Risk-ranking Model for Prioritising GMP Inspections - FDA's Pilot Model

GMP News No. 473

GMP News
5 October 2004

Risk-ranking Model for Prioritising
GMP Inspections - FDA's Pilot Model

In the following we have compiled excerpts from the speech of DAVID HOROWITZ, Esq., Director, Office of Compliance, CDER. He summarises the objectives of a risk-ranking model to prioritise manufacturing sites for GMP inspections as follows:

"How should we best allocate our very limited inspectional resources? Where should we go first so that we don't run out of GMP inspectional oversight resources before we get to some of the most important sites to look at. [...]

Although the agency has been implementing risk-based programs in some sense, a more systematic, rigorous risk-based approach will be developed.

Well, what we're talking about today, I think is just the first steps towards that end. This is a slide that amazes me, and it's the first time that I've presented it in public because I just couldn't believe the data, and I've presented the blue line before because there is a lot of evidence that our resources available to complete systems based inspections have declined significantly over the years."

Now, some of that decline has to do with resources being put into pre-approval inspections which have a GMP component to them, but that partly explains some of the decline, not entirely because it is quite precipitous, and I think the trend is likely to continue even though we've tried to stave off some of the decreases in the last few years.

But this green line is quite extraordinary because it shows tremendous growth in the number of domestic registered firms, and that surprised me particularly because as this industry is globalized, I thought there would be not such a steep increase in domestic firms. I expected to see just a steep increase in foreign firms.

And what I think this tells is something else that's been going on in the industry for the few years, and that's more use of contract facilities, more outsourcing and the phenomenon which is not something this group typically gets involved in of medical gas repackagers. A lot of these facilities starting in the '90s began registering with the FDA. Many of them were engaged in this activity before, but more and more started registering. [...]"

In the following, David Horowitz talks about the Guideline ICH Q9 "Quality by Design," which is currently being developed and harmonised:

"And so I'm going to look now at the working definitions from Q9 to sort of figure out what harm is and how to apply these terms."

"I recognize there was a spirited discussion on Q9. It's still very much a work in progress. These definitions aren't exactly the way we in FDA would have done it, but I think for our purposes today they're illustrative of how you might go about thinking about these issues.

All right. So if risk is about the probability and severity of harm, of course, the key is risk to what. In other words, the key is how you define harm, and the Q9 definitions sort of walk you through several definitions to actually figure out what harm in the context of pharmaceutical quality might be. [...]

So what we tried to do is look at the risks associated with each manufacturing site and aggregate them and rank them against the risk scores for the other manufacturing site. So our goal is to systematically incorporate our current knowledge about drug quality risks in an effort to prioritize sites for periodic systems based GMP inspections. [...]"

Then, David Horowitz began to explain which aspects/criteria have to be taken into account in assessing the contractor's risk.

"Well, we think that the effectiveness of the quality systems are predictive of that, and we believe that there is a connection between the compliance history or the inspectional record associated with the firm. Of course, not all violations are the same, but we do believe that there is some predictive aspects there.

Now, interestingly, one of the elements of risk is exposure, and I think it relates in part to severity and in part to probability, but if something goes wrong at a facility, the impact is likely to be much greater if the drugs are going to every household in the world or in America than if it's just a local facility producing a few drugs for the community.

So we felt that exposure of the drug products manufactured in a facility is a risk factor that ought to be considered by the agency in prioritizing its resources. [...]

Then another category of factors we categorized as the process factors, and I think this is intended to answer the question are some manufacturing processes for particular product classes more likely to go wrong than others? Intuitively we sense that some processes are more complex and some were simpler, but our data is very limited on this. We didn't have any good quantitative data."

The new risk-ranking model to prioritise manufacturing sites for FDA inspections will constitute an integral part of the "cGMP Initiative for the 21st Century." Our education courses always deal with the current trends in EU and FDA-GMP compliance.


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