Dr. Berardi published a new paper comparing the best-case scenario with the worst-case scenario to evaluate the impact of excipient change on nitrosamine formation. We may avoid the generation of NDSRIs without adding antioxidants in DP manufacturing.
And supplementary materials help us evaluate the impact of excipient change through a spreadsheet. It’s excellent!!
Just a question, we are reviewing the Excell worksheet of the paper published by Berardi, Jaspers and Dickhoff, and some of the tricks not explained in the topic “Lactose, Nitrosamine Risk?”, like how conversion factor should be applied, was very approached and well explained.
But a question that remain for me is if we use the rationale presented by Dr. Urquhart, I mean using the same example presented for him, the nitrosamine amount calculated in the Excell is not the same with the example. Is there another interpretation that we need considerer in this case?
And another doubt is why estimated weight of nitrite was multiplied by 6, if in the calculation we are already considering the maximum dosage of 300 mg? I mean we should multiply by 6 if we are using only one dosage e.g 50 mg? In the last column of the example, the title is “weight in a single dose”, but I just reach theses values using 300 mg in the calculation.
I’m right, or there is something hidden that I’m let getting away?
I will appreciate your help nitrosamines exchange community.
Thank you for asking. First, I want to focus on Dr. Urquhart’s presentation held two years ago. He explained the Conversion Factor as 1% for Dry formulation. The value of 1% is from EFPIA Workflow ver.1. On the other hand, Dr. Berardi used 13% for direct compression and 29% for wet granulation as CF. These values are from Dr. Moser’s paper.
Second, the daily dose of 300 mg in Dr. Urquhart’s slide means the amount of API. Though it may confuse you, 300 mg is the same as the weight of a 50 mg tablet. Six of 50 mg tablets will be taken at most in a day.
Dear @Yosukemino, many thanks for your reply. But only two more questions… If one tablet of 50 mg weight 300 mg, why the API was approached like 70 mg? And another question, I must to considerer the maximum daily dosage for a medicine or the weight of one tablet in the calculation?
Thank you @Yosukemino for your continuous support and for sharing these essential resources.
I’ve been using the Excel tool for Nitrosamine calculation, and I noticed that the tool only takes into account percentage of conversion for DC and WG formulations for secondary amines APIs in salt and base form. I’m currently working on a tertiary amine APIs formulations and was wondering if you have any ideas on percentage conversion for this specific category.
Thank you for asking. As far as I know, 13% of the Conversion Factor for DG and 29% for WG are from Moser’s publication. In the same publication, tertiary amine shows a conversion of 0.53% for DG and 0.24% for WG. But you should carefully apply the Conversion Factor to your products because the feature of tertiary amine depends on its structure.
I agree with you, @Naiffer_Host. According to the paper, the conversion rate significantly depends on the conditions and structure of amines. And Swiss medic demonstrated the step 1 risk assessment by the pharmaceutical companies was sometimes unreliable.
Especially for high-risk nitrosamines such as Category 1 or 2, confirmatory testing may be required.
Thank you @Yosukemino and @Naiffer_Host for your response. Could you recommend any specific references that provide detailed information on the conditions and structural characteristics of terstiary amines APIs that could lead to the formation of NDSRIs and should therefore be taken into account in the Risk Evaluation ?