Phathom Pharmaceuticals reported that it has detected trace levels of a nitrosamine impurity in their vonoprazan-based products (may be NDSRI, nitroso-Vonoprazan ? ) that is not described within the FDA Nitrosamine guidance document

Nitrosamines in the News
#1

Phathom Pharmaceuticals reported that it detected trace levels of a nitrosamine impurity (may be NDSRI, nitroso-Vonoprazan ?? ) that is not described within the FDA guidance document entitled “Control of Nitrosamine Impurities in Human Drugs – Guidance for Industry.” The Company is working with the FDA and plans to obtain approval of and implement an additional test method, specification, including a proposed acceptable intake limit, and additional controls to address this impurity prior to releasing their first vonoprazan-based products to the market. These additional activities will result in a delay of the planned VOQUEZNA DUAL PAK and VOQUEZNA TRIPLE PAK product launches. The Company currently expects the full commercial launch of these products, as well as, if approved VOQUEZNA tablets for EE, in the first quarter of 2023.

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Unofficial/official surrogates for read-across
#2

Vonoprazan
Smiles: Fc1ccccc1-c2cc(CNC)cn2S(=O)(=O)c3cccnc3

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image1200×1234 31.4 KB

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#3

This is obviously a secondary amine and this represents a high risk in terms of forming the NDSRI - NO-Vonoprazin. The challenge as with so many similar examples is what would be an appropriate AI. Illustrates again the need to have an effective interim position in terms of limits.

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#4

日本上市的样品我们检过，检出量1ppm，而且稳定性样品会显著增加

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#5

该亚硝胺的控制限度，控制在什么水平呢？什么时候会有控制限度的相关要求 出来？

#6

这个杂质控制限度现在有了吗？ @Naiffer_Host @AndyTeasdale @pragnesh

#7

这个杂质有控制限度了吗？目前可参考什么制订限度？

#8

Either,
(1) you can use nitrosamine TTC value
US - 26.5 ng/day
EU - 18 ng/day
(2) Derive AI based on read across chemical with the help of qualified toxicologist

#9

原研检出量大于1ppm，用这两个TTC的控制限度，都控不住。需要提高控制限度，EMA在2022年10月发布的问答文件
EMA亚硝胺问答文件-409815-20221013-英文-12版.pdf (591.5 KB)
（409815，12版）中，提出了178ng/天的总亚硝胺控制限度，是不是可以采用呢？

#10

I think, the decision whether to use TTC or 178 ng/day will be taken by regulators (FDA, EMA or PMDA) based on drug supply shortage possibility for the medicine involved. Also, if qualified toxicologist can justify the data using read across which support higher limit than TTC or 178 ng/day, it can be proposed as well.

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#11

The limit of N-nitroso-vonoprazan (NVP) is considered as 96ng/day which is the same as NDMA, according to this article.

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#12

@Xuguoqin would you be able to share more about how the impurity increase during storage?

#13

由API与辅料中的亚硝酸反应产生，同时稳定性放置过程中会持续增长，加速6个月可超出控制限度。[quote=“Naiffer_Host, post:12, topic:3278, full:true”]
@Xuguoqin would you be able to share more about how the impurity increase during storage?
[/quote]

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