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Impact Statement–Risk of nitrosamines being present in medicinal products

04 December 2019  
Posted by: Tamsin Marshall
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Impact Statement –

Risk of nitrosamines being present in medicinal products



This issue first came to light in the summer of 2018 when the impurity N-nitrosodimethylamine (NDMA) was discovered in a valsartan active pharmaceutical ingredient made by a Chinese API supplier. Subsequently, it was found NDMA and a similar chemical, NDEA, had contaminated certain valsartan APIs for years. See the PHSS Impact Statement dated 14 May 2019 entitled “Lessons from the Sartan incidents” for further background information.

Since that time products other than Sartan medicines e.g in pioglitazone hydrochloride and most recently Ranitidine medicines have been seen to be affected.


Impacts since the previous PHSS statement

  1. Additional multiple product recalls of sartans and ranitidine products across major markets. Further import restrictions imposed in USA and CEP status alterations in EU
  2. Ongoing investigation into how these impurities may be formed and come to contaminate finished pharmaceutical products.
  3. New methodology widely adopted by regulatory bodies to quantify low levels of these impurities


Current Status

  • On 11 November 2019 EMA issued a Q&A document on “Information on nitrosamines for marketing authorisation holders”. This 12-point Q&A indicates that all marketing authorisation holders (MAHs) of all human medicinal products containing chemically synthesised active pharmaceutical ingredients (APIs) should work with the manufacturers of their APIs and finished products in order to evaluate the risk of nitrosamines being present in their products, and take appropriate risk mitigating measures.
  • A risk-based prioritisation of products to be reviewed should be used and the outcome of the risk evaluation of all products should be concluded at the latest within 6 months of the publication of the Q&A i.e. by 11 April 2020.
  • Section 12 of the Q&A covers currently identified root causes for presence of nitrosamines. In this section the EMA has highlighted the involvement of agents such as sodium nitrite, and recovered solvents, but also reported that the use of certain packaging materials may contribute to contamination. Section 12, Point 8 notes that “Nitrosamine contamination has been observed by one MAH in a finished product stored in blister” and “the MAH has hypothesised that the lidding foil containing nitrocellulose printing primer may react with amines in the printing ink to generate nitrosamines, which would be transferred to the product under certain packaging process conditions”.
  • Readers attention is drawn to this EMA Q&A document which should be urgently and carefully reviewed for scope, methodology and timelines. The timeline for compliance is short and the clock has been ticking since 11 Nov 2019.
  • To view the original Q&A from EMA  please click on the hyperlink:-Q&A
  • To view the previous PHSS Impact Statement on this topic please view the entry for 14 May 2019 in the News section of the PHSS website or use the link May 11 PHSS statement



Malcolm Holmes

PHSS Pharmaceutical Regulatory SME

21 Nov 2019

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