Three days after propranolol was recalled, Pfizer Canada recalled all lots of Accuretic(quinapril hydrochloride and hydrochlorothiazide), which is also used for blood pressure medication, due to N-nitrosamine contamination.



Inactive ingredients used in the formulation is as follows;
candelilla wax, crospovidone, hydroxypropyl cellulose, hypromellose, iron oxide red, iron oxide yellow, lactose, magnesium carbonate, magnesium stearate, polyethylene glycol, povidone, and titanium dioxide

The API with the secondary amine might react with nitrite in excipients.


To add further, on 2022-03-04, Pfizer further highlighted the presence of N-Nitroso-hydrochlorothiazide in this product.

Accuretic (quinapril hydrochloride and hydrochlorothiazide): Nitrosamine Impurity - Canada.ca

Hi, @Sarada.jena. Thank you for adding the information. Yes, you are right. Both quinapril and hydrochlorothiazide have the structure of secondary amine. The total daily intake of these N-nitrosamines should be taken into account.

1 Like

Thanks for the info. At first for this nitrosamine, there is only one sp3 carbon adjacent to the nitroso group. I have seen strategies around putting this kind of nitrosamines out of the Cohort of concern, but now into ICH M7 (when there is no sp3 carbon). Of course this should be checked in detail.

As for awareness:

Pfizer Voluntary Nationwide Recall of Lots of ACCURETICTM (Quinapril HCl/Hydrochlorothiazide), Quinapril and Hydrochlorothiazide Tablets, and Quinapril HCl/Hydrochlorothiazide Tablets Due to N-NitrosoQuinapril Content | FDA

1 Like

According to @AndyTeasdale, this has triggered the request for information from Swiss Medic on several ACE inhibitor-related products.

The Quinapril recalls continue, the Australian FDA announced the recall of several lots of Quinapril following the confirmation of N-nitroso-quinapril impurity being present at levels higher than the acceptable level.

arn-report-20221216.pdf (115.5 KB)

1 Like

FDA posted yesterday (21-Dec-22) a voluntary recall by Lupin of Quinapril due presence of N-nitroso-Quinapril above the acceptable daily intake.
Does anybody know what limit manufacturers or regulators are working against?

Lupin Pharmaceuticals, Inc. Issues Voluntary Nationwide Recall of Four Lots of Quinapril Tablets Due to Potential Presence of N-Nitroso-Quinapril Impurity | FDA.


We are working with 18 ng/day default limits this moment.

1 Like

Dear all,
Please note that the EMA allowed a temporary AI (t-AI) of 178 ng/day
(total nitrosamines) for max 12 months (Q21), but this is valid for EU countries only; other authorities (e.g.FDA) may have a different approach.

Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products (rev.14)

kind regards


Adding to @paliog comment, β€œIt is expected that the t-AI would be used for a period of less than 12 months, as an exposure over this period of time is not expected to increase the theoretical overall lifetime risk above 1:100,000.”


What interim limit for N-Nitroso Quinapril we can propose ?

1 Like


@conudel Can you please help us understand and walk us through the potential definition of a limit for this impurity? Thanks

Good afternoon,

Does anybody can provide some insight about the TD50 for N-nitrosoquinapril?

Thank you in advance!

Best regards,

I tried to apply the read-across approach with known nitrosamines, but I cannot find a good model with carcinogenicity data (i.e. TD50).
Considering only the core of N-nitroso Quinapril, i.e. the first two position around the N-nitroso group, a possible model may be the Nitrosoiminodiacetic acid:


This substance is present in the Lhasa database and is negative in rat carcinogenicity studies:

It has been tested in 11 Ames tests, one positive and 10 negative:

Moreover, the considerations already made in my post on N-nitroso Ramipril could be applied also to N-nitroso Quinapril and other ACE-inhibitors.

Limit for Nitroso Ramipril

Summarizing, it is possible that N-Nitroso Quinapril may be not mutagen (or a very weak mutagen); but to demonstrate this you should perform a full Ames test with a negative result (and then further in vitro test).

In the meantime, I’m afraid you will have to apply the default limit (18 ng/day) or ask to the authorities to apply the EMA temporary limit (178 ng/day). The adoption of the t-AI is not automatic and is evaluated by the relevant authorities at the time of notification. Use of
the t-AI beyond 12 months will require additional consultation with competent authorities.