It may be a repeat question, however any assist in understanding the following is appreciated.
• Typically (excipient) samples are tested for presence of Nitrate and Nitrite or for the following 8 compounds potential nitrosamine contamination? -
NDMA, NDEA, NDBA, NDPA, NDIPA, NEIPA, NMBA, and NMPA.
• What LOD is acceptable for these compounds?
Thank you.
Premal
Dear Sir,
What LOD is acceptable for these compounds?
We can keep LOD as 10 %, Typical example is provided below for reference:
| XYZ API MDD (in mg): | 500 | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Sr. No | Name of N-Nitrosamine | (Impurity Code) Provided in guideline of | AI (ng/day) | Limit | LOD in ppm | LOQ in ppm | LOD in ppb | LOQ in ppb | ||||
| EMA | CA | US | BZ | in ppm | in ppb | 10% | 30% | 10% | 30% | |||
| 1 | N-Nitrosodiisopropylamine, | DIPNA | NDIPA | NDIPA | DIPNA | 26.5 | 0.053 | 53.000 | 0.005 | 0.016 | 5.300 | 15.900 |
| 2 | N-Nitrosoethylisopropylamine / N-Nitrosoisopropylethylamine (US) | EIPNA | NEIPA | NIPEA | EIPNA | 26.5 | 0.053 | 53.000 | 0.005 | 0.016 | 5.300 | 15.900 |
| 3 | N-Nitroso-di-n-butylamine | NDBA | NDBA | NDBA | 26.5 | 0.053 | 53.000 | 0.005 | 0.016 | 5.300 | 15.900 | |
| 4 | N-Nitrosodiethylamine | NDEA | NDEA | NDEA | NDEA | 26.5 | 0.053 | 53.000 | 0.005 | 0.016 | 5.300 | 15.900 |
| 5 | N-Nitrosodipropylamine | NDPA | NDPA | NDPA | 26.5 | 0.053 | 53.000 | 0.005 | 0.016 | 5.300 | 15.900 | |
| 6 | N-Nitroso-N-methylaniline / phenylmethylnitrosamine | NMPA | NMPA | 34.3 | 0.069 | 68.600 | 0.007 | 0.021 | 6.860 | 20.580 | ||
| 7 | N-Nitrosodimethylamine | NDMA | NDMA | NDMA | NDMA | 96.0 | 0.192 | 192.000 | 0.019 | 0.058 | 19.200 | 57.600 |
| 8 | N-Nitroso-N-methyl-4-aminobutyric acid / carboxypropylmethylnitrosamine | NMBA | NMBA | NMBA | NMBA | 96.0 | 0.192 | 192.000 | 0.019 | 0.058 | 19.200 | 57.600 |
There is no evidence of presence of N-Nitrosamines within excipients themselves and nor is there an effective mechanism for formation. I chair the IPEC taskforce in Europe and IPEC are currently seeking to update their position paper around this matter. Although in draft form the following statement is made:
Nitrosamines in Excipients
To date, only one excipient has been known to contain a nitrosamine: trolamine (triethanolamine) with the nitrosamine impurity N-nitrosodiethanolamine. In the European Pharmacopeia, the limit for N-nitrosodiethanolamine is established at 24 ppb.17 While this particular excipient may contain a nitrosamine impurity, this vulnerability is known and understood. The risk of an excipient introducing a nitrosamine directly to a drug product is not currently envisaged for any other product
Thank you, Andy. This is great news. However, more and more finished drug product manufacturers are seeking information on NDSRI’s level from excipient manufacturers by way of a statement specifically indicating compliance with FDA guideline on NDSRIs and completed 2023 IPEC-Federation Nitrosamine Risk Assessment Template for excipients.
In addition to the Andy’s response.
Excipients are more concerned for “nitrites and nitrates” levels, if these precursors are well controlled, it should be sufficient minimize risk of nitrosamine drug substance related impurities in drug products. In my view, this should be the expectation from drug product manufacturer’s on Excipient suppliers/Mfrs.
However, Excipients also be verified for possible formation of nitrosamines based on the process, but there is no much information available on the topic : Excipients are the direct source of NSAs, as carryoversin into DPs?.
Generally, it is very, very improbable that an excipient may contain nitrosamines, apart from the example of Trolamine (Ph.Eur), already mentioned by Andrew:
However, do not forget that many old products were formulated with diethanolamine (USP monograph).
After the recent CHMP SWP (EMA) opinion on diethanolamine as excipient:
CHMP SWP opinion on diethanolamine and coconut oil diethanolamine condensate as excipients
nearly all products containing diethanolamine (in Europe) were reformulated with Trolamine or Tromethamine (primary amine), but diethanolamine may be still present in other products around the world.
Moreover, USP monograph on diethanolamine has not been updated in the last years.
Current monograph does not contain any limit on N-nitrosodiethanolamine!
So, if any company has any product containing diethanolamine, it should reformulate the product and (in the meantime) test N-nitrosodiethanolamine by HPLC/MS (or with the Ph.Eur. method for Trolamine).
The issue is for nitrite and nitrate, most importantly nitrite. Although the questioner did not specifically ask the following question I would be interested in any input. What should be the level of detection for nitrites in excipients.
Manufacturers of excipients are beginning to offer “low nitrite” materials and the CoA’s are showing Not detected but there is no standardisation as to test procedures or LOD/LOQ.
So one supplier claims “nitrite free” with an LOD at the ppm level but 1 ppm is 1000ppb which is easily enough to cuase problems in the DP
Very good point GENERAPHARM. Trying to screen some of our excipients which are used in our production line, we understand that the common methods are used for the determination of majority of them have low sensitivity (1ppm or even more).
Only for MCC, was available a method with a LoD less than 100ppb.
This is the holy grail in terms of trying to predict how a formulation might behave from a nitrosamine formation perspective (taking out manufacturing processes from the equation).
There is no one simple answer currently that I am aware of - no one methodology that will work with all raw materials and down to a ppb level. There have been numerous different methods published over the past couple of years looking into the different analytical techniques and methods of detection, some of them claiming to have very low LOD/LOQ levels, but these have frequently been for only one particular raw material. The sample prep and level of sensitivity may well not be there for other raw materials. Add in to this the fact that sample prep can seemingly have a big impact upon the results generated, interference from chloride in some test methodologies etc. and it can be a very long and laborious process trying to develop the best method for all the raw materials that may be utilised within a single formulation, let alone across a portfolio of products within a company.
A suppliers claim of low nitrite I take with a pinch of salt until proven, especially as it is not always clear what it is low compared to. We don’t have established levels of low, and as pointed out 1ppm is still 1000ppb.
So, what is considered acceptable limit for Nitrate and Nitrite in excipient? <1.0 ppm?
Depends on the acceptable intake of the nitrosamine you want to control as well as your specific formulation.
There is no exact value that will work for all cases. Btw nitrate is not the topic but nitrite. Unless you see any reduction process that may make it relevant.