Method Equivalence criteria

[George T]

We are proposing a Method equivalence study suggestions, advice and input is greatly appreciated.

Our Lab hase developed and validated a HPLC assay method for the determination of methylparaben and propylparaben raw material. The USP method for each of these (Methyparaben and Propylparaben) is a titration involving the determination of the second inflection point for the determination of the endpoint.

Question:
As per the USP we must demonstrate that the alternate method is equivalent to or better than the USP method (the regulatory method). Does anyone have any suggestions on how to do this or comments on my proposed plan for demonstrating equivalence?

Proposed Plan:
From one lot of raw material prepare n= 6 replicate and analyze with the current USP monograph assay method.
From the same lot of material prepare n= 6 replicate and analyze with the alternate validated HPLC assay method.

Compare the averages, SD and %RSD for each set with each method.

The %RSD for both methods should be NMT 2.0% and the means of the averages for each method should not differ by more than 2.0%.

Any suggestions or comments would be appreciated.

Kindly,

[Dan]

George,

I think that you have already answered your own question/request. I would add/clarify two points:

The USP does allow for use of methods that are improvements over their own currently published method. I think that this is discussed in the Notices section of the USP (I may have remembered the wrong section). One reason for using a different method is for improvements in technology such as what you have done with your method. You may want to mention something about this in your protocol for your method comparison (i.e. state why you are using your alternate method rather than the USP one). Just one or two sentences would suffice.

I think that your plan for acceptance criteria is a good one. What I have done for the acceptance criteria for the comparison of methods is to use the same acceptance criteria for the intermediate precision data for the method validation. Essentially, you are doing the same type of data comparisons (and experiments) for intermediate precision and method comparison.

Oh, one last recommendation: state exactly how you will calculate the difference between method means. You mention using a difference of 2.0%. Is that an absolute difference? or a relative difference? Also, if it is a relative difference, you need to be clear on how the difference is calculated. You could use:

(A - B)/B X 100%

where A is your method mean and B is the mean from the USP method.

Regards,
Dan

[George T]

Dan,
Thank you very much for your reply. I just wanted to be sure I was on the right track, I have been involved in development and validation for quite a while but havent done an equivalence study in quite some time.
I was considering using a T-test to additionally show equivalence but I don't feel it is necessary.
Yes, I need to clarify absolute or relative difference I usually include an equations portion in my protocols to elucidate how the calculation should be performed and to eliminate any confusion.

Many thanks again for your input and clarifications, it is greatly appreciated.

Kindly,
George