Why EMA still assigns AI limits (CPCA) for nitrosamines in oncology drugs

Limits of Nitrosamines
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Hi All,

I would appreciate your insights regarding nitrosamine control in oncology products.
EMA has published Acceptable Intake (AI) limits for several nitrosamine impurities based on the Carcinogenic Potency Categorization Approach (CPCA), and these limits are being applied broadly across drug classes, including oncology drugs such as dasatinib, imatinib, ribociclib, olaparib, selumetinib, and others.
However, for oncology products, particularly those used in advanced or life-threatening cancer, ICH S9 allows for a more flexible, benefitā€“riskā€“based approach to impurity qualification. In such cases, impurities can often be qualified at higher levels under ICH Q3B principles, considering the severity of the indication and limited patient life expectancy.
Given this context, I am trying to understand:

  1. What is the rationale for EMA assigning CPCA-based AI limits to nitrosamines in oncology drugs (for advance-stage cancer) instead of applying ICH S9/Q3B qualification principles

In other words, should CPCA-derived AI limits be interpreted as a default starting point, with flexibility allowed under ICH S9, or as binding limits even in oncology settings?

Thank you in advance for your insights.

Regards

Sushant

2

Dear Sushant,

please note that the in order to apply limits according to ICHQ3 for the impurities in oncology drugs, it is necessary the indication of the drug to be only for ā€˜ā€˜advanced cancerā€™ā€™.

Otherwise, if there is another one indication, different to advanced cancer, then you should set the limits according to CPCA, for the worst case scenario.

N-nitrosoribociclib is a very characteristic case and a relevant discussion has been taken place before sometime

Novartis pauses some trials of cancer drug Kisqali to fix manufacturing

hope this helps

Christos

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Thanks @chrischar !
Just to complement, there are few drugs out there that while they are primaly used for ā€˜cancerā€™ treatment, they also have an expanded indication into other therapeutic areas (when used in very very low doses)

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Hi Christos and Naiffer,

Thank you both for answering to my query.

Regards

Sushant

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Sushant, I think many members have given responses which I agree with. Cancer drugs are not just one class. Just like cancer is a term for numerous diseases with some similarities, cancer drugs can vary significantly in how they work. We have products which are more for maintaining the remission which do not fall in S9 category. Some drugs are not cytotoxic. In those cases, the nitrosamine needs to be controlled. Now, at what level it should be controlled, is an entirely different topicā€¦

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Thank You @ASrinivasan

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Dear Sushant,

Thanks for your post!

Use Case:

We went through the submission of an advanced cancer drug, where the assessor was actually helping us pointing out that those class of producst can be treated with respect to ICH Q3B allowing higher limits, unless this products is not used otherwise (other indications, as described bei @Naiffer_Host )

In my humble opinion, if you explain your risk-based approach there is no argument against using Q3B principles for such a product. I think it is very important to also show authorities, different approaches, which are still safe for the patient to be used. It is the industries task to push conservativ limits when accaptable and not always go for the ā€œsafestā€ way. Otherwise the authorities only know one way and no alternative, if you know what I mean. :slight_smile:

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Hi @Georg_Ever2018

Thank you for sharing your experience. Absolutely. I agree, we have to push for what we can scientifically justify as the safe limit instead of relying only on CPCA.

Regards

Sushant

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