Chromatography Forum

My supervisor and I have been discussing this validation question for cGMP test procedures for over the counter pharmaceuticals in the USA. These are fragranced products, and there can sometimes be tiny peaks throughout a chromatogram, visible only when such chromotagrams are greatly zoomed using the data station software.

I've got a question about trace contribution of the product matrix: in this case a tiny peak that is not resolved from the peak of interest. The analyte of interest (the API) is significantly larger than any such response from a product placebo, typically more than 100 times larger or greater.

So the question is a general one: for selectivity, how small of contribution must the product matrix be and still be considered negligible for a cGMP test procedure and its validation? In the modern world of software and zooming, very little is "zero" these days. Thanks, and any official references or guidelines would be great.

Can we define a limit in our SOP, like any peak less than 0.5% of API peak area is insignificant? Thanks.

ICH guidance is 0.05%.

^ assuming peak is an unknown...

For known peaks, you go from area vs. API to w/w%. This means that you can have much larger than 0.05% area and be fine or <0.05% area and fail - it all depends on the relative responses (differences in exticntion coefficients at a given eave length, assuming UV/Vis detection).

Generally speaking, see ICH guidelines Q3B for drug products and Q3A for drug substances.

Report limits, identification threshold and qulification thresholds are all dose dependend, so the answer to your question if NMT 0,05% fits all cases is NO.

As the question concerns OTC products I assume you do not have to consult PGI (potential genotoxic impurities) guidelines.

I'm still not clear: do you mean 0.05% in the product , or not more than 0.05% response of the API ?

I think the question is how small can a peak be to be considered negligble, meaning not reportable. It is dependent on dosage, the minimum reporting threshold requirement is 0.05% of the reported result for a drug product. However there are exceptions, not all methods meet a limit of quantitation of 0.05%. OTC products have to follow the guidelines of toxic impurities, again dose dependent.

I think the question is how small can a peak be to be considered negligble, meaning not reportable. It is dependent on dosage, the minimum reporting threshold requirement is 0.05% of the reported result for a drug product. However there are exceptions, not all methods meet a limit of quantitation of 0.05%. OTC products have to follow the guidelines of toxic impurities, again dose dependent.

Stand corrected there, was stuck in the thinking that OTC products typically was old products not covered by new PGI guidelines.

So, in plain language, if my API is 0.5% in my finished product, then any matrix interference that would calculate as 0.05% of THAT or more, is too much to call insignificant?

Like 0.005 x 0.05% = 0.00025% ? So anything that would calculate as 0.00025% or more in my finished product would be too much to call insignificant or negligible?

Thanks, have not yet found anything in USP/ICH/cGMP that is NOT gray area....

One way is to calculate based on % Area such that (0.05%/100%)*peak area. This will give the peak area equivalent to 0.05% area which can be used as a guide.

One way is to calculate based on % Area such that (0.05%/100%)*peak area. This will give the peak area equivalent to 0.05% area which can be used as a guide.

Wow. 0.0005 or 0.05% of the API peak is pretty small. Welcome to the world of fragranced pharmaceuticals.

I was under the impression that 0.05% was the ICH reporting limit for impurities, not the non-interference/specificity criteria when determining the Assay of a main component in a product. An acceptable non-interference/specificity acceptance criteria I have routinely come accross is as follows:

Any interfering peaks that are within ± 5 % of the retention time of (insert name of component being assayed) are to have peak areas of ≤ 0.5% the mean Std A area or resolution ≥ 2.0.

In this case Std A represents an Assay Standard (for establishing system suitability) with a known concentration representing the nominal concentration of the corresponding component in your sample. Should your "interferring" fragrance peaks be less than 0.5%, they may be considered insignificant.

I was under the impression that 0.05% was the ICH reporting limit for impurities, not the non-interference/specificity criteria when determining the Assay of a main component in a product. An acceptable non-interference/specificity acceptance criteria I have routinely come accross is as follows:

Any interfering peaks that are within ± 5 % of the retention time of (insert name of component being assayed) are to have peak areas of ≤ 0.5% the mean Std A area or resolution ≥ 2.0.

In this case Std A represents an Assay Standard (for establishing system suitability) with a known concentration representing the nominal concentration of the corresponding component in your sample. Should your "interferring" fragrance peaks be less than 0.5%, they may be considered insignificant.

ejharrels - you state: "An acceptable non-interference/specificity acceptance criteria I have routinely come accross is as follows:
Any interfering peaks that are within ± 5 % of the retention time of (insert name of component being assayed) are to have peak areas of ≤ 0.5% the mean Std A area or resolution ≥ 2.0."

Can you please share the source for this?

Others: what do you do concerning this subject at your companies? Thanks.