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 coated tablets.

Click here for Update 9/2005.

Update 8/2000

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.

Update 9/2005

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 1, 2007.

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 impurity.

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 their specification.

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 us.