Dear All,
As a part of the mitigation strategy, we are all working to control the nitrite levels in excipients.
However in my observation, certain small nitrosamines (NDMA, NDEA, NDBA etc) are also observed in excipients at trace levels.
Has anyone else come across such an observation. If so, is there any literature regarding the same.
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To the best of our knowledge, the only case is N-nitrosodiethanolamine (impurity C), limited at 24 ppb in Trolamine (triethanolamine) monograph.
In which excipient you found nitrosamines? at which level (ppm or ppb) ?
Currently I have found it one of the placebo mixtures. I have ruled out any contamination. I am yet to individually test each excipient in the mix.
(Placebo contains common excipients like MCC, Povidone, Water, Aerosil, Mg stearate, Croscarmellose sodium, IPA, coating material etc)
The levels of NDEA is about 10 ppb. The API has no detectable level of NDEA (LOQ-5 ppb). The problem is that the drug has a high daily dose and the detectable level of NDEA in placebo (and subsequently in tablet) may cause the batches to fail.
In the past we discussed the theorethical risk regarding
4-(nitroso(vinyl)amino)butanoic acid
and N-Nitroso-2-pyrrolidone
from Povidone:
4-(nitroso(vinyl)amino)butanoic acid from Kollidon?
But the presence of NDEA in a placebo is quite strangeā¦
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Does your coating material contain a dye?
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My guess is that triethylamine must be used during excipient synthesis, that might have caused NDEA
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Polymers and dies are indeed a good first focus.
What is IPA and the coating material?
Polyvinylpyrrolidone is synthesized via a radical polymerization process.
Such processes often use amines like triethanolamine to initiate radical polymerization, explaining also why sometimes controls on triethanolamine are required: Reāevaluation of polyvinylpyrrolidone (E 1201) and polyvinylpolypyrrolidone (E 1202) as food additives and extension of use of polyvinylpyrrolidone (E 1201)
I donāt know if it is likely to see triethylamine being used in practice instead.
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We have experienced source of NDBA from one of the excipients, colloidal silicon dioxide. We also evaluated the chances of contamination but the sample, placebo and pure excipient also showing the presence. It could be due to packaging material since there is variation in pure excipient from same pack. We have communicated with the supplier but did not get the firm answer. However, in declaration supplier mentioned NDBA with some number (less that X ppm).
We are still evaluating the reason for getting this impurity. If anyone has more information or same experience, please share to group. Thank you.
Has this sent numerous people scampering off to review their risk assessments?
If there is NDBA present within colloidal silicon dioxide then this could potentially have a massive impact upon a lot of pharmaceutical tablet formulations. But not just pharmaceuticals, it is in lots of food stuffs as well.
Does it depend on the source of the silicon dioxide? Is it precipitated or formed from vapour phase hydrolysis of chlorosilanes?
@Shamkant does the amount seen in the raw material transfer through to the amount seen in the placebo or final product relative to the % w/w in the formulations?
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I believe it should be precipitated based on the data shared.
I donāt know how frequent the use of vapour phase hydrolysis of chlorosilanes for silicium dioxide is for pharmaceutical applications and what catalysts if any are being used in practice, from what I have seen declared for fumed silica, no secondary and tertiary amines.
I do know that high purity colloidal silica is also an important material for the semiconductor industry, driving innovation on the manufacturing. I believe in that context tetra-alkyl orthosilicates are increasingly used as raw material for manufacturing (which is also compatible with colloidal silica EP requirements). Tetra-alkyl orthosilicates can be hydrolysed to SiO2 and alcohol (or at higher temperatures degraded to SiO2 and an ether). The disadvantage is that an alcohol by-product is formed, that needs to be removed, but this process challenge is met in modern manufacturing. So, to minimize temperature, the hydrolysis process is typically performed, and this hydrolysis of tetra-alkyl orthosilicates is typically performed under basic catalysis, for example possibly with the use of dibutylamine (or diethylamine). A basic pH is also required to not end up with a silica gel, but to make colloidal silica.
Such direct use of dibutylamine as process catalyst seems to be compatible with the supplier deciding to test for NDBA, but I do not per se know if the standard processes for semiconductors colloidal silica are also used for pharma sources.
Dibutylamine is one of the patented bases for such processes. (WO/2020/179557 from FUSO CHEMICAL CO., LTD., I donāt know if they also supply colloidal silica for pharma applications, I expect they focus on semiconductors.)
A tetra-alkyl orthosilicate-based process can also use bases which are not amine-based, but the choice of bases also influence the temperature trajectory that is needed to get the particles I imagine.
Shamkant Shimpi, can you confirm that the silica you buy is not fumed silica, but precipitated?
Would you be able to disclose the location of the factory that makes your silica?
Did the < x ppm NDBA supplier reporting mean that x was the detection limit, did they actually see NDBA detection?
Has anyone else here seen declarations of secondary or tertiary amine use during the manufacturing of silica? And was it explicit use mentioning or omitting the group in a statement with what wasnāt used? I have always received a no use, but early on some manufacturers did indeed test for āstandardā nitrosamines.
Indeed good to stay vigilant on mass balances and risk for artefacts.
We have experienced random contamination with NDBA from syringe membrane filters, and this has been previously mentioned on the site by others. It appears that some plastic materials are contaminated, but could not find a reason for it.