Challenges for API Raw Material & DP regarding Excipient / APIs / Packaging?

My concern is about the risk of nitrosating agents or secondary/ tertiary amines with which purchased raw materials are contaminated. To minimize this risk, sending questionnaire to raw material manufactures is recommended by APIC. However the kind and number of raw materials are so huge. And those providers locate all over the world. Considering their markets, I’m worried they may not respond to our questionnaire.

A Japanese GE company proposed on the session that over one thousand of questionnaire had been sent to raw material and packaging manufactures. It seemed very tough to summarize the results.Of course I believe most of raw materials are generally free from nitrosating agents or secondary/ tertiary amines. Besides the trace amounts of contamination is not so significant in general, especially in the upstream of manufacturing process. However I’m not sure how to confirm our materials are free from contamination in real without testing or reviewing questionnaire answers. And input of nitrosating agent makes risk assessment complicated, because amine sources are frequently used in the manufacturing process.

How do you perform the risk assessment of raw materials concerned with nitrosating agent or amines contamination?


@Yosukemino We are commonly asked ‘what should be the Nitrate spec for Excipient/API/Ingredient?’, Nitrate on its own is not the sole cause of Nitrosamien formation. Only risk assessment and examination of the full process allows to make that call and define what levels if any represent a risk.

@DAB had a post in reference to the APIC guide, so I’m interested if she can share her experience based on the situation that you describe. It’s a reality that some (not all) API/Excipient manufacturers limit their assessment to a disclaimer on their CoA regarding the risk or content of nitrate/secondary amine. What’s the backup plan for this scenario.

Although not the same, but this publication shines some light on the risk of Nitrosamine formation using the content of Nitrate is water as a model.


Few months ago @AndyTeasdale and Ank Reumer (Nelson Labs) delivered a webinar ‘Hunt for N-Nitrosamines in Medicinal Products’ that illustrate some of these concepts in real scenarios


Hi Naiffer,
Though the title of this thread is Most burning challenge for API manufacturers, we are discussing about Nitrosamines in excipients which is a challenge for MAHs since many excipient suppliers are unable to provide this information. I tried if it was possible to edit the title but was unable to locate the option.
The approach that is being adopted is multidimensional since MAHs are not excipient mfrs and do not possess the knowledge of the excipient process and related controls , moreso many excipients are obtained from natural sources so assessing for Nitrosamines in them is also a challenge, nevertheless this needs to be done.

1)This requires extensive collaboration, knowledge sharing and sensitising the excipient manufacturers with respect to significance of assessing Nitrosamines in excipients . It also requires availability of resources like SMEs, Analytical capabilities at excipient mfrs end. This consumes time yet suppliers have started working on these aspects. Some of them are subcontracting the Analytical testing activities to a third party

2)Till date there’s no guidance document from any Regulatory agency on this topic. IPEC Europe n Americas have guidance documents available on this topic and these are being used as the basis of evaluating Nitrosamines risk assessments by suppliers. BASF has an Online link available for accessing this information , this is an excellent example of a proactive approach to collaborate with MAHs

  1. From the mfrs perspective, it is important rather mandatory to include evaluation of Nitrosamines in the Drug substance, product in the product development phase as a part of Quality by design approach to avoid expensive Product Recalls later especially in today’s times in a pandemic where drug supply chain shortages owing to these issues can prove detrimental to public health. Excipients and Primary pkg materials need to be evaluated for the information on Nitrosamines from the mfrs or suppliers before taking a decision on selecting them. The Nitrosamine assessment approach should also be performed for products in the market post approval where ICH Q12 concepts can be applied in context of Lifecycle mgt of Products n methods.

  2. Assessment of including Nitrosamine evaluation is being included in vendor qualification programmes by MAHs. Inability to provide this info by excipient n primary pkg material suppliers will eventually translate into loss of business because a MAH would not wish to collaborate with a supplier who is unable to provide assurance of the presence/absence of Nitrosamines in their products.

Since this is an evolving n emerging area for Industry wrt evaluation of Nitrosamines and the Analytical Technologies being employed , probably it would take some time for Industry to have a complete package available but it’s not impossible. What is needed at this time is collaboration between Regulators & Industry to have a comprehensive approach for assessment, testing not only in APIs n products but also extended to excipients and primary pkg materials. IPEC and Excipact collaborations can aid in achieving thos goal as these bodies govern the excipient mfrs and inclusion of Nitrosamine assessment n controls in Excipact certification pr9grammes can help immensely

The agencies are doing an excellent job of educating the Industry in terms of assessing Nitrosamines in substances and products. EDQM recently concluded a very detailed training programme on Impurities that also had presentations on Nitrosamines n mutagenic Imps and Interpretation of ICH M7


@Naiffer_Host @DAB
Thank you for sharing your thoughts. I really appreciate your help. And I agree acquiring information of nitrosamine impurities from API/ Excipient manufactures is a challenge for MAHs. As Naiffer implied, careful reviews of all manufacturing processes are important. The amount of nitrosating agents, 2ry amine sources, temperature, pH, and purge capability of the process are included it, I think.

And I’m sorry that my question was misleading. I intended raw materials used in API manufacturing processes. If nitrosating agents or 2ry amine sources are used as reagents during API manufacture, addition of their counterpart contained in purchased raw materials even at the impurity level can lead to serious risk, I’m concerned. I want to ask how to deal with this risk, the contamination of nitrosating agent or 2ry amine sources as the impurity in raw materials for API manufacture. Naiffer, could you please add raw materials for API manufacture or so to the title?

Raw material mfrs are similar to excipient mfrs, however different in details. And DAB’s posts are insightful. For excipient manufactures, risk assessment of nitrosamine may be mandatory in future to avoid losing chances of business. From this point, activity of BASF is helpful and interesting. Those collaborations are expected to be a key to solve the problem DAB mentioned that many excipient suppliers are unable to provide this information. The consortium of Lhasa to share the knowledge of impurity in excipient is also helpful.

And I’m also interested in the risk assessment of DP with API which has 2ry amine moiety. It should be carefully assessed, because nitrite contamination of excipient at impurity level can be serious risk. What do you think about it?


Drug product with a nitrosatable amine is definitely a high risk as you state. Nitrite is critical and, depending on the formulation you may have serious concerns regarding nitroamine formation

@GENERAPHARM Thank you for your comments. I agree with you. As @ASrinivasan mentioned in GDSR this year, lots of API are with nitrosatable amines.
D1S10-1-Srinivasan_p8.pdf (263.5 KB)

I’m not sure the results of the risk assessment of these drugs, however those should be carefully handled. And varenicline (Chantix) is voluntarily recalled due to the risk of nitrosamine impurity contamination. It has a secondary amine.

@Yosukemino I have included ‘API Raw materials’ as part of the thread title. Thanks for the clarification. I have uploaded the "Health Canada’ Q&A document on Nitrosamine, and It’s quite clear the call to API, Excipients, and ingredients manufacturers to openly assist on the risk assessment. Perhaps good conversation to have with suppliers

I am wondering if any of our API or Excipient manufacturers have a perspective to share with the community. Perhaps what are they doing differently to collaborate? @JavierFernandez @rwalliser @KariA @jakob.bonde @tsammeli @Narayana

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@Naiffer_Host Thank you very much for your kind response. I really appreciate it. From Canada Q&A, Excipient manufacturers have responsibility for risk assessment, however raw materials and packaging seem included in risk assessment of API and DP, respectively. Anyway I expect the good collaboration between DP manufactures and excipient ones.

Thanks for sharing @Naiffer_Host . The Health Canada Q&A document clearly describes the roles & responsibilities of various stakeholders involved in the Pharmaceutical Supply chain & it will be an extremely beneficial tool for MAHs to assess suitability of suppliers wrt Nitrosamine assessments.

I share a slide presented by Dr. @AndyTeasdale.

And I add the structure of nitrosamine impurities and APIs

Except for Deferasirox, those API have 2ry/3ry amines.

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Related to Excipients… At today’s workshop by Lhasa focused on the new ANVISA’s guideline, Grace Kocks (Application Scientist) provided some project updates related to VITIC ‘Nitrites in Excipient’. It’s a great initiative on data sharing, I’m curious how this tool and model can be used by a wider audience, and how can support MAHs. I believe @David shared resources and information in previous posts.
I know for a fact that Compendial expert committees are looking into this particular area, early collaboration, discussion, and involvement will definitely prevent divergence.

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@Naiffer_Host I am very interested in the generic and conservative 5 ppm of nitrite content mentioned by Dr. Urquhart. It is applicable to most of excipients from the results of VITIC consortium analysis. It’s helpful for rough and easy assessments aside from deep and detailed one. I want to know his control strategies much more. It is fantastic!!

I share a Q&A in Lhasa Limited Nitrosamine Impurity Workshop. NR who belongs to ANVISA recommends a holistic approach for risk assessment. Gathering information from suppliers as much as possible is important.

Lhasa Limited Nitrosamine Impurity Workshop-Q&A session

What approach should be adopted for risk assessment of excipients & packaging materials?
NR–You need a team to evaluate the possibility, raw material, packaging materials, excipients that have some possible impurities, you have to access and know this information. We encourage a holistic approach. At ANVISA we expect to receive all the information that companies can gather from their suppliers. The risk assessment should be done in all possible corners. If the excipients could be a risk,they should be evaluated. This may be a problem for some companies that deal with suppliers who do not provide this information. The companies then need to do this. We expect a deep evaluation for excipients. A real risk assessment!