Impurity qualification should look beyond the obvious: What did we learn from the Nitrosamine-Sartan Crisis?

Since July 2018 number of drug products that contained angiotensin II receptor blocker (ARB; also called ‘sartans’) have been recalled from the US and worldwide market due to presence of one or more nitrosamine impurities. The crisis unfolded when Prinston Pharmaceuticals Inc., a U.S. manufacturer of valsartan products contacted the US FDA on June 19, 2018 and informed about presence of N-nitrosodimethylamine (NDMA) in the API supplied to it by a Chinese API manufacturer Zhejiang Huahai Pharmaceutical Co. (ZHP). Subsequent investigations revealed presence of nitrosamine impurities in other ARBs, that forced number of pharmaceutical companies to recall their ‘sartan’ containing drug products.

The drugs involved are Valsartan, Losartan, Irbesartan, Azilsartan, Olmesartan, Eprosartan, Candesartan and Telmisartan. As of now, Valsartan and Losartan are the worst affected and several lots of these products have been recalled.

What are nitrosamines and why are they a health risk to patients?

Nitrosamines are chemical compounds in which a nitroso group is bonded to an amine.

Nitrosamine impurities are known environmental contaminants and low levels of nitrosamines can occur in certain food, especially cured meat, dairy product, latex products, and cigarette smoke. Notrosamines are highly DNA-reactive and cause mutation. About 90% of the 300 nitrosamines tested were deemed to be carcinogenic in a wide variety of experimental animals. Given its extremely high carcinogenic potency, nitrosamines, along with aflatoxin-like-, and alkyl-azoxy structures are considered under ‘cohort of concern’ according to ICH M7 guideline.

Nitrosamines are classified by the ICH M7(R1) Guideline as Class 1 impurities, “known mutagenic carcinogens,” based on both rodent carcinogenicity and mutagenicity data. They are categorized by the International Agency for Cancer Research (IARC) as 2A – Probable Carcinogens based on data on a number of species studied

What is the level of risk the contaminated medicines pose?

There is no immediate risk to patients. The EMA has estimated the highest possible cancer risk with these impurities, especially the one with valsartan. This was done by extrapolation of data from animal carcinogenicity studies. It concluded that if 100,000 patients took valsartan from Zhejiang Huahai (where the highest levels of impurities were found) every day for 6 years at the highest dose, there could be 22 extra cases of cancer due to NDMA over the lifetimes of those 100,000 patients. NDEA (n-nitroso diethylamine) in these medicines could lead to 8 extra cases in 100,000 patients taking the medicine at the highest dose every day for 4 years (6 and 4 years are the duration for which contaminated products are believed to have been there in the market). This is based on average levels of this impurity detected in the active substance from Zhejiang Huahai Pharmaceuticals (60 parts per million).

The estimated risk is very low compared with the lifetime risk of cancer in the EU (1 in 2).

What is the chemical reaction that mediates formation of nitrosamines?

Nitrosamines are produced by nitrosation reaction, in which nitrosonium ion (NO+) is added to an amine (–NH2). Under acidic conditions the nitrite forms nitrous acid (HNO2), which is protonated and splits into the nitrosonium cation (N≡O+) and water:

H2NO2+  → H2O + NO+.

The nitrosonium cation then reacts with an amine to produce nitrosamine.

How did nitrosamines get in to sartan drugs?

Nitrosamine impurities were detected only in sartans that possess a tetrazole ring (eg: Valsartan, Losartan, Irbisartan, Candesartan, etc.,). NDMA appears to be generated during the formation of the tetrazole ring by reaction of dimethylamine (which may be present as an impurity or degradant in the solvent dimethylformamide (DMF)) and sodium nitrite under acidic conditions (where nitrous acid is formed). Other N-nitrosamines could be generated with other solvents or under other specific reaction conditions where other amines are present.

Example: The solvent N-methylpyrrolidone can give rise to N-nitroso-N-methylamino butyric acid (NMBA); amine bases such as diisopropylethylamine [DIPEA] can give rise to N-nitrosodiisopropylamine [DIPNA) and N-nitrosoethylisopropylamine [EIPNA]).

These impurities may also result from the reuse of materials, such as solvents, during the API manufacturing process.

What regulatory measures were taken to minimise the health risk to patients?

The impurities were assessed by US FDA/EMA for their genotoxic and carcinogenic potential utilising the toxicological data available in public domain. As these impurities are highly DNA-reactive, they are assumed to follow a non-linear dose-response (non-threshold effect). Therefore, the acceptable intake was derived keeping in mind a target cancer risk of 1 in 100,000. The list of impurities assessed and the corresponding acceptable intake (AI) levels are summarised in the below table:

For NMBA, although the AI is 96 ng/day, US FDA has decided to allow losartan products with NMBA equivalent to up to 982 ng/day (9.82 ppm in a 100 mg tablet), on a case-by-case basis, for a short period (up to 6 months) to avoid supply shortage. This was based on the assessment that the cancer risk arising out of exposure to levels up to 982 ng/day for 6 month presents no meaningful difference when compared to cancer risk due to lifetime exposure to 96 ng/day.

The AIs recommended are temporary limits for a period of 6 months (US) to 2 years (Europe). This transition period is to allow the manufacturers to take appropriate measures to eliminate their occurrence in the product. Subsequently it is expected that the drug products should not contain any quantifiable level of nitrosamines in the sartan drug products (at least 10x lower than the recommended AI).

What are the regulator’s expectations from the manufacturers?

·     Companies should put in place testing regimes able to detect the smallest amounts of these impurities

·     Batches showing levels higher than the temporary allowed limit should be recalled

·     Companies should make the necessary changes to their manufacturing processes to reduce, eliminate, or avoid formation of NDMA during the process or from the finished AP

Learnings………

The nitrosamines observed in the sartan drug seem to be a by-product formed due to presence of conditions favourable for a nitrosation reaction. Therefore, any factor that can support a nitrosation reaction can give rise to nitrosamines. It is the industry practice and ICH M7 expectation that potential impurities are identified by way of a thorough review of the proposed manufacturing process. In the case of sartans, the manufacturers would have looked in to the obvious factors that might contribute to generation of nitrosamines. In order to prevent recurrence of similar crisis, the manufacturers should invest much more time and efforts in identifying much finer and subtle aspects such as presence of amine impurities in the reagents/solvents, generation of amine intermediates, the pH conditions under which reactions takes place, and the potential impact of reuse of solvents. It is obvious that maximum focus is given on reactions which are more downstream, but the current crisis tells us not to ignore even if it applies to upstream reactions. One should be aware about the possibility of nitrosamine generation when solvents such as DMF (dimethylformamide), DMA (dimethylacetamine), or DEA (diethylacetamide) are used in the manufacturing of a drug substance. From the point of preventing nitrosamines, all pharmaceutical manufacturing involving sodium nitrite requires special attention. However, in order to prevent occurrence of other highly potent carcinogenic impurities such as alky-azoxy impurities, one need to look beyond the obvious even if the reactions do not involve sodium nitrite. When a potential impurity is identified, a qualified toxicologist may be consulted in order to identify the level of health risk they pose to the patient. While highly carcinogenic impurities are not allowed in the pharmaceutical product, a toxicological evaluation helps to identify their level of concerns and based on which they may be controlled below the permissible limit. Alternatively, when these impurities are identified, there are ways to re-engineer manufacturing processes to find pathways that don’t create these by-products. The nitroso impurities are highly potent, and therefore they can cause harm even at very low level. When certain carcinogenic impurities are likely, although challenging, very sensitive analytical method need to be developed well in advance and efforts should be made to detect and quantify them in the drug substance. While the obvious measures are imperative, identification and prevention of nitrosamines calls for measures that goes beyond the obvious…….