Category 4 or 5 Potent Compounds: Understanding the Risks

Here at Affygility Solutions, we often get asked the questions "What makes a Category 4 or Category 5 potent compound?" In addition, we often get asked, "What are some examples of Category 4 or Category 5 potent compounds?" In this article, Dr. Joe Nieusma, Senior Toxicologist with Affygility Solutions and Dean M. Calhoun, CIH, President and CEO of Affygility Solutions discussed answers to these two questions.

What determines a Category 4 or 5 Potent Compound?

Dean Calhoun: Good afternoon, Joe. As you know, here at Affygility Solutions, we often get asked the question "What determines a Category 4 or 5 Potent Compound?" Can you provide some insight regarding this question?

Joe Nieusma: Well, Dean, that's really a good question and kind of a complex answer. But, really the determination of a Category 4 or Category 5 potent compounds comes from the evaluation of a compilation of toxicological data.

As you know, but many of our readers may not know, the categorization of a potent compound comes together by evaluating data in seventeen or eighteen different areas, and each one of those individual toxicological data areas go into determining an occupational exposure limit (OEL) or determining a control band, or if your simply looking to just categorize the compound into one of the many control bands out there—Category 1, Category 2, Category 3, Category 4, Category 5, or even Category 6—depending upon your company's own potent compound containment scheme—these individual items take into account the potency of the drug product—the acute toxicity. What is this drug going to do right away? These items take into account the warning properties of the compound, the onset of action. Is this drug product going to kill someone in an acute overexposure situation, or is it going to be something that is not as serious? How often do these adverse effects come into play? These acute, right-now health effects come into consideration when you're trying to decide what category to assign to a compound.

Obviously, in a Category 4 or Category 5 compound, you're going to have a lot of serious acute effects, and those acute effects are going to be life-threatening—potentially fatal, or these effects are going to happen real quickly, maybe within a hour. These compounds may also pose serious risks or even the threat of death. These are the types of compounds that are place in a Category 4 or Category 5 potent compound safety control band.

Other things that come into play: you talk about reversibility, and if you can treat these types of acute symptoms. Are they going to go away? Something that if they are exposed to, that won't go away, and that they have to deal with the rest of their life. Or, if it takes months or years for these effects to go away, these are characteristic of a Category 4 or Category 5 potent compound.

Now that leads right into the item: whether you need medical intervention—does it require heroic first aid to keep the person alive? We also consider items such as sensitization, irritation, and your immune system. Most people underestimate their immune system and the ability for it to decrease the quality of their life.

Then you have absorption potential. Is this going to absorb through your lungs? Is it going to absorb through your skin? Is this drug product going to get from the powder in the drum to systemic exposure, where bad things can possibly happen very, very quickly? All of these things come into play.

Then, of course, you look at chronic effects. Now chronic effects, those are things that can significantly decrease quality of life—debilitating changes that happen slowly. When you have those types of situations that can drive up that categorization of a compound, making it a Category 4 or Category 5 potent compound. And you look at the frequency and severity of those types of effects.

You then look at cumulative effects. You try to figure out that if the more that someone is exposed to these compounds, on an ongoing basis, is there going to be more of a danger of debilitating effects, of adverse effects, of drug effects from an occupational setting?

Then you also look at irreversible effects—items like mutagenicity, genotoxicity, items that change the structure of DNA. As you know, a lot of your cancer agents can have this type of effect; these types of drugs are trying to eliminate rapidly growing cells. This is also where carcinogenicity comes in: whether or not if it's going to cause cancer. Then of course, reproductive toxicity is considered—anything that happens with the developmental process, the reproductive process.

Each one of the above items are ranked, depending upon specific criteria to determine is it a Category 1, Category 2, Category 3, Category 4, or Category 5 potent compound. Therefore, using that set of data helps you come up with a whole picture approach to evaluating a compound—whether it is a Category 4 or Category 5 potent compound.

DC: Very good. Just a question here, you mentioned that there were 17–18 criteria here, and one of them was occupational exposure limit. Does a compound with a low occupational exposure limit always make it a Category 4 or 5 potent compound?

JN: Excellent question—and no it's not. That low occupational exposure limit (OEL) may not be based on real significant adverse effects. Maybe, the low OEL is based on the fact that it is a potent product that doesn't need much of the active pharmaceutical ingredient to do the job. You know there are some drug products, such as blood pressure medicine, that they lower blood pressure, that they increase patient's quality of life, they decrease cardiovascular morbidity and mortality, and they are not all that significant in an occupational setting. Yes, they may have a low occupational exposure limit, but they are Category 2 compounds. Excellent question.

DC: All right, thank you. Now that we have answered the questions on what determines a Category 4 or Category 5 potent compound, from your experience, what is the impact on a company when their compound is assigned to a Category 4 or Category 5 control band?

JN: Well, you know, some companies just aren't set up to handle these types of compounds, and when that's the case, and it's a significant business asset to have this product in the company's portfolio, then they are going to have to send it out for contract manufacturing. But if they are set up to handle these types of products—they have an isolation suite, they have the proper containment devices and engineering controls, administrative procedures, and personal protective equipment—then these products will get mainstreamed into their special manufacturing areas. If they have made that investment, then it's going to be seamless.

DC: Absolutely. Do you ever see a case where a compound was initially assigned to be a Category 4 or Category 5 compound, where after more clinical data comes in, is lowered to a Category 3 compound?

JN: Well, usually where you see that case is when a compound is dropped into a default control band, and of course, the default control band is over-conservative on the side of safety. And, because you lack data, you're just starting to perform the animal studies, it's always better to be over-conservative and use more containment than what you might think is necessary.

But as data comes in you re-evaluate; that's why toxicology is a dynamic science, that's why toxicology is a whole picture approach. You need to look at the new data and make those adjustments. But I have seen compounds that started out as a default Category 4 because of the intended indication and then as the data comes in, and that this compound doesn't act like they were expecting, then it's not as potent, not as toxic as they previously believed and then it's downgraded, maybe even to a Category 2.

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Examples of Category 4 and Category 5 Potent Compounds

DC: Great, that answers that question. Now, can you provide a few examples of Category 4 and Category 5 potent compounds and what characteristics makes those types of compounds?

JN: Sure, we could talk about a lot of different compounds, but let's discuss the ones that come right to the top of my head. One of these is Misoprostol and it's a good example. Misoprostol has a lot of reproductive effects and it gets a bad name because it is known in a lot of pharmaceutical circles as "the abortion pill." It's the "day-after pill," RU–486. It has some serious reproductive effects and these are fairly permanent, especially for the fetus. But in those types of situations you have to have your engineering controls and containment in order. It's definitely worth being a Category 4 compound.

Another good example is compound that is an opioid, analgesic compound related to fentanyl called carfentanil citrate, and it's a really heavy-duty animal tranquilizer. I believe it's what they put in the darts to knock down elephants. The thing about this compound is that you really have to have the antidote onsite because if there is ever any accidental exposure to this compound someone is going to be dead real quick, and, you know, that's the ultimate in adverse effects. This is the type of compound that requires heroic medical intervention if there ever is an accidental overexposure situation.

Here's another example: lactase. Lactase is the enzyme that is responsible for breaking lactose into simple sugars. Lactase is an enzyme; it's a protein that is added into milk to help those people that are lactose intolerant deal with those symptoms. Lactase being a protein, its ability to create hypersensitivity reactions or a sensitization reaction in the people exposed to this enzyme is tremendous. It's a powerful sensitizer. So what does that do? It drives an occupational exposure limit down into the basement. Just because of that sensitization and that involvement of the immune system, and that irreversible effect that happens upon occupational exposure, it drives lactase into a Category 4 or maybe even a Category 5 potent compound.

Then you have the granddaddy of them all: the poster child for highly potent drug products is that class of hormonal agents. You have your estrogen compounds that are commonly found in birth control pills. One of them is Norgestimate and we're talking about prototypical hormonal agents that are pregnancy category X compounds. This means that exposure to this agent will cause changes to the reproductive system. They are very potent; a milligram per day is probably the maximum therapeutic dose that you will see with this drug category.

There are irreversible effects associated with these types of compounds—they change the reproductive system, long-term exposure increases cancer risk. In addition, you have the cardiovascular effects of these particular drug products. These drug products increase the risk of heart attacks and stroke, or thromboembolism; that's where a blood clot forms and gets caught somewhere is the vascular system. Any estrogen compounds are solid candidates for being categorized as a Category 4 or Category 5 potent compound, and occupational exposure limits for these compounds are typically so low, and the cumulative effects are typically so prevalent, that in some cases you can't have employees work with this material everyday—that's an administrative control.

These hormonal drugs are your prototypical type of compounds that are Category 4 and Category 5 potent compounds. So there you have it; I believe I've given some pretty good examples of what makes a Category 4 or Category 5 potent compound. But, you just never know, because you have to look at that whole picture, that whole data view of toxicology, and that comes throughout the whole drug development process.

And if you don't know how these things interact, I would highly recommend Affygility Solutions' Advanced Topics in Potent Compound series. It's a 5-module webinar series and over the course of 10-hours you learn toxicology 101, you learn industrial hygiene, you learn advance toxicology, and ultimately you will learn where all the pieces of a potent compound safety program fit. You might not understand all the data, but at least you will understand how it all fits together.

DC: Well that was really good and we are almost out of time, so is there anything else that you would like to say before we end?

JN: No, nothing other than feel free to contact_us at Affygility Solutions if you need more information on occupational toxicology, industrial hygiene in the pharmaceutical industry, control banding, or on potent compound safety.

Published May 16, 2011

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