European Pharmacopoeia Updates: EDQM Tackles Nitrosamine Impurities

Published on: 
Pharmaceutical Technology, Pharmaceutical Technology, October 2021 Issue, Volume 45, Issue 10

Updates to Ph. Eur. include validated tests for N-nitrosamine impurities in sartan APIs.

Pharmaceutical Technology Europe asked Cathie Vielle, Head of the European Pharmacopoeia Department and Secretary to the Ph. Eur. Commission at the European Directorate for the Quality of Medicines & Healthcare (EDQM) about recent and planned updates to the European Pharmacopoeia (Ph. Eur.), the latest on nitrosamines, and the impact of COVID-19 on the industry.

Updates to Ph. Eur.

PTE: What updates or changes were made to the Ph. Eur. in 2021 that manufacturers should be aware of?

Vielle (EDQM): The new chapter ‘Test for bacterial endotoxins using recombinant factor C’ (2.6.32) describes a bacterial endotoxins test using a recombinant factor C based on the gene sequence of the horseshoe crab and fluorimetric detection. Although not a new topic for the Ph. Eur., its publication marks a significant step towards reducing the impact on an endangered species.

Regarding particulate matter, two texts should be mentioned: a new chapter ‘Recommendations on testing of particulate contamination: visible particles’ (5.17.2) provides information on visual inspection and control of visible particles in liquid preparations; and the revised chapter ‘Particulate contamination: sub-visible particles’ (2.9.19), which supplements the [Pharmacopoeial Discussion Group] PDG ( harmonized text. In addition, the revised general monograph Parenteral preparations (0520), published in Supplement 10.5, now describes the tests for particulate contamination—both visible and sub-visible particles—in the test section as release criteria and applies to all liquid parenteral preparations intended for injection or infusion.

Finally, a new general chapter on ‘Multivariate Statistical Process Control’ (5.28) was published in Supplement 10.4. The Ph. Eur. is the first pharmacopoeia to tackle this topic.

PTE: What updates are planned to the Ph. Eur. for 2022 that impact small-molecule drug development and manufacturing? For large molecules?

Vielle (EDQM): The Ph. Eur. Commission now foresees the complete replacement of the rabbit pyrogen test by suitable in vitro alternatives within approximately five years. Revisions to some 59 Ph. Eur. texts through the usual Pharmeuropa consultation process will start in 2022.

Several new general chapters will enter into force on 1 January 2022 after their publication in Supplement 10.6, including ‘N-nitrosamines in active substances’ (2.5.42), which provides three validated tests for N-nitrosamine impurities in ‘sartan’ active substances with a tetrazole ring and may also be used for the control of other APIs and medicines, and ‘Balances for analytical purposes’ (2.1.7).

Likewise for the revised General Notices, which include requirements for dissolution and disintegration tests. As of Supplement 10.7, the test for specific toxicity in guinea pigs will be deleted from 17 monographs for vaccines for human use.


PTE: What can you tell us about the following revisions, and have you received any feedback from the industry?

Vielle (EDQM): 2.6.16. ‘Tests for extraneous agents in viral vaccines for human use’—The revision of this general chapter will take into account comments received from Ph. Eur. users and clarify requirements for a number of extraneous agent tests. The scope of the avian leucosis virus test has been extended in view of the deletion of chapter 2.6.24.

2.6.40. ‘Monocyte-activation test for vaccines containing inherently pyrogenic components’—This is a new general chapter to encourage the use of the in vitro monocyte-activation test for vaccines containing inherently pyrogenic components.

2.8.2. ‘Foreign matter’—This general method has been revised to include more specific requirements for other foreign elements like moulds and animal contamination such as insects, and now states that any other unwanted matter (e.g., glass, plastic, or metal) should, as far as possible, be absent.

5.21. ‘Chemometric methods applied to analytical data’—Numerous sections of this chapter have been completely rewritten or updated and new sections/sub-sections introduced to take into account developments in data science techniques since its adoption in 2015.

Evolving situations

PTE: Can you give us an update on the nitrosamine contamination situation? What specific revisions to monographs have been made?

Vielle (EDQM): The five monographs on sartans with a tetrazole ring—Valsartan (2423), Losartan potassium (2232), Irbesartan (2465), Candesartan cilexetil (2573), and Olmesartan medoxomil (2600)—have been revised in line with the latest [European Medicines Agency] EMA [Committee for Medicinal Products for Human Use] CHMP regulatory recommendations. Hence, the control of N-nitrosamines has been moved to the Production section, which now requires a risk assessment and, if necessary, a modification of the manufacturing process and the implementation of a control strategy. They came into force on 1 April 2021.

For the general monographs Substances for pharmaceutical use (2034) and Pharmaceutical Preparations (2619), comments on the revision of the Production section received through Pharmeuropa are currently under review.

PTE: Finally, more than a year-and-a-half after the COVID-19 pandemic started, how has the industry changed and how has the pandemic impacted the EDQM?

Vielle (EDQM): The pandemic has definitely highlighted risks linked to the industry’s dependency on suppliers on different continents and to supply chain fragmentation and vulnerabilities. Whether this will change how industry operates remains to be seen.

The EDQM’s priority from the outset has been to ensure continued supply of our products and services, especially of the reference standards required to produce medicines and release them to the market. Staff commitment, our flexibility, and careful production planning has made this possible. We have also further increased our interaction with regulators, industry, and the world pharmacopoeias to ensure good quality medicines are available and support the development of COVID-19 vaccines and medicines.

The lockdowns and increased teleworking have entirely changed our working methods and have made us fast-track digital transformation.

Article Details

Pharmaceutical Technology Europe
Volume 33, Number 10
October 2021
Pages: 44-45


When referring to this article, please cite it as S. Haigney, "European Pharmacopoeia Updates: EDQM Tackles Nitrosamine Impurities," Pharmaceutical Technology Europe 33 (10) 2021.