliance action. So, a firm has one chance to convince the FDA they have the issue(s) in hand and are taking appropriate action. Similarly, an unsatisfactory response may lead to a warning letter and/or additional compliance actions like a seizure.
For products manufactured outside the US, imposition of an import alert can have financial consequences for the company. Consent decree agreements and fines can also have financial consequences including the “lost opportunities” category while the firm is focusing on meeting the requirements of the agreement. Downplaying the 483 content and, more importantly, not responding seriously and completely to the observations can have unfortunate costly consequences.
Tell us what you think below? Do you think the FDA has changed? What role do 483s play in your intelligence-gathering and decision-making?
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