USP tailing spec question

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Can a LC method in which the main peak has a tailing of 2.6 be validated and accepted by FDA?

A little back story. Main compound is a zwitterion while the impurities are not.

Side note: When I think of tailing I envision a long curved broad peak. The 2.6 tailing I see here is more like a CE peak, sharp front portion of peak and sharp back portion, maybe 80° slope. What gives? thx
The method can be validated. You have a non-linear adsorption isotherm of the main component. Reducing the injection volume and/or the concentration of the main component is likely to reduce the tailing factor of the peak.

Do you use a reference solution containing the main component at low concentration for the determination of impurities? The main peak on the chromatogram of this reference solution may be symmetric.

Do you use a solution for SST (to check the peak-resolving ability of the system) containing the main component at 100% level and the impurities at the highest permissible level or around it? You just have to show that the resolution (or the peak-to-valley ratio) for the critical pair of peaks is sufficiently high. The asymmetry of the main peak is of minor importance if the peaks of impurities can be separated from the main peak.
Mike H. wrote:
Can a LC method in which the main peak has a tailing of 2.6 be validated and accepted by FDA?

A little back story. Main compound is a zwitterion while the impurities are not.

Side note: When I think of tailing I envision a long curved broad peak. The 2.6 tailing I see here is more like a CE peak, sharp front portion of peak and sharp back portion, maybe 80° slope. What gives? thx


It's also important to realize that USP and FDA are not one in the same. The FDA generally uses USP guidelines as to what is or isn't acceptable or they use the guidelines in various general chapters because these guidelines are generally agreed upon as a good reference point or a good practice by industry. In terms of chromatography, USP <621> has a set of guidelines and rules that govern how you can modify already published USP methods in the various monographs. In turn, if you are following an already published method from a specific monograph, then you are bound to ensuring you meet the already published acceptance criteria.

On the other hand, there are plenty of non-USP published customer or manufacturer specific methods out there that are also valid for analysis of various molecules and or impurities that may or may not also have a USP published method.

It's important to know that if you are validating your own method you plan to submit to the FDA, you are the one determining what is and isn't acceptable criteria and it is your job to provide sufficiently robust, accurate and precise data to show that the method is adequate for the purpose it plans to serve.

It will be up to you to determine if tailing is or isn't a criteria you need to even require as a suitability requirement, and if it is then you need to determine, per your method and goals, what is and isn't an acceptable value.
In years past, I successfully developed, fully validated, and submitted stability indicating HPLC methods to the FDA for compounds with tailing factors >2. Different gradients, reagents, and LC columns would not budge that stubborn compound to Tf < 2. The FDA accepted the ANADA applications. This was around year 2011.
"TF < 2" is a *suggestion*, not a requirement.
-- Tom Jupille
LC Resources / Separation Science Associates
tjupille@lcresources.com
+ 1 (925) 297-5374
ty
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