Dear colleagues,
Given the recent increase in attention to inactive ingredients and their potential role as sources of nitrosation due to nitrite content, manufacturers of excipients have begun performing nitrite testing and implementing controls. In some cases, they apply a limit of 500 ng/g, while in others this limit is reduced to 18 ng/g.
My question is: Is there a clear regulatory approach or generally accepted criteria for defining a safety limit for nitrites in excipients? Additionally, what calculations or risk-assessment principles do raw-material manufacturers use when establishing and justifying these nitrite limits?
I think a general limit would be quite tricky to implement. For example, if you have an API with a high tendency to form nitroso derivatives and also a small acceptable intake, then a small limit makes sense. However, you also need to know the exact reaction kinetics to perform any meaningful calculations. Factors such as heat, moisture content, pH, etc., all vary from product to product.
If you use processes that involve a lot of air (e.g., a fluidized bed mixer), even NOx can become a source of nitrosating agents. So there are many variables that normally no one really knows. You would need to know the exact conversion rate, which I doubt anybody has.
It would also make more sense to include this information in the manufacturing formula of each product rather than trying to set a specification for the excipient, because every formulation will behave differently. At the end of the day, using ultra-low nitrite content excipients when it’s not necessary will consume a lot of money.
If you identify nitrite as the ultimate root cause, then the use of scavengers could also be assessed. This approach would make the product safer. It requires more work upfront, but it will pay off in the long run.
I would like to add that in case of high levels of NDSRIs in the final product, close to or even more than the acceptance intake, the usage of low-nitrite excipients should be the beginning of any risk mitigation plan, as it could face the problem without any reformulation.
Dear colleagues thanks for your response
All of this is clear — these are general established principles that, I assume, are followed by everyone.
However, the question specifically concerns excipients, where specifications may include a nitrite limit or a declaration of low nitrite content, indicating a certain threshold (for example, one well-known manufacturer sets a limit of 500 ng/g). This leads to the question: on what scientific or regulatory basis is any proposed limit in an excipient considered safe or regarded as “low nitrite content”?
By the same reasoning, why couldn’t 600 ng/g also be considered safe or be selected as an acceptable limit? In essence, what is the justification or scientific rationale for establishing nitrite limits in excipients?
there is no such ‘‘official’’ limit for the nitrites in excipients and in my opinion will never be set. Is also a matter of marketing as more and more companies offers ‘‘low nitrite’’ content.
Having in mind that the average value of total nitrites in a tablet is 1-2 ppm, a quantity of nitrites less than 0.5ppm could be considered ‘‘low’’. Of course is important to take into consideration and the usual quantity of nitrites in each excipient.
For example, there is a company which offers microcrystalline cellulose in quantities less than 0.1ppm and cross carmellose sodium (CCS) in quantities less than 0.8ppm. CCS usually is quite burden with nitrites (up to 8 ppm). So, values of nitrites at 0.8ppm could be considered as ‘‘low nitrite’’. That said, it is not possible to have one common limit for ‘‘low nitrites’’ for all the excipients.
Overall, the most important is the quantity of nitrites of the excipients to be written on the CoA of them.
Dear thanks to very informative response. So, average value of total nitrites in a tablet should be 1-2 ppm. Can you share information about acceptance criteria for nitrite content in liquid dosage forms? Thanks in advance.
i would like to clarify that 1-2 ppm is the common content of nitrites in tablets according to the literature and not the ‘‘target’’ quantity or acceptance criterion.
Regarding the nitrites in liquid dosage forms i do not have any experience or knowledge on this.
From a scientific perspective, defining an acceptance criterion in this context simply does not make sense. If the manufacturer states that the level is, for example, below 1 ppm, then that should be verified. While quantity can certainly play a role in some cases, it does not universally apply. The chemical and physical conditions vary so significantly from one product to another that setting a universal limit is, in fact, impractical and adds little scientific value. In reality, these “limits” often serve more as marketing measures than as meaningful risk controls. Of course, lower levels are always preferable because they reduce risk, but ultimately, imposing arbitrary limits would only lead to unnecessary resource expenditure without improving safety in a scientifically relevant way.