Expert: Nitrosamines ‘Can Slip Through the Manufacturing Process,’ Making Reference Standards Essential to Avoid This Carcinogen in the Drug Supply Chain

Pharmacy Times interviewed Edwin Gump, PhD, vice president of the Small Molecules Department at US Pharmacopeia (USP), on USP’s reference standards that were released in July 2020 to support manufacturers and regulators in analyzing and monitoring potentially harmful nitrosamine impurities in the drug supply chain.

This is the second video in the video series collaboration between Pharmacy Times and USP, which looks to highlight USP’s work in the present day and over its 200 year history to support the pharmacist, as well as to present USP’s perspective on timely and topical issues in the field.

In this edition of the video series collaboration, Gump addresses the critical role USP’s reference standards play in keeping patients safe from harmful contaminants such as nitrosamines.

Alana Hippensteele: So, Dr. Gump, what is the small molecules department at USP?

Edwin Gump: So, thank you for having me on, first off. As you know, there are a lot of different types of medicines. There are biological medicines, which are proteins, there are cell therapies. Small molecules, or chemical medicines, are those medicines that are chemically synthesized. So, a lot of the prescription drugs that most people take tend to be chemical medicines.

So, the Small Molecules Department at USP is a department that was specifically focused on these types of medicines. As I'm sure you know, USP's mission is to promote the quality of medicines, and one of the ways we do that is by developing public standards that help ensure the quality of those medicines.

In the small molecules department, basically, we work on those generic prescription small chemical medicines. We produce the standards working with our expert volunteers for that class of medicines.

Alana Hippensteele: That's fascinating. What is the USP Nitrosamines Joint Subcommittee, and why was it established?

Edwin Gump: So maybe I'll start with the second half of that question first. Going back to about the summer of 2018, there was the discovery of N-Nitrosodimethylamine, which is a type of nitrosamine in the prescription drug valsartan.

Following that, there was the discovery of similar nitrosamines in other drugs within that same class, the angiotensin II receptor blockers. Nitrosamines have been subsequently discovered in a couple of other medicines.

So, there was clearly a quality need related to that issue. The way we work to address it is by establishing that joint subcommittee for nitrosamines. Essentially, what this committee was is we pulled together a number of our existing volunteers that had certain expertise. So, people who have expertise in trace level analysis for impurities. We have people who are from the pharmaceutical industry and understand how to control drugs, how to manufacture. We also had government liaisons from FDA, in this case, someone from the European Directorate for Quality of Medicines.

So, we were trying to bring together all the right expertise to then talk about how USP creates standards, information, or tools to help global regulators and help industry get a better handle on controlling these dangerous impurities.

Alana Hippensteele: Right. Why are nitrosamines of such particular concern?

Edwin Gump: So, I'm not a toxicologist, but nitrosamines, from my reading, these are compounds that have been studied for a number of years. There’s at least a number of compounds in this class that are known mutagenic carcinogens. So, they're basically fairly nasty cancer-causing actives.

One of the things that makes nitrosamines really tricky is that they actually can be formed very simply through really simple chemistries. The building blocks that you need to create nitrosamines are all around us in nature, and so they can form very easily.

When you're concerned about ultratrace levels of these being present, that creates a problem for control. So, people may be aware that nitrosamines can be in bacon, grilled meats, and sometimes in water. So, in a lot of ways, they're pretty ubiquitous. If you look low enough, you can probably find them.

But the one place that people don't really have a choice—you can choose not to eat that grilled burger—but people shouldn't have to make a choice or have concerns about the quality of their medicines. That's why it's really important that we get a handle on the issue of nitrosamines and medicines, and really so that people can feel good about trusting their medicines and taking the ones that they need.

Alana Hippensteele: So, where do nitrosamines appear in the drug supply chain?

Edwin Gump: So, it's a really good question. So, I just kind of alluded to the fact that nitrosamines can form in a lot of different ways through really common building blocks. So, as a result, the ways that they can get into the supply chain are actually quite varied.

They can be formed at the manufacturing site when they're creating the active pharmaceutical ingredient in the chemical synthetic manufacturing process, if the right building blocks come together, as was the case for valsartan.

In another case, ranitidine, it appears this molecule was a little bit unstable, and so it actually degraded itself to produce the nitrosamine contamination.

There's been other examples where it appears that there's some sort of reaction that's going on in the drug product, and so presumably excipient related that is somehow contributing to the presence of nitrosamines in certain formulations.

So, it's really pretty varied, and as a result, it's really important for manufacturers to perform proper risk assessments, and wherever there's a risk, then we really need to look and make sure that any risk is properly mitigated.

Alana Hippensteele: So, Dr. Gump, how will these new reference standards help prevent tainted medicines from reaching patients?

Edwin Gump: That's a great question. So, I think I mentioned that manufacturers have a responsibility to evaluate their processes and their products and look for chances where they could have a risk of nitrosamines.

So, if there's a risk present, then manufacturers need to dig in and do more, which might include testing their products to confirm that there's no presence of nitrosamines.

So, and again, I think I mentioned, we're talking about really ultratrace levels, part per million, part per billion. So, these are not easy analyses to perform. They require highly complex analytical equipment, and with any test, you need to kind of have what's the control to that test.

People can think of these nitrosamine reference standards like a control standard. These are highly characterized materials that manufacturers can now use in their tests to ensure that when they perform that test, the test is accurate, the test is precise, that they are detecting to the appropriate levels that they need to control for the presence of nitrosamines.

So, having the reference standards is a really important tool for manufacturers. The fact that we characterize the quality appropriately is an important part of ensuring that when results get generated, we're making sure those are the right results.

Alana Hippensteele: Right, that makes sense. If nitrosamine impurities in the drug supply chain are a known issue, is it possible that there are other harmful impurities present that may also need to be addressed as well?

Edwin Gump: It's a good question. So, one of the things that I think the pharmaceutical industry has generally for the most part done very well is looked at impurities. I think nitrosamines, for the reasons I just described, are kind of a unique case where they can sort of crop up.

They aren't necessarily readily identified as part of the components during the manufacturing process, and so they sort of slip through. Whereas, other types of impurities, I think, manufacturers have a much better handle on how to control those.

I'm certainly not going to tell you that there couldn't be cases where those impurities could end up in a medicine if the quality is not there, which in part is why USP is doing what it's doing and creating standards so that we can help industry ensure that the quality of those medicines is there and really to bolster public trust in the quality of their medicines.

It really is, I think, a lot better than people think. You tend to hear about the few problems that occur, but you don't hear about the millions or billions of pills that get distributed every year and help people deal with their health conditions.

Alana Hippensteele: Absolutely. Yeah, that's a great point. What is the role of the pharmacist in supporting the safety of drugs within the supply chain?

Edwin Gump: Well, one of the roles I think is really important, and I kind of alluded to this is, medicines, when they're made and developed, manufacturers do a lot of work to identify under what conditions those medicines are stable. How do you store them, how do you handle them, and how do you protect them from light—these types of things.

So, I think a really important job that pharmacists do is making sure that medicines get properly handled, teaching their patients how also to properly handle them. If medicines don't get handled properly or they're stored at conditions that might not be optimal, then there's the chance that these medicines do degrade and could produce some impurities, which if taken to an extreme, could be unsafe.

Alana Hippensteele: Right, that makes sense. What is on the horizon for the small molecules department at USP?

Edwin Gump: So, it's a very timely question. We're actually moving to the future right now.

The way small molecules used to function is we were sort of almost an artisanal shop where each of the people working within the group had their portfolio of medicines that they would work on standards for. What we're trying to do is, and what we recognize is that doesn't necessarily mean that we're working on the standards that are most important, that are the most impactful for the medicines, that are most utilized around the world.

So, given that we have limited resources, as does everyone, we're sort of shifting away from that model to one where we're focusing a lot more on the medicines that we, from the data, we have that appear to be the most heavily utilized, or certainly if there are quality issues that get identified, we certainly are looking to work on standards that are going to help improve those types of situations.

So, what we're hoping to do is by shifting our model, move to a place where we're actually having a bigger public health impact for people out there who rely on safe medicines.

Alana Hippensteele: Right, yeah. That's sounds like a great forward movement. What are your hopes for the future in the small molecules field of pharmacy?

Edwin Gump: Well, I think basically to keep moving in the direction we're moving.

Obviously, we want to do our part to make sure that things, like nitrosamines or other harmful impurities or other issues related to quality, get taken care of, and that people can really feel confident and rely on their medicines.

The US medicines supply is probably the safest, or as safe as any in the world, and we want to make sure that the public really feels confident when they need to take a medicine that they can do so and not have other things they have to concern themselves about like nitrosamines.

Alana Hippensteele: Right, absolutely. That makes complete sense and sounds like really important work. Thank you so much for taking the time to speak with me today, Dr. Gump.

Edwin Gump: It was my pleasure, thank you.