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

Still the bottom line is manufacturing practices that are not adhered to, whether at contractors’ facilities or within the company.  It’s very much about the need to build quality in.

In one case, for instance, an excipient used for one parenteral product,  a medically necessary and important product at that, had  high endotoxin loads.

You must build in upstream controls for the process and with your supplier.

In this case, we were dealing with an oil-based formulation, using a natural oil, and the oil permitted, or even actively promoted, the growth of endotoxins. 

These are the types of things you want to look at in your supply risk management manual, for instance, potential endotoxin levels for natural vs. synthetic.  Natural products can be more difficult to control.

The company ultimately discontinued the product, leaving a void in the market place rather than try to fix the problem with their supplier. Again, these are the kind of issues that we are seeing, They are basically GMP staples.

Steven Wolfgang: Many of the shortages have to do with products of marginal quality that have been on the market for a long period of time. Whenever there is a realization that the quality of the product is marginal such that something needs to be done, it can take a fairly significant effort to bring that product back up to level of expectation.

 It is clearly not like it a single one time occurrence; I think we have a problem that has been around. Glass delamination, for instance, is nothing new.

Another thing that is prompting the shortages is the change in the management of the pharma supply chain, which is not yet robust enough to withstand hiccups. As pharma’s supply chain becomes more globalized it is very important that from one end to the other that the manufactures have a good understanding of where potential bottlenecks or short circuits can occur or a short circuit in the supply chain. As we look at these problems, down the road, we want to consider some of the things Richard was talking about regarding supply chain risk

Rick Friedman: Pricing does play a part. The company discontined the product that I was just telling you about, in the anecdote about the endotoxins.

 I think it was about a fifty-cent-per-bottle product, so maybe they didn’t feel that it was going to be profitable to invest in the remediation of the process and work with the supplier.

That is a shame because it’s an important product that needs to be on the market and it is pretty tight these days. But there are pricing realities.

There have to be some solutions discussed by the Rx 360’s of the world, the IPEAs, concerning uniform excipient GMPs.  Such systemic improvements will make a difference for manufacturers and purchasers of raw materials because this is a systemic problem. 

Q - The reporting policy under the field alert regulation is inconsistently applied across the field offices.Is anything being done to define or clarify the reporting end of the field alert regulation and to establish a consistent policy?

Barry Rothman: I am not clear on where inconsistency is, but I believe the question is expressing the concern that, during an onsite investigation, reviewing adverse events, an investigator may make decision that something should have been reported, which wasn’t.  If you read the regulation literally, anything that could cause product to be adulterated or misbranded should be reported.

I think that you’re going to see a little bit of variation between investigators as long as we are using human investigators.  It’s also going to be part of “what are we seeing at the firm. Are these isolated incidents? Maybe there wasn’t a report that should have been there. Was the risk less than significant?” 

If there are more significant things that investigators are finding that aren’t being reported by the company, the investigators are not discussing these findings in a vaccum, but bringing issues up with supervisors.

We’re encouraging earlier communication with Center partners.  These are the types of things we’re doing to encourage consistency.

The reports themselves reflect communication with D.O.  We have started recent teleconferences to discuss across the field, Center, my office and the field to discuss reporting timeframes, mechanism and consistent processes for reviewing adverse effects in the field during inspections

The reports themselves as they come in are reviewed both by the district office as well and we have communications about significant issues that are discovered.

Rick Friedman: Consults during inspections are sometimes difficult, in cases where we don’t have the chance to do some frontloading and proactive communications. The Center, as part of regulatory recommendation, still looks at all potential adulterations to determine whether or not they’re violations. In some cases, we determine that they didn’t violate regulations, but in a lot of cases, they do. 

There’s probably underreporting, in many cases, within the industry. 

Richard Davis: I have the benefit of having worked in the FDA and I’ve also been on the industry side and running quality organizations, and I’ve seen this in consulting as well. When I get a call about a particular issue and the question, ‘Do I need to report this?’ My first question is: What do you think? What’s the violation, what’s the issue, what’s the root cause?

You may not have all the answers, in which case there’s a provision that says, ‘File it anyway, since you have time to do the investigation and communicate with the Agency.’