FDA Fields Tough Questions About Inspections, Challenges Pharma to Be Open, Honest

I’ve seen situations where we have submitted something, sometimes thirty days or forty five days from the event, but we had already submitted an alert so the Agency knew what we were doing. We were talking with them, telling them when we were going to send the report in.

If you’re saying,‘ I don’t know if I really want to send this. We haven’t done enough to get the information we need.’  Six months later when product is out there, you don’t want to be in a [bad] position… it is better for both sides to get the things filed, do all of our work, make sure we get it documented, and make sure there is communication on both sides.

Barry Rothman: You need to form the relationships with your District Offices so that you can pick up the phone and say, ‘This is what we are seeing. Do you think it is reportable? These are the things we are doing to investigate it and making our determination.’

If you have had that discussion, then it’s likely you’re not going to have a problem.

This approach will open lines of communication. If we think there is a significant issue that we think needs to be reported, we will tell you.

Q -  Risk-based supply management means doing the right level of management, in some cases more and in some cases less. However, management often means doing more with the same resources. Do you expect supplier oversight, in general, to require more effort and resource than are  typically [allocated]  today?

Richard Davis:  We need more resources associated with risk management because the whole supply chain has been globalized.

Years ago, when companies were manufacturing their own API’s and most of the excipients were from well-known companies, this was not such a problem.  Today, however, you could do some really detailed mapping [on ingredients for your product] and still be surprised by where product is coming from and who is touching it.

Rick Friedman: No organization is successful with risk management, unless it supports it, both philosophically and financially.

Quality assurance sometimes gets short shrift or there are not enough qualified personnel. Sometimes it is good to have someone with a production background or other experience in the industry, in QA, so they can ask the tough questions.

It has to do with qualifications, but also a lot to do with resources because you actually have to pay more for better people in QA.

In inspections in Europe and the U.S, I have seen some cases where a quality assurance associate with one or two years experience with a pharmaceutical degree was thought to be qualified enough to ask the tough questions in a complex laboratory OOS or manufacturing investigation.

You need qualified personnel in QA overseeing the operations and asking the tough questions. If you don’t have a strong quality management system, and address problems as they come up, then, ultimately, they will come back up later on, we all know that,. That is when you really need to have good QA people in sufficient numbers and I think that it is lacking right now in the industry. External audits need to be improved. 

Q-  What is FDA’s position with regard to Rx-360, IPEA and third-party quality auditors? I don’t think industry will accept third party audits without formal comments from FDA.

Steven Wolfgang: This question suggests that the industry is not poised to use third parties until the FDA speaks out on what the ground rules are for doing that. If that is the case then I believe that FDA will, at some point, make some kind of formal statement.

But the third party has to meet your expectations. In other words, you would need to qualify them as if they were one of your suppliers.  I’m not really sure what [additional] FDA guidance you would need in order to use that kind of an approach.

Q: Briefly discuss the difference between Annual Product Reviews and Stage-Three Process Verification.  APR’s are done only once a year, so, presumably, they wouldn’t meet requirements set for continuous process verification.

Rick Friedman: Annual verifications aren’t sufficient. While FDA has only sporadically asked those questions in inspections over the years, I remember a manufacturer that lacked about three months of process control and  recently was subject to a regulatory action.

211.110 has always said that a company is responsible for using measures such as statistical process control (SPC) and for looking at a valid history of batches to determine what the proper limits are and whether they are remaining within those limits.  This control is basic to any industry that produces

So if you take 211.110 and marry that to 211.180, which says that you should review of your procedures and specifications at least once a year to make sure they are still valid.  There is an annual review, but there’s also the ongoing need to evaluate and monitor process performance, which can be a near-term trend of two or three weeks where everything’s going out of control.

Over the years,  I’ve seen situations at a number of places where a process is running along really well for years, even five to ten years, where it has great history and then suddenly, control goes awry.

A root cause analysis is really important and often problems can be traced to is raw materials

Sometimes problems are due to untested attributes of the raw materials that are certainly not named in the USP or other compendia, which  focus on chemical and microbiological but don’t look at physical attributes.