Dean Calhoun: Joe, as you know, we routinely come across occupational exposure limits for the same exact active pharmaceutical ingredient that have different numerical values. Could you provide a little insight into way this might be the case?

Joe Nieusma: Sure Dean. That's a good point, and occupational exposure limits are about as unique as the companies that derive them.

You know, there is a lot of good publications that have come out of Merck. Bruce Naumann and Ed Sargent, and the good work that they have done at Merck to really set up the infrastructure for how occupational exposure limits are derived. Well, that's the starting point and after that starting point - which may provide a general equation where everyone seems to be sitting on first base, if you will.

Well, the way they actually run the bases is unique as the individual company. And, each individual company has their own internal policies and procedures, which really drive what is a priority when setting their occupational exposure limits. What that leads to is different starting points. It leads to different critical endpoints of what's important, what's not important, and what falls in between those two.

The critical endpoint, in some population that's chosen, is really what drives the OEL because where you start and all the uncertainty that factored in changes that number from one company to another company. And, unfortunately, some companies are stuck in the original paradigm of we're going to take the least conservative starting point [Editor's note: Joe means the lowest dose] and we're going to divide by 10, divide by 10, divide by 10, and divide by 10. Then, before you know it, you have a significant amount of uncertainty placed upon a very conservative starting point and that's your occupational exposure limit.

Some companies have policies that say, "You know what, anything that has a possibility or a shred of evidence that suggests that it might be a reproductive hazard then we're going to bury that in control bands that ensure that there's absolutely zero risk to our employees." That's a company policy or paradigm that some people follow, that becomes that company's choice.

Then, there are other companies that are more progressive and say "Well, let's look at what the science says. Let's see what this whole picture of toxicology data is saying as to where this occupational exposure limit should be set. It's those companies that are really leading the charge when it comes to honing the process of setting occupational exposure limits so that the science is in charge and not the unrealistic fears of people that are at those companies.

If your occupational exposure limit is based in science it's always going to be defensible. If your occupational exposure limit is based on company policy from times gone by, then that's going to be a little bit more difficult to justify or to uphold.

To say, "This is where this number needs to be" and it takes out all of your occupational toxicologist's professional judgment, because if you know that an occupational exposure limit needs to be set at "X", but company policy say it needs to be "X minus three orders of magnitude" then why do you even bother having the toxicologist, because you are not upholding the science? You're not listening to what the data is telling you and you don't have, in my opinion, a scientifically justified occupational exposure limit.

So it's the different policies, it's the different uncertainties, it's the different starting point—all of these things combined to generate different occupational exposure limits for the same active pharmaceutical ingredient.

And, when your shopping around for the OEL that is best for company, you need to have a good understanding of what's important to you, what you're trying to do, and what are your goals. What are you trying to do with that active pharmaceutical ingredient and that protective occupational exposure limit? If you know that going in, then you can sift through why those OELs are different and figure out which one will be best for your pharmaceutical company.

DC: That leads us to this next question. Sometimes, we find that these numbers can vary by an order of magnitude or more. Is one of these numbers more correct than the others?

JN: That's a great question and it goes back to the old adage "That if you put five toxicologist in a room and ask them a question, those five toxicologist will come up with at least six different opinions on it." With that in mind, no, none of the OELs are more correct then the other, and none of OELs are more incorrect than the other.

It all comes back to "What is the basis for the occupational exposure limit? What is the foundation?" You know I always I always tend to talk about a potent compound program and a containment protection system as a "brick wall." And, in order to make a solid brick wall you have to have a solid foundation. You have to have bricks that you understand. All of the tox data is the bricks, the containment technologies are the bricks, and the policies and procedures are the foundation.

So you need to know how you're going to solve the problem, then you look at the bricks in order to solve the problem and depending upon how these things actually occur, makes these numbers get set to where they get set, and it all depends upon these companies policies and procedures.

So if your company is historically very conservative, and placing a lot of investment in containment technologies and containment systems, then you're going to see OELs that tend to be lower. If your company hasn't made those investments, then maybe you're going to see OELs that are higher than most.

But, usually in my experience over the past 22 years or so—maybe even more now—that if you let the science do the talking then you're going to be in the right neighborhood. You have to look at the whole picture and all of the data, and you need to understand what that data means.

Hopefully that's clear. Did I answer the question?

DC: Yes. But one of the things that I would like to mention is that when we talk about the science...the science can improve over time.

Some of these OELs that we have looked at before were based on studies or based data that were very early in the drug development process, and there were a lot of uncertainty factors because there were a lot of data gaps. So as the drug development process advances and the drug hopefully makes it to market, you see a lot of experience with that drug in a much larger population. That data, that experience should actually have you go back and revisit that OEL to make sure that it's current; that it's based on current data.

Joe, do you have anything to comment on that?

JN: Actually that's a great point and I'm sorry I forgot to mention it.

Yes, so a lot of companies will set an OEL or a containment exposure control band early in development, or as early as they feel comfortable when they have a little bit of data. And it's a dynamic process and the OEL should be revisited or reevaluated as you know more about the drug product and as it gets closer to being marketed and there's more toxicology data.

Perhaps that OEL goes up—and we're going to talk about that more in a minute as to what the advantage of that is—but, in my experience again, companies set an OEL and there it sits. The OEL could be 5, 10, 15, or even 25 years old and very few companies actually have the time and the resources to go back and revisit those OELs that are already set.

So, unless there's an issue, or a problem, or some possible improvement, there's very little change that companies are going to go back and incorporated those items into OELs; they just don't have the resources. They are worried about tomorrow's drug, not a drug that is 15 years old. That's unfortunate because you could probably go back relatively easy to make sure that those numbers are still protective or maybe too conservative and perhaps affect the bottom line.

It's this type of analysis that could be quite helpful for the company that has multiple drugs in their portfolio and that they spend a significant amount of money in containment technologies. Because if you can "down-regulate" a drug out of a high containment suite and get it into a general manufacturing suite, then that's a huge advantage. That's huge for scheduling, for manufacturing, for personnel, for all of the other logistical issues of making drugs.

DC: Well that leads us right into our next question: "What is the impact of an occupational exposure limit that is either too conservative or an OEL that's too high?" What are your thoughts on that question?

JN: Well, first we will talk about the ones that are too conservative, and that's usually where things start out. So, if someone is asking for an OEL that doesn't have a whole lot of data, then they use a lot of uncertainty factors—and there are a lot of those you can pick from—but what happens is that the uncertainty is high so the OEL is low.

And then if the OEL is low, you need higher containment, more advanced technology, and greater levels of personal protective equipment. You need a containment suite, you need closed systems, whatever it is, it's more expensive to make that drug product because of the containment that needed to control airborne exposures to below the OEL.

Generally in those situations, when there's not a whole lot of data and you set an OEL, that drives it into a containment suite then that drives costs up. Contract manufacturers have to charge more money because the suites are in limited supply, the timeline to get your drug manufactured goes way out because you have to get in line with everyone else's potent compound to get into that manufacturing suite. It becomes a pinch point – a bottleneck in the drug manufacturing process.

Setting an OEL that is too low, that drives your drug product into that sort of thing costs more money...way more money. If you could just spend that more money on a couple more toxicology tests, it would benefit you. You can call Affygility Solutions and ask, "What kind of tests do we need to do to set a good OEL?" So, the more science you have, the more likely you're to get a more reliable, less uncertain OEL. So that's how too low of an OEL can affect the process.

If you set an OEL too high, well that's even worse. If it's too high and people are exposed to a drug product, and they have to endure occupational exposure and are having adverse effects because of that drug product, then that's completely unacceptable in an environmental, health and safety type of field. Nobody wants to see employees hurt. Nobody wants to see employees going home with less capacity than they had when they arrived at work in the morning.

An OEL that is too high, that allow adverse effects to occur is unacceptable; it's a toxicologist not doing their job. Maybe you don't have the cost of containment or the cost of manufacturing, but you have it in human costs. You have it with people paying with pain and, in my opinion, completely unacceptable.

That's why the OEL has to be done correctly, and when you get people playing toxicologist for a pharmaceutical company that don't have the training, and they're are missing some of what the data is telling them, your OEL could end up on either end of that spectrum. It could be too conservative and it costs unnecessary dollars for containment, or you can be not conservative enough and you're costing in people's pain – changes to the physiology of your employee population.

Both of the extreme ends are bad, I believe not being low enough is worse, because then people get hurt. Those are the impacts of an OEL that is too conservative or one that's too high.

DC: Well, that does it and we are out of time, so I do appreciate your time today.