Introduction to Nitrosamines: Definition, Sources, and Risks
Introduction to Nitrosamines: Definition, Sources, and Risks
𝑁 -nitroso compounds (-N2O) that can act as potent mutagenic carcinogens under the ICH M7(R1) Guideline.
Global
concern triggered in 2018 by the discovery of NDMA in Valsartan (Sartans).
Initially in
July 2018 - sartans with tetrazole ring containing products was triggered to
assess the impact of N-nitrosamine impurities on the benefit-risk
balance of valsartan medicinal products
Later in 2019,
it was also identified in non-Sartans e.g. ranitidine, pioglitazone by
API manufacturer.
N-nitrosamines
have been found in sartans with a tetrazole ring but also in other
API/medicinal products (e.g. ranitidine) on 10 September 2019 the EMA’s
Executive Director initiated a procedure under Article 5(3) of Regulation EC
(No) 726/2004, and requested the CHMP (Committee for Medicinal Products for
Human Use ) to further investigate the issues - detection, management and
prevention of presence of N-nitrosamines in medicinal products for human
use.
On 31 January
2019, EMA’s CHMP concluded its Article 31 review setting temporary limits on
the API applicable within a transition period of two years and defining
stricter long-term requirements based on technical limits
Subsequent to
the Sartans Art. 31 referral, one API manufacturer informed the EU authorities
and European Directorate for the Quality of Medicines (EDQM) that it had
discovered NDMA in some batches of its pioglitazone API. The NDMA levels in the
concerned pioglitazone batches were below the interim limits set for sartans
(based on ICH M7(R1) ) but the presence nonetheless of an N-nitrosamine
in a non-sartan API was a significant finding. As a precaution, the EDQM
reviewed immediately all Certificate of Suitability to the monographs of the
European Pharmacopoeia (CEP) applications for this substance and in April 2019,
EMA and National Competent Authorities (NCAs) requested that MAHs for
pioglitazone who were using certain reagents in their manufacturing processes
check their processes, to rule out the presence of N-nitrosamines.
In July 2019,
EDQM received information on a new N-nitrosamine N-nitrosomethylphenylamine
(NMPA) – in valsartan from another API manufacturer. The levels detected for
products in the EU/EEA were below the ICH M7(R1) limit calculated for NMPA at
the time based on methodologies referenced in the outcome of the Article 31
review.
In September
2019, at the request of the European Commission, an Article 31 review was
initiated for ranitidine containing medicines (EMEA/H/A-31/1491) 2after tests
showed that some of these products contained NDMA, both in API and finished
products. In a number of EU countries, national authorities initiated recalls
of ranitidine medicines from pharmacies.
In May 2019,
the Lessons Learnt Exercise was initiated within the European network to
determine what lessons can be drawn from cases of unexpected presence of N-nitrosamine
impurities in sartans. A final report for this exercise was published on 24
June 20203
ICH M7(R1) principles for substances of the “cohort of concern”
A "cohort
of concern" (CoC) refers to specific classes of chemicals, like
aflatoxin-like compounds, N-nitroso compounds, and alkyl azoxy compounds, that
are recognized as potent carcinogens, posing significant cancer risks even at
very low exposure levels below the general safety limits (TTC)
Health
Authorities have extended the scope of assessments and published regarding
certain types of nitrosamine impurities, referred as nitrosamine drug
substance-related impurities (NDSRIs), detected in certain drug products
Quality and safety aspects
• Root causes
for presence of N-nitrosamines and proposed measures to mitigate it
• Consideration
for analytical method development to identify and quantify N-nitrosamines
in drug substances and medicinal products.
•
Considerations for calculating risk for exposed patients in case of in case of
detection of N-nitrosamines in medicinal product(s).
• Methodology
for defining limits for N-nitrosamines in medicinal products.
Root Causes for Formation of Nitrosamine Impurities
- API, Raw materials, solvents, or catalysts
- Cross-contamination in shared manufacturing facilities
- Leachables from packaging (e.g., nitrocellulose liners).
- Reaction between secondary/tertiary amines and nitrosating agents (e.g., nitrites) under acidic conditions
