Do we need to study Nitrosamine impurity for Topical creams/ointments?

This was a questions raised by participant on USP’s <1469> GC webinar.

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Hi Naiffer@Naiffer_Host
That was an interesting question & am in agreement to your response in the session.
The guidelines form EMA & FDA donot specify route of administration of drug products for assessment of Nitrosamine Imps.

EMA Q&A guidance document states that 'MAHs/Applicants of all human medicinal products should ensure that the presence of nitrosamines is controlled and kept as low as possible, irrespective of marketing status or the type of product (e.g.generics and over the counter (OTC) products).'

The term all human products does include Topical creams/ointments, Impurity testing is performed for Topical creams/ointments,gels for oral use (buccal cavity) so Nitrosamines should not be an exception.
What needs more clarity from the Regulators is how to establish Nitrosamine limits for dermal products.Since Nitrosamines are potential carcinogens so there also needs to be an understanding of permitted daily exposures from the dermal route.

Most of the Topicals are either aqueous gels or oil in water, water in oil emulsions, hence understanding excipient interactions from the Nitrosamine perspective would be important.

What is important is to perform a thorough Risk assessment for the presence of Nitrosamines in API,excipients being employed in the formulation, any container closure interaction capable of introducing Nitrosamines, excipient-excipient, excipient API intercations, stability issues , process parameters need to be evaluated wrt potential risks involved.
Intend to take the limits & exposure aspects with the Regulators ,will revert back on the same.

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Depends on the API when it comes to FDA. According to FDA, nitrosamines need to be evaluated in all dosage forms for synthetic API. Also, creams and ointments have been known to have nitrosamine risk for a long time. That was my Ph.D. topic.

One of the well known source of nitrosamines, triethanol amine and also diethanol amine are present in many excipients. They give rise to NDELA (nitrosodiethanol amine).


Hi, to derive cutaneous or transdermal PDE, please consider bioavailbility of impurity by Dermal route. For cutaneous PDE refer recently revised ICH Q3 D guideline.


@MonazBmysorewala Thanks for sharing special considerations. Do you know of any work or research related to Nitrosamine in Topicals or dermal administration route type?

Dear Naiffer,

Thank you for your response. Let me see what I can find out.
Thanking you in anticipation.

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This part is very interesting. I remember in the last FDA Nitrosamines workshop where the invited experts highly suggested to do not use NOEL data to calculate limits for genotoxic impurities in general. And for ICH Q3D guideline, NOEL can be used to calculate PDEs. However, the PDE concept have been applied to Nitrosamines Permitted daily exposure limits for noteworthy N-nitrosamines.

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Thank you for sharing insights.
I am able to locate article, however, it is paid and may be helpful to guide for Nitrosamines qualification in Dermal products.

Contamination of toiletries and cosmetic products with volatile and nonvolatile N-nitroso carcinogens- B. Spiegelhalder &

Journal of Cancer Research and Clinical Oncology volume 108, pages160–163 (1984)Cite this article


Commercially available cosmetics and toiletries were analyzed for contamination with volatile and nonvolatile N-nitrosamines. Of a total of 145 samples analyzed 50 were found to contain N-nitrosodimethylamine (max. value found 24 μg/kg), 26 samples were contaminated with N-nitrosomorpholine (max. value found 640 μg/kg), and 25 samples contained N-nitrosodiethanolamine, a non-volatile carcinogen (max. value found 1400 μg/kg). The results are discussed and compared with other published data on NDEIA in cosmetics, with reference to potential human exposure and to possible preventive measures.


Another article :

Scientific Committee on Consumer Safety SCCS Opinion on NDELA in Cosmetic Products and Nitrosamines in Balloons The SCCS adopted this opinion at its 15th plenary meeting of 26 – 27 June 2012


Nitrosamines definitely need to be monitored in topical dosage form. the predominant nitrosamine in topical dosage form is NDELA (nitrosodiethanol amine). This was the topic of my PhD.

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Thank you for sharing. Your PhD topic is very interesting. At Guidance Note 2 in EFPIA DP Workflow, triethanolamine is considered as excipient with concerns.

It is common excipient used in topical products for multiple purposes. And EFPIA also pointed out that published calculation is helpful to estimate conversion for a solution based formulation.

NDELA in topical products should be carefully assessed, if triethanolamine is used for formulation with nitrite sources.

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Hi Team.
As @DAB is mentioning EMA and FDA both are indicating the need in evaluate nitrosamine in all formulations.
To support this I can tell you that we have been working with some of the major drug but also personal care producers on this topic.
We are preparing a technical note that I can share with anyone interested on the topic.


Thanks for the update Ferran @Frabaneda .
To summarize, any product meant for consumption/application by patients needs to be assessed for absence of Nitrosamines. This assurance from MAHs is required by Regulators.
Looking forward to more information about your work & experiences , pl do share the Technical note with the community.
Thanks :slight_smile:

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Dear Ferran, very interested to get your technical note if feasible.

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Hi Respected Members,
Please find update with respect to Nitrosamine Reporting Format.
Thanking you in anticipation.