@trust_user_a@trust_user_b@trust_user_c Another milestone for our Nitrosamine Knowledge Community … We are beyond excited about the launch of the new Nitrosamine Exchange - Analytical Hub!
Our entire community across the world reacted swiftly to address the new and previously unrecognized risk associated with the safety and quality of medicines due to the presence of nitrosamine impurities. In response to the challenge posed by the presence of nitrosamines
in pharmaceuticals, Pharmacopeias around the world supported manufacturers and regulators with standards as well as other tools and solutions to test for and assess the risk of nitrosamine
impurities. The USP’s Nitrosamine team has been working to develop sensitive and selective analytical procedures for nitrosamines monitoring in pharmaceuticals.
The Analytical Hub is a public repository of non-compendial analytical methods developed to provide an analytical resource to monitor nitrosamine impurities in drug products, drug substances, or other matrices. It is intended as a resource for informational purposes only and not as a USP-NF compendial documentary standard. The analytical methods, aka “Application Notes” are developed by USP staff without a public comment period. They do not reflect USP or USP’s Expert Body opinions on future revisions to the official text of the USP-NF. The procedures described in the analytical notes should be validated by the user for the intended use
USP’s scientists have curated the analytical methods described in the analytical notes through internal development/validation or scientific review of non-compendial donations. If you are interested in donating an analytical method for the hub, collaborating with USP for the development of a novel method, or inquiring about specific analytical methods needs, please do by messaging @Naiffer_Host - community manager
Access the Analytical Hub inside the community here:
If you would like to invite a colleague or members of your team to join Nitrosamine Exchange and explore the new Analytical Hub, follow this two steps:
@Naiffer_Host
Is it possible to share nitrite methodology as well? I know that the group from Lhasa has some specific guidance around the method and validation that may be mutually beneficial to post.
@jason.brown we have used a colometric method for the determination of nitrite in pharmaceutical drugs using Dapsone and N-Naphthylethylene diamine using spectrophotometer at wavelength 525nm using 10cm cuvette to incrase the response, the advantiges of the method:
-simple (in HPLC method there is difficulty in separating the peak interferences)
-use the complete tablet
-no interference from the active or excipient in the reading.
-number of tablets can be increased to raise the response. @Naiffer_Host is there is a specific limit for the Nitrite content in the drug product to be used, asside from the content of Nitrosamine, or how this could be determined.
There is no specific limit for nitrite per se - it will depend on numerous factors as to what could be an acceptable limit for each individual product; reactivity of the amine, conditions during and method of manufacture of the product etc.
Remember that nitrite levels in raw materials are typically being measured in ppm for many materials, and we are dealing with ppb levels of nitrosamines formed - there will nearly always be sufficient nitrite present for the reaction to take place, if the conditions are right.
@MarkS@Naiffer_Host Dears I am trying to find way to set a limit for the Nitrite in a product which have an API having tertiary or secondary amine/s, I will suppose that the API dose not have Nitroseamine (i.e Nitroseamine free), say for example NDMA is the suppose Nitroseamine to be performed, and the excipient is liable to contain Nitrite, what could be the acceptable level of Nitrite in total excipient (placebo) based on the limit of NDMA?, just brain storming to try to control the nitrite.
thanks,
Hussein Salem
@hussein.salem My personal view on this is not to try and set a limit for nitrite in the rest of the formulation.
If your risk assessment has identified the potential for the formation of NDMA then the next stage is to test and see how much NDMA is actually being formed. Then identify ways to minimise this formation. Concentrating solely on the level of nitrite and trying to control it in the raw materials can be a frustrating, and ultimately unsuccessful, route to obtaining suitable nitrosamine levels in the finished product.
Nitrites in raw materials are a contributory cause, but the rate of formation can be impacted by many factors:
API reactivity (small molecule versus large sterically hindered molecule; other functional groups present etc. etc. etc.)
API to excipient ratio
manufacturing process
presence or absence of nitrite scavengers
other individual factors to the product manufacture
Controlling the level of nitrite within one or all excipients will help reduce overall nitrosamine formation, but controlling or changing other factors may have a quicker and bigger impact.
The only nitrite level you could set to potentially guarantee a lack of nitrosamine formation would be zero nitrite, but this is not a realistic goal to achieve, nitrites are everywhere when you look for them, and even then you may find unexpected routes for nitrosamine formation. Finding a test method that is capable of accurately measuring the level of nitrite, in the presence of all of the excipients, to the levels that would be necessary, would also be a huge task.
I forgot to say, you can pretty easily calculate a nitrite level, if you so wish.
If your nitrosamine of concern is NDMA, then you know the permitted daily limit in ng, the molecular weight of the nitrosamine, the molecular weight of the nitrite ion and the stoichiometry of the reaction to form the nitrosamine, and so a quick calculation will give you the weight of nitrite.
Combine that with the weight of your excipients and the posology of your product, and you will be able to calculate the required maximum level of nitrite within your placebo per dose.
This is assuming a 100% reaction rate, which is unlikely to be realistic. Depending on the format of your product (solid, liquid, suspension etc.) you can apply rough correction factors, I think I have seen 15-20% conversion for solid dose tablets as an example - but these will depend upon the conditions in your manufacturing process.
If you then want to be able to apply skip testing on release then you’ll need to apply a 30% max of that value, and ultimately to be low enough to avoid release testing at all then this becomes 10%.
@MarkS First of all, I would like to thank you for your valuable opinion and discussion, as mentioned previousely, i supposed that NDMA is the Nitrosamine expected, based in your ideas, we will analze the API first to see the Nitroseamine content, analyze the Nitrite content of the placebo (total nitrite), then the finished product manfactured from this API and excipient (placebo) will be analyzed for NDMA intially (zero time) and at the end of the shelf life, this will be our strategy to apply your idea. thanks.
