EP Residual Solvents (2.4.24)

[Charles A. Burger]

I know there have been threads in the past regarding the USP <467> residual solvents general method, but I don't remember seeing anything on the EP version of this analysis.

If anyone has worked in depth with this general method? I would appreciate a chance to ask a few questions.

[krickos]

Hi

The "lack" of general EP 2.4.24 discussions is partly beacuse it was implemented much earlier than the 467 chapter update in USP. EP related questions lately as I recall have been more technical-troubleshooting.

Generally I personnaly avoid using the EP/USP general procedures and validate my own based on the EP/USP columns to speed up analysis. But also to increase sensitivity as Europe(EMEA) has a guide for when you can exclude class 2 solvents, requirements in short is that:
Class 2 solvent is not used in the last process step, at least 3 consectutive full scale batches or 6 clinical batches shows not more than 10% of the ICH Q3C limit for class 2 solvent of interest.

So already here the general procedures are often inadequte for justifing specifications.

USP/EP sample preparations and chromatographic conditions are quite identical/harmonized which is good of course for global suppliers. Appears to be some minor differences regarding prefered aprotic solvent (DMSO/DMF) and number of standards used. But as I said I avoid those.

Some other observations:
Both EP/USP seems to have recognized that the general headspace settings (likely based on PE HS40s or similar) is inadequate for like Agilents HS ie transferline/valve/loop temperatures may be increased to avoid contamination/carry over.

EP has recognized that the general sample preparation may be insufficient to reach accepteble sensitivity and may be increased. I think we had a good example a time back here where the general procedure worked for benzene if sample was prepared in water but failed when DMF was used.

Sorry can not help with details.

[Charles A. Burger]

My apologies for bringing this up, but it's been a real long time since I've had to run this and now that I am re-reading this method, I actually will not curse the USP like I used too.

One of our long term projects is to create our own in house methodology that's flexible to take on a majority of raw materials that we may encounter. However, the short term is need is to get the product analyzed with this method.

Hopefully this is simple to answer.

My API that I have to analyze has 4 known solvents. They are Acetone, Ethanol, Chloroform and Toluene. When reading the 2.4.24, I noticed at the very beginning, stipulations that make it either a limit test or an quantitative test.

"The test procedures described in this general method may be used:"

"ii. as a limit test for Class 1 and Class 2 residual solvents when present in an active substance, excipient or medicinal product."
"iii. for the quantification of Class 2 solvents when the limits are greater than 1000 ppm (0.1%) or for the quantification of Class 3 solvents when required"

And at the end of the method part iii is essentially repeated:

"when a residual solvent (Class 2 or Class 3) is present at a level of 0.1% or greater then the content may be quantitatively determened by the method of standard additions."

With all of that being stated in the EP; 1) isn't this already a standard addition analysis and 2) shouldn't I be able to use the LOD for control of the Acetone and Ethanol and use 2.4.24 as just a limit test for the other 2 solvents since ther limits are 60 and 890 ppm respectively.

[krickos]

Hi Charles

No need to apologize, I think you ask adequate questions.

With all of that being stated in the EP; 1) isn't this already a standard addition analysis and 2) shouldn't I be able to use the LOD for control of the Acetone and Ethanol and use 2.4.24 as just a limit test for the other 2 solvents since ther limits are 60 and 890 ppm respectively.

1. I think you refere to reference solution a1 and c here. a1 is for class 1 solvents so its not relevant for your case, while c might be. Technically you can use a single point standard addition for both limit test and quantative purposes.

2. Yes EP open ups for that approach and we have had some regulatory sucess using it but it may raise questions (ie why not include it while you already run a GC-HS test?). In our cases we more often had the case where water by KF titration has been mandatory and we did not want to add loss of drying-so we specified the class 2 solvents, the class 3 solvents went into a total limit (0,5%).