IPEC Europe announces the availability of the revised “Questionnaire for Excipient Nitrosamines Risk Evaluation” (Version 4, 2022) . First published in December 2019 and updated in 2021, the Questionnaire has proven useful to excipient producers and MAHs.
This version is updated to remain contemporary with the EMA Q&A on Nitrosamines and clarifies that excipient manufacturers are not required to conduct a nitrosamine risk assessment without specific knowledge of the actual and specific drug product formulation and properties of the active product.
Hi Naiffer @Naiffer_Host
Thanks for checking out on me. Am doing well.
I have been on short browsing visits to the community over the past few months. Not actively engaged here as was unable to devote more time here due to additional professional engagements. Will share the details soon.
I too have missed my engagement here, it keeps me updated on the world of Nitrosamines
I look forward to more engagements and interactions in the community in 2023. You bring enormous positive engagement in the community and it’s really shaped up so well in the past year and a half. Thanks for leading this effort which has been of enormous benefit and provides a common platform for engagement both to the Industry and Regulators
Sincerely,
Archana
I want to hear your opinion about the amounts of nitrites in excipients. Can we estimate the amount of nitrite as “zero” when the answer from the excipient supplier declares their products are free from nitrites/ amine/ nitrosamine contamination under EMA/ FDA guidance without the measured value? Or can we assign 2ppm as a general value?
The IPEC mentioned in the position paper, “excipient manufacturers may be able to provide information that would potentially exclude the presence of nitrosamines, nitrosating agents (nitrites), or vulnerable amines, but they generally will not possess analytical testing data on these substances”. According to it, they can estimate those amounts from their knowledge of the product in some cases. Of course, it should be considered depending on the potential risk. I consider the risk ignorable and assign zero.
Hi,
in my modest opinion it is not always possible to assign a zero value relying only on the manufacturer declaration. I would like to remember that not all excipients manufacturers work according to GMP. For some of them the main markets are the food or cosmetic market and the pharmaceutical market is only a minimal part of the business.
So, a manufacturer could declare the excipient “free of nitrites” because he does not use them in the manufacturing process, but they may be already present in the starting materials (eg. vegetable or mineral starting materials) or may be an unidentified impurity of the manufacturing process.
Another issue is the content of nitrates; some celluloses made with nitric acid have a low content of nitrites (0.2-0.4 ppm) but with a high content of nitrates (90-120 ppm), so we cannot totally exclude an interaction with other excipients which may reduce nitrates to nitrites.
I think that the best way to evaluate the nitrite risk requires a minimum knowledge of the manufacturing process of the excipient; it is negligible for liquid excipients with a final distillation step (e.g. ethanol, propylene glycol, etc) and inorganic excipients made at very high temperature (e.g. fumed silica), but it should be evaluated case by case in all other cases. Of course the manufacturer declaration is a basic requirement , but it cannot be a certification of “zero-level” of nitrites.
Thank you for sharing your thoughts. Yes, you are right. I appreciate your help. The excipient manufacturer honestly provides us with the results of the risk assessment, but the answer looks without serious consideration in some cases. As you pointed out, this declaration may mean simply that no nitrites are used in manufacturing. The excipient manufacturer does not have the analytical data. It may just be hope or speculation.
And I will keep in mind that excipients from natural origins, nitrate used in the manufacturing process, and the purification method of the product are all important. When the manufacturing process of the excipient is not open, we can ask further questions to get information such as the origin of the excipient, the use of nitric acid, and how to purify the products. Anyway, we should evaluate the possible risk appropriately. And if the risk is considered uncertain or unignorable, we proceed to the measurement or another way.
I would also say as per conservativism, 0 level of nitrate shoud not be considered for excipients, unless a clear understanding of the process is known. Also considering the 2 ppm value for excipients without nitrite data as per EPFIA.
Regarding nitrate content, I would also say that in a common finished product manuf. process, their reduction should not happen. For certain excipients it may be worth checking if any reductive agent is present but in general should not happen in a meaningful way. Also, is one of the reasons why in IPEQ questionnaire, nitrates content was deleted.
In summary, we should know how our raw materials are being manufactured.
Hi @Yosukemino ,
That’s an interesting question that many of us are dealing with.
Considering a value of zero implies absence of Nitrite in an excipient and that I feel is a risky proposition unless the excipient supplier tests the samples at their end using sensitive Analytical methods and declares the results that are zero on its COA.
Most of the excipient suppliers only perform a Risk Assessment which is based upon consideration of following Risk factors:
-the use of sodium nitrite or any other nitrite or nitrosating agent in the manufacturing process, water quality assessment for water used for the manufacturing process, the presence of secondary or tertiary amine during the manufacturing process, the presence of any amide, primary amine or ammonium salt in any raw material, catalyst, intermediate, etc. used in the manufacturing process, the use of multipurpose equipment during the manufacturing process
Hence, assigning values to Nitrite content on the basis of only Risk assessments is not a a scientifically viable option.
Excipient mfrs donot come under the Regulatory purview of the Agencies and hence the onus is on the MAH to ensure the Risk Assessment provided by the Excipient supplier is adequate & conclusive to confirm absence of nitrites, nitrosating agents that can lead to potential formation of Nitrosamines in a product. Hence, MAHs need to ensure to have a comprehensive Supplier Qualification programme in place to ensure that the supplier chosen is the one with minimum risks. This would include evaluating the excipient mfg process, sources of RM and if required testing of samples to confirm Nitrite levels. A value can be assigned only after having a realistic idea of the actual content which may be negligible or very low in some cases, but the question is how low enough and that can only be ascertained by testing, Hence, my opinion is arbitarily assigning a zero is risky.
Hope this helps.
I agree with points given by @paliog@Diego_HM@DAB. We can not consider value zero only based on excipient mfg declaration. @Yosukemino similar recommendation details are given in same document which you quoted in section “Responsibilities of Excipient Users”
I understood score of zero, in this case, is far from conservatism. If zero is assigned, MAH should search for justification. It’s MAH’s responsibility.
The discussion two weeks ago revealed that MAH in Japan was worried about the answer from excipient suppliers. Excipient suppliers were considered uncooperative because their responses did not include measured values of nitrite, amine, and nitrosamine. As @DAB pointed out, most excipient suppliers estimate a risk based only on specific risk factors. In addition, they did not disclose the synthetic information of the products. But that doesn’t seem to be uncommon.
To make our risk assessment robust, we will search for justification. It may be faster to take a measurement positively when the API (or impurity) has a secondary or specific tertiary amine.
