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Updated: Apr 26, 2021

Impact Paper | Open Access | Published 26th April 2021

Impact statement - Nitrosamines / Sartans / Metformin

Malcolm Holmes C.Chem MRSC | EJPPS | 261, (2021) | Cite this article | Download this PDF Paper

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PHSS has published two previous impact statements on contamination with nitrosamines and recognise that readers should now be well aware of the issues, particularly if they manufacture or buy in Active Pharmaceutical Ingredients which may by way of their chemical structure or, as part of their manufacturing processes, be susceptible to the development of N- nitrosamines. Nevertheless, we feel it important, in part because of the rapid implementation of the Ph. Eur sartan monographs, but also because of certain other factors to raise the subject again.

Ph. Eur -Rapid implementation of the revised sartan monographs on 1 April 2021

The five monographs on sartans with a tetrazole ring, namely Valsartan (2423), Losartan potassium (2232), Irbesartan (2465), Candesartan cilexetil (2573) and Olmesartan medoxomil (2600) have been revised to align them with the latest regulatory recommendations issued by the CHMP that were published on 13 November 2020 on the EMA’s website. The revision concerns a rewording of the “Production” section and deletion of the N-nitrosamines test section. These revised monographs were not published in Pharmeuropa for public enquiry as the changes made are in line with the CHMP recommendations. In addition, to ensure that the implementation date for the Ph. Eur. requirements is aligned with regulatory decisions as much as possible, the Ph. Eur. Commission has decided to publish the monographs under the rapid-revision procedure. The implementation date for the five revised monographs has therefore been set as 1 April 2021. The PDF versions of these monographs can be downloaded from the EDQM website and contain a production statement to the effect “As N-nitrosamines are classified as probable human carcinogens, their presence in XXX YYY should be avoided or limited as much as possible. For this reason, manufacturers of XXX YYY for human use are expected to perform an assessment of the risk of N- nitrosamine formation and contamination during their manufacturing process; if this assessment identifies a potential risk, the manufacturing process should be modified to minimise contamination and a control strategy implemented to detect and control N-nitrosamine impurities in XXX YYY. The general chapter 2.5.42. N- Nitrosamines in active substances is available to assist manufacturers.”

See:- sartans monographs

Ph.Eur N-Nitrosamines in active substances- New General Chapter

This chapter has been elaborated with the objective of developing validated limit tests for N-nitrosamine impurities in “sartan” active substances with a tetrazole ring, following the EC’s Implementing Decision concerning, in the framework of Article31 of Directive 2001/83/EC of the European Parliament and of the Council, the marketing authorisations of medicinal products for human use which contain these active substances (EMA/248364/2019Rev1). During publication in Pharmeuropa 32.2, an updated CHMP opinion pursuant toArticle5(3) of Regulation (EC)No726/2004 referral for nitrosamine impurities inhuman medicinal products has been published, making a quantitative determination of N-nitrosamine impurities necessary in certain cases. On November13,2020, the EMA published a news announcing that “EMA’s human medicines committee (CHMP) has aligned recommendations for limiting nitrosamine impurities in sartan medicines with recent recommendations it issued for other classes of medicines.”

See:- N-nitrosamines in active substances

NMDA contamination of metformin medicines

As well as Sartans and ranitidine medicines, a number of regulatory agencies are also looking at metformin medicines which are a common and well tolerated medicine for the treatment of Type II diabetes. In respect of the latter the Australian TGA has recently published the following comment / decision, which it made by following Quality Risk Management principles.

Metformin- (Australian TGA) Low levels of contamination with N-nitrosodimethylamine (NDMA)

Recently, TGA's laboratories completed testing a selection of immediate- and extended-release metformin medicines for the presence of NDMA. This found that approximately 30% of batches contained levels of NDMA that modestly exceed the acceptable limit (less than twice the limit).

One batch was found to have higher levels (4.4-times the limit). Only limited stock of this batch has been supplied, and it has now been recalled from wholesalers.

Metformin is an important treatment for diabetes. The risks from not treating diabetes are far greater than the risks posed by the levels of NDMA seen to date.

The TGA has carefully considered the risk for patients from batches that modestly exceed the limit. This included an analysis of the commonly prescribed doses of metformin using data from the general practice program. Overall, the risk is considered to be very low for patients on both immediate- and extended-release products. The TGA investigation indicates that the majority of patients would not be exposed to levels of NDMA that exceed the acceptable intake limit.

The limits set by the TGA for NDMA are very conservative. They are calculated to ensure that an individuals' excess cancer risk would not exceed 1:100,000 if that individual was on the maximum daily dose of the medicine for 70 years. As most individuals do not take the maximum daily dose, and are not using metformin for this long, the risks are very low.

See:- Metformin alert(TGA)


NMDA is not going to just go away.

Companies and particularly QPs and process developers will need to remain very vigilant to the risks of it being present in any of their products or being created in their or their supplier’s processes. This will be particularly important when suppliers or supply facilities are changed or when process changes or process “improvements” are made to their own or their suppliers processes.

Likewise, a high level of awareness must be kept on regulatory approaches to minimising and / or controlling this issue.

It is relatively rare that an issue such as this arises, but with continually improving analytical technologies and subsequently on levels of detection of impurities it is not the first time and will not be the last.


Author Information

Prepared by Malcolm Holmes C.Chem MRSC

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