USP <467> Residual solvents

[vdnsrinivas]

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

[sdegrace]

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

[vdnsrinivas]

Thanks for the constructive information Stephen!

[krickos]

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.....)