Abstract
With the finalization of the ICH Q14 Analytical Procedure Development guideline, how to apply enhanced approaches (such as analytical quality by design (AQbD)) to develop an analytical procedure, and to propose Established Conditions (ECs) and corresponding reporting categories, is increasingly being discussed. To gain practical experience in applying an enhanced approach for method development and identifying ECs, we developed, validated, and implemented an analytical procedure for a nitrosamine drug substance-related impurity (NDSRI). Here, as an example of the application of Q12 Lifecycle Management guideline principles in regards to analytical procedures, we briefly elaborate how: 1) the principles documented in the ICH Q14 guideline for analytical procedure development were applied, with the focus on identifying an Analytical Target Profile (ATP), knowledge management and risk assessment; 2) analytical procedure robustness according to the recommendations in ICH Q2(R2) Validation of Analytical Procedure guideline and Q14, were evaluated; and 3) mass spectrometry ECs and associated proposed reporting categories were proposed.
Community members, greetings!
I frequently get asked about the analytical attributes a nitrosamine testing method should carry… This week’s publication from FDA is a fantastic case on the exceptional use of ICHQ14, ICH Q2(R2), and USP <1220>
Naiffer thank you for the post. Very valuable information for analytical scientists. But, a little disappointment over the recovery limits of 85-115%.This criteria too stringent to accept.
pls provide the link or completed pdf document for thorough understanding of the FDA publication.
thanks a lot Naiffer for the sharing information.
I agree with RCREDDYP.
The limits are quite stringent for LC or GC/MS analysis.
I would expect something like 70-130% for QL level and 80-120% for all the other levels.
Hi, this article can we consider for future validations or already done validations?
USFDA will make it as a guideline soon? if it so for example a method with an LC-MS instrument is unable to provide recovery in the range of 85-115% but in giving in the range of 70-130% then that validation not acceptable to FDA?
Can anybody clarify?
With some nitrosamines in complex matrix, recovery of 85-115% is very difficult, if not impossible. The paper is just a recommendation regarding what you should strife for, it is not a rule. If you are unable to meet the above recovery range, you should provide justificaiton and your efforts. But remember that when it comes to generics, there is always a comparison done. So, if one of the generic sponsors has met the criteria, you may get a deficiency.
Naifer, I was about to ask you about this when I saw your wonderful summary. I dont see this to be free online. I am being asked to pay $39 etc. Could you share the link to the free version that you mentioned.
The article in question discusses a mass spectrometry analytical method for detecting N-nitrosobumetanide and addresses the associated detection challenges.
Here are some key points:
Using a risk-based approach, the authors found UV detectors to be inadequate, leading to the adoption of mass spectrometry. This decision is well-justified given its enhanced sensitivity and ability to handle sodium adducts.
The method’s flexibility is a significant strength. It incorporates robust control strategies, such as the internal standard normalized matrix effect (IS-nME) and the quantifier/qualifier ratio. This flexibility allows for adaptation and revalidation if necessary, and the fact that adjustments to mass spectrometer parameters do not affect performance further underscores its robustness.
The method effectively demonstrates how to apply ICH Q12, Q14, and Q2(R2) guidelines in practice. This highlights the overall relevance of the work and its objective by applying these guidelines in the challenging area of nitrosamines.
Finally, the authors distinguish between performance-based and parameter-based approaches:
Parameter-based approaches focus on specific method parameters to ensure reliability, while performance-based approaches assess overall method performance under varied conditions, allowing for greater flexibility.
@Koumine I want to bring to your attention that the extract you are showing is not part of the USP <1469> chapter. The tables were part of the original proposal in Pharmacopeial Forum, but got deleted. Also, the amount of research done in the nitrosamines testing space has evolved from the original publication.
When it comes to analytical attributes I refer to the collaborative study conducted by FDA with other agencies on the testing of Nitrosamines.
I think your suggestion is very good.
The current information is mainly in the specification part,
but there is relatively little information on the analysis method part.
I hope everyone can share more relevant information.
When I analyzes NDSRIs of API,
the analytical method provided by the API manufacturer does not evaluate the recovery of spiked QC sample during the running.
So, when the equipment I used is different with the Vender of API (the parameters of MSMS are different) ),
I cannot confirm whether the analytical performance of this method can be reproduced.
I would like to know, in the formal LCMSMS analysis,
which analytical performance parameters need to be determined during the sample analysis?
