Latest! EMA regulatory strategy adjustment for drug nitrosamine impurities_CPHI Pharma Online

Since the large-scale recall of sartan drugs due to nitrosamine impurity contamination in 2018, regulatory authorities have significantly increased the control
of nitrosamine potential carcinogens.
EMA and CMDh are also constantly updating the regulatory policies on nitrosamine impurities on the "What's New" page under their official websites, providing the latest regulatory policy guidance for pharmaceutical manufacturers and CDMOs, reflecting the latest knowledge and policy adjustments
.

Recently, EMA published the Q&A update on its What's New webpage on the "Q&A on the comments of marketing authorization holders/applicants on CHMP on Article 5(3) of Regulation No.
726(EC)/2004 Referral of Nitrosamine Impurities in Medicinal Products for Human Use", now the 14th amendment
.
The document contains two important updates
(questions 10, 21).

Question 10: Upper limit of nitrosamine impurities in pharmaceutical products

Two new nitrosamine compounds, 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NKK), and N-nitrosoyl, are added to the document table, and the corresponding ADI (Acceptable Daily Intake) is specified Allowable daily intake) The limit is 100 ng/day
.

The limits of nitrosoduloxetine come from structure-activity relations; The limit value of NKK is based on the TD50 data in the carcinogenic potency database (CPDB) of multiple compounds
.

Figure 1 Chemical structure of NKK and N-nitrosoduloxetine

Image source: References

It is worth noting that NKK is a simple nitrosamine impurity, which, like common NDMA, NDEA and other nitrosamine compounds, may be produced indiscriminately in the process of
API or finished drug production.
For example, NMDA is produced
by the interaction of dimethylamine impurities in DMF with nitrite under acidic conditions.
These impurities have been studied for a long time, and their carcinogenicity and mutagenicity are fully supported by data, so the upper limit of the content of these impurities in the drug is calculated by a reasonable ADI value combined with the dose of these drugs, so it is relatively reasonable
.

N-nitrosoduloxetine belongs to the nitrosamine drug substance related impurities (NDSRI), which is based on drugs
.
NDSRI refers to the type of drug molecules that are themselves involved in the formation of nitrosamine impurities, and these drugs usually contain secondary amine structures that provide secondary amino units
for the formation of nitrosamines.
For example, the nitrosamine impurity N-nitrosorasagiline found in the drug Rasagiline (commercial name: Azilect?) for the treatment of Parkinson's disease; and N-nitrosoaurrine found in Orphenadrine
, a drug for arteriosclerosis, spontaneous and encephalitic Parkinson's disease.

Similarly, N-nitrosoduloxetine, which is an NDSRI, can in principle only appear in
duloxetine (duloxetine) drugs.
The upper limit of nitrosamine impurities associated with these products is specified very low
relative to pure nitrosamine impurities such as NDMA and NDEA.
The EMA previously stipulated that if a drug has formed nitrosamine-like impurities, but the specific limit is not defined in the EMA guidelines, the ADI standard
of 18 ng/day will be uniformly applied.
The 100 ng/day limit set for N-nitrosoduloxetine is a relief to the production of the antidepressant duloxetine to some extent
.

The ADI settings for EMA for nitrosamine-simple and NDSRI impurities are shown in Figure 2
.
Those marked in the Source item belong to NDSRI
.

Figure 2 EMA regulations on nitrosamine impurities in drugs and the upper limit of ADI (the updated part is in the red rectangular box)

Image source: References

Question 21: What are the criteria for controlling nitrosamines before determining substance-specific ADI?

If a new type of nitrosamine impurity is present, but the ADI has not been determined due to lack of toxicological data, the provisional limit t-ADI is 178 ng/day (total nitrosamine impurities).

This t-ADI value is valid for 12 months, i.
e.
during this period, no regulatory intervention (recall, etc.
)
is required for batches with total nitrosamine levels below 178 ng/day.
If this period is exceeded, a special agreement
with the regulatory authorities is required.
The t-ADI value cannot be used automatically and needs to be evaluated on a case-by-case basis with regulatory authorities
.

Obviously, compared to the undifferentiated 18 ng/day, this regulation also greatly relieves the pressure
of drug production that may produce NDSRI impurities.
This is a very important regulatory strategy adjustment
.

Resources:

       ECA Academy.
Nitrosamine Impurities: Further Update of EMA's Question and Answer Document.
26.
10.
2022