Calculation of Maximum Daily Dose (MDD) for 2 Strengths

Limits of Nitrosamines
1
Gemini said

Hello everyone,

I hope all is well. I have a question regarding nitrosamine limits and analysis. I would be very grateful if you could provide guidance on the following matter.

In a fixed-dose combination product containing two active pharmaceutical ingredients (APIs) and two strengths, how should I determine the nitrosamine limits? Assuming the risk of nitrosamine formation originates from API B, the product details are as follows:

Drug Product No Amount of API A (MDD: 5mg/day) Amount of API B (MDD: 60 mg/day)
1 1 mg 17 mg
2 2.5 mg 20 mg

Product 1: Based on the MDD of API B, a maximum of 3 tablets can be taken daily.

  • Product 2: Based on the MDD of API A, a maximum of 2 tablets can be taken daily.

In this case:

  1. Should I use an MDD of 51 mg/day for Product 1?

  2. Should I use an MDD of 40 mg/day for Product 2?
    Or should I apply a universal MDD of 60 mg/day for all calculations?

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2

Dear Hasan,

If the posology is absolutely clear that MDD of API restricts use of this drug product formulation to two tablets per day, that is the maximum dosing of APIs you need to consider (5 mg of API A + 40 mg of API B)

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3

i agree with Javier,

and as the risk of nitrosamine is due to B, the MDD for the calculation of the spec.limit, which you should use, is : 40mg/day.

thank you

Christos

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4

Thank you for your answers,

Is my calculation for the NDMA limit below correct in this case?

For Product 1, MDD of API B = 51 mg/day

NDMA limit (ppm) = (96 ng/day) / (51 mg/day) = 1.88 ppm

For Product 2, MDD of API B = 40 mg/day

NDMA limit (ppm) = (96 ng/day) / (40 mg/day) = 2.4 ppm

In this scenario, two different limits emerge for products with two different dosages. Is this situation acceptable?

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5

You have to add universal MDD in this case.

If you have to go with alternate option you need to communicate with respective regulatory agencies.

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6

Dear Hasan,

of course the scenario of the two different limits is acceptable, as the maximum total daily quantity of NDMA in each product which will be taken from the patient would be the same, 96ng/day:

1.88x51 (3 tablets of product 1)=99

2.4 x 40 (t tablets of product 2)=96

what it is important is that the method should be validated at the lower level (10% of the 1.88ppm or 0.19ppm) and the range should cover also the higher limit (2.4ppm)

thanks

Christos

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