Compliance News - July 2007 

USP <467>: Residual Solvents —Delayed to July 2008

Organic volatile impurities can result from the manufacture of active pharmaceuticals, excipients, or other drug products. Other factors such as packaging, transportation and storage can also impact residual solvents.

Because of their proven or potential toxicity the level of residual solvents is controlled through national and international guidelines. Thus all drug substances, excipients, and products are subject to relevant control of residual solvents. For example, ICH has published a new list with lower limits in 2003 (1).USP has developed a general chapter <467> (2) for the characterization of residual solvents using gas chromatography with headspace sampler. The final release of the procedure was scheduled for July 2007, but now has been delayed until July 2008 (3).

Changes to Previous Versions

The revised text will be published in Pharmacopeial Forum 33(5). Changes include:

• Title change: On July 1, 2008, the title of General Chapter <467> will change from Organic Volatile Impurities to Residual Solvents.
• Other analytical procedures: The section in General Chapter <467> titled Other Analytical Procedures will be retained as official text until July 1, 2008.
• Monographs that contain the Test for Organic Volatile Impurities will keep this test as an official requirement until July 1, 2008. After that date, the General Notices statement will apply to all monographs.

Pharmaceutical manufacturers that adopt the requirements of General Chapter <467> Residual Solvents prior to July 1, 2008 are considered to meet the monograph requirements for organic volatile impurities. This approach also is suitable for other official articles.

Agilent’s Offering

Agilent has developed new technology for Headspace GC and GC/MSD that conforms to the USP <467> and overcomes limitations previously experienced with traditional procedures (3). The instrumentation and applications have been described earlier this year (4).

Main features and benefits of the new Agilent 7890A GC and procedure are:

• Backflush and faster oven cool-downs for shorter GC cycle time
• New Capillary Flow Technology eliminates atmospheric pressure influences in headspace GC
• Automatic sample introduction of volatile compounds
• Easy-to-use Lab Monitor & Diagnostic Software provides higher uptime, automatic documentation of maintenance
• Faster electronics result in more performance, synchronous SIM/Scan in GC/MSD
• Trace Ion Detection Technology provides more capabilities at trace levels in GC/MSD
• Availability of suitable GC column phases as required by USP <467>

Agilent Technolgies has also developed application notes with recommendations for optimization (5, 6). In addition, a free residual solvents information kit including a poster with a list of all class 1 to 3 solvents with concentration limits and retention time information, and further useful flow charts and tables is available for free. Laboratories can use it to educate staff on the new USP chapter (7).

References

1. United States Food and Drug Administration (FDA), Guidance for Industry: Q3C, Impurities: Residual Solvents, ICH, 2003
2. USP draft chapter <467>: Residual Solvents
3. Revision Bulletin, General Chapter <467>, June 15, 2007
   
4. Compliance News March 2007
5. A. Gudat and R.L. Firor, The Determination of Residual Solvents in Pharmaceuticals Using the Agilent G1888 Headspace/6890N GC/5975 Inert MSD, Agilent Application Note, Publication Number 5989-3196EN, June 2006
6. A. Gudat, R.L. Firor and U.Bober, Better Precision, Sensitivity, and Higher Sample Throughput for the Analysis of Residual Solvents in Pharmaceuticals, Agilent Application Note, Publication Number 5989-6023EN
7. Free residual solvents information kit including a new poster:
   All the facts about Residual Solvent Analysis with GC and GC/MS