Chromatography Forum

Hello,
I have a doubt regarding USP <467> residual solvents: I am testing an Drug substance which has residuals (Methanol, Chloroform) of Class 2 and (Acetone and Ethyl acetate) of Class 3. Can I give a justification by running a quantification method for Class 2 and LOD calculation for Class 3 residuals as mentioned in USP <467> (0.5% or 5000ppm) seperately??

Thanks,
Srinivas

As long as your LOD passes the class 3 limit, I think you are technically allowed, irrespective of whether your process contains class 2 solvents - provided your QA people don't give you any heat. The only trouble is, as you quite sure that you are going to pass the class 3 limit? What if you are close to the line and class 2's present were to push you over?

I have had this problem of a mixture of class 2 and class 3 solvents many times, and I have never chosen the approach of doing class 3 by LOD. Normally, I would develop and validate a method specifically optimized for all of the actual solvents in the process, class 2 and 3. I detest the USP<467> methods, and they're almost as much work to validate for your product as just validating a method from scratch. Plus they do not address class 3 solvents as well, which can be acutally very important to individually identify and quantify.

Normally I find our customers are very interested in the class 3 solvents, plus you never know what can happen down the road. See what happened with THF, and look at how hexane is a class 2 solvent, but somehow heptane is class 3 - can you really be sure that at some point in the future heptane won't be reclassified, or else someone will notice there is a different between n-heptane and heptanes and make you address it, for example?

My advice is don't try to get out of it - just cover your class 3's at the same time as you do your class 2's. I find the LOD thing is only really useful if you only have class 3's present and the LOD is simple and unproblematic.

Stephen

Thanks for the constructive information Stephen!

or else someone will notice there is a different between n-heptane and heptanes and make you address it, for example?

yepp happened to us some time ago (ohh so your heptane used in process (suppliers) "only" have ~50% n-heptane.....)