An Overview of Nitrosated Drug Substance Related Impurities (NDSRIs)
Nitrosamines in Drug Substance (DS)
In 2018 health authorities became aware of the nitrosamine N-nitrosodimethylamine (NDMA) in valsartan drug substance. The investigations expanded, NDMA and other potent nitrosamines were found in the more drugs in sartan family. In late 2019, nitrosamines were also identified in drug substances like pioglitazone and ranitidine. Nitrosamines are classified as probable human carcinogens and included as part of the “cohort of concern” due to their carcinogenic risk. Daily acceptable intake (AI) levels for these small nitrosamines have been determined and range from 26-100 ng/day (Ref. 3). In most of these cases the nitrosamine formation was ultimately linked to the several factors like presence or formation of secondary amines, solvents, reagents during manufacturing processes of the drug substance.
The NDMA source in ranitidine was different, and could not be linked to the drug substance manufacturing process. In April 2020, Emery Pharma was responsible for identifying that NDMA levels in ranitidine (Zantac) drug substance or drug product could grow significantly upon exposure to elevated temperatures. Such post manufacture growth had never been seen for any nitrosamine. We filed a citizen petition to the FDA regarding our findings. As a result, the FDA issued a nationwide recall, see more. This case was unique in that the source of nitrite (for the nitrosation reaction) comes from the DS itself -the ranitidine vinyl nitro moiety.
Concerning NDMA levels were then detected in certain metformin drug products, but not the metformin drug substance. In February 2021 the FDA released the first nitrosamine guidance document (Ref. 3) which largely focused on recommendations for reducing formation of NDMA like nitrosamines during DS manufacturing processes. At this time, DS manufacturing processes are thought to be largely de-risked and under control. This first guidance mentioned nitrosamine formation in drug products, but no examples had been demonstrated at that time.
Nitrosated Drug Substance Related Impurities -NDSRIs
In the subsequent three years (2021-2023) it became obvious that nitrosation of secondary amines can occur uniquely in drug products. It was realized that all commonly used pharmaceutical excipients have sub- to several ppm nitrite ion contamination, such that a typical oral tablet dosage form will contain about 1 ppm nitrite (Ref. 1). The largest risk is if your DS has a secondary amine moiety. Reaction of the drug secondary amine with the trace nitrite forms a NDSRI (Scheme 1).
(Scheme 1)
At least four drug products were voluntarily recalled during the last few years due to the presence of NDSRIs: varenicline, propranolol, quinapril, and dabigatran etexilate. In addition to the nitrosation of a DS secondary amine, secondary amine degradates of a DS (which itself has no secondary amines) can also nitrosate to form problematic NDSRIs. Examples of degradate nitrosation appear to be the NDMA formed in metformin drug products, the voluntary recalls due to the NSDRIs in rifampin, rifapentine and orphenadrine, and the NDSRI in sitagliptin. There were no established AI limits for these NSDRIs at the time of the recalls.
In August, 2023 the FDA issued a guidance for setting the daily AI for any NSDRI given its molecular structure (Ref. 2). It applies to all drugs already approved as well as all drugs in development. The guidance uses the Predicted Carcinogenic Potency Categorization approach. This approach gives four different daily AI levels ranging from 1500 ng/day to 27 ng/day depending on the details of the specific NDSRI structure (Table 1, column 1). The FDA looked at secondary amines in marketed drugs, allowed them to hypothetically nitrosate, and used the Potency Categorization process/procedure to assign daily AI for 263 cases. The rough breakdown of those cases among the four AI limits is shown in the second column of Table 1.
The third column assumes a 300 mg tablet, and a molecular weight of 300 g/mol in order to get a sense of how much of the ~1 ppm nitrite in a tablet would have to react with (the drug secondary amine) to give each NDSRI limit. Three of four cases require 20% or less of the impurity nitrite to react. The last column in Table 1 highlights how much lower these daily AI levels are than the Q3B 0.1% reporting threshold, ranging from 30-fold lower to 2000-fold lower (assumes a 50 mg potency dosage form).
Innovators with drugs on the market currently have been given until the end of 2025 to bring all products into compliance with Table 1, through a combination of risk analysis and confirmatory testing. All new NDA submissions are expected to comply with Table 1 in terms of NDSRI content in DP at manufacture and through shelf life. Detailed control strategies are expected if NDSRIs approach the relevant limits in Table 1. Confirmatory testing for (lack of) potential NDSRIs can be expected, particularly if the NDSRI in question has the lower AI levels in Table 1.
Emery Pharma can assist in managing the NDSRI risk in your drug product
Secondary amine containing DS. Our chemists can synthesize a small quantity of the nitrosated secondary amine of your DS. This can be done early in development such that the NDSRI risk can be understood in time to appropriately react. We have expertise in understanding how excipient properties can drive nitrosation (pH, formaldehyde evolution (Ref. 4)) and how manufacturing processes can influence nitrosation yields. Early understanding allows for development of a robust control strategy.
Tertiary amine containing DS. Tertiary amine drug substances are not without risk. About 10-15% of tertiary amines in DS will be able to undergo rapid de-alkylation upon nitrosation (Ref. 5). This results in a nitrosated secondary amine, with the same efficiently as direct secondary amine nitrosation. Another risk of tertiary amines is oxidation to the N-oxide which can result in formation of a secondary amine degradate. The secondary amine degradate can then nitrosate (examples above). This is shown in Scheme 2.
Our experts can assess if your tertiary amine can undergo rapid de-alkylation and test that assessment in the laboratory. We can also determine if your formulation is at risk to drive the oxidation in Scheme 2, and predict/demonstrate the secondary amine structure that will result. The RT of the secondary amine can then be monitored at any level of detectability the client deems necessary. The secondary amine and/or its associated NDSRI can be provided.
Tertiary amide DS. Hydrolytic degradation is common in solid dosage forms. A tertiary amide may be able to undergo hydrolysis more readily if the amide bond is activated. The result is a secondary amine which could nitrosate. This is shown generally in Scheme 3.
Our experience with predictive forced stress testing can demonstrate if your tertiary amide DS is at risk to form a secondary amine in your DP on stability. The secondary amine RT can then be monitored, and if necessary, the nitrosated secondary amine NDSRI can be provided.
References:
- Boetzel R. et al. “A nitrite excipient database: A useful tool to support N-Nitrosamine risk assessments for drug products”. Pharm. Sci. 2023 (112) 1615-1624.
- August 2023, FDA: “Recommended Acceptable Intake Limits for Nitrosamine Drug Substance Related Impurities (NDSRIs) Guidance for Industry”
- February 2021, FDA. “Control of Nitrosamine Impurities in Human Drugs- Guidance for Industry”
- Harmon P. “Trace Aldehydes in solid oral dosage forms as catalysts for nitrosating secondary amines” Pharm. Sci. 2023 (112) 1216-1219.
- Burns MJ et al. “Revisiting the landscape of potential small and drug substance related nitrosamines in pharmaceuticals” Phar. Sci. 2023 (112) 3005-3011