FDA on Compliance Issues in Pharma

During a Q&A session at the 2022 PDA/FDA Joint Regulatory Conference in mid-September in Washington, D.C., CDER Office of Compliance Director Donald Ashley and Office Director of the Office of Manufacturing Quality Francis Godwin provided insight regarding compliance issues in pharma companies.

The following questions from attendees were among those addressed:

• What factors are considered by FDA when determining inspection classification and the agency response?
• Why do some companies seem to have persistent compliance issues?
• What is recommended when responding to 483 observations?

Question: When your office is reviewing an Official Action Indicated (OAI) case, do you take the firm’s compliance history into account?

“Yes, we do,” Godwin stated. “One of the questions when we are looking at an inspection outcome, or sample outcome is, ‘Is this the same as it was before, or is it something different?’ That is based in part on what other information we have. If it is the first time we have ever been there, we do not really know much about it. So, we are assuming it is a clear picture.

“But we do know that there are trajectories. Sometimes firms are in an episodic event where they are in and out of compliance. Sometimes they are much higher and we are looking at the calculus to say, ‘Is this a firm that has been in and out of compliance, has gotten warning letters, and been cleaned up?’

“We would also ask ourselves, ‘Are they falling down again, and do we need to get them back up? Or is this a firm that is much more mature, has a higher level of quality and they slipped, so we just need to help them a little bit? And that is where we may schedule a regulatory meeting versus something more aggressive.”

Question: Why do you think some companies have persistent compliance issues while others have strong compliance records?

“It gets back to some of the myths and misconceptions that I talked about during my presentation,” Ashley replied.  “There are people who think they should just do the absolute minimum to meet the lowest possible level of quality that they think will get them to pass an inspection.

“Presumably they think it is because doing more is going to be too costly. But the truth of the matter is that negative consequences flow from those types of actions and in the long run end up costing the companies more.

“Then by contrast there are people who understand actual quality management systems (QMS). It is going to be good for patients, it is going to be good for the quality of the product. But in the long run, it also can be good for the company too because it offers predictability and a positive reputation for the company.”

Question: Do you have any recommendations on how 483 responses can be improved so they lead to more sustainable solutions and corrections?

“If you have an FDA inspection and you get issued a 483,” Godwin began, “understand that when FDA looks at the response, we are going to ask, ‘are the findings the tip of the iceberg, or is this it? Is this something unique?’

“One of the things we recommend is that when you are creating a 483 response, do not just look at the one thing that was cited in the 483. Investigators are there for a few days. They are not going to do a complete audit of everything. They are going to look for examples and point them out. And so, we are asking, ‘is this the tip of the iceberg?’

“Also, is it the same everywhere? Say, as an example, that an investigator finds that you missed a stability sampling and testing time point and your response is, ‘yes, we did. We went back and tested that one sample. It is good.’ When we review that, we are going to have the question, ‘What about the rest of them? Did you test any of the others? What is going on?’

“21 CFR 211.192 is kind of the bread and butter CFR for quality oversight of systems. If you find a problem you look at it. Also, look at it and ask, is this problem limited to here or does it affect other things?

“And when you are crafting a 483 response, keep that in mind because you want to look at what was found by the investigators and understand what is going on. FDA is going to ask, ‘Is this a bigger thing that affects other drugs or other lots?’ That really helps us in terms of knowing what to do.”