Limits to use in a validation

[KM-USA]

For our validated assays of pharmaceutical actives in our finished consumer products we use FDA ORA limits of 95.0 - 105.0% recovery and RSD of 2% or less, no problem there.

But the question is what to use when we need to validate an assay for an impurity in our finished product, in the range of 5 to 100 ppm? I see where the Australian Veterinary Pharma has a range of 75 - 125% for less than 0.1% in the product and AOAC has 85-115% for 10 ppm level, and I've seen USP monographs for impurities with a 500 ppm maximum have RSD less than 5.0 as their requirement. Is there any guidance for ICH or USP on this, and with a source reference, if possible? Thanks.

Australian Veterinary Pharma
http://www.apvma.gov.au/publications/gu ... ethods.pdf
Active/impurity content % Acceptable mean recovery
≥ 10% level in product 98 –102%
≥ 1% level in product 90 –110%
0.1 – 1% level in product 80 – 120%
< 0.1% level in product 75 – 125%

[krickos]

Hi
Sorry, not to my knowledge, you could look at PGI guidelines at FDA and EMEA as PGIs typically fall into the the trace category. In those cases limit tests rather than quantification is known to be approved depending on case. When I state known to be approved I mean both company specific procedures and exsiting monographs in USP/EP.

As a side note, 500ppm=0,05% is on the lower side yes but above reporting limit (0,03%) of high dose drug substance synthetic/degradation impurities, so maybe not the best example as covered by ICH Q3A.

APVMA is I know the only agency that states target recovery but also RSD for % level, a good starting point.

Another side note, you may want to check out USP 621 for RSD for assays, think its been harmonized with EP, so if limit is like 99,0-101,0% you would rather look at RSD closer to NMT 1,0% than 2% as ICH Q2 refers to pharmacopieas for SSTs. I think that FDA ORA limit is linked to the old reviewrs guidance from ~1994.

[KM-USA]

The ORA-LAB.5.4.5 copy I have was revised April 2009.

It states: Acceptance Criteria: 97.0% - 103.0% recovery for each spike level for APIs; 95.0% - 105.0% for finished dosage forms. Our company's products are finished dosage forms.

See http://www.fda.gov/downloads/ScienceRes ... 173090.pdf

[krickos]

ahh

right mixed it up drug products and drug substances