MS Method Development Criterias?

Confirmatory Testing & Analytical Challenges
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Posting in behalf of one of our community members!

We are currently working on a product containing nortriptyline, and we are in the process of developing/validating a quantification method for N-nitroso-nortriptyline (NNNT).

I would greatly appreciate your input on the following topics:

1. Contribution of the analytical method to nitrosamine formation

  • How to assess whether the quantification method itself may promote in situ NNNT formation during sample preparation or analysis
  • Practical strategies to mitigate or eliminate this risk (e.g., control of pH, temperature, nitrite sources, use of scavengers, etc.)

2. Approaches to justify NNNT increase over time

  • Scientific and regulatory approaches to support that NNNT levels may inherently increase over time in the product
  • How to demonstrate that this increase may not be fully controllable despite appropriate formulation and manufacturing controls
  • Strategies to justify and set a stability limit/specification that appropriately reflects this behavior

Your experience and perspective on these points would be extremely valuable for our assessment and development strategy.

Thank you very much in advance for your support.

Kindest regards,

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  1. I’ve heard of using approx. 1% pyrrolidine or 1.5% ascorbic acid in the sample prep. Do some solution stability with and without these & see if there is a difference. I’ve actively used ascorbic acid. Certainly, there is a lot of info about sonication, etc. promoting formation.
  2. It’s well understood that many NDSRIs increase over time due to the slow solid state reaction. Long term, regulatory bodies will be expecting demonstration of control in a written control strategy. One needs to create a stability regression with a large enough body of data to exhibit this control. Understanding and defining the CQAs will create the active end both this control. For example, higher nitrite concentrations leads to quicker nitrosation.
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