Option 2.
The Option 2 calculation takes into account that for many formulations, a given drug substance or excipient may be only a
very small component of the final drug product. In such a case, the PDE value for each component can be calculated using the
equation under Option 1 and then the total PDE value can be added. If the total PDE value for the drug product is below the
specification listed in the Class 2 Residual Solvent table, then the drug product meets the specification.
"If your drug is extremely potent and you are going to give much less of it, then you are actually allowed to have a higher
amount of solvent as a percentage because the amount of drug you are giving overall is much less," says Dr. Jon Brice. "This
is why it is a risk-based approach. Instead of saying the specification is 100 ppm and there is no discussing it, you are
allowed to take other things into consideration. A solvent may be higher than the specification when you test your API, but
if you are not using very much of it, and it is going into a formulation that will be given not very often, then it might
be that by the time you get to the drug product your overall limit is not that high."
Testing the final drug product.
Sometimes during processing, a residual solvent is driven off, such as by drying or evaporation, so a final drug product
could end up with a lower residual solvent content than the calculated predicted value. In that case, the finished drug product
can be tested directly. "What you are really accountable for is what comes out at the end from a solvents perspective," says
Dr. Jon Brice. "Solvents are known impurities. It's not like doing an HPLC [high-performance liquid chromatography] impurities
test, where there could be compounds that you've never seen before. Everyone knows where the solvents come in their methods,
and we have a lot of GC [gas chromatography] methods that are dedicated to just solvent identification and quantitation."
Contract analysts worry, however, that some of their pharmaceutical company clients are relying too much on drug-product testing.
"We're finding these methods weren't designed to perform that well for some finished products," says Schumacher, who suggests
it is best to monitor and conduct as much testing as possible on API and excipients before the finished product. "Once it
is finished product, many times you have mixed solubility issues with the various product components, and in this situation
the method doesn't necessarily work very well."
Methods and modifications
Unlike ICH Q3C, USP ‹467› includes an analytical testing methods section, "Identification, Control, and Quantification of Residual Solvents."
Not surprisingly, the recommended methods are based on headspace GC flame-ionization detection (GC-FID). GC-FID has been
known for at least the past 10 years to be more efficient, accurate, and gentler on the column than direct-injection techniques.
For Class 3 residual solvents at or below the 5000 ppm concentration limit (solvent limit ≤50 mg/day), USP ‹467› refers to "‹731› Loss on Drying" (LOD) for cases in which the monograph for an article contains an LOD procedure. For
a few specific monographed items, however, analysts can apply the monograph LOD to monitor Class 3 solvents. "It's a small
fraction of all the excipients and other drug substances. It's certainly less than 5%," says Schumacher. "Before the revisions
to ‹467›, it was common practice to correct LOD results for moisture content by an alternate technique such as Karl Fischer
to obtain residual solvents data, but this is no longer an acceptable practice."
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