Adverse Reactions

Pitfalls in Pharmaceutical Production: Protecting the Actual Drug Makers

July 27, 2023 Elizabeth M. Vancza, PhD, DABT, Merck & Co. Inc. Season 3 Episode 6
Adverse Reactions
Pitfalls in Pharmaceutical Production: Protecting the Actual Drug Makers
Show Notes Transcript Chapter Markers

While pharmaceuticals provide positive benefits for patients, what about workers that may be exposed during production? Elizabeth M. Vancza, Merck & Co. Inc., reveals to co-hosts Anne Chappelle and David Faulkner the role of occupational toxicologists in understanding the exposure risks of pharmaceuticals, chemicals, and other substances that may affect worker health, as well as how to protect them from these exposures.

About the Guest

Elizabeth M. Vancza, PhD, DABT, is currently an Associate Director of Occupational Toxicology at Merck & Co. Inc., where she assists business operations in the areas of occupational toxicology, potent compound safety evaluation and awareness, product quality/safety, and hazard/risk assessment. Before joining Merck in 2021, she worked as an occupational toxicologist for SafeBridge Consultants for over 10 years, serving clients worldwide, primarily from the pharmaceutical and biotechnology industries.

Dr. Vancza earned her PhD and MS degrees from New York University, with respective concentrations in inhalation toxicology and immunotoxicology, and she remains a guest lecturer for the graduate program in the areas of risk assessment and genomics. She also is an Associate Member of the Occupational Alliance for Risk Science (OARS) Workplace Environmental Exposure Level (WEEL) Committee.  

Dr. Vancza joined the Society of Toxicology (SOT) in 2004 and has remained an active member through her involvement on various committees and student outreach efforts for several Specialty Sections, Regional Chapters, and Special Interest Groups. She most recently completed a three-year term as Vice President (year one), President (year two), and Past President (year three) for the SOT Northeast Regional Chapter in 2021.

[00:00:00] Adverse Reactions “Decompose” Theme Music

[00:00:05] David Faulkner: Hello and welcome to Adverse Reactions.

[00:00:08] Anne Chappelle: This season, our theme is intersections, where we see toxicology intersect with another science.

[00:00:15] David Faulkner: Well, a lot of other sciences.

No person is an island, and no discipline has all the answers. But when scientific fields collide, some really interesting things happen. I’m David Faulkner,

[00:00:27] Anne Chappelle: and I’m Anne Chapelle. 

[00:00:28] David Faulkner: Welcome to Adverse Reactions Season 3: Intersections.

[00:00:32] Adverse Reactions “Decompose” Theme Music

[00:00:39] David Faulkner: Thanks for joining us for today’s episode, “Pitfalls in Pharmaceutical Production: Protecting the Actual Drug Makers.”

[00:00:46] Elizabeth Vancza: But with that increase in potency, if you’re looking at this from a workplace lens, that means that you have to be more stringent in how you’re handling it because the adverse effects that could happen just in an off-target population, if there’s a spill or if there’s an accidental release of something, it could be much more severe.

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[00:01:12] Anne Chappelle: I’m really excited that Elizabeth Vancza, otherwise known as Liz, was able to carve time out of her schedule today to join us. Thank you so much for spending some time with us.

[00:01:23] Elizabeth Vancza: Thank you so much, Anne. I really appreciate the invitation. I’m excited.

[00:01:26] David Faulkner: It’s great to have you here.

So, why don’t we start out with your superhero origin story. How did you get into the field that you’re in, and what is the field that you’re doing?

[00:01:35] Elizabeth Vancza: I am in the field of occupational toxicology. I’ve been an occupational toxicologist in one way or another for over 12 years now. For the first 10 years, I was in a consulting company, performing occupational tox, and I am now currently with a larger pharmaceutical company.

It’s a small field or subfield, but the very first record of a report in the field of occupational toxicology was Paracelsus himself. So, it was written in terminology as an alchemist would describe it, but it was 100% all about inhalation of crystalline silica in miners. So, I always like to point that out, it’s small, but it’s—

[00:02:14] Anne Chappelle: mighty. 

[00:02:15] Elizabeth Vancza: Exactly. The father of toxicology published on that.

My origin story is I fell into occupational toxicology by chance. When I was really young, I thought I was gonna save the world from pollution. I was going to join the EPA and set all these laws and save the world. That kind of led me to a path of, “I wanna do science, and I want to understand how things work and how I can save the world.” 

I got a degree in biology, with minors in environmental science and chemistry. From there, I was trying to understand how I could put all of that together into a career that was more interdisciplinary, and I just happened to have a organic chemistry professor who one day told me, “Have you ever thought about toxicology?” I said, “What’s toxicology?” So, he kind of gave me some information, said, “It’s really a marriage of all of the things that you’re interested in with a public health twist,” I was like, “Oh, okay.” Plus, it’s the study of poison, so that’s just cool. 

That led me to graduate school. I went on and did both my masters and PhD with concentrations in immunotoxicology and inhalation toxicology at NYU. I always had this in the back of my mind, I wanted to help with pollution and everything else, so that is where I steered towards inhalation toxicology. My PhD thesis was all about susceptibility to inhalation of ozone, so I was really interested in trying to help with setting limits and protecting folks from inhaling different pollutants like ozone. 

And I was giving a poster at SOT before I graduated. I got approached by someone, a friend, who had been in occupational toxicology, and he says, “We have a job opening. Would you be interested in occupational?” And I said, “Well, I don’t really know what it is, but let’s have a conversation.”

Turns out, the number one way that workers are exposed in the workplace is by inhalation. Secondary would be dermal exposure. The training that I got as an inhalation toxicologist translated really well to an occupational setting.

One thing led to another. I’ve realized there was this whole other subfield of toxicology beyond academia and whatnot to maybe not necessarily work at EPA and save the world, but I could protect a lot of people by going into this more applied subfield. I do enjoy that occupational toxicology is much more of an applied science as opposed to traditional toxicology roles, even within chemical companies or within pharma. You’re not in a lab necessarily. You’re not running studies or things like that, but you are interpreting the studies and then applying that to different situations in the workplace. 

[00:04:45] Anne Chappelle: I always felt that I was a really terrible researcher. I was really happy to get out of the lab and assemble data into some kind of meaningful big picture. I think that’s one of the things about, when you look at your career path, do you go into academia? Do you go into industry or regulatory, like with a governmental-type position? That wasn’t me. You know, I think it was kind of a natural progression then onto industry. Sounds like you felt the same.

[00:05:13] Elizabeth Vancza: Oh, yeah, 100%. Especially in graduate school, it was very focused, and I’m a whole picture person. I’m completely on the same page as you, Anne. Just being able to have the knowledge and being able to apply what I’ve learned to protect so many different people who don’t even realize that they might be even at risk of being exposed, I just think it was just such a rewarding idea.

So, I took the plunge, and actually, I went directly from graduate school to consulting, and that’s something else that a lot of people turn their head a little bit and say, “Wait, you were a consultant first? That’s usually what you do at the end of your career.” For me, it was a no brainer, and it was such a rewarding experience. The variety of projects I was able to work on as a consultant and the different types of people I was able to meet and just the way I was exposed to how different companies will do specific tasks in a completely different way. It was just really interesting being able to see the variations and variability in techniques and controls and just the problem solving of a small biotech company versus a large pharma company. It was just really eye-opening—and so worthwhile. I loved my experience as a consultant, so I would recommend it to anybody who’s thinking about a first career move. Don’t shy away from consulting. 

[00:06:29] David Faulkner: Oh, absolutely. That was my initial plan was to do consulting when I first got outta grad school cuz for the very reasons that you mentioned. I was just like, I wanna see the world—in a world of toxicology.” I, by serendipity, ended up in a bit of a different place, but I think it’s a really cool and valuable experience to do something like that. 

My background is more in the chemical industry side of things, where the goal is to develop things that are not going to linger in the body. They’re not going to have a pharmacological effect. And you have the exact opposite problem. If you’re successful, then, you do have these persistent things that are very active, and it just is fascinating to me how you can use similar tools to work on these very opposed sides of product development.

[00:07:14] Elizabeth Vancza: I think that’s what separates general industry or the chemical industry from the pharmaceutical industry is the product that you’re making; it’s being made with the intent of causing a physiological or a biological effect. So, if it doesn’t cause an effect, then, it’s not going to be a good drug. So, you really want to have something that’s going to cause that biological activity. 

The occupational toxicologist lies in making sure that it does protect the patient. It does what it’s supposed to do with the patient, but at the same time, it does not do that in a workplace setting for the people that are making it. Probably a good example would be, let’s say you’re working in a factory and the product that you’re making is some kind of blood pressure medicine. Some of the blood pressure medicines out there would be considered more potent, meaning that it takes a very low amount to cause a biological or a physiological effect.

That’s wonderful for a patient, maybe they only have to take their medicine once a day, but for someone working in a factory on the line, if there’s an exposure, that person’s blood pressure could drop dangerously low; they might pass out on the job. I mean, there’s a reason why you’re not supposed to handle machinery and things like that when you take certain drugs. Taking that warning label that’s already on the drugs and equating that to what someone is doing in a workplace, that’s where you have to, as an occupational toxicologist, you have to understand the whole picture. You have to really understand not only what the drugs can do or what the chemicals can do but also how that translates to what people are doing, what tasks are being done in a workplace setting. 

It is very, very interactive and very collaborative with other divisions and other professionals with any industry, whether that’s pharma or chemical, because you have to understand some of the engineering controls that are at play. You have to understand who the different stakeholders are. You’re also considering patient safety as a secondary thing. You’re not only concerned about the safety of the immediate manufacturing facility, you’re wondering about what’s gonna happen down the line once it’s already left your facility, once it’s out there. So, a lot of actually the occupational toxicology departments have a dual role, not only of worker safety but also of product safety. That’s something that I’ve seen much, much more as I’ve continued my career in the field. And that was a tangent, but—

[00:09:34] David Faulkner:  No, it was great. That was fantastic. 

[00:09:37] Anne Chappelle: How early do you say that you work with these discovery chemists? Where do you see your role as an occ-tox in terms of the discovery process? 

[00:09:46] Elizabeth Vancza: Honestly, the sooner the occupational toxicology team is aware of a new program or new product the better because if you have those early conversations and those early collaborations, it makes the drug development process so much smoother, and it prevents any hiccups or anything like that. Occupational toxicology, really the team, we have touches all the way from discovery to marketing. We are involved and are woven in as this hidden guardian in the background.

I guess you could think about it in terms of productivity, too. Not only are you trying to make a good product, you wanna make it well so that the less hiccups you have early on, that translates to a faster development timeline, which translates to getting the drugs to the patients faster. That translates to more people being helped faster. So, the sooner the better.

[00:10:37] David Faulkner: This is something that I think is really important: the fact that everybody’s familiar with pharmaceuticals, but those drugs need to be manufactured by somebody. And we’re not just looking at drugists mixing medicines in an apothecary with a mortar and pestle anymore. It’s this really big industrial project to make these drugs. I’m curious what sort of inputs you have in things like plants for manufacturing to protect the workers because it seems like these are important things to think about when you’re just even deciding how you’re gonna put this together in a scalable way.

[00:11:17] Elizabeth Vancza: Oh, 100%. I’d say that while the design and facility design, things like that, that’s kind of out of the purview of the occupational toxicologists, it’s important for the occupational toxicologists to be aware of what’s going on so that they can inform the folks who are designing the plant what’s gonna be handled, and then, we can tell them about the hazards of the materials. And then, they can use that information to then design facilities that are necessary. 

At the same time, if they already have a facility, they might come to us and say, “What do you think? Can we handle this, that, and the other in this facility knowing that we can handle up to this airborne concentration?” And then, we can take a look and then give them a “Yay” or “Nay” or say, “Well, you can handle it, but you should work with industrial hygiene to make sure that you have the appropriate personal protective equipment”. Maybe you need to limit the quantities or maybe you need to handle it in a specific type of equipment, something like that. We are there to inform on what the hazard is, and then, the industrial hygienists and engineers take that information and then apply it to whatever the environment is—be it a lab scale, pilot plant scale, commercial scale. And it’s really an interactive and interdisciplinary effort.

[00:12:35] David Faulkner: Gotta be a people person. 

[00:12:37] Elizabeth Vancza: Exactly. My day-to-day, I talk to so many people. My experience consulting and being able to network and speak with very different types of people from different companies, different areas, honing those communication skills has really helped me so much in my career—then and now. 

[00:12:55] David Faulkner: See people—it’s important as scientists. You do need to learn how talk to people. You need to learn how to write!

[00:13:02] Anne Chappelle: So, one of the challenges of occ-tox is a lack of data on certain mechanisms. A worker population and a patient population are inherently different, and the things you care about as an adverse effect in a worker population might be different than what you would think about in a patient population. So, could you talk a little bit about how you’re able to get some of this data that is not relevant for drug development per se, but it’s relevant for assessing worker safety?

[00:13:36] Elizabeth Vancza: As an occupational toxicologist, you might not have a large data set, especially early on when you’re working in pharma, but understanding the idea that the compound is intended do a certain thing. We rely heavily on mechanism of action. So, what is the compound going to do? That’s gonna be our first question in our hazard identification.

And the second question would be, with pharma, you’re very fortunate in that you have another team of toxicologists who are in there doing early tox work. Safety pharmacology data is usually very ample, and we can use that information to get an idea of how potent or non-potent a compound is. And using at least those two, we can get a general idea of how hazardous a compound will be. 

And then, of course, if you’re doing an assessment on a specific compound, it really is a living document that starts at discovery. As you get more data, you can refine it; you add more to it. And then, once you get to clinical trials, that’s when you move from your qualitative assessment—we call it occupational exposure banding techniques—to more of a quantitative assessment where you’re setting a specific target level. So, while you have that number, then, engineering and IH can come up with a plan for controlling the exposures, and then, they can also use your specific target to verify if those controls are working. So, there’s really three different pillars in occupational safety: that includes occupational tox doing the hazard assessment, and then there’s the hierarchy of controls to control the hazard, and then the verification of the controls, which is the exposure assessment. So, there’s really three things working all together at once. 

[00:15:18] David Faulkner: I really like how, if you’re doing your job right, then, nobody knows that you’ve done it. What about cases where things have not gone that way? Do have any examples of interesting high-profile cases where maybe somebody didn’t quite do their homework and illustrated why this field is so important?

[00:15:37] Elizabeth Vancza: When I mentioned talking about qualitative versus quantitative assessments, the occupational exposure band is more of the early-on bucketing system to get an idea of general recommendations for how to handle things when you don’t have a lot of data.

It was all born out of the molecular biology explosion of the 80s. Back in the day, it used to be that for every compound or every chemical, you would develop an OEL, but when molecular biology took off in the 80s, things were being developed faster than the EH&S resources could develop the limits. So, there was a lot of exposure being reported just at various companies from lab workers because they were discovering a new chemical, and they just had it on the benchtop and then they were getting effects: rashes, coughs, things like that. It was then that several of the larger companies got together to come up with a system for how to at least inform the folks of the hazards early on in discovery. 

[00:16:35] David Faulkner: I feel like this has been a lot of what I’ve been really excited about—the nuts bolts of managing risk in pharmaceutical production—just because it’s such an alien thing to me. 

Recently, I saw that you did an interview with the HPAPI. What is that?

[00:16:52] Elizabeth Vancza: HPAPI stands for the High Potency Active Pharmaceutical Ingredients Summit, and it’s basically a collection of professionals getting together to talk about pain points that we see in pharmaceutical industry, just from a safety perspective or risk perspective. 

In general, as the science and technology is getting more and more innovative, chemists are just doing some amazing work to make drugs more permeable into our systems, make them last longer so that patients don’t have to take drugs as often. If you think of someone, for example, who has cancer, maybe there’s so many things going on with them that it would be much easier on them and their families if they don’t have to have chemo every day, or they don’t have to take drugs every day—maybe once every couple weeks. It’s just, um, quality of life kind of balance. 

But with that increase in potency, if you’re looking at this from a workplace lens, that means that you have to be more stringent in how you’re handling it because the adverse effects that could happen just in an off-target population, if there’s a spill or if there’s an accidental release of something, it could be much more severe.

So, the HPAPI Summit was just a group of folks getting together, discussing pain points, and I was talking about this whole idea of one of the newest modalities in the cancer research area are antibody drug conjugates or ADCs. What you’re essentially doing is, you are taking a drug that’s found to be much too toxic to be used in general, but, with the new technologies, being able to link it through chemistry to something that’s not as potent, you can lessen its overall hazard while still targeting the cancer cells just as well, or even better, than before. 

There’s been an explosion of new drugs coming out worldwide in this realm. I call it the conjugation landscape. They just continue to evolve at an alarming rate. We are now understanding that we can conjugate different types of drugs to antibodies, or we can conjugate different types of drugs to something like smaller peptides. Or they could be conjugated to pegs, which are more polymers, or they can even be conjugated to oligonucleotides. So again, increased specificity. I like to call it the plug-and-play of conjugation landscape in pharma. 

It’s just really interesting to see what’s happening. From an occupational toxicology perspective, as all this conjugation technology is improving, we have to be equally as vigilant in understanding the hazards, not only of the conjugates as a whole but also of the new types of, we call them carrier molecules. If that’s gonna be an antibody, a peptide, a pegylated something, an oligo versus the actual drug. Because when you put two things together in any kind of conjugate form, depending on physical conditions that you’re in or whatever environment you’re in, it may not stay together 100% all of the time. You might have things break up, so you might have accidental release of one part, both parts. Being aware and cognizant of that and trying to work that into our occupational assessments, how we can best assess the hazards to make sure that the development continues without any glitches and workers are safe. 

[00:20:15] Anne Chappelle: Since we are called Adverse Reactions, what was the biggest adverse reaction that you might have had? 

[00:20:23] Elizabeth Vancza: My biggest adverse reaction was probably in graduate school. I worked on a project for four years on inhalation of diesel. The exposure system just didn’t work, and I had to scrap the project and start again in year four. 

[00:20:37] David Faulkner: Oh, no.

[00:20:38] Anne Chappelle: Oh, that’s horrible. 

[00:20:40] Elizabeth Vancza: I always remember this. I sat down with my PI, and we said, “OK, we have to abandon this project, regroup.” I said, “Hold on a second.” I went to my favorite vending machine. I got a soda. I went outside. I drank my soda. I took some deep breaths. I wiped a tear or two, went back inside, and what happened was I was able to salvage a lot of the information I had already gotten and combine it with an earlier rotation to come up with an even better project that allowed me to get more into the genetics and genomics of my research question. So, at the end of the day, it was a much better path. And looking back now, at the time I was devastated, but having lived through that and still being excited about toxicology—excited about what I do—you realize that bad things are just a part of life and just because bad things happen, doesn’t mean you have to have a bad reaction. You can move forward.

[00:21:33] Anne Chappelle: Thank you, Liz, for joining us today on Adverse Reactions

[00:21:38] Elizabeth Vancza: Thank you for having me.

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[00:21:46] David Faulkner: On next week’s episode of Adverse Reactions, we talk with Claudia Polsky about the intersection of toxicology, environmental health law, and justice.  

[00:21:55] Claudia Polsky: My personal passion is around environmental health, which I would define as the realm of involuntary exposure to toxic chemicals, ionizing and non-ionizing radiation, pollution in all forms. This is a place where the law is not particularly powerful. The law is ironically better at protecting salmon than protecting people.

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[00:22:23] Anne Chappelle: Thank you, all, for joining us for this episode of Adverse Reactions, presented by the Society of Toxicology. 

[00:22:30] David Faulkner: And thank you to Dave Leve at Ma3stro Studios, 

[00:22:33] Anne Chappelle: that’s Ma3stro with a three, not an E, 

[00:22:36] David Faulkner: who created and produced all the music for Adverse Reactions, including the theme song, "Decompose." 

[00:22:42] Anne Chappelle: The viewpoints and information presented in Adverse Reactions represent those of the participating individuals. Although the Society of Toxicology holds the copyright to this production, it has, 

[00:22:53] David Faulkner: definitely,

[00:22:54] Anne Chappelle: not vetted or reviewed the information presented herein,

[00:22:59] David Faulkner: nor does presenting and distributing this podcast represent any proposal or endorsement of any position by the Society.

[00:23:05] Anne Chappelle: You can find out more information about the show at 

[00:23:10] David Faulkner: and more information about the Society of Toxicology on Facebook, Instagram, LinkedIn, and Twitter. 

[00:23:16] Anne Chappelle: I’m Anne Chappelle, 

[00:23:18] David Faulkner: and I’m David Faulkner. 

[00:23:19] Anne Chappelle: This podcast was approved by Anne’s mom.

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[00:23:29] End of Episode

Introduction to the Episode
Discovering the World of Occupational Toxicology
What Does an Occupational Toxicologist Do?
When to Engage Occupational Toxicologists in the Drug Development Pipeline?
The Importance of Facility Design
A Dearth of Data
Occupational Toxicology Explodes in the 1980s
HPAPI and Antibody Drug Conjugates
What Was a Significant Adverse Reaction in Your Life?
Episode Credits