USP <467> OVI
There are many
different solvents which are used in pharmaceutical manufacturing.
USP mandates that at least six of these solvents be monitored
in finished products: benzene, chloroform, 1,4-dioxane, ethylene
oxide, methylene chloride and trichloroethylene. The methods
of analysis are given in USP <467>, Organic Volatile Impurities.
Currently, five methods are in place under <467>. These are
Methods I, IV, V, VI, and a method for methylene chloride in
Click here for Update 9/2005.
As of August 1, 2000 per the Pharmacopeial Forum, Volume
26, Number 4, benzene is no longer included in Table 1 of Method
<467>, Organic Volatile Impurities (OVI). Benzene may still
be required in specific monographs.
USP Methods for OVI
These methods all use gas chromatography (GC) to measure
the levels of the compounds of interest, but allow GCMS
to confirm identity in complex chromatograms. Methods II and
III were removed between USP 22 and 23. Methods for ethylene
oxide are given in each individual monograph, not in <467>.
Methods I, V and VI are direct injection methods, where the
sample is dissolved in water (or other suitable solvent) and
directly injected into the GC. They differ primarily
in the GC column and conditions used for analysis. Method
IV, and the method for methylene chloride in coated tablets,
are headspace methods. Here, the sample is dissolved in a solvent
, heated (usually to 80°C), and an aliquot of headspace injected.
Methods II and III from USP 22 were purge-and-trap methods.
These involved dissolving a portion of sample in water, then
purging with helium to transfer the volatiles to the vapor phase.
They are then trapped using a sorbent trap. When purging is
complete, the trap is rapidly heated and the volatiles swept
into the GC column. Method II used GC, while method
III used GCMS.
All of the numbered methods are designed to measure the amount
of the solvents listed above. However, many other solvents can
also be determined. We have used these methods to measure acetonitrile,
isopropanol, ethyl acetate, toluene, methanol, dimethylformamide,
and many others.
USP has published changes to Chapter <467>, Organic Volatile
Impurities. These changes harmonize USP with the European Pharmacopoeia,
to a large extent. Although the changes were introduced into
the General Chapter, from a practical standpoint they are not
yet in use, since individual monographs still cite the "Other
Analytical Procedures," which are the traditional methods that
have been in place for some time.
However, in the most recent Pharmacopeial Forum (Vol. 31(5),
Sept-Oct 2005), USP is announcing their intent to delete the
Other Analytical Procedures and move toward the new methods.
The monograph revisions will appear in USP 29-NF 24, with a
delayed implementation date of Jan 1, 2007. This will delete
the requirement for Organic Volatile Impurities, and add a requirement
for Residual Solvents. The revised method is slated to become
official with the First Interim Revision on Feb 1, 2006, and
the Other Analytical Procedures officially deleted as of Jan
Although these changes are still several months off, we want
to make our clients aware of the impact this will have on monograph
testing. The new Chapter is a significant modification from
the current procedure, which tests for only four compounds under
well-defined conditions (with a few exceptions). The new procedure
calls for much more extensive analysis, using a preliminary
screening GC analysis, followed be a confirmatory GC analysis
using a dissimilar column. If any compound is detected using
both systems, a third analysis will be necessary to quantify
|The potential list of analytes
is significantly longer (57 solvents are listed). Some compounds
listed in the Chapter are known to not be amenable to the headspace
injection conditions listed, and USP requests that validated
methods be submitted for possible inclusion in the relevant
Those 57 solvents are divided into three classes, based on
their potential hazard. Class 1 compounds are those which have
unacceptable toxicities and should be avoided in manufacturing
whenever possible. These include benzene, carbon tetrachloride,
1,1-dichloroethane, 1,2-dichloroethylene and 1,1,1-trichloroethane.
Class 2 solvents have less toxicity and should be limited. Class
3 solvents are less toxic still and should be used in place
of Class 1 and 2 compounds where practical.
The news is not all bad, however. Only solvents used in the
manufacture of a drug product need to be tested for. For the
least toxic Class 3 Residual Solvents, a simple Loss on Drying
analysis may be enough to verify that they are not present above
the specification of 0.5%. For the more severe Class 1 and Class
2 compounds, testing of a drug product may be avoided if it
can be shown that, based on the solvent content of the raw materials,
the drug product cannot possibly contain any solvents above
There will probably be more revisions to the methods in the
coming months. We will do our best to keep you apprised of these
changes, and how they will affect your testing needs. If you
have any questions about these issues, feel free to contact
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