Japan - What's next on Nitrosamine?

Last week (Oct 8th) Japan’s Drug Evaluation and Control Division, Pharmaceutical Affairs, Ministry of Health, Labour and Welfare posted a notification “Voluntary Inspection on the Risk of Nitrosamines Contamination in Pharmaceutical Products”

The intention is to instruct the manufacturers and distributors under your jurisdiction to conduct self-inspections on the risk of contamination with nitrosamines, in cooperation with manufacturers involved in the manufacture or packaging of APIs or preparations, suppliers of additives, reagents, and container closure systems, and the API’s National Administrator.
In order to facilitate this self-inspection, a separate question and answer document (Q&A) will be prepared, and an administrative notice will be issued shortly.

Eligeble drugs includes:

  1. Chemically synthesized ethical drugs, drugs requiring medical advice and OTC drugs.
  2. Biologics with high risk of contamination with the following nitrosamines:
  • Biologics that contain chemically synthesized fragments and have risk factors equivalent to those of chemically synthesized active ingredients.
  • Manufactured using a process of intentional addition of a nitrosating reagent
  • Packaged using specific primary packaging materials (such as blister packs containing nitrocellulose)

The limits for nitrosamines in pharmaceutical products:

Guidance document here: IDRAC_336737_10-Oct-2021_Notification_ PSEHB_PED No. 1008_1, PSEHB_PSD No. 1008_1, PSEHB_CND No. 100.pdf (160.3 KB)


Thank you for sharing. Guidance is only in Japanese and it clearly mentions to refer to EMA and FDA guidance, which is translated in Japanese and uploaded on the homepage, to perform risk assessment. Acceptable intake and calculation looks based on EMA guidance.

Though LTL approach was described in the draft version of this document, it was removed. And Q&A will be disclosed in future, then I will share it. As this guidance does not include details, it will be considered on a case-by-case basis, I think.


Thanks @Yosukemino @Naiffer_Host , pl keep the community updated if there’s any additional perspective from the Japanese Regulators in addition to the FDA"s n EMA’s perspective :crossed_fingers:

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Thanks, Yosuke
I have the interested to know what new perspectives will be listed in Japanese Guidance and Q&A.

Thank you for asking, @ymleefn. In Japanese Guidance, root causes and testing methods refer to EMA and FDA guidance. And risk assessment and confirmatory testing should be finished until April 2023 and October 2024, respectively. Q&A is likely to be announced in December 2021 or later. However, questions have been collected in closed communities, not in public, unfortunately. As pharmaceutical companies in Japan are now embarrassed due to a lack of information, what and how to do in risk assessment, nitrosamine WG is planning to support us, I guess.

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