How the FDA has changed, How the 483 has changed, & how we should use 483s to get smarter

Barbara UngerBarbara 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 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 interpretation of US GMPs and have regulatory authorities that may not be as mature as, for example, the FDA or EMA. FDA is not the only regulatory authority impacted by this change.   As a result we see FDA collaborating with other regulatory agencies, such as the EMA, so that both may make most effective use of their resources. This also requires FDA to develop new ways to assess the risk 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?

Forms 483 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 form 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, forms 483 are very useful in identifying the specific instances that were troubling to investigators. My focus is not on the finding specific statement that identifies the regulation in question. I’m interested in the actual activity that 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 form 483 items doesn’t give an accurate perspective on the firm’s GMP status. 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 form 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 form 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 forms 483 issued to the company, even if issued to different sites.

Bottom line, forms 483 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 forms 483 remain important and how the firm addresses them has become more important. Years ago companies and FDA would have multiple rounds of communication about responses to a form 483 before either 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 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 form 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 does the 483 play in your intelligence-gathering and decision-making?

For the weekly GMP REGULATORY INTELLIGENCE newsletter written by Barb, click here.

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CORRECTED: An earlier version of this post stated that a firm has 51 business days to respond. We corrected this typo – it is 15 business days, not 51 business days.

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