Guidance to avoid Nitrosamines in Biological Medicines

Following the outcome of the Article 31 referral on sartans with a tetrazole ring and the knowledge acquired on N-nitrosamines in medicinal products, EMA together with the EU Network and international partners has continued the review to identify if there are any consequences for medicinal products outside the class of sartans.

Taking into account that N-nitrosamines have been found in sartans with a tetrazole ring but also in other API/medicinal products in September 2019 the CHMP’s opinion was sought by the EMA’s Executive Director in accordance with Article 5(3) of Regulation (EC) No 726/2004 regarding the detection, management and prevention of presence of N-nitrosamines in medicinal products for human use.

The CHMP adopted a scientific opinion in June 2020, which recommended reviewing biological medicines in addition to medicines containing chemically synthesised active substances.

The risk of presence of nitrosamines must be evaluated by the MAHs/Applicants. In case of risk, confirmatory testing must be performed.

  • A risk evaluation/risk assessment for the presence of nitrosamines must be submitted for new marketing authorization applications at the time of submission, and for already authorized medicinal products containing chemically synthesised active pharmaceutical ingredients (APIs) as per the ‘call for review’:

And for biological medicinal products in a similar exercise, as per instructions to be published in a ‘Questions and Answers document’:

  • The approach for risk evaluation/risk assessment should cover manufacturing processes of active substance and finished product in consideration of the root-causes, and subsequent confirmatory testing in the finished product in case a risk is identified
  • Although the overall risk of presence of nitrosamines in biological medicinal products is considered very low, the following risk factors should be taken into consideration:
    • Biologicals containing chemically synthesized fragments, where risk factors similar to chemically synthesized active substances are present,
    • Biologicals using processes where nitrosating reagents are deliberately added,
    • or those packaged in certain primary packaging material, such as blister packs containing nitrocellulose.

For details see CHMP – Assessment Report:

If you need any clarification or support to help implement the responsibilities of an MAH with regard to Nitrosamines reporting contact us and Ivowen will gladly assist you in a timely manner.

Written by Nanda Naik

New pharmaceutical water quality guideline from February 2021

In 2018 the EMA had a public consultation (15th Nov 2018 – 15th May 2019) on draft guidance for industry on the pharmaceutical use of different grades of water in the manufacture of active substances and medicinal products. This consultation has resulted in an update to the old 2002 guidelines and the new guideline will come into effect from February 2021.

Within the guideline, it is stated that the European Pharmacopoeia (Ph. Eur.) has set quality standards for three grades of water: water for injections (WFI), purified water and water for preparation of extracts. EMA also notes that potable water, while not covered by a pharmaceutical monograph, “is the prescribed source feed water for the production of pharmacopeial grade waters,” and must comply with the regulations on water intended for human consumption of a quality equivalent to that defined in Directive 98/83/EC or laid down by the competent authority.

The guideline itself provides recommendations for the minimum acceptable quality of water to be used for different uses and applications, including the manufacture of sterile and nonsterile medicinal products, active substances and water used for cleaning and rinsing equipment and container/closures for medicinal products.

The note for guidance has been updated to reflect the following changes in the European Pharmacopoeia:

  • revised monograph for Water for Injections (0169) allowing the possibility to use methods other than distillation for producing water of injectable quality (this change brings the Ph. Eur. more closely in line with the US Pharmacopeia and the Japanese Pharmacopoeia, allowing production of WFI by distillation or by a purification process proven “equivalent or superior to distillation”, and “by distillation or by reverse osmosis and/or ultrafiltration”, respectively);
  • new monograph for Water for preparation of extracts (2249);
  • suppression of the monograph for Water, highly purified (1927).

The guideline has also been updated to reflect current expectations for the minimum acceptable quality of water used in the manufacture of active substances and medicinal products for human and veterinary use.

The guideline can be read in conjunction with the questions and answers on production of water for injections by non-distillation methods – reverse osmosis and biofilms and control strategies and the comments received on the draft guideline

Written by Emily Fletcher