Cerulean’s John Avellanet interviewed in The Silver Sheet on rapidly responding to an FDA inspection

“It’s important when firms write response letters that they address the specific observations that were written down on the FDA-483,” said Stephen Rabe, a compliance officer in the FDA’s Cincinnati District Office. “And yet the huge part that is often missing from response letters:  The company addresses individual observations, but it doesn’t really get to the solution of the problem.”

Drafting a meaty response letter that thoroughly addresses inspectional observations became even more challenging after FDA placed increased pressure on manufacturers to respond within 15 workdays after the close of an inspection.

“For many companies,” said John Avellanet, Managing Director & Principal of FDA consulting firm Cerulean Associates LLC, “those 15 days are a panicked rush.”

“FDA will tell you that 15 days is 15 business days, Monday through Friday. However, firms should think about those 15 days in terms of 15 calendar days. The reason to do it this way is three-fold:

  1. First, you help everyone in the organization understand that this the number one, top priority right now. A poor response guarantees a stricter regulatory enforcement action which then guarantees a decline in the value of the company and yearly sales revenue. It’s a 1:1:1 relationship.
  2. Second, you actually end up giving yourself a nice buffer so you have a couple of days to sit on your response, and think about it. Is there something that, on second thought, should be added, clarified, tweaked, etc.?
  3. And third, you make sure that FDA receives your response within that window and can take the time to review your response. You want to avoid the 30-second glance-over.”

Put Only Practical Timelines in Response

It’s important to include only practical corrective actions and timeframes in an FDA-483 response.

“You need to be realistic about timeframes,” said FDA district officer Rabe, “so when we go back there, everything is corrected, because if there are still problems, you’re going to get written up for them again. And, if you just got a warning letter, the next step for us would maybe be to ask for an injunction or some other more serious action because you haven’t fixed the problems, especially when you said they would be fixed.”

Avellanet urged manufacturers to not only be honest about timeframes, but to provide solid evidence of progress as well. “If you look at a lot of FDA enforcement correspondence, the agency is constantly noting that a firm’s 15-day response was insufficient. One reason is because when the firm said a problem was going to take six months to fix, the firm failed to tell the agency why it was going to take six months and then what the interim milestone steps and due dates would be,” said Avellanet. “You want to be able to say in your written response, ‘Here is our plan, here are the specific items within that plan that we are going to accomplish, here are the various milestones within that plan, and here are the final completion target dates for each element in the plan.’ In other words, FDA should be able to take what you provided, show back up in 3 months, 6 months, or a year, and know exactly where you are on solving the issues and why. If you aren’t providing that level-setting in your 15-day response, get outside help now.”

“Remember,” advised Cerulean’s John Avellanet, “once you get the FDA-483, the clock starts ticking the minute the investigator walks out the door. I suggest you encapsulate a simple checklist or observation-closure matrix in your SOP on inspection handling. Match the initial observation, the symptom, to the person held accountable in your organization for closing the gap, and then match that to the proof – the records generated – as a result of the gap closure.”

Post-Inspection Response Checklist

“First,” said Avellanet, “review all the observations that require a fix. If the investigator cites “Your change control forms were inadequate or insufficient because they were missing signatures,” your problem is not really that you have some missing signatures on a few change control forms. That’s just a symptom. Those signatures are missing for a reason. It could be your change control process is too convoluted and you need to streamline your procedures, it could be your compliance training is ineffective, and so on. You have to pause, step back and look for the underlying problem. That’s what the agency wants to see.”

“Now, 15 days can be a tight timeframe in which to do that, so you need a structured, simplified process. I have my clients use an observation-closure matrix. By listing out the documentation to be used to prove a fix, it’s easy to see if you’re inadvertently only focusing on the symptomatic FDA-483 or are tackling the larger, more systemic control breakdown. The former would only have a little bit of documentation such as an updated SOP, whereas the latter, more systemic view will need more documentation such as the revised change control SOP, a streamlined process map, a set of revised training, a revised form, and so on).”

Firms should then assemble a draft response that ensures each observation has been adequately addressed. Manufacturers should then share the draft response and potential proof verification records with their legal counsel.

“You want to have a legal review of your response and supporting evidence for two reasons,” Avellanet said. “One, you don’t want to accidentally commit your organization to do something that you can’t fulfill. And two, if push comes to shove, and a worst-case scenario develops, your legal team is not going to be happy to be brought in after the fact.”

Finally, the company would finalize its response and verification records, and submit those to FDA.

Convene a Quality System Management Review

It’s also helpful for manufacturers to hold an abbreviated quality system management review (QSMR) during FDA’s 15-day timeframe.

“In an ideal world, firms would hold that meeting regularly, but the reality is that a lot of firms still wait until the FDA inspection and they have problems. Think about holding an abbreviated or rapid QSMR focused only on FDA-483 observations and associated activities,” said Avellanet. “This allows you, for every FDA-483 observation, to go two steps beyond. The first step is the one that everyone always thinks of: ‘Okay, FDA cited us for this change control issue, so we’ll look at our overall change control process.'”

Take a “second step beyond by formulating a set of metrics that can show where you are today, where you’re going to be in the future, and how things have improved. So if we stay with our change control example, one metric could be the number of change controls, or the turnaround time, or the number of post-change control minor fixes/tweaks that have to be done after the fact,” Avellanet said.

“Those metrics do two things for you. One, they’re great for management. It’s crystal clear that you’re making progress and being productive. Metrics are easily grasped. Second, FDA likes metrics as proof. There is very little argument.”

“For example, which is more powerful:  stating that ‘We revised our change control process to be more streamlined and reduce the risk of missing signatures,’ OR, ‘We revised our change control process, etc., and now manufacturing cycle time has gone from 30 days to 25 days, the number of change controls has dropped by 50%, the product rejection rate has declined by 5%, and so on.'”

If a company doesn’t have time to hold a QSMR during the first 15 days after the inspection, it should plan to conduct one as soon as possible.

“If you miss this window of opportunity, it is far too easy to slip back into the way you were doing things before. It’s just human nature,” noted Avellanet. “If you can hold an abbreviated QSMR focused on the FDA-483 observations – a QSMR that takes less than 72 hours to prepare for and conduct – then you are on your way to thinking proactively about your quality system and how to cost-effectively, and compliantly, operate in a state-of-control.”

Conduct a Mock Inspection and Gap Analysis

After the 15-day window passes, firms may want to hire a third party to conduct a mock FDA inspection to prepare for when the agency returns.

Further, “you should conduct a gap analysis,” Avellanet said. “Do not limit the independent FDA auditor to just the FDA-483s. Remember that 483s are symptoms and FDA will use those as the starting point for their follow-up inspection.”

“Thus, you will want the auditor to come in and say, ‘Okay, here are the issues you have from a regulatory standpoint still, but you may also want to revise your clean room training. The way you’re training people is not as effective as if you were to take a different approach.'”

“In other words, you’re trying to find areas related to the FDA-483 wherein you can show improvements that go above and beyond complying with the letter of the law. FDA views the laws and regulations as minimum requirements – the starting line, not the finish line.”

Next, “review the results of the mock FDA inspection and gap analysis, and then set up projects to address the gaps and enable business success for the next two to three years,” said Avellanet. So, 15 calendar days, observation-closure matrix, supporting proof, then a rapid QSMR, and a mock FDA inspection leading to longer-term gap closures and business improvements like quality system streamlining and lean compliance. That’s how to go from panic to success.”

Excerpted from original January 2011 publication in “The Silver Sheet”

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