Validation

[amirchem]

Hello everyone
I hope you could answer me the following question:
What steps should be taken to properly validate the method for quantifying impurities as a percent of the peak of active substance in drug product?
So far I have only validated methods utilizing external standards.

Thank you

[Sallybeetle]

In past jobs, I have:
1. Determined a Relative Response Factor (rrf) at specification level of identified impurity: Impurity Response/Main Analyte Response*Impurity Concentration/Main Analyte Concentration = Decimal Number. This can be used in method calculations to convert observed Impurity response to concentration without use of an external impurity standard using main analyte standard response and concentration.

2. If must use Area Percent Specification, then can use RRF determination during validation, e.g. determine what concentration of impurity produces the upper specification Area%. Then, this can be correlated to the different requirements of validation, e.g. accuracy, linearity, etc. For example, Accuracy for an impurity is generally determined at three different levels spanning 50% - 120% of specification. Since we know what concentration produces 100% of specification, we can formulate the Accuracy solutions.

For the Impurity validation, we always included the Main Analyte Peak at 100% of test concentration, e.g. accuracy, linearity, etc. This is important, since the Main Analyte will always be present when the product is tested for impurities.

Generally, we always did all validation tests required for the Main Analyte, except for forced degradation studies.

Hope this helps.

[jLeonelli]

Do you perform a main analyte linearity (LOQ - 100% conc) for UNKNOWN impurities that are calculated from the main analyte (within the same solution) and reported as normalized peak area percentage?

[Sallybeetle]

If the product exhibited unidentified impurity peaks, then sometimes we would perform precision at the main analyte LOQ concentration. And, sometimes we would perform an Accuracy/Recovery experiment at main analyte LOQ, e.g. using solution with main analyte at LOQ calculated against an external standard at the higher test concentration. You could do a linearity from 50 - 120% of impurity specification concentration using the main analyte, especially if none of the impurities have been identified.

[jLeonelli]

Thanks for your response! May I ask what setting you are in? I am in an FDA regulated, GMP compliant pharmaceutical lab.

I have 2 known impurities and usually 3 unknown impurities. For the 2 knowns, I have validated specificity, linearity, accuracy&precision, ruggedness, robstness and LOD/LOQ. We are now involved in the method transfer and the recieving department is requesting I perform a linearity of the main analyte which is used to calculate the unknowns. We use a stock solution for impurity analysis therefore my linearity would have to be from 0.005 - 5mg/mL of the main analyte. I thought because we are not using any external standard of the main analyte for calculation linearity was unnecessary. Agree or no?

Thanks again!

[Sallybeetle]

I am in a cGMP regulated laboratory.

Your dilemma is very interesting.

I would ask the requesting departement what they are requiring. I would think that the validation of the known impurities done thus far would be quite enough. However, if they are requesting linearity of the main analyte, I would assume that it would either be linearity of main analyte at 80 - 120% of main analyte test concentration OR linearity of main analyte concentrations similar to that performed for the 2 known impurities.

Previously, I worked in a contract laboratory with many clients, and I do not remember ever having to do linearity from LOQ to 120% main analyte test concentration.

Please this post with their answer.

[JNF]

Hi Sallybeetle,

In my lab we do linearity of the main compound at the concentration level of the unknowns (acceptance criteria levels) to prove that the main compound can be used as external standard at that level: We do inject during regular runs/analysis a standard of the main compound at the same concentration level as the max limit for the unknown (or known but not certified) impurities.
Ciao
JNF

[Sallybeetle]

I did some more research on the impurities validation question and I found an ICH Q2B document (Validation of Analytical Procedures: Methodology) online that indicates the following under the Range section:

"The specified range is normally derived from linearity studies and depends on the intended application of the procedure....

- for the determination of an impurity: from the reporting level of an impurity1 to 120% of the specification; for impurities known to be unusually potent or to produce toxic or unexpected pharmacological effects, the detection/quantitation limit should be commensurate with the level at which the impurities must be controlled....

Note: for validation of impurity test procedures carried out during development, it may be necessary to consider the range around a suggested (probable) limit;...

- if assay and purity are performed together as one test and only a 100% standard is used, linearity should cover the range from the reporting level of the impurities1 to 120% of the assay specification;..."