Potential Topic for an event concerning obtaining the right level of Nitrosamine Risk Assessment information from your CMOs

Hi My Fearless Nitrosaters,

I wanted to ask a question to determine if people in the Exchange would find value in an event if the topic was to cover the following:

“Benchmarking on obtaining more robust nitrosamine assessment information from API CMOs (including solvent information) and drug product CMOs (including the excipient suppliers).”**

It can sometimes be challenging to obtain detailed information for nitrosamine assessments concerning the solvent suppliers that my CMO’s use for API synthesis. It is also sometimes difficult to get drug product CMO’s to have the appropriate level of detail in the nitrosamine assessments (especially information concerning excipients). Has anyone else run into this issue? How did you solve it? If you feel that this topic is worthy of a conversation, please like or leave a comment.

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Thanks @DanitaBroyles for the idea… When we thought it was a thing of the past, the more we discussed risk assessment, the more gaps we identified.

Allow me to express my concern. It has become increasingly common to encounter companies’ risk assessments founded solely upon terse, single-page documents provided by their suppliers, bearing the familiar refrain of being “free of ANY Nitrosamines.” While such assertions would be assuring if substantiated by robust investigation and accompanying data, regrettably, this is often not true.

Another prevalent approach involves the deployment of the ‘screen of Nitrosamines,’ wherein samples undergo scrutiny against a panel encompassing 6, 7, or 12 Nitrosamines. While this method provides insight into the absence of the screened impurities, it does not confer unequivocal assurance regarding the absence of Nitrosamines without comprehensive assessment.

Accessing essential information from suppliers presents, in many cases, an uphill challenge, exacerbated by the tools such as questionnaires or checklists that claim enough to meet regulatory mandates. Despite their utility in facilitating information gathering, these tools lack regulatory validation as the official means to conduct comprehensive risk assessments.

In a more critical situation (paraphrasing), “Our products contain secondary or tertiary amines. There is a possible introduction of Nitrites from the raw material.” However, “We do not intend to develop a method to test the product for nitrosamines, nitrates, or nitrites.” It leaves one with the lingering sentiment of being wished ‘Good Luck!’ in navigating potential risks.

Nevertheless, many organizations are doing a fantastic job conducting risk assessments. Suppliers sharing critical information about potential solvents, starting materials, intermediates, or specific impurities that can be critical nitrosamine precursors should not be considered sharing confidential information. In my presentations, I have shown successful examples of how some suppliers share all this crucial information without disclosing the ‘secret recipe’.

Innovative methodologies such as ‘purge’ calculations, spearheaded by @AndyTeasdale, are gaining traction in enhancing the efficacy of nitrosamine assessments conducted by suppliers.

Can you share best practices on your team or suppliers that make Risk Assessment a breeze for you?

@trust_user_a @trust_user_b @trust_user_c

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@DanitaBroyles It is challenging to convince API suppliers and CMOs to provide a robust risk assessment for nitrosamines especially NDSRIs and believe you are not alone in this. In cases where suppliers were reluctant to conduct confirmatory testing/assessments, we have internal process of testing for a potential nitrosamines using a scientifically sound method (exploratory testing). In this way, as a MAH we take full responsibility to minimize the patients’ expose to nitrosamines.

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Another statement I see from excipient manufacturers is, “No nitrosamine is intentionally added”. Who adds nitrosamines intentionally?

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Thank you so much for your insight Naiffer. I sometimes feel like I have to pull companies to catch up with what needs to be done. I am so thankful for the Nitrosamines Exchange Community. I have learned so much, and I can always depend on the “Nitrosators” to help out! Thanks for tagging Andy! @AndyTeasdale I may initiate a conversation with you concerning purge calculations if that is okay with you. :slight_smile:

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Hi @krishmnt, is there high level steps that you could share in your company’s process? I am glad that other companies are finding solutions to this issue. I sometimes felt like I was alone, and I am the primary person who is trying to get the CMOs to provide these assessments.

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That is almost laughable if it wouldn’t be so tragic. When you receive the “checklists” from excipient suppliers, do you go straight to assessing nitrosamine impact using a worst case scenario? (meaning you look at the Lhasa database and assume the maximum amount of nitrosating agents found for that excipient then calculate any potential nitrosamine formation?)

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The message is very clear that the onus and burden lies on the generic companies who are supplying products to the market. The expectation from agencies is that it is the ultimate responsibility of drug product manufacturers that they should control all nitrosamines carrying from all sources. The situation has become more challenging as the drug product manufacturers are asked to confirm the absence studies for those Nitrosamines supposed to be originated from starting materials/ Impurities (Process & Degradants) .This in turn creates more pressure on analytical labs and people. Hence, generic drug product manufacturers are squeezed between vendors and regulatory agencies.

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I do agree with team that still excipients vendor are not too serious about the Nitrosamines & simply providing the assessment as- No Nitrosamines are present. This happens because these vendors are still not under the purview of FDA for Nitrosamine regulations, so they are trying to complete the formal documentations. I think excipients vendor also should have these regulations.

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Hi @DanitaBroyles,

This is an important topic that you have touched upon.

If theoretical assessment indicates there is risk of nitrosamine formation, then even if the API supplier provides a statement that there is no risk, we should insist on analytical testing data especially for small molecule nitrosamines.

For NDSRIs, currently validated methods are not available for all and it is difficult for CMOs to provide analytical data. I am not aware of any CMO providing statements for NDSRIs. In such cases, it becomes essential that we perform theoretical risk assessment and estimate the amount of NDSRI that will form (Refer: Modeling the Impact of Excipients Selection on Nitrosamine Formation towards Risk Mitigation - PubMed) and if this value is exceeding the CPCA derived AI limit, then analytical testing is required.

Given the frequency of this topic, I have been thinking for a bit that it may be good to setup a live discussion.

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A little bit off topic, but your remark reminds me of a regrettable story early '00 in Japan where the anti-obesity API fenfluramine (prohibited in 1977 in US due to adverse reaction linked to cardiac abnormalities) was mimicked in a Chinese dietary supplement for weight loss by adding around 3% N-nitroso-fenfluramine. However, NFEN doesn’t inhibit appetite, but might induce hepatopathy including biliary congestion and nephropathy. Different users died (estimated daily intake 0.52 mg/kg bw) due to severe liver suffering (possibly linked with CYP2C19 poor metabolizer phenotype).

N-ニトロソ-フェンフルラミンの検出等について (mhlw.go.jp)
Satoh, Kanako, et al. “Effects of N-Nitrosofenfluramine, a Component of Chinese Dietary Supplement for Weight Loss, on CD-1 Mice.” Archives of Toxicology, vol. 80, no. 9, 2006, pp. 605–613.
NAKADAI, Ari, et al. “Determination of the Optical Purity of N-Nitrosofenfluramine Found in the Chinese Slimming Diet.” Yakugaku Zasshi, vol. 123, no. 9, 2003, pp. 805–809.
Kaddoumi, Amal, et al. “Pharmacokinetic Properties of N-Nitrosofenfluramine after Its Administration to Rats.” Biomedical Chromatography, vol. 25, no. 5, 2011, pp. 579–587.
Kawaguchi, T, et al. “SEVERE HEPATOTOXICITY ASSOCIATED WITH A N-NITROSOFENFLURAMINE-CONTAINING WEIGHT-LOSS SUPPLEMENT: REPORT OF THREE CASES.” Journal of Gastroenterology and Hepatology, vol. 19, no. 3, 2004, pp. 349–350.
Kaddoumi, Amal, et al. “Hair Analysis for Fenfluramine and Norfenfluramine as Biomarkers for N-Nitrosofenfluramine Ingestion.” Forensic Science International, vol. 146, no. 1, 2004, pp. 39–46.
Nakagawa, Yoshio, et al. “N-Nitrosofenfluramine Induces Cytotoxicity via Mitochondrial Dysfunction and Oxidative Stress in Isolated Rat Hepatocytes.” Archives of Toxicology, vol. 79, no. 6, 2005, pp. 312–320.
Nakagawa, Yoshio, et al. “Role of Mitochondrial Membrane Permeability Transition in N-Nitrosofenfluramine-Induced Cell Injury in Rat Hepatocytes.” European Journal of Pharmacology, vol. 529, no. 1, 2006, pp. 33–39.
Nakagawa, Yoshio, et al. “ATP-Generating Glycolytic Substrates Prevent N-Nitrosofenfluramine-Induced Cytotoxicity in Isolated Rat Hepatocytes.” Chemico-Biological Interactions, vol. 164, no. 1, 2006, pp. 93–101.
Lau, Gilbert, et al. “1. A Fatal Case of Hepatic Failure Possibly Induced by Nitrosofenfluramine.” Medicine, Science, and the Law, vol. 44, no. 3, 2004, pp. 252–263.

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OMG! did not know this :hushed:. As I always say, be careful of supplements.

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Demonstrating the applicability of purge calculations towards nitrosamines is actually a topic we are currently preparing a paper for. It is not ready for submission just yet but watch this space. In terms of CMO’s providing sufficient analyses, this will forever be a challenge. One suggestion could be for the CMO to perform the purge calculation themselves, and provide the necessary information almost like a CoA, though there are likely to be barriers to this approach.

Also, Barbara Scott (FDA) was asked essentially this question at the recent Lhasa Regulatory and Industry symposium in Brasilia. Her answer was essentially that the CMO/supplier must provide sufficient detail to allow a proper risk assessment, or an analytical testing strategy would be necessary by the MAH (as @krishmnt suggests). Alternatively an API supplier could seek approval of the API directly with regulatory agencies and thereby avoid the need to further disclose information they deem sensitive.

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Jason, I am sure we can entertain the idea of a live discussion on this topic. What’s on your mind in terms of format/agenda?

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@MichaelBurns Thanks! This is a great “best practices” conversation. :slight_smile:

Thanks, Michael, for sharing that insight from the workshop! That’s a very interesting statement indeed. I will assume that the API supplier seeking approval is referring to DMF. Are the agencies consistently reviewing the risk of Nitrosamines in the information that API manufacturers include in their DMF applications?

I wouldn’t like to misinterpret her comment (which was caveated as her opinion and not a position from the FDA) but I took the same interpretation as you. Similarly I can’t comment on your second point.

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To be honest with CMOs for finished products, in my experience a good percentage do not give the full overview that ends up with the decision of going for confirmatory testing or theoretical calculations.

The issue is when the expected nitrosamine is under Category 1 and 2, any theoretical calculation if the MDD is in mg/day would end recommending analytical testing.

Now, for APIs we have received better quality of evaluations and in some cases even analytical data. Nonetheless, still some cases where only a kind of questionarie is being forwarded where further follow up questions are needed.

Finally, excipients, reagents, etc. we have seen that +/- most of the time we have proceeded with nitrite testing when there is a high risk as nitrite data from the supplier is not available at all.

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