Thank you for the clarification, @Alaaelkazak. In your case, 12.8 ng of nitrosamine is contained in DP. If you want to demonstrate less than 10% of AI, the maximum amount is 3.7 ng. Then less than 9.25 ng/g is required for the result of analysis in your calculation.
When we decide the amounts of impurities in DP, we consider the total amount of 400mg as 100mg, API total amounts. Then, the actual analysis result of 32 ng/g will be converted to “128 ng/g”. “128ng/g” is 34.59% of the 370 ppb and beyond 10% of AI. “37 ng/g” in tablet (or in 100mg API) is the maximum.
Most of FDA laboratory results reported as microgram/tablets. So actual limit per day can be calculated by multiplying microgram/tablets x no.of tablets administered per day based on max. daily dose
If I have fixed dose combination product containing two API’s and each API having individual nitrosamine formation possibilities , in this case how total impurities can be calculated for US submission.
As per US FDA guidance if more than one
of the nitrosamine impurities identified, a recommended limit for total impurities is not more than 26.5 ng/day which is very conservative as compared to EMEA and without clarity how MDD should be calculated (Is it summation of two API MDD ?)
I agree with your context
If more than one N-nitrosamine is included on the specification, the total risk level calculated for all identified N-nitrosamines should
not exceed 1 in 100,000. This could be achieved for example by the following specifications: each individual N-nitrosamine should be
below its own acceptable limit and the following equation also should be satisfied: [(Imp 1 level / Imp 1 limit) + (Imp 2 level / Imp 2
limit) + etc…] x 100% ≤ 100%
Do you think it is suitable.
This is the source:
If more than one N-nitrosamine is included on the specification, the contribution of each N-nitrosamine relative to its individual acceptable limit
is taken into account and summed up to a total % of expected N-nitrosamine control limits.
I think this also a great example for limit calculation of DP:
Thanks. This is practical approach accepted by EMEA
However as per US FDA if more than one
of the nitrosamine impurities identified and the total quantity of nitrosamine impurities exceeds 26.5 ng/day (the AI for the most potent nitrosamines) based on
the maximum daily dose (MDD), the manufacturer should contact the Agency for evaluation.
For drug products with an MDD of less than 880 mg/day, a recommended limit for total
nitrosamines of 0.03 ppm is not more than 26.5 ng/day and is considered acceptable. For drug
products with an MDD above 880 mg/day, the limit for total nitrosamines should be adjusted so
as not to exceed the recommended limit of 26.5 ng/day. However MDD calculation in case of fixed combination drug product not clarified.
I want to guidance on MDD.
Suppose My product having multiple strength (10, 25, 50, 75, 100 & 150 mg) with does proportionate formulation and MDD is 300mg.
My drug substance related nitrosamine limit is having 37 ng/day.
Considering MDD 37 ng/day and MDD the limit in ppm will be 0.12 ppm.
However considering individual strength MDD (as per label/SmpC) the limits in ppm for this impurity will be different for each strength, however limits ng/day will be same.
10 mg is having daily allowable tablets is 5, hence can we consider MDD 50 mg for strength 10 mg and calculated limit in ppm is 0.74 ppm
25 mg is having daily allowable tablets is 4, hence can we consider MDD 100 mg for strength 25 mg and calculated limit in ppm is 0.37 ppm
100 mg is having daily allowable tablets is 2, hence can we consider MDD 200 mg for strength 100 mg and calculated limit in ppm is 0.185 ppm
150 mg is having daily allowable tablets is 2, hence can we consider MDD 300 mg for strength 150 mg and calculated limit in ppm is 0.12 ppm
As per above mentioned approach can we justify the limits??
Thank you for asking me, @Yuvraj. I’m not sure I can answer correctly. If a patient takes five of 10 mg tablets alone at most at any time, 0.74 ppm is justified. If a patient takes tablets with multiple strengths to 300 mg, you should consider the MDD as 300 mg.
And EMA Q&A mentioned that if a product is available in multiple strengths of the same dosage form with the same risk factors applicable to each, then testing could be rationalised by testing only the worst-case scenario strength and the worst-case approach should be justified by the MAH on a case-by-case basis. You may consider the 30 tablets of 10 mg as the worst case here as well because the amount of nitrosating agents will be the maximum for NDSRIs.
If you need further help, do not hesitate to ask me.
Thanks for your valuable guidance, however as per EMA Q&A it is applicable to testing of only worst case scenario strength and other batches will be not tested. If we are tested all strength batches what would be the approach for considering MDD.
According EMA Q&A
“The conversion to a specification limit in ppm for a particular medicinal product is calculated by dividing the respective above limit (ng) by the maximum daily dose (mg) of a given product as reflected in the SmPC.
The maximum daily dose is defined in line with the definition of the product strength in the Guideline on the SmPC.”
So if you have different SmPC for each dose than you can established diferent limits for each dose, but if have only one SmPC than limit is the same for each dose.
Weight Drug: 50 mg
MDD API: 10 mg
10 mg of API per 50 mg of drug
Possible present nitrosamine in the API: NDMA
AI limit NDMA: 96 ng/day
Max amount NDMA present in the API:
96 ng/day / 10 mg/day = 9.6 ng of NDMA / 1 mg of API =9.6 ppm (of NDMA)
Max amount NDMA present in the Drug:
96 ng/day / 50 mg/day = 1.92 ng of NDMA / 1 mg of Drug = 1.92 ppm (of NDMA)
1.92 ng of NDMA / 1mg of Drug x (50 mg of Drug / 10 mg of API) = 9.6 ng of NDMA / 1mg of API
This means that the total amount of NDMA present in the pharmaceutical product may not be higher than 9.6 ppm calculated by API and 1.92 ppm calculated by Drug. It is just the difference of expression and the limit is same (96 ng/day). When conducting experiments, the preparation of samples is carried out with drugs. The results of the analysis need to be converted by the ratio of API and Drug.
It would be of great help if someone could share experience with limit calculation of nitrosamine impurity in finished products, liquid forms for topical administration. I understand the general principle, the ppm limit by dividing the AI (ng/day) / MDD (mg). I also do understand that the MDD refers to the API (mg).
Is the same principle applicable for the topical liquid forms as for oral solid forms? I am asking that because MDD of the product is rather big, more than 5 grams, and API in the product is in relatively small quantities.
What if the nitrosamine impurity source in this product is not API, but excipients. Does it matter for limit derivation in final product? Do I still use API MDD same as in solid forms?
It would also be great if there was an EU (or any other) relevant reference for that.
If someone has any advice on this thank you !
To the best of my knowledge, there is no specific guideline for excipients.
It is always the AI (ng/day) of the nitrosamine which drives everything.
If a nitrosamine may arise from an excipient or its impuritiy (e.g. Trolamine contains up to 0.5% w/w (5000 ppm) of diethanolamine), you should consider the MDD of the excipient derived from the MDD of the drug product.
Only in this way you could define a limit (in ppm) respect to the excipient and compare, if necessary, the amount in the excipient itself with the amount in the drug product. In this case the MDD of the API may be useful only to calculate the MDD of the drug product.
I hope I answered your question
@paliog thank you very much for the input!
using the ‘MDD’ of the excipient (according to the MDD of drug product) definitely crossed my mind and is doable and logical.
Although, there is no mention of such operation anywhere in EU guidelines. I even tried to consult FDA guidelines, but with the same result.
You are right. Only the EMA Q&A (page 23) quickly mentioned the excipients, without further indications.
“Testing of raw materials (e.g. excipients) should also be considered if these are potential sources of nitrosamine impurities.”
But if you test an excipient, you also need an acceptance limit. You may calculate a limit in ppm on the xcipient (as suggested before) or take the raw result (ppm) and follow the reverse route to calculate the daily intake in ng/day.
Both routes are valid.
The reason because excipients are not mentioned in the guidelines is due to the fact that very often they are precursors of nitrosamine formation, due to nitrite or peroxides.
@Wolffi any thoughts on this?
Thoughts yes, solutions unfortunately not.
Already, I once had the case where an excipient in a liquid topical dosage form was a hypothetical source of nitrosamine and no MDD could be defined from the literature. In this case, and in the absence of guidelines on excipients, I used the logical conclusion described by @paliog and theoretically calculated the MDD based on that of the drug product. Since the potentially resulting compound according to CPCA resulted in an AI of 1500 ng/day and did not appear to be a “real” nitrosamine, this was enough for me to argue in the risk assessment.
However, it is definitely a very interesting topic, as an MDD of f.e. 40 g may be reached with topical applications. Unfortunately, there is still no separation of oral and topical dosage forms with regard to criticality or limit values.