A Study of Nitrosamine Impurities and Regulations Governing their Presence in Drug Products

Manufacturers were requested to review and modify their manufacturing processes to reduce nitrosamine impurities to the degree practically possible in the European Union (EU) following an Article 31 evaluation of sartans at risk of harbouring nitrosamine impurities (those containing a tetrazole ring). The implementation of these measures has been given a two-year transitional period. Interim limitations, as shown in Table 1, are being imposed to items during this transitional phase. Batches of product that contain both NDMA and NDEA or that exceed these limits for a single impurity are prohibited in the EU. The European Pharmacopoeia’s drug substance descriptions for the sartan series are currently being updated to include nitrosamine testing. The general monograph for APIs (General monograph 2034), which is currently being revised, will also provide the necessary tests. Several sartan drugs were temporarily removed from the EU market as a result of these actions. Many have now re-entered the market, although the EU encouraged consumers not to cease. Taking their medications. Similar to how the FDA sought to identify and recall medications with nitrosamine content over what was considered appropriate, it has published a list of ARB drugs.¹⁰ The USFDA emphasized, as did the EMA, that the low risk of continuing the prescriptions with these impurities outweighs the consequences of abruptly stopping them (such as a stroke). More recently, ranitidine and nizatidine product batches have been found to contain NDMA impurity levels. For individuals with diseases like heartburn and stomach ulcers, ranitidine medications are frequently used to control the production of stomach acid. Both over-the-counter and prescription versions are offered. Reactions from regulatory agencies have ranged. Swiss medic, Health Canada, and a few specific national regulatory bodies in Europe took preventative actions to either or prohibit the sale of all ranitidine products until batch analyses show that NDMA levels were below permissible ranges. In order to determine if patients using ranitidine are at any risk from NDMA, the EMA is presently assessing the data that is available. Only if test findings indicate NDMA levels above the intermediate levels have¹¹ other bodies, including the USFDA, asked for voluntary recalls of items.¹² The majority of ranitidine and nizatidine products have levels of DMA that, according to the USFDA, are comparable to those that would be present in typical foods such grilled or smoked meats.Many companies have initiated voluntary ranitidine product recalls as a preventative measures The EMA has asked all FPPs to analyse the possibility of nitrosamines being present in all products containing chemically synthesised active components, as a precautionary measure. Despite the fact that the vast majority of medicines are not expected to produce nitrosamines, firms have been asked to do this precautionary review due to the possibility of cross contamination or accidental introduction of amines and nitrites. These reviews should include all facets of the manufacturing process, including the production of FPP, and should be comprehensive in scope. The EMA has asked MAHS to finish this review in six months.

The FDA has been tasked with “protecting the public health by maintaining the safety, efficacy, and assurance of human and veterinary medication products, biological products, and medical devices…,” and is housed within the US Department of Health and Human Services. Brand name prescription pharmaceuticals, generic medications, and non-prescription (over-the-counter) drug items are all regulated by the FDA. FDA approval of a drug indicates that the FDA has deemed the drug to be both safe and effective. Nevertheless, issues that affect the safety of certified items do arise. A drug recall may result when issues arise that influence the efficiency of drug goods. “A voluntary action performed by the corporation at any moment to remove a deficient drug product from the market” is the concept of a drug recall. When a pharmaceutical product is deemed harmful for patients or when FDA regulations have not been followed, a recall is either announced by the FDA or the medication company. Mislabeling, contamination, the existence of contaminants, and a lack of sterility are a few of the many causes of drug recalls. According to one count, the FDA has declared 226 medicine recalls in the last two years. Given that “…not all recalls are published on FDA.gov or in the mainstream media,” the total number of drug recalls is probably far higher. FDA was informed of valsartan by one source in June 2018 the manufacturing of pharmacological compounds regarding the existence of an impurity identified as N-Nitrosodimethylamine (NDMA). Additional FDA investigation revealed that N-Nitrosodiethylamine (NDEA), another Nitrosamine impurity, was also detected in prescription substances from various manufacturers of valsartan and other medications at levels that were inadequate. The FDA announced “interim acceptable limits” for these Nitrosamine impurities in ARB medications as a key measure because there was no acceptable limit in the specification for Nitrosamines. It was advised to remove drug substances and drug products from the market if they exceeded certain limit levels. The FDA suggested that the producers of pharmaceutical products analyze samples from each batch or lot of pharmaceutical ingredients used in the production of pharmaceutical products for the US market to see if any nitrosamine impurities were present. Additionally, FDA has released validated techniques for locating and measuring NDMA and NDEA components in all ARB medicinal ingredients as well as some medication products.

The Therapeutic Goods Administration (TGA) of Australia issued guidelines for “sartan” blood pressure medicines with respect to presence of Nitrosamine impurities.

In recent years, there has been an increase in the number of medicinal product recalls. This is now a pervasive problem, and manufacturers need to be ready for any crises that may arise from unsuccessful product recalls. Both regulatory agencies and patients have severe concerns about the occurrence of nitrosamine impurities in prescription goods. Over 1400 product batches have been withdrawn or recalled, because the amount of nitrosamines present is greater than the daily permissible limit, from the markets in the previous two years.^43–45 Numerous pharmaceutical products containing the APIs valsartan, irbesartan, losartan, metformin, ranitidine, and nizatidine were removed off from the market or were recalled as a result These drug products were found to contain three different types of nitrosamine impurities.⁴⁶ To avoid a scarcity on the market, the FDA did not recall the life-saving drugs rifampin and rifapentine. These medicinal products’ MNP and CPNP sources are still being looked into. According to the FDA, the range of daily nitrosamine intake that is considered to be safe for most people is 26.5 to 96 ng per day. Losartan has been related to the most product recalls (almost 24% of the total), with 324 batches containing this medication being taken off the market. A careful investigation of the FDA information finds that medication items containing “sartans” are to responsible for almost 81% of the recalls. In addition to sartans, combination products containing sartans co-formulated with other APIs accounted for around 42% of the total.⁴⁷ Numerous blood pressure drugs are being withdrawn by Pfizer and other organizations because they contain higher quantities of nitrosamine.⁴⁸ The various drug products recalled by the companies for the presence of nitrosamine are mentioned in Table 2.

The results of sartans review suggested that, depending on API and drug product production methods, there is a possibility that nitrosamines will be present in APIs for other drugs. As a result, in September 2019, EMA formally requested that all MAHs for medications containing chemically synthesized active ingredients assess the risk of N-Nitrosamines in their products and implement the necessary risk mitigation strategies.^49,50 The following actions should be taken in the call for review:⁵¹

Step 1: To identify active ingredients and drug products at risk of N-Nitrosamine production or (cross-) contamination, perform a risk evaluation. The current cut-off date for chemical medications is 31 March 2021, and the topic of this dissertation is focused on this step.

Step 2: Confirmatory testing should be carried out on the items that were shown to be susceptible to Nitrosamine contamination or production.

Step 3: MAHs should make any necessary revisions to the dossier if the presence of nitrosamine(s) is confirmed (e.g. changes to their manufacturing processes). Steps 2 and 3 for chemical medicines must be finished by September 26, 2022.⁵²

According to their anticipated significance in the global risk, various impact factors (ratios) were assigned to each of the mentioned potential causes in order to establish a classification of the global risk. As previously indicated, the drug Ranitidine Generis 150/300mg, which has been recently prohibited from the EU due to the presence of low quantities of NDMA, was subjected to this technique after it was produced while testing the medication Losartan Generis 50mg/100mg. The drug Losartan Generis 50mg/100mg was selected because, at the time this research was initiated, it was one of the few medicines for which Generis Farmecêutica, S.A. already possessed a sizable amount of data on the API production process. In addition, this medication is used to treat hypertension, one of the most prevalent long-term medical conditions, therefore it was thought that the existence of nitrosamine impurities in this medication would have a significant negative influence on public health. The choice of Ranitidine Generis 150/300mg was made since it was one of the products for which a greater quantity of information was already accessible and because, at the time, it was one of the newest products with proven nitrosamine impurity presence.

Awareness in the mutagenic and carcinogenic potential has increased in consequence to the latest discovery of Nitrosamine impurities on several commercially available medications. Due to the solvent, catalyst, and raw materials utilized throughout the production process, these impurities developed on the drug product. To manage various nitrosamine impurity, the various regulatory agencies have issued to alter the production process’s control procedures, so that these impurities can be avoided. Impurities in manufactured biological and pharmacological products are located using validated analytical techniques. Based on the maximum daily dose, the overall amount of nitrosamine impurities should not be more than 26.5 ng/day (acceptable intake of nitrosamine).

The carcinogenic properties of nitrosamines, which are genotoxic contaminants, make them a grave danger to all life on earth. Regulatory organisations including CDSCO, the US-FDA, and the European Medicines Agency (EMA) have continuously worked to quantify the amine impurities found in food products and other intermediates in chemical synthesis in an effort to address this global problem. Researching novel approaches and methodologies for the accurate estimate of nitrosamine impurities from diverse pharmaceutical APIs, however, is a difficult challenge for scientists, researchers and industrialists. Their high hydrophilicity and low molecular weight are the main issues.

The authors are thankful to Shri Vishnu College of Pharmacy for providing necessary facilities.