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

Last month in Bethesda, at a conference on the Current Challenges of GMPs, presented by Pharma Conference, Inc., FDA officials took FDA’s transparency mandate to new levels, by discussing some of the issues they are seeing at pharmaceutical manufacturing and quality operations.

By Agnes Shanley, Editor in Chief

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Last month in Bethesda, at a conference on the Current Challenges of GMPs, presented by Pharma Conference, Inc., FDA officials took FDA’s transparency mandate to new levels, by discussing some of the issues they are seeing at pharmaceutical manufacturing and quality operations. 

They also addressed some critical questions from industry involving the consistency of field inspections, individual inspector styles, and problems with the review process.

This openness was particularly evident in an audience Question and Answer session chaired by Rick Friedman, Director of FDA’s Division of Manufacturing and Product Quality, Barry Rothman, Supervisory consumer safety, and Steven Wolfgang consumer safety officer.

Questions ranged from quality management and contractor oversight, to issues of risk management and the need to “do more with less.”  Friedman noted the need to staff QA units with more seasoned professionals, especially those with manufacturing experience.  He also noted that the drug industry still underreported internal QC issues, a fact that can come back to haunt any manufacturer during a recall. 

All three connected today’s drug shortages to insufficient supplier oversight.

Here is some of what they had to say.  (For more, and some video clips, stay tuned).

Q - Recently there seems to be an increased concern about particulate matter, especially glass particles and metal fragments, in oral and liquid solid dosage forms. Has there been a shift in the Agency’s perception of risk presented by very small, low levels of particulates?

Rick Friedman: Risk hasn’t changed.  It never changes. Perceptions and assessments of risk include people’s expert opinions and you look at probability, severity, detectability. 

Part of it also depends on what type of particle is present, what type of metal, and how large the particles are.

There is also a question about patient population, for instance, whether it’s a pediatric medication, and dosage type (tablet or injectable).  These factors effect risk severity.

When investigators see [particulate issues at a facility] and we see there is a trend, at FDA we start to get worried.

When a manufacturer sees that components are coming in that contain metal and glass particulates, we wonder how they are responding to their supplier.  Are they returning the API lot to the vendor, saying ‘This is not my standard, I don’t want metal and glass in my API,’ or are they simply forward processing the faulty materials?

These are the kind of things that we want you to think about from the good manufacturing practice and prevention point of view.

We want you to be thinking about the prevalence of the problem and whether there is a pattern, and also, how you work with the supplier when you get a product that is below your standards.

We want to know ‘What was your reaction to that API, what do you do?’

Q -  Does the FDA have a policy about the number of the investigators that can be assigned to an inspection? The number assigned continues to increase. When more than three investigators are present, it really taxes a company’s ability to support the inspection.

Barry Rothman:  This phenomenon has become prevalent recently. In the past three years, we’ve hired about 600-800 new inspectors,  and what better experience can a new investigator get than to be out in the field with another investigator?   You’re seeing teams of three, four, of sometimes even five. 

This trend should slow as these new investigators become more experienced and start to work more independently.

If you are being taken in too many directions at one time and don’t have enough employees to fulfill the requests and when you start to hear complaints from clients that you’re not being timely with fulfillment, you need to connect with a lead investigator, there is always a lead investigator assigned who should identify him or herself at the onset of the inspection.

Tell him or her that you are being stretched beyond your capabilities. Discuss when you can reasonably provide the records that are being requested. Respond to the inquiries that they are making.

If you don’t get resolution there, then you should go to the District Office and contact a supervisor. If you don’t feel comfortable calling the District Office, call me, I am always happy to take your call.

Q - . What is causing drug shortages today?

Barry Rothman: At Team Biologics, we inspect a lot of single-source suppliers.  Keep in mind that there is a difference between policy and investigation.

An investigator is a fact witness.  He or she is going to conduct the inspections and gather evidence to determine whether or not you are in compliance with regulation, and, at the bottom line, whether or not you are in a state of control. 

He or she will do this, whether or not you are a single-source supplier. It is going to be the same every time.  

The rest of us will then get together and talk about the potential impact of having to take the product off the market.

Rick Friedman: There are many factors causing the shortages.  Half of the cases are not drug quality problems specifically at the facilities. Sometimes they reflect sourcing problems for API, or issues like that.

Factors that have to do with quality or manufacturing practice typically involve  problems that aren’t brand new to the company that haven’t been resolved over time. There can, rarely, be total “out of the blue” surprises, which are rare but can occur  due to polymorphs, precipitation or some other chemical physical phenomena that the manufacturer is dealing with.

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