What actions should a pharma company take upon receiving a form 483 from FDA after a manufacturing facility inspection? What are key elements in submitting a response to the 483 that the agency will find acceptable? How important are these actions in avoiding additional enforcement actions by FDA?

At the 48th annual International GMP Conference held in early March 2024 at the University of Georgia in Athens, Georgia, Parexel Vice President, Technical-Strategic Compliance Consulting and former FDA Drug National Expert Investigator Ileana Barreto-Pettit shared her perspectives on these topics from many years of experience at FDA.

She began her discussion by asking, “How many times have you seen in a warning letter, ‘your response to the 483 was inadequate’ even though you spent hours, and hours, and hours, and you had consultants, and you had everybody under the sun writing the 483 response, and the FDA still finds it inadequate?”

Barreto-Pettit discussed the immediate actions she recommends taking after receiving a 483 and the elements of a good 483 response.

Post-483 Actions

After receiving a 483, the first action she recommended is to assemble a cross-functional team that includes the appropriate subject matter experts, managers, and representatives from impacted areas including quality, production, and the laboratory, for example. The team will need to evaluate the inspection observations, build consensus on the impact, and decide on steps to be taken to address the observations.

Of key importance, Barreto-Pettit emphasized, is a retrospective review. “The FDA always wants to know, because of these inadequate controls you have, what is the impact to products in the market?” She commented that such reviews “can be very difficult to do, depending on the observations.”

Regarding manufacturing deficiencies, “because of this deficiency, what is impacted? And it’s not only the product that was cited, it’s not only for the equipment that was cited, you have to extend it. And that is where a lot of companies fail. What about any of the other batches that were manufactured in that same room under the same controls?”

Product that may have been impacted may need to be recalled, and those recalls should take place quickly. For product in the company’s distribution warehouses, “do you need to do any type of health hazard evaluation as part of your decision-making? You need to determine whether you have to do any notifications or whether you need to shut down your operations because the deficiencies are so egregious and you cannot fix them quickly.” That evaluation may include performing additional testing, for example, of retain samples.

Responding to the 483

“You may only have one opportunity to prevent a warning letter,” Barreto-Pettit pointed out. “You either do a good job at preventing it, or you are going to have a long remediation activity.”

The FDA 483 response must be written in a way such that it assures the FDA that company is performing the necessary corrections in a holistic way.

In the response it is important to include analysis and reviews not only for other products in the facility that may have been impacted, but for other sites as well, to confirm that similar issues do not exist at other company sites. If FDA were to inspect another company site and find the same issues, that would constitute a repeat observation and tell the agency that review and remediation activities had not been extended to other facilities.

Barreto-Pettit explained that completing all the CAPAs is not required for a response, but that it is important to provide as much information as possible including immediate actions and estimated completion time for the longer term activities.

When writing a response, she recommended, for each one, “consider past, present, and future” impact to all batches and facilities. “What are the necessary corrections to correct them right now and in the long term? And how to prevent this from happening again?”

“You don’t want to see ‘this is a recurring observation’ in a 483, ever. That means the CAPAs that you had in the past were not effective,” the former FDA National Expert emphasized.

She summarized “actions to consider” when responding to a 483 (see Figure 1, Actions to Consider).


Ileana responding to a 483 Figure 1.pptx

Figure 1 | Actions to Consider


Regarding which observations in the 483 should be more highly prioritized, Barreto-Pettit commented that although the investigator lists the observations in order beginning with the most serious first, “in the investigator’s mind, that may have been it, but you know your processes better. You know your products. You need to take a look at that. Which one do you need to address right away, immediately, because that has the most impact to the patient that is going to be taking this medication?”

That risk assessment needs to be “very clear.” Perform a risk assessment to determine which should be addressed immediately and which ones can wait.

Independent Review

Barreto-Pettit emphasized that once the response is complete, it is important to have an independent review of the response by a knowledgeable third party prior to submission to the agency.

“Why do you think a third party is not only recommended, but is also required in many warning letters by the FDA? It is because people don’t always see their own mistakes. You can tell a story, and it seems perfectly clear to you, until you have somebody that doesn’t know your operations, doesn’t know your product, doesn’t know your process, who reads it and responds, ‘I have no idea what you are saying here.’”

“Remember the FDA is going to be reading it. It is not going to be the investigator that is familiar with your company. It is going to be a compliance officer, in CDER, who has never been in your facility, who may have a good EIR [Establishment Inspection Report], or maybe a not-so-good EIR, and is going to try to figure out what you are saying in your response. The third party review, I think, is always very important to have.”

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