NDSRIs - 40% of APIs and 30% of API impurities

Research highlighted: Landscape of potential nitrosamines in pharmaceuticals

Summary of research published in the Journal of Pharmaceutical Sciences Volume 112, Issue 5, P1287-1304, May 2023. Originally published Nov. 16, 2022?

To access the entire open-access paper, visit: “The Landscape of Potential Small and Drug Substance Related Nitrosamines in Pharmaceuticals ”?

Key takeaways?

• The prevalence of nitrosamines in pharmaceutical products is broader than expected. Approximately 40% of APIs and 30% of API impurities listed in the GSRS database are potential nitrosamine precursors, meaning they are vulnerable to formation of nitrosamines depending on the conditions.??
• Drugs in the same class often share similar characteristics in their chemical structures, making some classes of drugs potentially more prone to nitrosamine formation. Examples of these drug classes include beta adrenoreceptor blockers and beta agonists (beta blockers); angiotensin-converting-enzyme (ACE) inhibitors; some serotonin norepinephrine reuptake inhibitors (SNRIs); aminoquinoline antimalarial drugs; tricyclic antidepressants; triptans; and thienopyridines.?
• Although nitrosamines are considered carcinogens, there are virtually no data available on in vivo carcinogenicity or mutagenicity. This makes it difficult to determine reasonable acceptable intake (AI) limits. This in silico analysis revealed some important findings, however.?
• Regulatory agencies, industry, and health authorities need to collaborate in determining safe AI levels for nitrosamine impurities. If AIs are not harmonized, this will not only further complicate efforts to bring nitrosamine content of drug products into a safe and acceptable range but also replicate unnecessary discovery work.??

Background and introduction?

Since the 2018 discovery of nitrosamine impurities in some drugs used to treat hypertension, nitrosamines have been found in several other commonly prescribed medicines. In addition to simple potent nitrosamines (e.g., nitrosodimethylamine (NDMA) and nitrosodiethylamine (NDEA)), drug-specific nitrosamines, also called nitrosamine drug substance-related impurities (NDSRIs) have also been detected. Because of the many ways nitrosamines can form, many active pharmaceutical ingredients (APIs), under the right conditions, have the potential to form nitrosamines.?

The International Committee for Harmonization (ICH) and the World Health Organization’s International Agency for Research on Cancer (WHO IARC) have classified nitrosamines as “probable or possible carcinogens.” Animal studies suggest that specific nitrosamines may have high potency as carcinogens and mutagens.??

Due to their potency, nitrosamines are part of the “cohort of concern” according to the International Council for Harmonization (ICH) M7 guideline, which means they need to be controlled to acceptably low levels. But acceptable intake (AI) limits for nitrosamines formed from specific drug substances are difficult to determine, so an AI for all nitrosamines has been set at 18 or 26.5 nanograms per day by the European Medicine Agency and U.S. Food and Drug Administration, respectively.??

The U.S. Food and Drug Administration (FDA) has released guidance stating that drug manufacturers should evaluate their products for nitrosamine impurities. Specifically, drug makers should assess all the possible ways that nitrosamines could enter their drug products. Because the chemical conditions under which nitrosamines can form are not uncommon, the list of potential sources can be long. Nitrosamines can be present in the starting materials used to make drugs. They can also be formed in the chemical reactions that occur during drug production. Nitrosamine impurities can even form during storage of the finished, packaged drug product.?

The current study?

An in-silico analysis was performed on more than 12,000 APIs and API-related impurities and degradants from the Global Substance Registration System (GSRS). Their chemical structures were analyzed for characteristics that make them vulnerable to forming nitrosamines under certain relevant conditions.??

Carcinogenic potency and chemical structure?

Estimating the carcinogenic potential of nitrosamines is difficult for NDSRIs because robust experimental data are not available.?In lieu of experimental data for the NDSRI in question, a “read across” approach can be used, but it has limitations. A read across approach looks at the most structurally similar nitrosamine (to the nitrosamine in question) that has reliable data. It assumes that carcinogenic potency is directly related to chemical structure, so nitrosamines with similar chemical structures should have similar potencies. While conclusions drawn from this type of “proxy” data is sometimes all that’s available, the structure-activity relationship to estimate carcinogenic potency of nitrosamines is an approximation. In reality, different features of the chemical structure can increase or reduce a substance’s carcinogenic potency.?

Study findings?

The in-silico analysis of this study found that a substantial proportion (40%) of the active pharmaceutical ingredients (APIs) in the drugs listed in the Global Substance Registration System (GSRS) are potential nitrosamine precursors. In addition, 30% of API impurities listed in GSRS are potential nitrosamine precursors. These percentages are higher than expected, suggesting that the problem of nitrosamine impurities in medications may be more widespread than initially thought. To confirm the GSRS results, several other databases of APIs and API impurities were also analyzed, with similar results. NDMA and NDEA continue to be the main sources of risk due to their frequency of occurrence.?

It is important to note that, because the analysis was done in silico (using computer programs, not actual samples in a lab), the nitrosamine impurities identified in this study are hypothetical and potential. Based on the substances’ chemical structures, nitrosamine impurities could form, but only under suitable conditions. The conditions that play a role include pH, temperature, particle size, formulation, catalysts, and packaging, as well as the availability of substances that can cause nitrosamine formation.?

Potency of nitrosamines is an important characteristic and is often difficult to assess. The analysis showed that nitrosamines can have chemical features that increase potency, features that decrease potency, and some have both at the same time. In contrast, some nitrosamines have no features relevant to potency.?

Drugs in the same class often share similar characteristics in their chemical structures, making some classes of drugs potentially more prone to nitrosamine formation. Examples of these drug classes include beta adrenoreceptor blockers and beta agonists (beta blockers); angiotensin-converting-enzyme (ACE) inhibitors; some serotonin norepinephrine reuptake inhibitors (SNRIs); aminoquinoline antimalarial drugs; tricyclic antidepressants; triptans; and thienopyridines.??

Discussion??

Various parameters can impact the nitrosamine content of the finished drug product, and modifying these parameters can be effective strategies for lowering nitrosamine content. The approach for modifying a parameter depends on when and how the nitrosamines are generated. Parameters to potentially adjust include pH, formulation, purification steps, water content, primary packaging, and storage conditions.?

To test whether unacceptable levels of impurities are present in a drug product, suitable analytical methods are needed. Developing such a method requires trustworthy reference material. Reference materials are available for the small and potent standard nitrosamines, but availability is insufficient for NDSRIs. There is a limited number of compendial reference standards for nitrosamine testing, and coverage with commercial standards is very limited.?

Similarly, data on carcinogenicity and mutagenicity are available for simple nitrosamines, but rarely for NDSRIs. Because these data are lacking, in silico analyses like the one performed in this study are typically used to predict mutagenicity of these impurities, according to the ICH M7 guideline.??

For any given drug, there may be multiple points in the manufacturing process where nitrosamines can form. Once these points are identified and understood, they can be targeted as opportunities to reduce the total nitrosamine content. Manufacturing modifications can include switching raw materials suppliers, performing additional purification steps to purge nitrosamines and/or adjusting formulations and environmental conditions to be less favorable for nitrosamine formation.??

These approaches for lowering nitrosamine levels may seem straightforward, but they can have far-reaching ramifications. Any modifications must be carefully evaluated, as they can affect other properties of the drug product with unintended consequences, such as altering critical quality attributes. Such process changes require time-consuming development efforts, followed by regulatory submissions and approvals. Making such modifications can be particularly challenging once the commercial process has been finalized and approved so, the earlier such fixes are made, the better.?

To access the entire open-access paper, visit: “The Landscape of Potential Small and Drug Substance Related Nitrosamines in Pharmaceuticals .”