Nitrosamine : An epic Saga

As the nitrosamine story unfolds, global health authorities have united in requiring that #Drug Product Manufacturers (DPM) complete comprehensive risk assessments of all Drug Products, in order to determine the potential for nitrosamine formation in their products.

Background:

Beginning in July 2018, A sartan drug product Valsartan were subject to recalls due to N-nitrosodimethylamine (#NDMA) , which traced back to a change in the synthetic process for the active pharmaceutical ingredient (API).

U.S. Food and Drug Administration (#FDA) posted a press release in which FDA requested drug manufacturers to immediately withdraw all prescription (RX) and over-the-counter (OTC) drugs containing the active pharmaceutical ingredient (API) ranitidine from the market due to NDMA contamination.

What is Nitrosamine Impurity...? and Why USFDA or Drug Product Manufactures Recalled many products from market?

You might be aware that few chemicals are highly carcinogenic these chemicals can cause or promote cancer and those chemicals are called #Carcinogen”. If Present in Drug Substance, they possess High risk of Safety to patient. ?Nitrosamine impurities also probable human carcinogens. They were classified under the category of “cohort of concern in #ICH M7(R1)

“Cohort of concern means chemicals of high potent #Mutagenic carcinogens. These Mutagenic carcinogens can cause genetic mutation (changes in the genetic information) and also carcinogenic (causes or promote #cancer ).

Chemically Nitrosamines are formed by reaction between secondary, tertiary, or quaternary amines and nitrous acid (nitrite salts under acidic conditions) by nitrosating reaction.

That is the reason why FDA is so concerned about #Nitrosamine and compounds comes under cohort of concern consists of some specific chemical functional groups such as aflatoxin like, N-nitroso and alkyl-azoxy compounds.?

How many Nitrosamine impurities are there?

As of now, seven impurities are given in USP<1469>. They are NDMA, NMBA, NDEA, NEIPA, NDIPA, NMPA, NDBA and their standards developed by #USP. There may be other impurities?also.

FDA is reviewing product related nitrosamines like - N-Nitroso Rasagiline etc. if we compare limits for such impurities with the general nitrosamines like NDMA NDEA etc are very very low.?Since then, nitrosamine contamination has also been reported in nizatidine,rifampin, metformin, rifapentine, varenicline, irbesartan, and sitagliptin and other critical APIs.

Recently published guidance by EMA for the product specific limits where many of the prone molecules limits have been recommended. If the molecule is susceptible to form Nitroso imp and the limit is not mentioned in any of the guidance, we need to follow 18 ng #AI limit.

#Chemistry of Nitrosamine Formation

How Nitrosamines are formed and What are the sources?

Nitrosamines are formed by reaction between secondary, tertiary, or quaternary amines and nitrous acid (nitrite salts under acidic conditions) by nitrosating reaction.

Basically, formation of n-nitrosamines in medicinal products comes from the confluence of three factors: 1. Nitrite/ Nitrate?or Nitrosating Agent 2. A secondary, tertiary, or quaternary #amine 3. Appropriate conditions (for example elevated temperatures, acidic conditions, liquid phase) for the aforementioned to react

So, as of now 3 root causes have been identified for the formation of genotoxic Nitroso impurity in the chemical process 1. Due to Process component 2. molecule containing tetrazole rings like Sartans 3. Molecule can form complex with Nitro group.

(A) Generation of Nitrosonium Ion (B) Formation of Nitrosamine?

Which are the products impacted by Nitrosamine ?

Valsartan was the first product which was recalled by FDA in July 2018 from five pharmaceutical companies but for all these five companies, the API supplier was Zhejiang Huahai Pharmaceuticals, Linhai, China and FDA first find the traces of these impurities in this Losartan API. After that in ranitidine and metformin, the traces of Nitrosamine were identified and there were several recalls.

Recently in 30th Mar 2022 Pfizer has issued a voluntary recall of Accuretic (quinapril HCl/hydrochlorothiazide) tablets distributed by Pfizer as well as two authorized generics distributed by Greenstone (quinapril and hydrochlorothiazide and quinapril HCl/hydrochlorothiazide) on a consumer level due to the presence of a nitrosamine

Last week Lupin Pharmaceuticals recalled four lots of Quinapril Tablets because the medication has too much of the nitrosamine impurity N-Nitroso-Quinapril.

Hence, it is imperative that the pharmaceutical industry needs to look beyond the obvious to understand the potential sources of nitrosamine formation and add proper controls.

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