"Specifications in Class 2 solvents is an area where there is a lot of confusion and is probably the biggest concern we have
from an excipient perspective," says David Schoneker, director of global regulatory affairs at Colorcon (West Point, PA) and
Chair of IPEC-Americas. "A lot of people have not really read it. They look at the Class 2 limits, where it lists a particular solvent, and think
it's the maximum level you can use in any ingredient. They then go to suppliers and say they can't use it if it's higher than
that level. There are many excipients that commonly have those residual solvents with levels that are higher than those listed
in the table, and there is no problem with that because the levels are for the drug product and not for the individual ingredient."
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One of the ways to demonstrate that the finished product complies with the specifications is by knowing the residual solvent
information for the various components of the formulation, that is, the excipients as well as the active pharmaceutical ingredient
"You have to go back and look at your ingredients," says Schwarzwalder. "The USP chapter does apply to the excipients in your product and to the API, but only through the product. That was a distinction
that was missing in the OVI requirement that USP applied previously. You can have an ingredient that has a higher level of Class 2 solvent in it, if it's necessary, provided
that when you take that ingredient and mix it into the product you don't go over the final limit. You have the flexibility
to formulate your product in an appropriate manner and without applying an arbitrary standard to each individual ingredient."
Calculating the options
USP ‹467› provides concentration limits for Class 1 solvents, which as noted in the text should not be used in the manufacture
of drug substances, excipients, and finished product. In addition, the chapter considers Class 3 solvents in amounts of 50
g per day or less to be acceptable without justification. Most of the solvents fall under the Class 2 category.
Option 1. Key to understanding the limits for Class 2 solvents is understanding that they were calculated using what ICH and USP call the "Option 1" method. This method uses the listed PDE value in mg per day for a given Class 2 residual solvent, and
calculates the concentration ppm limits according to the equation:
Concentration (ppm) = (1000 mg/mL × PDE)/dose
This calculation applies for any daily dose that is equal to or less than 10 g. According to USP ‹467›, "If all drug substances and excipients in a formulation meet the limits in Option 1, these components may be used
in any proportion. No further calculation is necessary provided the daily dose does not exceed 10 g." This option also allows
manufacturers to skip the need to test the final drug product for residual solvents if the raw materials suppliers report
that their product is below the listed limits.
Of course, not every formulation will have all of its components fall within the Option 1 limits. "There are a lot of high-quality
excipients that have specifications in the USP monograph higher than those levels, and because it's a residual from the manufacturing process the level would not be easy
to lower," says Schoneker. "That doesn't mean there is anything wrong or that the process used to make that excipient has
to change. If you read through what it says in both the ICH document and the USP document, it clearly says you can use excipients with levels that are higher than those listed in the Class 2 levels table.
You just have to use the Option 2 calculation."