Understanding the Impact Nitrosamine Impurities Can Have in the Work of Pharmacy Professionals

Pharmacy Times® interviewed Naiffer Romero, MSc, MPH, principal scientist - scientific affairs at U.S. Pharmacopeia (USP), on the potential occurrence of nitrosamine impurities, as well as a newer kind of nitrosamine, in the development and manufacturing of pharmaceutical and other products, and his work to regulate these impurities and ensure medication quality.

Alana Hippensteele: Hi, I’m Alana Hippensteele with Pharmacy Times. The Pharmacy Times audience has probably heard about occasional recalls in recent years of pharmaceutical products due to the discovery of nitrosamine impurities. As pharmacists know, the potential for impurities is a fact of life for the development and manufacturing of pharmaceutical and other products—but it’s the job of industry and regulators to ensure that, if they are present, they remain within acceptable levels to ensure quality and safety for patients.

Today we have the opportunity to sit down with a scientist from an organization whose mission it is to help manufacturers ensure this quality for medications—The United States Pharmacopeia, or USP. Here to talk about the challenges—and his role in working to overcome them and find solutions—is USP scientist Naiffer Romero.

So Naiffer, can you remind our readers and audience: what is USP, and what is your role in the organization?

Naiffer Romero: USP is a 200-year-old standard-setting organization whose standards are being used by manufacturers and regulatory agencies around the world to confirm and check the quality of medications, foods, and ingredients within all these products. In recent years, USP staff alongside industry regulators have really turned their attention into these nitrosamine impurities appearing in different pharmaceutical products in search of solutions to really control them, identify them, discover them, and really understand the science behind all these, in support of trust in medications and the safety of the patients at the end of the day.

Alana Hippensteele: That's a really important point. So, would you mind giving us some background on the nitrosamines issue? And why exactly are they a concern?

Naiffer Romero: Absolutely. Nitrosamines are organic chemical compounds that may be present in low levels in a wide variety of products, such as meat, food, cosmetics, and other sources—even vegetables are known to be some sort of source of nitrosamines. However, the whole discussion is all around limits. It’s around amounts or exposures to these. Overall, these compounds are considered potentially carcinogenic. Interestingly enough, when they are metabolized by the liver, they are converted into a chemical agent that can damage the DNA, and because of that, they link to cancer.

Starting in 2018, concerning levels of these impurities were found in commonly prescribed medications for blood pressure, diabetes, and other conditions. Image Credit: Adobe Stock - MQ-Illustrations

Starting in 2018, concerning levels of these impurities were found in commonly prescribed medications for blood pressure, diabetes, and other conditions. Of course, the presence of these types of impurities, which are potentially carcinogenic, really became a concern to regulators and to manufacturers of all these medications. The discovery of these impurities has resulted in recalls that may leave pharmacies unable to dispense some of these treatment to patients, depending on the nature and the limit found in some of these medications. To assess the control and the presence of these nitrosamine impurities in medicines, the U.S. FDA and regulators around the globe have worked together and issued a series of public health alerts and guidances for manufacturers to really tackle this issue of the presence of these types of impurities in medications.

Product recalls, due to the discovery of these nitrosamine impurities, could lead to medicine shortages. We know that. However, we're doing at the end of the day what is the safest thing for the patient, and it's trying to remove these medications that can potentially be harmful to patients. So that's all the work that regulators and industry are doing to try to identify them, find them, and remove them from the supply chain and medications.

Alana Hippensteele: Right. It seems like the nitrosamines issue has been particularly challenging for industry and regulators. Is this true? And would you mind shedding some further light on that issue?

Naiffer Romero: When we talk about nitrosamines, nobody has all the answers. This is an issue or challenge that has been new to regulators, has been new to industry, has really been new for everybody. So, there’s not a single body that has all the answers. The only way to really advance these challenges has been through research, through collaboration and really working together. Nitrosamines are—we frequently learn about new things on it every day. Nitrosamines can be present at the active pharmaceutical ingredient (or API) level, but they can also be formed throughout the manufacturing of a drug product. It can be formed during the stability or during the storage of that material. So, the diversity of sources of these nitrosamines, it's really a challenge for everybody. And, as I said before, it really takes the entire process and all the players in the process of manufacturing a product working together to really emerge successfully from all this.

Also, every day, we learn about the signs of nitrosamines. And these signs continue to evolve. And it's really becoming challenging, challenging to access all this information. Every day, we learn about new research, about new findings, about a new regulation, about a new measure to control these impurities, about a new mitigation strategy that is presented from the scientific community. And a challenge that we face as a scientific community is making sure that everybody has access to this information. Nitrosamines are not unique to any industry, they are not unique to an innovator product versus a generic product, or to a country or to a region. It really affects the entire pharmaceutical industry. So, it will take the entire pharmaceutical industry working really together and sharing information, sharing best practices to really emerge successfully as a community out of these challenges that nitrosamines really pose to us.

Alana Hippensteele: So, I recently learned that there is also a newer kind of nitrosamine. Would you mind explaining and telling us a little bit more about that?

Naiffer Romero: Absolutely. So, until mid-2021, we were dealing with what are called simple structure nitrosamines, or simple nitrosamines, which are the impurities that have a fairly simple chemical structure. But at the end of that year a new wave or a new type of nitrosamines emerged. And we saw that reflected in the updates and revisions of a lot of regulatory guidance, where these new sort of structures were defined as NDSRIs. That's the acronym for nitrosamine drug substance-related impurities. What does that mean? It really means that these nitrosamines now are not an impurity that are formed as part of a parallel reaction or a part of an impurity. Actually now these impurities can form in the molecule of the ingredient, or the active ingredient itself.

So, as a new class of nitrosamines, it comes with a whole new set of challenges. Some of those challenges are really to understand the signs, the chemistry of formation of these structures. They are not formed throughout the manufacturing process. For the most part, these impurities are now formed once the product is sitting on the shelf during that storage of the medication. So, the challenge is hard change, and it has shift from what we were dealing in the past three years. Aside from that, also the toxicology components of that. So, a lot of the studies of these impurities are connected to understanding the potential genotoxicity that these structures have on the organism, on the patient potentially. So, understand this new set of impurities, this new wave of nitrosamine impurities, represent a whole new challenge, because these are structures that have never been really studied broadly. So again, there’s a whole new wave of research that needs to take place to truly understand the potential genotoxicity, the potency of genotoxicity of these new structures.

Alana Hippensteele: Right, that’s a really interesting point. So, what's the impact nitrosamines are having for our audience of pharmacy professionals, including those who may be working directly with patients or other healthcare professionals, and how might they be coming into contact with this issue?

Naiffer Romero: Absolutely. So, when nitrosamines emerged, all we learned was these medications are now contaminated with these potential genotoxic impurities. And that really woke up a real concern for patients, for physicians, for prescribers, for pharmacists. What we really need to understand is that the discovery of these impurities, it's really becoming or they're really emerging because industry, because regulators now have better technology. And they're doing really the due diligence to remove any foreign substance that is not what was intended to be in that medication. So, the discovery of this, it's actually a result of manufacturers and regulators doing all the due diligence to remove anything that that can potentially be harmful to the patient. So, I think it's really important that prescribers, pharmacists, and patients understand that when they see a medication being recalled, because of the presence of these nitrosamines, they feel confident that industry and regulators are doing their work to identify and remove these medications that are contaminated with these impurities out of the supply chain, because otherwise it will represent definitely a risk for the patients at the end of the day.

Alana Hippensteele: Right. Speaking about the importance of collaboration, can you tell us how USP is working with others to find solutions to the challenges posed by nitrosamines in pharmaceuticals?

Naiffer Romero: Yeah, so as I mentioned before, the emerging of these impurities had really prompted the entire scientific community to do a lot of research to generate a lot of information, a lot of data points that can help us make educated decisions about what to do with these impurities, how to modify the production of a medication, how to modify the ingredients that are used to make medications to prevent the formation of these impurities. And in the same way, the regulators are setting the path to follow on all these. All this information, as you can probably imagine, is scattered all over the place. So, one of our contributions to all this has been, how can we find a venue, how can we find a place to really bring all this information together for everybody to have access in a centralized location? Moreover, the scientific discussions that are taking place all around the world, how can we leverage those discussions, those learnings, those lessons learned across the entire pharmaceutical landscape. As I said, this is not a problem for a country, this is not a problem isolated to a particular product or particular industry. So, access to that information is key.

So, as a solution to that, one of the initiatives that we started developing at USP was creating a sort of an online community. This online community serves as a common place for all scientists – or really anybody working on the nitrosamine challenges – to really come together and be able to network, be able to interact, to be able to share information, to be up to date on what's happening outside their regions, outside their industry, outside their countries, what other regulators are doing in the arena of nitrosamines. So, we built this community called the Nitrosamines Exchange. And we like to call it the one-stop shop for all things nitrosamines, because that's really what we would love to do as a contribution to advancing the challenge of nitrosamines. Aside from that, we have also developed a series of resources and compendial tools that also help guide industry on how to tackle some of the challenges that nitrosamines represent at the active ingredient manufacturing level, at the finished dosage form level, or even in the operational components of creating and bringing that medication to the patient.

So, we have tackled some of these aspects through our compendial venues, through general chapters, through providing analytical methods for our scientists to be able to also test and identify the levels where these impurities are in their medications, providing reference standards as well—trustable reference standards that they can utilize to run all this analysis in the lab, and finally, something that we recently launched as part of the community is something that we call the Analytical Hub. As a scientist, when we need analytical methods to test the presence of these impurities and quantify these impurities in the medications, we need analytical methods. The reality is that all these analytical methods are, as information, spread all over the place. So, we challenged ourselves. Can we build a sort of repository of information for these analytical methods and host or provide a home for anybody to come and have this repository of analytical methods that they can utilize in their labs to do all this analysis? So, we started that at the beginning of this year, and there has been really tremendous feedback that we have received from our users and stakeholders about being able to now access this large number of analytical methods that can help, definitely, the development and the acceleration of all the testing that they have to do in their labs.

Alana Hippensteele: That is really interesting and a lot of collaboration, which is amazing. Could you talk about the importance of quality testing and method validation in pharmaceuticals and specifically when it comes to impurities?

Naiffer Romero: Absolutely. So, impurities, I think as you pointed out in your opening remarks, are there. It's a matter of how do we identify them, we understand them, and how do we try to mitigate and remove them from that medication? Again, we're talking about chemical entities that react with everything that it's around, that compound. So, validation and analytical methods are a key, a fundamental component for us to be able to identify those impurities, understand where they're forming and at what levels, and it's also a tool that has been used to be able to save whatever mitigation mechanism we have. It's really working to remove them from that medication. So, the analytical component, it's an extremely important tool to enable to move this, and identify and quantify the presence of this. As I pointed out previously, an essential part of the effort that USPhas put into this is the general chapter, and the general chapter contains a series of analytical methods that can be utilized as a starting point for tailoring that analytical method for a particular product, when it comes to quantifying and detecting these impurities in these medications.

Alana Hippensteele: Absolutely. Would you mind telling us a bit more about some of the research USP has contributed to this field?

Naiffer Romero: Yes, we've recently collaborated with others outside USP. As I said, this is work that will take a village, and the village being the entire pharmaceutical industry and regulators working together to emerge successfully out of this. So, we’ve realized that, and we have pioneered a series of collaborations outside USP on doing research that actually started out as a discussion topic on the Nitrosamines Exchange. We really wanted to understand, with the emerging of these NDSRIs or nitrosamine drug substance-related impurities, and we really wanted to learn more about the potential—how big is the potential of these new impurities in drug substances, and also in drug products to form nitrosamines. We conducted a theoretical in-silico analysis of more than 12,000 molecules, including active molecules and also impurities that have been associated with this active since we’ve known of them. So, we really wanted to see and ask ourselves, how many of these impurities, how many of these actives can potentially – theoretically speaking – form these impurities. I’ve got to say, we found that the presence of these nitrosamines in pharmaceuticals is likely to be very big, okay, because a lot of our actives contain the precursor, contain those chemical groups that can actually react and form this nitrosamine. Does that mean that every molecule that we identify is contaminated with nitrosamines? Absolutely not. And again, this was a very first step toward trying to understand from a very high level, the potential risks that we will face when it comes to these complex nitrosamines. However, we know as we have learned, understanding the chemistry of it, there are additional conditions that we need to evaluate for that chemistry or for that reaction to take place.

Another thing that we need to really understand, and again, it's something that the science continues to advance on, is to understand, it's not about the presence of a chemical entity or a chemical group that will react and form a nitrosamine. It's what surrounds that chemical compound. So, there's a there's a bulkiness, if you will, using a simple term, that can be around that group that can favor or not the reaction so it can facilitate or not the reaction. Again, we're talking about chemical structures that are a lot bigger than just a single group. And again, it's all these factors that need to be really well understood, if we want to get to a point where we can theoretically predict whether a structure will form a nitrosamine or not. As I said, the science continues to advance, research on this continues to advance, and regulators and manufacturers continue to do a lot of work trying to understand the structures and what’s their true potential to form the nitrosamines. In addition to that, once they’ve formed the nitrosamines, are they truly genotoxics? We know that not all nitrosamines have the same potency when it comes to genotoxicity. So, it's also necessary to understand the true potency that these structures have, one versus another one.

Alana Hippensteele:This is a really important and complex issue. Do you have any closing thoughts?

Naiffer Romero: I think the importance of assessing products throughout their development to ensure quality, so patients can get the medication they need, it's essential. And I'll repeat it—the fact that we're seeing the identification and the emerging of these kinds of impurities and really the attention that regulators and manufacturers are putting to that speak to that concern that we need to provide safe medications to the patient. It’s important also, that it will take a village. It will take a lot of collaboration, it will take a community approach for us to solve this problem. Not a single organization, not a single regulatory body will have the answers for everything. So, it will really take a joint effort to solve the complexity of the challenge of nitrosamines. Also, the global nature of our pharmaceutical supply chains demands the diligence and demands collaboration between manufacturers, regulatory agencies, pharmacopoeias. It’s really everybody involved in the making of that medication that needs to really come together. Understand that we are facing a challenge where the only way to emerge successful is if we all collaborate together.