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USP has issued a bulletin pushing back the date of
implementation of the General Notices statement on Residual Solvents from
July 1, 2007 to July 1, 2008. As before
we still offer the new methods as well as the old Organic Volatile
Impurities <467> method. For the new method we need to know what
compounds to look for as that will determine what specific method to follow
for testing.
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USP Revision Bulletin
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USP <467> Residual Solvents 4/2007
There are many
different solvents which are used in pharmaceutical manufacturing.
Previously this test was called Organic
Volatile Impurities (OVI). As most of you probably already know,
major changes to USP <467> are on the horizon (July 1, 2007). These changes
have been in the works for a few years now, in an effort to harmonize USP
requirements to the European Pharmacopoeia (EP).
The first change is in the title of the Chapter itself: Residual Solvents
(RS) is replacing Organic Volatile Impurities (OVI). The new RS chapter now
potentially tests for 53 individual solvents,
instead of the four under OVI. However, the test methodology has (in some
ways) been simplified, as the Chapter now describes only headspace
conditions for analysis, similar to the old OVI Method IV.
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Class 1, 2 and 3 Solvents
The 53 compounds are broken into three classes. Class 1 solvents
should not be employed due to high toxicity or deleterious effects on
the environment, unless their use is unavoidable. Class 2 solvents are
less toxic, but should still be limited. Their concentration limits
range from 50-3880 ppm. Class 3 solvents are not known to present a
health hazard at levels normally acceptable in pharmaceuticals (< 5000
ppm).
There is also a major change in how the testing is applied.
Individual monographs will no longer list a Residual Solvent
requirement. However, that does not mean that the testing is
not required. It has been replaced by a statement in the General
Notices, requiring that Residual Solvents be controlled in drug product.
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Maximum Limits
This leads to one of the primary issues regarding the new requirements.
The maximum limits apply ONLY to finished goods (drug products). Drug
substances, along with excipients, can exceed the concentration limits given
in the Chapter, although they must then be labeled to that effect. Also, the
concentration limits given assume a daily dose of 10 grams. For smaller
doses, limits are expressed as a Permissible Daily Exposure (PDE), given in
micrograms per day. This is a function of the dosage of the drug product,
including all excipients. In the final analysis, it is the PDE that is the
determining factor as to whether a product meets the specifications or not.
USP gives different options to determine this.
USP<467> Residual Solvents
to be published in the second supplement to USP 30 |
An important ramification of this new approach is that, based on knowledge of
the raw materials which go into the manufacture of a drug product, the final
product may not need to be tested. If, for example, all of the raw materials
meet the maximum concentration limits, and the daily dose of the drug
product is 10 g or less, then the final product will meet the specification
and no testing is required (assuming a dose of 10 g or less). This is
referred to by USP as Option 1. Also, if the amounts of residual solvents in
the drug substance and each of the excipients is known, then the amount
present in the drug product can be calculated based on the formulation. If
this calculation yields an amount less than the concentration limit, the
product passes under Option 2. If the limit is exceeded, the product can
still be analyzed to determine if the RS content was reduced during the
manufacturing process to a level which would meet the specification.
Manufacturers are allowed to use RS contents from Certificates of Analysis
to perform these calculations. |
The Analysis
The analytical approach described in the Chapter has also been changed. As
stated above, only headspace conditions are given. Summarized, a sample is
first screened for all of the Class 1 and Class 2 solvents that are amenable
to the method (Procedure A). If no peaks are detected, the sample meets the
specification. If any peaks corresponding to a solvent are detected, the
sample is analyzed again using a different type of GC column (Procedure B).
If no peak corresponding to the solvent tentatively identified
in Procedure A is detected in Procedure B, then the sample meets the
specification. However, if the presence of the solvent is confirmed by
Procedure B, the sample is analyzed again in order to quantify the amount of
solvent present (Procedure C). This is accomplished using the conditions
from either Procedure A or Procedure B, whichever gives superior
performance. |
For
a quotation...
Also check out these related pages:
USP<467>
OVI
the old version
WCAS Residual Solvents
a GCMS alternative to USP<467> OVI |
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