SEPTIA NURMALA
Have you ever wondered about the different components that made up your pills when you want to swallow one? One looks a bright orange color, while the other is a heart-shaped pellet so minute it could sit on the tip of your finger. Constituents for a tablet can be divided generally into active pharmaceutical ingredients (API) and non-active substances — better known as excipients. During the manufacturing process, both API and excipients are exposed to water, heat, and other conditions that could change their properties physically and chemically. This alteration, while sometimes can be negligible as it does not change the potency of the drug products, can pose certain risks to consumers. One notable example is, in 2018-2019, the US FDA detected cancer-causing impurities in a group of drugs that control blood pressure, prompting manufacturers and distributors to recall their products.
The impurities found 4 years ago belong to a group called nitrosamines. In its most basic form, nitrosamines consist of two linked nitrogen atoms with two carbon and oxygen at the opposite end of the nitrogen bridge. With such a simple structure derived from a vulnerable amine, nitrosamines have the potential to form and stay — but how likely?
Out in the Journal of Pharmaceutical Science, a group of researchers assessed the prevalence of nitrosamines formation through a computational study. What started as a curiosity for Dr. Joerg Schlingemann – the corresponding author of the study – snowballed into a collaborative project between different stakeholders. “I’m involved in doing a risk assessment on the probability of having nitrosamine impurities in our drug products,” said Schlingemann, a principal expert on quality control systems at Merck KGaA. “I was interested to find out which percentage of drugs and drug impurities would actually be affected if API contains vulnerable amine.”
Schlingemann looked up global data of API structure from a database to evaluate which type of amine the drug structures belong to if any. Amines can be classified based on the amount of carbon they are attached to. One carbon attached to the nitrogen is called primary, two are known as secondary, and three carbon joints flocking the nitrogen are in the tertiary amine group. Of the three, only secondary and tertiary amines are nitrosatable, and both have different reaction rates to form nitrosamine. There are two different possibilities for nitrosamine formation. The first one is when the API releases the nitrosamine group, known as small and potent nitrosamines, or API forms complex API-related nitrosamines - known as Nitrosamine Drug Substance Related Impurities (NDSRI). Different versions have different toxicity. “General toxicity of NDSRIs are mostly reduced because you have [fewer] nitrosamine functions per mass unit,” Schlingemann said.
Schlingemann coded the analysis with statistical software which took him a few days to code until he presented it to colleagues. Once his colleague knew, the collaboration kicked off, garnering a large swath of experts from different institutions such as the United States Pharmacopoeia (USP), Lhasa Limited, and AstraZeneca.
Using a bigger and more comprehensive database of ingredients provided by the USP, Schlingemann and team evaluated more than 12,000 APIs, API-related impurities, and degradant structures. To identify the secondary and tertiary amines, the team matched the structure they extracted with patterns of vulnerable amines. After that, they transformed the parent structure into potential nitrosamines, getting insights into the nitrosamine formation mechanism in the process. Additionally, the researchers also calculated the susceptibility of amines to undergo nitrosation by measuring the basicity values. The higher the basicity, substances are less likely subjected to nitrosation.
Not only did the team investigate the formation of nitrosamines, but they also evaluated their potency by categorizing it into four groups: nitrosamines with increased potency; nitrosamines with decreased potency; nitrosamines with no features from either list; and nitrosamines with the feature from both lists. The team inferred the potency data from the genotoxicity, immunogenicity, and carcinogenicity of the substance.
The team revealed that around 40% of API is nitrosamine precursors from secondary and tertiary amines. “It sounds alarming at first, but to get nitrosamine from the tertiary amines they need to undergo nitrosative dealkylation [where] it will be a much slower reaction,” Schlingemann said. Due to that reason, there is less risk from tertiary amines compared to secondary amines. Still, potential nitrosamine from the secondary amines weigh up to 20% out of the total APIs they checked from their databases.
Other than the types of amines, the molecular weight also accounts for the toxicity risk nitrosamine has. Schlingemann argued that “NDSRI structures have high molecular weight so they will not be as easy to metabolically activate.” Meanwhile, for small nitrosamines such as NDMA that could be found in heartburn reliever drug Ranitidine, the acceptable intake limit is 96 nanograms per day – very low as it snuggles easily in the metabolic enzyme in the human liver.
Perhaps the most alarming discovery is that a blood pressure-controlling agent beta-adrenoreceptor blocker class has the highest risk of forming NDSRI. This drug, which consists of propranolol and bisoprolol for example, is consumed daily by millions of hypertensive people. Second on the list is another blood pressure-controlling agent from the ACE inhibitor class like captopril and ramipril which is also routinely consumed.
But the risk is not immediate. “It’s quite difficult, especially to solve the issue with NDSRI,” Schlingemann said. To prevent the formation of small nitrosamines like NDMA, industries could switch to pure API with less residual NDMA foundation during the manufacturing process. “But for NDSRI, since the vulnerable part is the API itself, the only mitigation you would have is to prevent nitrosation,” Schlingemann said. Indeed, nitrosamine formation depends on reaction conditions such as pH, temperature, formulation, the presence of catalysts, and much more. “For marketed products, the only short-term solution is to find low nitrite excipients, which may or may not be available for your formulation. If you are still in formulation development you may consider the addition of a nitrite scavenger,” explained Schlingemann. But changing formulation is not feasible for marketed products as it will take years for worldwide approval.
However, with all the challenges facing the industry right now, a collaboration between manufacturers, not-for-profits, and regulators is crucial. For Schlingemann alone, the experience of collaborating with different stakeholders was “cool and fascinating” as it was new in his experience. “Pharmaceutical companies tend to be a bit secretive by tradition, but nitrosamines are not development projects,” he added, “They are affecting the whole industry and not sharing knowledge does not create a competitive advantage, rather the opposite as you may miss important information or developments if you do not share the knowledge yourself.”
References
US Food and Drug Administration. (2019). FDA Updates and Press Announcements on Angiotensin II Receptor Blocker (ARB) Recalls (Valsartan, Losartan, and Irbesartan). Retrieved from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-angiotensin-ii-receptor-blocker-arb-recalls-valsartan-losartan [Accessed: Jan 30, 2023]
Schlingemann, J., et al. (2022). ‘The Landscape of Potential Small and Drug Substance Related Nitrosamines in Pharmaceuticals’, Journal of Pharmaceutical Sciences, available: https://doi.org/10.1016/j.xphs.2022.11.013
Gagne, J. (2019). ‘Popular heartburn drug ranitidine recalled: What you need to know and do’, Harvard Health Publishing, available: https://www.health.harvard.edu/blog/popular-heartburn-drug-ranitidine-recalled-what-you-need-to-know-and-do-2019092817911
US Food and Drug Administration. (2019). Laboratory Tests | Ranitidine. Retrieved from: https://www.fda.gov/drugs/drug-safety-and-availability/laboratory-tests-ranitidine#:~:text=For%20reference%2C%20consuming%20up%20to,ingestion%20based%20on%20lifetime%20exposure.