Hello everyone 
,
I have just recently started working in pharma field.
I’m currently going through many guidelines about nitrosoamine’s.
The approach given in the ANVISA and EMA/409815/2020 Rev.8 about setting limit for more than 2 nitrosoamine is given and i;m not able to get hold of the same.
If anyone of you could help me in understanding the same it would be of great help.
Thanking you all in advance 
emphasized text
@PauloEliandro @AmandaGuiraldelli any guidance on this post? Thx
Hi @Anu
the limit recommended to control more than 1 nitrosamines is the following: the sum of the nitrosamines should not exceed 26.5ng/day.
The example you added in your post showed 3 options where NDMA and NDEA were identified during risk assessment.
the limit for the sum should be 26.5ng/day / 300mg = 88ppb
option 1 says that you should establish a unique limit for the sum of NDEA and NDMA (88ppb)
option 2 and 3: you can establish limits for the individual nitrosamines but the sum of them should not exceed 88ppb
Please let me know if there is some specific question you would like to discuss.
Best,
Amanda
@AmandaGuiraldelli
Hi Amanda,
As you said that, “option 2 and 3: you can establish limits for the individual nitrosamines but the sum of them should not exceed 88ppb”
However, as per guidance, for option 2 thers is no sum of total impurities. Actually it is individual nitrosamines establish limit only based on % ratio of Nitrosamines.
For option 3, sum of total impurities based on % of nitrosamines, sum should not cross more than 100%.
Please correct me, if i am wrong.
Thank’s
Nilesh
Thank you replying.
But i didn’t really understood.
I’m still not able to get the ratio approach.
88ppb is about NDEA, so what about NDMA?
Sorry to trouble you, but could you please put some light on the same.
Thank you in advance. :smiley
In the FDA guidance you will find a recommendation that for cases where more than one nitrosamine is identified during risk assessment, the sum of these nitrosamines should not exceed 26.5ng/day.
@AmandaGuiraldelli
You are right as per USFDA guidance, the sum of these nitrosamines should not exceed 26.5ng/day, moreover 26.5ng/day is used as default option, if new nitrosamine is detected
@Anu @AmandaGuiraldelli
I think, Anu wants to understand, as per EMA guidance total Nitrosamine limit.
as per EMA default option is
As per EMA total nitrosamine shown in below table
If your product contains 2 Nitrosamine (i.e. NDMA & NDEA) & your maximum dose is 300 mg
then Individual limit in ppm, with respect to AI limit, will be
NDEA: 26.5 ng/day / 300 mg/day= 88 ppb = most potent N-nitrosamine
NDMA: 96.0 ng/day / 300 mg/day= 320 ppb
As per Option 1, for total Nitrosamine is need to consider the most potent N-nitrosamine limit (i.e.88 ppb), Your batch data is showing in table that NDMA 38ppb & NDEA is 44ppb (total will be 82ppb) which meets the option 1
As per option 2 fixed, for Fixed approach (e.g.20:80ratio)
Total Nitrosamine is not require, need to consider the individual limit based on % ratio
Your batch data is showing in table that NDMA 38ppb & NDEA is 44ppb, which meets the option 2 fixed approach
As per option 2 flexible, Flexible approach, there total impurities limit should not cross the 100%
Need to calculate the each % of limit based on batch data & Each AI limit. Then total % of Nitrosamine impurities should not cross more than 100%
Total NNA impurities will be NMDA (=38/320 * 100 = 12%) + NDEA (=44/88 *100 = 50%)
Total NNA impurities = 12+50 = 62 % (sum is less than 100% only)
@Anu hope you understand…
@AmandaGuiraldelli correct me if something, i interpreted wrongly as per EMA guidance.
Thanks
Nilesh
Hello, I still do not understand the fixed approach according to EMA. How do you know since the beginning that the ratio is 20-80? I understand it is an example, but I do not understand how they come to that ratio. Is it some kind of mean from the real results they obtained? If so, does it mean that within time that ratio can be different (for instance during the shelf-life of the medicinal product)?
