Clearing the Air on Residual Solvents - Pharmaceutical Technology

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Clearing the Air on Residual Solvents
USP 9467: Residual Solvents will take effect on July 1, 2008. But does the industry understand these specifications—and is it prepared?


Pharmaceutical Technology


USP ‹467› says that other Class 3 residual solvents should be identified and quantified using methods outlined for Class 1 and Class 2 solvents "with appropriate modifications." But, this may not be easy. "It's not as simple as just running Class 1 and Class 2," says Schumacher. "Companies may find all of a sudden that they are in a position where they need results and they may not have performed the background or have the lab do the background work to develop a method or validate a method to cover their other residual solvents needs. Without a specific monograph saying you can use loss on drying, they are not going to be able to, and [companies] have been used to doing that to cover their bases on Class 3 compounds."

The methods outlined for Class 1 and Class 2 residual solvents can be complex, as some analysts suggest. USP ‹467› outlines three procedures (Procedures A, B, C), prepared differently for water-soluble versus water-insoluble articles, all based on GC-FID.

"The concept here is procedure A is running the work on one specific column, and procedure B is running on an orthogonal column," says Schumacher. "Some compounds will elute better on one versus the other, which laboratories need to give some consideration as well, depending on what compound lists are submitted. And then the C procedure is the true quantitative procedure. A and B are actually semi-quantitative procedures. Their results are acceptable proof negative. If solvent results are below applicable limits, then you don't need to do any further testing. If any solvent exceeds one of the limits, then procedure C applies, which is actually a single-point method of additional spiking of a sample matrix to detemine a quantitative value. You do not need to run procedure A, B, and C in a circumstance where you know what compound list you are looking for. If you have a definiticve compound list and you know what you need to monitor, in theory you can go right to procedure C."

One laboratory has helped its clients understand better the various methodologies by categorizing the list of Class 2 solvents even further, referring to "mix A," "mix B" and "mix C" compounds (1). As Schumacher observes, "The reality is that the prescripted testing only covers a very narrow range of compounds. Only the Class 1 and Class 2 mix A and Class 2 mix B compounds have specific scripted tests," says Schumacher. "Once you run into Class 2 mix C and Class 3, the methodology is not specifically established. So some level of validation will be required," adds Travis Emig, director of pharmaceutical chemistry at Lancaster Laboratories.

One group of Class 2 solvents, however, "are not readily detected by headspace injection conditions," as described in the chapter. As mentioned previously, testing may need to be developed or modified for monitoring Class 3 compounds as well, and sample matrix issues may not allow direct application of ‹467› methodology. For these reasons, USP ‹467› leaves room for manufactures to develop "other appropriate validated procedures," and analysts need only to test for the solvents that are "likely to be present."

Analysts will be the first to make note of the modifications that will help guide the development of these appropriate validated methods."What a lot of what people have found is that there are problems with running <467> verbatim," says Schumacher. "We found problems with running on some headspace systems because specific wording in <467> conflicts with manufacturer design. As 467 is written, procedure A allows the use of a more-narrow bore-diameter column but procedure B does not. I've seen application notes for running <467> that basically have columns that aren't allowed in <467>."

Residual impact

The effect on excipient suppliers. "The best way to control solvents is to control your processes, know your supplier, understand, and try to limit the amount of solvent that you use to what you really need," says Schwarzwalder.


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