Method Development - Impurities

[cody84]

Hey all, I was wondering if there are any exact criteria for percent recovery for impurities. I've seen different numbers all over, and we go by 98%-102% in-house. I can't seem to find any. I'm looking for a specific reference like ICH or FDA. Can anyone direct me??

It would help actually to have all acceptance criteria if possible!

Thanks guys

[krickos]

Hi Cody

It is quite challaging to get a consensus on that topic, consequently there are no ICH guidelines on that topic, which in part is good.

Acceptance criterias should be based on the purpose of the method as inclined in validation guidelines. So one actually have to do some thinking on the validation protocol.

To take some extreme comparision: on one side you have a validation of a class 1 solvent (single digit ppm) with GC-HS based on pharmacopiea methods on the other side you have an assay of drug substance or drug product. From a precision point of view the pharmacopieas accept a RSD of 15% for the assay one usually mention the old 2,0% limit or these days rather 1,0% or even just under that.
Consequently recovery criteras wont be the same.

However the AUstralien authorities are the only one that I know of that have issued a validation guideline where acceptances criterias linked to concentrations level have been expressed for precision and accuracy/recovery.
Their approach is quite sound and we tend to borrow criterias from it.

Here is link:
http://www.apvma.gov.au/publications/gu ... ethods.pdf

[cody84]

Thanks Krickos,
I will advise my manager of this. This validation is so confusing...

[cody84]

Ok now I'm second guessing the mean recovery...do you use the END mean recovery for example: The average from these recovery results 50% spec - 98%, 100% spec - 97%, 150% spec - 99%
or the average from each concentration of spec/nominal?

[krickos]

Hi Cody

If you read the ICHQ2 (R1) guideline and check the recommended data section (4.3) for quantification of impurities you will note that it is hard to comply with that text using a mean off all recoveries over the range.

Consequently we always report the mean recovery (and sometimes individual ones to regulatory authorities) for each concentration level. So far I have never seen only a single average % recovery covering all concentrations levels in an impurity validation report.

[cody84]

What would you do in the case where your standard for spiking is extremely expensive and your recovery was not the greatest?

[krickos]

What would you do in the case where your standard for spiking is extremely expensive and your recovery was not the greatest?

Thats two quite different questions.

1. In the pharma buisness the guidelines deals with either availble impurities or non availble ones. There is no in between in my experiance. Consequently I doubt the cost of an availeble impurity would be viable argument with a regulatory reviwer.
Thats usually nothing compared to being forced to have them custom made that we have been forced to on occasion when in house resources has been strained.

2. Poor recovery. Well we (the forum) need more detailed info on that one because there could be a bunch of reasons for that. Different response factor, close to the LOQ or all over the range, trace analysis vs "normal ranges"? chemistry issues? ectetera.